[Ultrastructural characteristics of the bronchial epithelium in pulmonary tuberculosis (according to biopsy material)]. Biopsy materials of the wall of the lobar and segmental bronchi obtained from 345 patients with pulmonary tuberculosis were studied. In 25 patients pathohistological investigations were supplemented with electron-microscopy studies. Of 345 biopsy specimens tuberculous inflammation was found in 5 cases. The ultrastructural analysis showed the sequence of changes occurring in the cells of the bronchial epithelium in chronic inflammation: in the development of sclerotic changes in the wall of the bronchus hyperplasia of ultrastructures was followed by their diminution and desctruction.


Immunosuppressive therapy and virus-cores in HBAg-positive chronic hepatitis. Three liver biopsies were carried out in a case of chronic active hepatitis with persistent HB-antigenemia. Virus-cores could not be detected in the liver cell nuclei by electron microscopy before immunosuppressive therapy. Intranuclear, ring-shaped virus-cores of 20-25 nm diameter appeared in almost every hepatocyte examined during immunosuppression.


[Isolation and characterization of 11-S-globulins from sunflower seeds (Helianthus annuus L.)]. The isolation of II-S globulin, which is homogenous on sedimentation and gel chromatography (s020, w = II,8 S), from sunflower seeds is achieved by cryoprecipitation from solutions of high ion strength (I approximately 0.5 to 1.8) with simultaneous reduction of the salt concentration (I approximately 0.3) and repeated gel chromatography on Sephadex G-200. By this technique, the 7-S component which occurs in small quantity is isolated too. In solutions of low ion strength (I less than 0,3), the II-S globulin dissociates to give a 7-S component. At high or low pH values (greater than 9.0 and less than 3.0, respectively), the latter dissociates to give a 3-S component, and in the presence of urea it further dissociates to give subunits. In the presence of sodium of sodium chloride, the dissociation of the 3-S component may be inhibited. The various steps of dissociation can be studied by means of ultracentrifugal sedimentation, gel chromatography and gel electrophoresis.


[Radio-anatomy of uterine malformations]. 33 cases of uterine anomalies were studied from the external morphological point of views as well as by hysterography. These cases were grouped according to R. Mussel's classification (1964) which is itself the synthesis of radiological and anatomical investigations.


[Method of purification of water by means of ion-exchange cellulose fibers]. A new method of and an arrangement for continuous ion-exchange purification of water from admixtures contained therein in the form of dissolved electrolyte ions have been devised. As a basic working element for this purpose serves anion-exchange tape made of anion-exchange cellulose fibre (ICF) that enables a continuous purification of water from impurities contained therein the be effected as needed.


[Clinico-immunologic shifts in pleural empyema in patients of different age]. In 218 patients the causes of pleural empyema, the state of immunological indices and treatment have been studied in relation to patient's age. It is demonstrated that the most inadequate protection potential, conditioned by an insufficient specific resistance, is observed in children and patients over 50 years of age. The treatment of pleural empyema is usually started with a puncture method of administering antibiotics, enzymes and general analeptic drugs. In children due to a rapidly progressing intoxication and pulmonary insufficiency thoracocentesis was employed in 55.5%, in patients aged from 16 to 50 years pleurectomy and other operative procedures were accomplished. In patients over 50 years of age a puncture method and thoracocentesis were applied, surgery being used only in 10.4 per cent.


[Heparin therapy in liver cirrhosis].

[Heparin therapy in liver cirrhosis]. In 80 patients suffering from liver cirrhosis and coagulation disorders a rapid and significant restitution of the disturbed coagulation system can be expected by a therapy with low doses of Heparin.


Errors of drug prescribing.

Errors of drug prescribing. Seven thousand five hundred and twenty-six prescriptions written for eight hundred and forty patients in three hospital wards have been analysed for errors of drug use and errors of prescription writing. 2. According to the criteria adopted for this survey, more than 3% of prescriptions contained an error of drug use and more than 30% an error of prescription writing. 3. The incidence of adverse drug reactions, overdosage and undertreatment might be reduced by more careful prescribing.


Evaluation of tolerance after continuous and prolonged oral administration of salbutamol to asthmatic patients. Salbutamol (8 mg) was administered twice daily as a sustained release formulation to twenty-four asthmatic patients for up to four weeks under double-blind conditions. 2. The ability of bronchial smooth muscle to respond was determined by monitoring the response to salbutamol (200 mug) administered by aerosol at set intervals three times a week. 3. There was no evidence of diminishing response during the study period. 4. It is concluded that tolerance to salbutamol does not occur at therapeutic dose levels and that clinical observations of tolerance may be due to other factors.


Cellular immunocompetence in melanoma: effect of extent of disease and immunotherapy. Cell mediated immunocompetence was measured serially in 35 patients with malignant melanoma in order to determine the effect of extent of disease and prognosis as well as the influence of BCG immunotherapy on immune reactivity. Compared with normal adult controls, statistically significant lymphopenia occurred only in patients with widespread disease. Seventeen of 21 patients with negative pre-therapy PPD skin test converted to skin test positivity. PHA blastogenesis was depressed only in patients in the pre-terminal stages of their disease using optimal mitogen concentrations for stimulation. Threshold concentrations of this mitogen more clearly demonstrated a depressed responsiveness which correlated in severity with extent of disease. PPD induced blastogenesis was normal or increased in the majority of patients; however, the degree of stimulation by PPD was less in the BCG induced convertors than in those patients who were skin test positive before BCG treatment. Comparison of the pre- and post BCG assessments reveals no significant differences except in relation to PPD conversion. We conclude that using threshold concentrations of PHA, impaired responses are regularly associated with disease beyond the regional lymph nodes. Routine assessment of lymphocyte function by these parameters did not provide information that was not available from clinical evaluation.


Horizontal studies of cell mediated immune reactions to autologous tumour antigens in patients with operable mammary carcinoma. The leucocyte migration and guinea-pig macrophage migration procedures were used to assess cell mediated, tumour directed immune reactions in patients with mammary carcinoma undergoing simple mastectomy with or without post-operative irradiation. Forty-seven per cent of patients reacted to autologous tumour antigens and 40% to allogeneic antigens when tested 7 days after operation; 23% reacted to autologous antigens at 2 months, 19% at 6 months and 34% at 1 year after surgery. Reactions to benign tissue fractions were rare. Better discrimination between test and control subjects was obtained when 3000 g sediments rather than nuclei-depleted homogenates (extracts) were used. Irradiation 3-7 weeks post-operatively did not depress the in vitro response at 2 months and yielded a higher rate of positive reactions at 6 months. Correlations of serial LMT responses with certain clinical findings are discussed.


Levamisole treatment of local and metastatic growth of transplanted rat tumours. Levamisole has been examined for its ability to control local growth and pulmonary metastases of transplanted rat tumours. The compound did not suppress subcutaneous growth of 3-methylcholanthrene induced sarcomata when administered systemically in a variety of regimens, or when injected in admixture with tumour cells. In addition, levamisole treatment failed to suppress pulmonary growth of intravenously transferred sarcoma cells or spontaneous pulmonary metastases appearing after surgical removal of a transplanted epithelioma.


Augmentation of cytotoxic drug action and X-irradiation by antibodies. The effect of an antiserum containing antibodies against cell surface components of PyBHK cells on the action of certain anticancer agents has been studied using a colony formation inhibition assay. The effects of x-rays, chlorambucil, CCNU and possibly ICRF 159 are augmented by the antiserum whereas methotrexate and vinblastine are not.


The natural history of metastasis of syngeneic murine squamous carcinoma and the prognostic implications of primary tumour size and duration of growth. A study has been made of the natural history of metastasis of a spontaneous murine squamous carcinoma implanted into syngeneic recipients--a situation where biologically different tumours and variable "host resistance" are not complicating issues. The time distrubution of deaths from metastatic disease was incompatible with a log-normal distribution but was accurately described by an exponential pattern of survival following an initial lag. While the average life of doomed mice correlated with predictions based on growth rates, there was a wide range of survival times indicating random influences on the evolution of metastitic disease. Insofar as tumours which grew to 20 mm3 or less in 5 days after tumour cell injection failed to initiate metastases, while tumours which reached a size of 120 mm3 or greater (irrespective of duration) produced metastases in 38/39 mice, tumour size was a prognostic index. However, within the size range 33-150 mm3 the correlation between metastatic risk and size was not statistically significant. No correlation between metastatic risk and duration of tumour growth from 6 to 29 days was observed. Two integral functions of tumour size and duration were tested but neither gave a better correlation with metastatic risk than did size alone.


Immunoreactive calcitonin production by human lung carcinoma cells in culture. Monolayer cultures have been established from a poorly differentiated carcinoma of the lung. Homogeneous cell growth and morphology have been maintained for over 18 months through more than 80 subculture passages, and the cells have been found to produce both immunoreactive calcitonin and an immunoreactive carcinoembryonic antigen-like material.


The effect of anaesthetics on blood perfusion in transplanted mouse tumours. Rubidium-86, 125I-human serum albumin and 51Cr-labelled red cells have been used to investigate the effects of the anaesthetics Nembutal (pentobarbitone sodium) and urethane on blood perfusion, blood volume and albumin leakage in 5 types of transplanted mouse tumour and in normal organs. Nembutal was found to increase the relative blood perfusion by a factor of 1-3 to 2-0 in tumours and by a factor of 1-7 to 3-0 in kidneys but muscle perfusion fell to 0-3-0-5 that of controls. The effects of urethane were found to be dose dependent, generally in the same direction as for Nembutal, and smaller. Both anaesthetics reduced the blood volume of tumours (except for the C3H mammary carcinoma) and of kidneys by factors of 0-2 to 0-8. The duration of anaesthesia had no effect on the plateau values of relative blood perfusion and blood volume in either tumours or normal organs, but Nembutal delayed slightly the 86Rb uptake and decreased the rate of albumin leakage.


The results of radiotherapy for Hodgkins' disease. The results of radiation therapy in 212 patients with stages I and II Hodgkin's disease treated between 1963 and 1973 show that approximately 60% remain disease-free following treatment. Multiple node involvement in stage II, particularly associated with infraclavicular node disease, is identified as a group where the relapse rate is high. This presentation is associated particularly with NS. In a group of 78 patients treated with radiotherapy following staging laparotomy and splenectomy approximately 80% remain in complete remission. The preliminary results of treatment in PS IIIa patients are substantially the same as those for PS I and II; the results of treatment for NS and MC disease are similar. The significance of involvement of the spleen is discussed. Although it is probable that Hodgkin's disease spreads to the spleen through the blood stream it is suggested that splenic involvement does not necessarily indicate that the involvement of other extralymphatic structures such as liver and marrow has occurred. However, when the nodes in the porta hepatis are involved splenic Hodgkin's disease may well be associated with an increased risk of occult hepatic infiltration.


Myelopathy simulating spinal cord tumor. Three cases of demyelinating or necrotizing myelopathy are presented in which gradual onset of symptoms, slowly progressive course and widened cord shadow on myelography led to the erroneous diagnosis of intramedullary spinal cord neoplasm. Two of the cases also had inconclusive surgical explorations. We would suggest that patients who seem to have even a typical clinical and myelographic picutre of an intrinsic cord neoplasm have a period of further observation before radiotherapy is begun and that a vigorous search be made for evidence of disseminated disease.


Ventriculogastrostomy, an alternative means for CSF diversion: a preliminary study. The feasibility of gastric CSF diversion in the management of hydrocephalus is evaluated in laboratory and clinical settings. A technique for ventriculogastrostomy is described and evaluated initially in 8 mongrel dogs. All distal shunts remained patent to the time of sacrifice. None of the animals exhibited leakage of gastric contents around the tubing. Cultures of the components of the shunting system and gastric mucosa were sterile. Clinical evaluation in a 3 week-old child is discussed. The trial was terminated at 3 weeks postsurgery because of the occurrance of an E. coli ventriculitis which was considered to be secondary to a preoperative conjunctivitis in which the organism was identical. It is concluded that there is good experimental evidence to support the concept of effectiveness of ventriculogastrostomy in the treatment of selected cases of hydrocephalus.


Pathogenesis of spike-wave status: a clinical-pathological study implicating cerebellar disturbance. If cerebellar Purkinje cells function in a manner so as to terminate at least some types of seizures or to prevent their clinical development then loss of Purkinje cells should predispose to the prolonged or continuous occurance of these seizures. This study presents clinical data that may document such an instance and cites the supporting experimental data.


Etiologies of Parkinsonism.

Etiologies of Parkinsonism. A case report is presented of a patient with Parkinsonism. Three contributory etiological factors are considered with the conclusion that craniocerebral trauma may have been the most significant cause of Parkinsonism in this individual.


[Coronary fistula in the right ventricle]. A case of fistula between the left coronary artery and the right ventricle in a girl aged 14 months is described. The description of the case deals with the semeiological classification of cardiocoronary fistulas, the means of investigation and differential diagnostics. The therapy is purely surgical and consists in isolation, ligature and dissection of the anomalous coronary.


[Echinococcic cyst of the thyroid].

[Echinococcic cyst of the thyroid]. The Authors, starting from observation of a hydatid cyst of the thyroid, make an examination of this very rare pathological occurrence. They then put forward and evaluate the fundamental problem linked to this localisation of hydatidosis, a problem which can be summed up as the lack of pathological identification of the clinical pattern and the consequent ease of making a diagnostic error. They conclude by stating that the sole differential diagnostic criterion in relation to other diseases that may be considered (cystic uninodular goitre, adenoma, epithelial cyst, haematic pseudocyst) consists in the simple recollection of the possible existence of this very rare localisation of the echinococcus.


[Surgical anatomy of the peritoneal fringes at the level of the terminal ileal loop]. The Authors give a detailed picture of the peritoneal fringe of the terminal ileum. With the help of an iconography they describe the possible anatomical variations according with the surgical possibilities.


[Chromosomal diseases of surgical interest]. After a short review of the most common chromosomic diseases, the possibility of surgical action in some of these "chromosomic patients" is suggested. This possibility would appear to arise from a careful analysis involving various health components. In conclusion some working hypotheses which might be developed in the by no means distant future are discussed.


[A case of non-familial ulcer mutilating acropathy of the foot]. A case of non-familial pseudo-syringomyelic acropathy is presented; in view of its rarity, numerous hypotheses had to be considered with regard both to diagnosis and to pathogenesis. It was first taken to be an undoubted case of osteomyelitis, but the rapid advance of the osteolytic form, which resisted all treatment both local and general, whether antibiotic, surgical or orthopaedic, led to consideration of the possibility of sarcoma or some other benign tumoral form. The conclusion was reached that doubtful diagnosis can be settled only by bioptic examination, whereas aetiopathogenetic doubts still remain within the field of hypotheses (Lattuada).


[Method of construction of the EDF plaster-of-paris corset for correction of progressive scoliosis]. Some technical details are given with regard to making up the E.D.F. corrective corset used by the authors, who have wide experience in the bloodless treatment of infantile and youthful evolutive scoliosis, with a view to a wider spread of prophylaxis and treatment appliances by the Higher Health Boards today in operation.


[Clinico-statistical studies of the tibial varism frequent among the school population of the Chiavenna valley and its relation to varus arthropathy of the knee in adults]. 384 adolescents in Chiavenna schools were examined in a study of the considerable incidence of tibia vara, seen as a first step towards the patterns of varizing arthrosic deformation of the knee in adults of the same zone; at the same time indications on prophylactic-preventive measures in the field of scholastic and sport medicine were given.


[Delirium and ecstasy. The phenomenon of toxic ecstasy in young men]. In the whole history of mankind, hallucinogenic drugs have played a big part in religious and cult practices and have transmitted special religious experiences during a drug-induced ecstasy. The present extension of drug consumption with a view to solving personal conflicts and transitory experience of happiness, as well as the unsuccessful 'quest for God' of many young drug consumers should be understood in the context of the specific drug effects, of the technological developments of our times, as well as of the change and breakdown of religious and cult traditions. This desperate quest for happiness and religious experience calls for a critical reflection about the present sociocultural developments and raises the question of the necessity of an authentic religious life.


Uretero-calicostomy.

Uretero-calicostomy. Implantation of the ureter into the calyx is indicated in cases of uretero-pelvic stricture when anastomosis of the ureter with the pelvis is impossible. Results of this procedure performed in ten cases are presented. In two cases the same kidney was operated upon twice; in five cases the results were satisfactory; in two cases the results were poor, and in one case the time of observation is too short for proper evaluation.


Characteristics of the tumours of the urinary tract in patients with endemic nephropathy. The authors have studies in detail the development of tumours in the urinary tract of patients with endemic nephropathy (EN). They have found tumours in about 40% of these patients. They have performed operations for tumours of the urinary tract in 88 patients with EN, with a different localization in the upper part of the urinary tract. In 10% of the cases they have found bilateral tumours. The histological examination has revealed papillary tumours of a malignant character. They have shown specific symptoms of these tumours, not found with other tumours of the urinary tract. The main symptom is renal insufficiency which causes the death of the patients. The evolution of these tumours is comparatively slow and the nature of EN has determined the operative approach of the authors, a radical operation with haemodialysis when indicated. The paper is illustrated with four typical cases.


Urological implications of food refining. Evidence is accumulating that food-refining, which results in over-nutrition which carbohydrates as well as deficiency of fibre, protein, etc., is an important factor in the causation of many modern diseases. This concept has important implications for the urologist and may assist in the prevention of common urological problems such as renal calculus and infection.


Transurethral resection for the assessment and treatment of vesical neoplasms: a review of 840 consecutive cases. Non-infiltrating (T1), and superficially infiltrating (T2), vesical neoplasms can be treated satisfactorily by transurethral resection. Some T3 neoplasms can be treated this way, but most will require radiotherapy. The assessment and treatment of 840 cases are presented. Survival rates of 62% in T1 cases, 59% in T2 cases, and 20% in T3 cases are reported in 465 cases followed up for 5 years.


Contribution to the study of the development of the terminal portion of the Wolffian duct and the ureter. Ten human embryos ranging from 10 to 20 mm in vertex-coccyx length (Horizons XVI and XVII Streeter) aged between 33 +/- 1 and 39 +/- 1 days, were studied in order to interpret the mechanism which determines the displacement of the ureter from the dorsal part of the Wolffian duct toward the lateral wall of the bladder. We demonstrated that this movement occurs due to the fact that the duct common to the ureter and the Wolffian duct undergoes a process of internal rotation before it is absorbed by the urogenital sinus. This determines that the ureteral orifice enter the urogenital sinus laterally with respect to the Wolffian duct. This absorption indicates that the mucosa of the trigone is of mesoblastic origin and the remainder of the besical of endoblastic origin. The origin of the muscular apparatus of the detrusor is entirely mesoblastic.


Development of the innervation of the ureter. The development of the adrenergic and cholinergic innervation of the ureter was studied by specific neurohistochemical methods. At birth, the musculature is devoid of adrenergic nerves. The first adrenergic nerve terminals start to appear 3--4 days after birth. During the following 4--6 weeks, the density of the nervous net-work increases rapidly to reach the final adult pattern of innervation. Cholinergic nerves were observed already before birth and their density increased rapidly during the first postnatal month. The development of a functional adrenergic neurotransmission appears later than the cholinergic innervation. Cholinergic nerves are thought to be possible sensory receptors. The development of the autonomic innervation appears to be related to the underlying maturation of the smooth musculature.


Vitamin B12 absorption in patients with ileal conduits. The absorption of vitamin B12 was assessed using the 58Co-absorption test (Schilling test) in 39 patients in whom ileal loops had been used as urinary diversion after excision of the bladder for transitional cell carcinoma. 29% of the patients were found to absorb less than 12% of the offered dose of labelled vitamin B12 after excluding gastric-mediated malabsorption by the modified Schilling test. Examination of haemoglobin, MCV or vitamin B12 in the peripheral blood gave unreliable indications of the absorptive ability of these patients.


Continent ileal bladder: an experimental study in dogs. A method for constructing a continent ileal bladder has been tested in dogs. The requirements for a continent ileal bladder: continence, reservoir function, prevention of reflux, could be fulfilled in our experimental study.


Hydrostatic bladder distension - physiology and clinical application. Studies of bladder flow during hydrostatic distention using radioactive clearance techniques and progressive diminution in blood flow as bladder pressure rises. At systolic blood pressure blood flow is minimal. Prolonged hydrostatic distention has been used as a method of therapy in those patients with urgency of urine and urge incontinence with satisfactory early clinical results and impressive changes in the cystometrogram.


Destructive forms of renal tuberculosis. The incidence of renal tuberculosis has declined slowly in recent years, but its development has also changed. There are silent forms with few symptoms of spread and without very great bladder pain; nevertheless these forms can be very destructive, and even on first presentation may show a destroyed kidney. Our Urological Clinic in Belgrade treated 1,890 patients during a period of 23 years. We cannot incriminate streptomycin or PAS as the only causes of a tendency to fibrosis or for the silent forms of ureteric stenosis. Yet it seems certain that the pathogenesis of the tubercle bacillus changed in different persons under treatment with streptomycin and other antibiotics. The following represents the renal tuberculosis cases we have seen in the Urological Clinic in Belgrade during 1950--1972.


Use of the Otis urethrotome in the treatment of urethral strictures and congenital urethral stenoses. Internal urethrotomy using the Otis urethrotome is described in detail. Performing this procedure in 23 patients with urethral strictures, no further dilatations of the urethra were necessary in approximately 60%. If internal urethrotomy, which offers the advantages of having a very low rate of complications and which may be repeated, proves unsuccessful, a urethroplasty can still be carried out. As a preliminary procedure to transurethral resection of the prostate by cold punch technique, internal urethrotomy appears to be of great value in preventing urethral strictures - as demonstrated by follow-up studies in 351 patients.


Experiences based on the classification of bladder tumours according to the TNM system. Since 1967 we employ the TNM system of the UICC for the classification of bladder tumours. Cystography, pelvic arteriography and lymphography were carried out for the classification. 393 patients were examined by means of the X-ray methods. 323 patients were classified according to the TNM system. The 'P' stage was stated in 134 patients. This group of patients enabled a control of the pre-therapeutical classification. We found extensive conformity between pre-operative and post-operative diagnoses. The methods of classification tested by us allow an exact diagnosis.


Diagnositc and therapeutic patterns of bladder tumours. The clinical findings and results obtained in a group of 100 patients with bladder tumours are presented. These patients were controlled during a 5-year period, and submitted to the same patterns of investigation and treatment. The treatment instituted was cobalt therapy together with 5-fluorouracil, followed by surgical intervention. The results have been evaluated according to the outcome and survival rates obtained.


New aspects in combined treatment of urinary bladder carcinoma. To further improve the results of treatment of malignant processes of the urinary bladder, the authors reviewed in detail 420 cases under combined treatment. They found the following results: (1) In 96 (38.4%) out of 250 cases, the cystoscopically normal mucosa distant from the tumour showed histologically definite cancer tissue. (2) The destruction of residual tumour elements by ionising energy after operation depends on the relation between tumour and connective tissue. If there is sufficient connective tissue residual tumours may be destroyed in all probability, otherwise prognosis is poor. (3) In case of tumour cell mass formation in the microspace without active connective tissue, a curative effect by means of ionising energy after operation is not to be exptected, whether there is a multilocular development of carcinoma or not. Surgical treatment has to be extended according to the condition.


Traumatic ruptures of the urethra in children. Considering 4 cases of urethral injuries in male children, the authors' attitude regarding pelvic factors with urethral trauma is described. They insist on the importance of intravenous urography in fresh injuries, which is very helpful to diagnose the legend of the upper and lower urinary tract. Regarding dilatation treatment of urethral injuries, resection of the urethral stenosis, followed up by direct suture of the urethra is suggested as the best treatment.


Segmental urethrectomy and urethrorrhaphy for treatment of fresh and late traumatic urethral lesions. For 16 years we have used segmental urethrectomy with end-to-end urethrorrhaphy for treatment of traumatic urethral lesions, in preference to two-stage urethroplasties. The approach has been transperineal, retropubic, and if necessary transpubic. Good results in 41 cases with long-term follow-up allow us to say that this is a good operation. It provides in two thirds of the patients a correct and stable urethral stream, complete bladder emptying, and does not affect urinary control or sexual function if this was normal following the injury.


The prosthetic replacement of the ureter: experimental and clinical results. The authors present their experience over several years in replacement of the ureter by a silicone prosthesis. This includes experimental work in dogs and clinical application performed in three different ways: (1) A uretero-vesical or pelvo-vesical bridge. Trials were started in 1967 and on the whole the results have been good, although in some cases deterioration was noted after a few months (18-20). The quality of the results obtained experimentally, encouraged clinical application and the authors employed ten prostheses in patients with advanced carcinoma and obstruction. The results have been excellent and a cutaneous fistula or diversion has been avoided. (2) Segmental replacement of the lumbo-iliac ureter. In experiments in 15 dogs, there were nine successful results, with survival periods of from 19 to 25 months. One patient has been treated with an immediate good result. (3) A renal-ureteric bridge. By implanting the top end of the prosthesis in the lower calyx and at the lower end in the lumbo-iliac ureter, the pelvis and proximal ureter are by-passed. This procedure has been applied in one patient. He has been followed up for only 4 months, but the results appear to be excellent.


Diagnostic and therapeutic problems in 10 cases of pheochromocytomae. Ten cases of pheochromocytomae, of which eight were benign and two malignant have been considered. All patients presented with hypertension, either paroxysmal (7 cases) or permanent (3 cases). It is essential to emphasize that the initial symptomatology of these patients on their admission to the hospital was often atypical and misleading: in 2 cases, the symptomatology was urological, in 2 cases psychatric and in one digestive. Quantitative determination of catecholamines and their metabolites was positive in 7 cases out of 10. Retropneumoperitoneal insufflation combined with intravenous urography and tomographies provided valuable information in each case. The surgical removal of these tumours, which was unilateral and in normal position, in each case, was carried out without complications. Sudden blood pressure variations observed during the operation could be controlled without difficulty. In 6 patients, the blood pressure became normal and remained so for 4 years. In 2 other patients, the blood pressure came back to normal after the operation, but presented a slight increase 1 year later. Pheochromocytomae, which are often masked by a misleading symptomatology, must be systematically searched for in all hypertensive patients, despite the characteristics of the hypertension. Surgical removal, if done early enough, produces cure of the hypertension.


Experimental urinary stone formation following persorption. The 'effect of Herbst' was combined with the production of renal calcium oxalate sediments by oral administration of ethyleneglycol and acidification with NH4Cl. This investigation was made to see whether persorbed bodies may form nuclei in crystallization in the genesis of stone. Lead sulphide crystals and 45Ca-labelled calcium oxalate crystals were used as persorbable model bodies. It became apparent that lead sulphide crystals given by mouth could be found both in the urine and kidneys, but these did not form nuclei in calcium oxalate sediments. Radioactive-labelled calcium, however, could be proved histoautoradiographically within the renal concretions. Our experiments showed that persorbed calcium oxalate crystals can represent nuclei for stone formation.


Doxycycline levels in prostatic tissue and blood. Doxycycline was administered orally to 23 patients scheduled for prostatectomy or radical cystectomy. Blood and prostatic tissue samples were collected simultaneously during operation and subsequently assayed for doxycycline levels. The concentration of doxycycline in the prostatic tissue was on average 2.75 mug/g which is far above the therapeutic level. The lowest level recorded was 0.85 mug and the highest was 4.81 mug. The findings suggest a tendency for this antibiotic to accumulate in prostatic tissue. This is in agreement with the clinical observations of the good effect of doxycycline treatment in patients with chronic bacterial prostatitis.


Duraplasty of the urinary bladder--results after two to six years. Duraplasty of the urinary bladder is indicated in contracted bladder to enlarge the capacity and also after bladder wall resection for carcinoma of the bladder. A series of 34 patients followed up for 2-6 years is reported.


Variations of origin of the renal artery: a review covering 403 aortographies. With 403 aortographies made for various reasons, the authors study the level of origin of renal arteries in respect to the lumbar vertebrae. They compare the information supplied by arteriography with the findings of classical authors after dissection. When there are two kidneys, and one artery per kidney, these arteries originate at the level of the first two lumbar vertebrae, the right artery at the same level or above the left artery. Special cases are also considered, as for instance kidneys vascularized by several arteries, single kidneys and fused renal masses, amongst which the horseshoe kidney is the commonest. The interest of this study, in relation to both the removal or reparative renal surgery, and to renal transplantation is here emphasized.


The effectiveness of transrectal aspiration cytology in the diagnosis of prostatic cancer. A study was undertaken in 403 patients suspected on rectal examination of carcinoma of the prostate, comparing the accuracy of cytological examination after aspiration biopsy with a Franzen's needle and transrectal punch biopsy for histological diagnosis. The results indicated 93.35% cytological accuracy. In 2.39% of the cases cancer was not detected cytologically. In 3.72% of the cases, a cytological diagnosis was made but not a histological one. This emphasizes the great value of the thin needle biopsy. Its advantage is that the examination can be carried out at any time, without preparation, narcosis or danger to the patient. Moreover, it allows a control of, and gives preliminary information on the success of hormone or radiotherapy.


Urethral duplications in the male.

Urethral duplications in the male. A classification of duplications of the male urethra has been presented together with our clinical experience. The commonest variety is epispadiac form which may be complete, incomplete or abortive. Less common are the hypospadiac forms and very much rarer are the spindle urethras where the bladder neck and also the distal urethra are single. The bifid urethra with pre-anal accessory track is relatively common but has often gone unrecognised.


Treatment of cystinuria with Thiola (alpha-mercaptopropionyl glycine). Nine cystinuric patients (8 females and 1 male) with recurrent L-cystine stone formation have been treated since 1971 with the new drug Thiola (alpha-mercaptopropionyl glycine). Thiola was found to be more effective than D-penicillamine in dissolving L-cystine. In two case a partial dissolution was observed after 20 months of Thiola administration. In four cases further stone growth was stopped. In the last two cases stone growth occurred even after administration of Thiola. Tolerance of the drug was good, and no serious effects were observed sufficient to interrupt treatment.


Controlled prevention of post-operative thrombosis in urological diseases with depot heparin. The frequency of venous thrombosis after urological operation was investigated by means of iodine fibrinogen in 65 patients chosen at random. 34 patients were treated with depot heparin (Calciparin). Out of 31 patients, 18 (58%) presented an increase of the fibrinogen radioactivity. Moreover, these 18 untreated patients presented clinical signs of thrombosis. On the other hand, the fibrinogen radioactivity was increased in 4 patients (12%) of the Calciparin group. Comparison of the results of the control group and the experimental group is quite significant. The advantage of the prevention of thrombosis is more obvious in longer lasting operations.


The value of standard diet in urolithiasis. The excretion of magnesium, calcium, zinc and citric acid was determined in the urine of 11 patients with urinary calculi and in 5 healthy subjects on a standard diet for a period of 5 days. It was found that there was more or less distinct dependence of electrolytes and citric acid on the standard diet. In order to obtain accurate results, mineral metabolism in stone patients can only be investigated under defined conditions (i.e. the standard diet). The excretion of magnesium and citric acid in the urine was reduced in patients with calcium oxalate stone, while that of calcium and zinc was increased.


The influence of polyglycolic acid (Dexon) on the formation of urinary calculi in rats fed with oxamide. Rats fed with 2% oxamide diet were considered as a model for the patient with a tendency to stone formation. Polyglycolic acid (Dexon) sary stream caused formation of oxamide deposits in a percentage as high as that observed with silk sutures. A high degree of toxicity was observed with the chosen concentration of oxamide diet (weight loss, mortality). The importance of oxamide concentration is underlined for further experiments on the influence of suture material on urinary infection and stone formation.


Echinococcal cyst of the adrenal gland.

Echinococcal cyst of the adrenal gland. A very rare case of echinococcal cyst of the adrenal gland is reported. Other organs were free of echinococcal cysts. Treatment consisted of surgical removal of the adrenal cyst through a subcostal incision.


Duplication of the urethra--transurethral treatment. A case of partial duplication of the male urethra is reported. Treatment consisted in transurethral section of the septum between the bulbar urethra and accessory urethral canal by internal urethrotomy.


Regeneration of 2.5 cm of the ureter.

Regeneration of 2.5 cm of the ureter. Regeneration of the ureter from a strip of healthy wall is well known. Regeneration after loss of the whole is an unusual phenomenon. A case of regeneration is presented after complete loss of 2.5 cm. Urography 1-5 years afterwards showed a normally functioning kidney. Bibliography of experimental and clinical work is discussed.


The possible role of transurethral resection in the dissemination of prostatic cancer. Prostatic carcinoma often reveals two different forms of tumour growth: (1) vigorous, almost therapy-resistant local growth, with absent or very slow metastasis (group 1), and (2) slight local growth responsive to therapy, combined however with swiftly forming distant metastasis (group 2). Two groups of such patients were examined in relation to primary findings and clinical course. Two factors were found in which they markedly differ. (1) The histological findings: in group 1 significantly more mature cancer forms appeared. (2) TREATMENT: a strikingly higher number of transurethral resections were performed upon in group 2 patient. The difference in the clinical development of prostatic cancer seems to be due to variations in the biology (as yet unknown) but may be partly to operative interference.


Vasectomy in prostatic surgery.

Vasectomy in prostatic surgery. A prospective study was conducted to evaluate the usefulness of vasectomy in prostatic surgery. The results showed that vasectomy does not reduce the incidence of epididymitis. Since vasectomy is not without disadvantages (such as sterility, some prolongation of the operation and the possible occurrence of complications) vasectomy as a routine in prostatic surgery is not indicated.


Surgical technique and results of primary repair in recent urethral injuries: a review of 49 consecutive cases. Late results after primary repair in 49 recent urethral injuries of the urethra treated through a perineal approach by sutures of realignment with splinting, and suprapublic and perineal drainage were assessed by measuring urethral flow, urethrography, urine analysis and other examinations. In 15 straddle injuries the results were excellent. Of 34 injuries associated with pelvic fracture 50% had satisfactory results. 12% had marked, but tolerable difficulties in micturition. Important details of operative technique are mentioned. A preference for primary repair in comparison with early cybstostomy and delayed reconstruction of the urethra is confirmed.


Development of the smooth muscle of the ureter and vesical trigone: histological investigation in human fetus. The development of the muscular tissue of the ureter, ureterovesical junction and vesical trigone in the human fetus has been investigated using serial histological sections. The muscular tissue firstly appears in the lumbar tract of the ureter and the further smooth muscle development occurs in a cranio-caudal direction. The muscular tissue in the intravesical portion of the ureter is present only in fetuses between 22 and 24 weeks. The development of the muscular tissue of the trigone is dependent upon the development of smooth muscle of this tract.


Obstruction and normal recanalization of the ureter in the human embryo. Its relation to congenital ureteric obstruction. In this work, after the study of 45 normal human embryos of 5-55 mm from vertex to coccyx, it is shown that the ureteric ducts, which in the first phases of development are permeable (embryos of 5-13 mm), constantly undergo a process of obstruction and posterior recanalization of their lumen, which takes place when they are from 14 to 22 mm. These processes begin in the middle zone of the ureters and progress proximally and distally until they cover its entire length, for which these ducts, which in embryos of approximately 17 mm in length form solid cords, but in the embryos of 23 mm are totally permeable. This obstructive process is found in relation to atrophy and loss of activity of the mesonephros, while that of recanalization follows the intense longitudinal growth of the ureters in this phase of development. These modifications, which the ureteric lumen normally undergoes during its embryonic development, are of great importance for correct interpretation of the pathogenic mechanism of congenital ureteric strictures and valves.


Sodium cellulose phosphate-induced increment in urinary calcium/magnesium ratio. In 19 adult patients, with renal stones containing calcium and hypercalciuria, urinary calcium and magnesium excretion and urinary calcium/magnesium ratio was investigated before and during 4 days of treatment with sodium cellulose phosphate. Urinary magnesium excretion fell following sodium cellulose phosphate therapy in all but 1 patient investigated: in 9 patients by less than 50% and in 10 by more than 50% of the pretreatment values. In the latter group of patients urinary calcium/magnesium ratio increased significantly from the mean values ( +/- SD) 3.2 +/- 1.1 to 6.77 +/- 6.9. In 6 patients serum magnesium absorption is suggested, and routine serum and urinary magnesium analysis with the early treatment of magnesium deficiency in patients treated with sodium cellulose phosphate are recommended.


Sigmoid kidney associated with renal adenocarcinoma. A rare case of adenocarcinoma in a sigmoid kidney is reported. The literature is reviewed and the operative technique described. Preoperative arteriogram and cavogram are an essential part of the evaluation and provide aid in the surgical approach.


Properties of acebutolol in twenty patients with cardiac arrhythmias. Acebutolol (M & B 17,803 A), a new cardioselective beta-adrenergic blocking agent, was given intravenously to 20 selected patients with various cardiac arrhythmias. Cumulative doses ranging from 12.5 to 50 mg were moderately or highly effective in 4 out of 4 patients with sinus tachycardia, 2 out of 3 patients with premature atrial beats, 3 out of 4 patients with premature ventricular beats, 3 out of 5 patients with atrial fibrillation (one was converted to sinus rhythm) and in 2 out of 3 patients with atrial flutter. The drug was ineffective in one patient with atrial tachycardia. Mild systolic hypotension occured in two patients with recent myocardial infarction and there was some aggravation of a preexisting bronchospasm in a patient with congestive heart failure secondary to hyper-thyroidism. It was concluded that acebutolol is a cardioselective beta-blocker which by intravenous route may be useful in the treatment of selected cardiac arrhythmias.


A comparison of plasma levels of L(+) pseudoephedrine following different formulations, and their relation to cardiovascular and subjective effects in man. Plasma concentrations of L(+)pseudoephedrine administered in clinically used dosages were determined by gas liquid chromatography using a nitrogen sensitive detector. They were measured after administered of an immediate release formulation (Sudafed) given in either a single dose of 180 mg, or three divided doses of 60 mg, and also after administration of two different sustained release preparations containing 180 mg. Ten subjects each received five treatment regimes, administration being ordered in a balanced design based on 2 five sided Latin squares. Significant differences were found between plasma concentrations and rates of urinary excretion of L(+)pseudoephedrine following administration of the different preparations. Peak plasma concentrations were greatest after 180 mg of the immediate release preparation while more sustained elevations of concentration followed administration of both sustained release preparations and the immediate release preparation in repeated doses. Despite these differences in plasma concentration significant differences in heart rate, blood pressure, or subjective ratings of mental state rarely occured, and the reasons for this are discussed. In a second study, one of the sustained release preparations was administered to 10 subjects at a dose of 180 mg twice daily for two weeks, and plasma concentrations and effects were measured. L(+)pseudoephedrine plasma levels reached a plateau in 3 days producing increased heart rate initially insomnia occurred but this disappeared after 3 days.


Pharmacokinetics in the elderly.

Pharmacokinetics in the elderly. The pharmacokinetics of sulphamethizole, paracetamol and phenylbutazone were investigated and compared in young and geriatric subjects. The rate and extent of absorption of the drugs did not appear to be affected by increasing subject age. However, the mean half-lives for sulphamethizole and paracetamol were significantly increased in the geriatric subjects. A number of correlations are presented between the elimination rate constants of the drugs and certain subject parameters and variables. The elimination of phenylbutazone was found not to be influenced significantly by subject age. The apparent volumes of distribution of the three drugs were not age-dependent.


Interaction of diphenylhydantoin (DPH) and tolbutamide in man. The influence of tolbutamide administration on the plasma concentrations of diphenylhydantoin (DPH) was investigated in seventeen long-stay patients with epilepsy. Tolbutamide, 0.5 g 2-3x daily, considerably increased the proportion of non-protein-bound DPH in plasma (mean: 44.6% of control values). The increase was transient, unlike the decrease found in total plasma DPH-concentration (approx. 10% of control values). In vitro experiments confirmed that the interaction between DPH and tolbutamide was due to displacement of DPH from plasma proteins. Some factors that limit the capacity to metabolise DPH in the liver are discussed; they may increase the risk of DPH-intoxication in patients who take sulphonyl-ureas.


Acetylation of procaine amide in man. A preliminary communication. The metabolism of procaine amide was studied in 41 cardiac patients who had achieved steady state plasma concentrations of the drug. Acetylated procaine amide accounted for 31 +/- 12% (range 16-63%) of the overall urinary recovery of the drug and is therefore a main metabolite in man. Plasma levels of the metabolite were usually lower but sometimes exceeded those of the parent compound with variations between 1 and 15 mug/ml. The metabolite had a weaker effect than procaine amide on the maximal electrical driving velocity of isolated atrial strips from guinea pig.


The effect of buffered aspirin on plasma indomethacin. Plasma indomethacin levels have been compared in 10 subjects following 100 mg of indomethacin from two different formulations, with similar disintegration and dissolution profiles. In four of these ten subjects plasma indomethacin levels were estimated after pretreatment with, and concurrent administration of, a buffered aspirin. The percentage of protein binding of indomethacin in the presence of salicylate was also estimated. No significant differences between peak plasma indomethacin levels with or without buffered aspirin were detected, but the rate of indomethacin absorption as shown by plasma levels, was significantly increased by pretreatment with and concurrent administration of, buffered aspirin. This was associated with a marked increase in side effects.


Plasma level and broncholytic effect of choline theophyllinate after a single dose of a press-coated tablet formulation. The broncholytic effect and plasma concentrations of theophylline in 10 asthmatic patients were studied for 8 hours after a single dose of 600 mg choline theophyllinate in press-coated 200 mg tablets. Therapeutic concentrations of theophylline were rapidly achieved and the plasma peak averaged 10.4 mug/ml after 2 hours. The broncholytic effect was closely related to the plasma level of theophylline. The largest change was in FEV1, which was significantly increased 1 to 6 hours after the dose. No patient complained of adverse effects. A theophylline concentration of 7 mug/ml plasma was adequate for a broncholytic effect, but a higher level was required for a maximal response. The results provide a basis for further studies to establish a dosage schedule suitable for prolonged therapy.


Plasma theophylline level and ventilatory function in chronic obstructive pulmonary disease during prolonged oral treatment with choline theophyllinate. Plasma levels of theophylline and broncholytic activity have been studied in 12 patients with chronic obstructive pulmonary disease during prolonged oral treatment with choline theophyllinate, administered as a press-coated tablet (BrondaxinR). The plasma levels determined immediately before and 80 minutes after each dose showed very good agreement with those calculated on the basis of data from a previous single dose study. The plasma concentration and improvement in ventilatory function were closely correlated throughout the 48 hours of the study. A tendency towards further reduction of bronchial obstruction was observed during the second day, despite essentially unchanged plasma levels of theophylline. The results provide a rational basis for determination of an optimal dose schedule for oral treatment with choline theophyllinate to reduce the symptoms of obstructive bronchial disease.


Persistent parotid pain due to guanacline. Details are given of 17 patients who developed parotid pain during treatment with guanacline and which persisted after cessation of guanacline for upto five and a half years. These patients are compared with 17 patients who received similar treatment with guanacline and who did not develop parotid pain. There was no significant difference between patients who experienced parotid pain and those who did not with respect to sex, age, clinical diagnosis, blood urea, previous hypotensive therapy or other drugs given concurrently with guanacline. There was a slightly greater association of parotid pain with other side effects and with a larger daily dose of guanacline. It is suggested that persistent parotid pain after guanacline therapy is due to prolonged or permanent selective sympathetic nerve damage in the region of the cervical sympathetic nerve supply to the salivary glands.


General pharmacokinetic equations for linear mammillary models with drug absorption into peripheral compartments. General equations are derived for the disposition functions of any compartment in a linear mammillary model, when the system input occurs into a peripheral compartment. Laplace transforms and matrix algebra are used to derive these equations. Equations describing the time-course of a drug in any compartment are readily obtainable using disposition and input functions.


The measurement of drug consumption. Drugs for diabetes in Northern Ireland, Norway and Sweden. The consumption of insulin and oral antidiabetic drugs was measured at the gross sales level in Sweden and Norway and at the prescription level in Northern Ireland. ""Agreed daily doses'' were used as units of comparison, which defined as follows: insulin 40 I.U., tolbutamide 1 g, acetohexamide 500 mg etc. Consumption was expressed as the number of ""agreed daily doses'' per 1,000 inhabitants per day. This provided a rough estimate of the number of subjects for whom the drug had been prescribed per 1,000 population. The data were collected during the three months April-June 1971. Marked differences in the consumption of antidiabetic drugs were found between the three countries and also between areas within each country. The consumption of insulin was similar in Norway and Northern Ireland (3.5 and 3.9 agreed daily doses per 1,000 inhabitants per day), but almost twice as high in Sweden. In Norway much lower use was found in certain rural areas. The variation in the consumption of oral antidiabetic drugs was even more marked. Surprisingly, consumption was considerably higher in Sweden (15.8) than in the nearby Norway (7.3), and was even lower in Northern Ireland (4.3). The major use was of sulphonylureas, especially chlorpropamide. Within the countries there was marked regional variation in the choice of individual biguanides and sulphonylureas. The data are discussed in relation to such factors as the incidence of diabetes, the sole use of dietary treatment etc. It is concluded that studies in depth, which link the actual use of drugs by patients to diagnosis, diabetic symptoms and clinical outcome of treatment are necessary in order to explore the reasons behind the marked geographical differences and to define a rational drug policy. However, the methods described in the study may be used for early detection of gross national differences in drug utilization, the further investigation of which may reveal to be of great public health interest.


Distribution and elimination kinetics of carbamazepine in man. Carbamazepine (2.7-3 mg/kg) was administered orally as an alcoholic solution (50% v/v) to eight healthy volunteers. Two of the subjects were also given 50 mg and 100 mg of carbamazepine in alcoholic solution and 200 mg as a tablet. Plasma concentrations, which were analysed by mass fragmentography, reached a maximum 1-7 hours after dosing, and then declined monoexponentially with half-lives ranging from 24 to 46 hours. The half-lives were independent of dose. The apparent distribution volume ranged from 0.79 to 1.40 1/kg. It was found that 72% of carbamazepine was bound to plasma proteins with little interindividual variation, and this was not influenced by the presence of diphenylhydantoin or phenobarbital in therapeutic concentrations. The pharmacokinetic parameters calculated from single oral doses were used to predict the steady-state plasma concentration expected after treatment with multiple doses of 200 mg three times daily. The predicted steady-state concentration was 2-3 times higher than that reported in patients undergoing chronic treatment with carbamazepine at this dose level, i.e. the pharmacokinetics of carbamazepine apparently change during multiple dosing.


Concentrations of the vasodilator isosorbide dinitrate and its metabolites in the blood of human subjects. An oral dose of 5 mg of 14C-isosorbide dinitrate was rapidly absorbed, biotransformed and excreted by human subjects. Peak whole blood concentrations of radioactivity were reached after 1.5 to 2 hours and declined relatively slowly. The radioactivity in whole blood mainly represented metabolites, isosorbide mononitrates. The peak concentrations found were 4.5, 11.7 and 34.3 ng/ml of isosorbide dinitrate, isosorbide 2-mononitrate and isosorbide 5-mononitrate, respectively, in the blood of one subject and 5.9, 15 and 61.3 ng/ml, respectively, in the blood of another subject. However, concentrations of the metabolites declined relatively slowly during 6 h after the oral urine of the first day (ca. 78%). The results showed that isosorbide mononitrates were available to contribute to the pharmacological action.


Excretion of norephedrine by man after oral administration of oxyfedrine. After oral administration of oxyfedrine to healthy volunteers, norephedrine was identified in the urine by thin layer chromatography and gas liquid chromatography and mass spectrography. 30 hours after single oral doses of 8, 16 or 24 mg of oxyfedrine, about 4, 8 and 9 mg, respectively, of norephedrine were found in the urine, i.e. on a molar base 75-100% of the dose was excreted as norephedrine. The peak of excretion occurred within 2-4 hours after administration of the drug. No accumulation of oxyfedrine and/or its metabolite was observed after administration of 16 mg of oxyfedrine t.i.d. for three days. It could not be decided whether oxyfedrine was metabolized to norephedrine by liver enzymes, as in rats, or was spontaneously degraded to norephedrine, e.g. in duodenal fluid before absorption. 30-150 min after oral oxyfedrine (24 mg) norephedrine was demonstrable in duodenal fluid. Thus, in addition to the direct beta-sympathomimetic effects of oxyfedrine, it may also have indirect sympathomimetic effects because of the noradrenaline-releasing properties of its metabolite norephedrine.


Haemodynamic effects of intravenous disopyramide in heart failure. The haemodynamic effects of disopyramide have been studied in 11 patients with manifest or imminent heart failure. Disopyramide, 2 mg per kg body weight, was given intravenously during right and left heart catheterisation. The cardiac index decreased by an average of 28% (p less than 0.01); mean maximal left and right ventricular end-diastolic pressures were increased by 5.0+/-0.9 mm Hg (p less than 0.01) and 5.0+/-0.6 mm Hg (p less than 0.05), respectively; and left ventricular systolic pressure fell slightly but significantly (p less than 0.05). No significant change in right ventricular systolic pressure was seen. Pulmonary wedge pressure rose on average by 2.7 mm Hg (p less than 0.05). No significant change in heart rate was observed in 5 patients with sinus rhythm. In 6 patients with atrial fibrillation, there was a significant (p less than 0.01) increase in heart rate; the average increase in heart rate for the entire group was 19.6 beats per minute. The maximum effect on all the  parameters occurred 7-11 minutes after the injection, and it gradually subsided during the following 10 minutes. It was concluded that disopyramide had a potentially serious myocardial depressant effect.


Effects of intravenous propranolol and metoprolol and their interaction with isoprenaline on pulmonary function, heart rate and blood pressure in asthmatics. The effects of propranolol (0.06 mg/kg i.v.), the selective beta1-receptor antagonist metoprolol (0.12 mg/kg i.v.) and a placebo on pulmonary function, heart rate and blood pressure have been compared in asthmatics. The interaction of these drugs with increasing doses of isoprenaline on the same variables was also studied. The two beta-blockers reduced resting heart rate to the same extent, indicating the same degree of blockade of cardiac beta-receptors. Both beta-blockers reduced the basal forced expiratory volume in one second (FEV1), and the effect tended to be more pronounced after propranolol. Isoprenaline caused a dose-dependent  increase in FEV1 and vital capacity (VC). These effects  were almost completely blocked by propranolol, whereas after metoprolol the changes approached that of the placebo. The isoprenaline-induced increase in heart rate and fall in diastolic blood pressure was also inhibited to a considerably greater extent by propranolol than by metoprolol. The results show a selectivity of metoprolol for so-called beta1-receptors and indicate that metoprolol may be used in asthmatics provided that it is combined with beta2-receptor-stimulating drugs.


Correlation between increased dopamine-beta-hydroxylase activity and catecholamine concentration in plasma: determination of acute changes in sympathetic activity in man. In 11 healthy untrained volunteers the increase in plasma dopamine-beta-hydroxylase (DBH) activity during graded physical exercise has been examined as a true measure of increased activity of the sympathetic nervous system. The correlation between DBH activity, catecholamine concentration (CA) in plasma and heart rate was studied. When work on an electrically braked bicycle ergometer was gradually increased from 12.5 to 100, 200 and 300 watts there was a linear increase in DBH activity and heart rate; the increase in CA concentrations followed an exponential function. The peak values for DBH activity and CA concentration in plasma after the 300 watt work load (as percentages of the resting levels) were 130+/-3% and 820+/-71%, respectively; the adrenaline concentration in plasma increased only to 150+/-19% (p less than 0.05). There were significant correlations between heart rate and work load, DBH and work load and log CA and work load. The data imply direct correlations between heart rate and DBH, heart rate and log CA and DBH and log CA. The exponential increase in noradrenaline concentration in plasma might be due either to a greater net ""overflow'' from sympathetic nerve endings, and/or to increased secretion by the adrenal medulla. In the latter case, the release of noradrenaline would not be accompanied by secretion either of adrenaline or DBH. After work ceased there were sharp falls in heart rate and CA concentration, which indicate an immediate drop in sympathetic activity. DBH activity in plasma returned to normal very slowly; it reached half maximum values after 20-22 min. It is concluded that increased sympathetic activity in man can be estimated in vivo as changes in DBH and/or CA concentration in plasma. In contrast, a rapid decrease in sympathetic activity is directly reflected only by a rapid fall in the plasma concentrations of CA.


Pilot study of the effect of terodiline chloride (Bicor) in obstructive pulmonary disease. Terodiline chloride, 150 mg daily, was administered to 10 patients with obstructive pulmonary disease, and pulmonary function tests were performed before and during two weeks of therapy. Serious side effects of anticholinergic type developed in two patients who stopped treatment. Two patients were excluded from the trial for other reasons. The remaining six patients showed signs of bronchodilation. Owing to the high incidence of side effects, treatment with more than 75 mg terodiline chloride per day is impracticable.


Effects of metoprolol and propranolol on furosemide-stimulated renin release in healthy subjects. The effects of single doses of the beta1-receptor antagonist metoprolol (40 mg orally), propranolol (40 mg orally) and placebo were compared on furosemide-stimulated plasma renin activity (PRA) in seven healthy subjects. In the placebo studies, PRA increased by 0.59+/-0.18 ng x ml-1 x h-1 60 minutes after intravenous administration of 30-60 mg furosemide. After propranolol and metoprolol, the corresponding increases in PRA were significantly less pronounced amounting to 0.16+/-0.06 and 0.24+/-0.08 ng x ml-1 x h-1, respectively. The resting heart rate was reduced to the same extent after the two beta-blockers, which means that the two drugs had been given in equipotent beta1-receptor blocking doses. It is suggested that the release of renin from the kidney may partly be mediated via an adrenergic beta1-receptor.


Pharmacokinetics and side-effects of clonazepam and its 7-amino-metabolite in man. Clonazepam (CNP) and its principal metabolite in plasma, 7-amino-CNP (ACNP), have been investigated in a prospective study of 27 newly diagnosed epileptics and correlated with specified side-effects. At a daily dose of 6 mg, the average plasma levels of both substances were about 50ng/ml, and individual values ranged from 30 to about 80 ng/ml. There was a linear correlation between changes in dose and the resulting plasma levels, which indicates first order elimination kinetics. Side-effects were frequent, but neither their severity nor their occurrence could be related to plasma levels or to the rate of increase in plasma concentration of the drug. Three out of five patients who developed serious dysphoria had significantly high CNP levels. The concentration of ACNP was considerably increased in four patients who subsequently suffered from withdrawal symptoms. Drug interaction with diphenylhydantoin, i.e. decreased CNP level, was observed in all five patients who received both compounds. In general it is not yet possible to define an upper limit for the plasma levels of CNP and ACNP at which toxicity occurs. In patients treated with conventional doses of CNP, measurement of plasma concentration is not required, except in special circumstances, because of the lack of correlation between plasma level and side-effects.


Pharmacokinetics of 5,6-trans-25-hydroxycholecalciferol, a synthetic analogue of vitamin D3, in man. Vitamin D analogues of high biological activity are probably useful in the treatment of renal osteodystrophy. The pharmacokinetics of the synthetic compound 5,6-trans-25-hydroxycholecalciferol have been studied in healthy subjects who were of normal vitamin D status. In comparison to natural 25-hydroxy-cholecalciferol, serum levels of the analogue were lower and its half-life in blood after oral or intravenous administration was considerably shorter. In normal subjects no increase of dihydroxylated metabolites in serum was observed within seven days of an intravenous dose.


On the pharmacokinetics of phenacetin in man. The pharmacokinetic characteristics of the analgesic phenacetin have been determined in six healthy adults. After rapid i.v. injection of 250 mg phenacetin, the log plasma concentrations versus time curves were evaluated according to the rules of a two-compartment open model. The elimination half-life (t1/2)beta varied from 37 to 74 minutes. The volume of distribution (Vd)beta ranged from 1.0 to 2.1 1 per kg body weight. The total clearance of the drug was high and approximated the average value of hepatic blood flow in normal adults. In agreement with this finding, the bioavailability of a small oral dose of phenacetin (0.25 g) was almost nil, as the bulk of the drug was cleared during its first  pass through the liver. With large oral doses (1.0 g) the first-pass effect decreased and availability increased. The results are discussed and related to current general views of the liver-first-pass phenomenon.


The protein binding of some drugs in plasma from patients with alcoholic liver disease. The binding of 5 drugs to plasma proteins from patients with alcoholic liver disease has been studied by in vitro techniques and compared to that from normal subjects. The binding of quinidine is decreased in such patients. For this reason, if in patients with alcoholic liver disease treated for coincidental arrhythmias with quinidine, plasma quinidine concentrations are measured, allowance for the decreased binding must be made in interpreting the concentration measurements. Diphenylhydantoin binding was normal or near normal in most of the patients' plasma samples. The other drugs tested, fluorescein, dapsone, and triamterene, had decreased binding in the patients' plasma samples.


Anticoagulant effect and plasma kinetics of fluorophenindione after a single dose in man. After administration of a single  loading dose (80 mg p.o.) of fluorophenindione, the prothrombin level decreased to 37% in 24 h, and the effect lasted for 48 h. Accordingly, fluorophenindione can be classified as an anticoagulant with an ""intermediate'' effect. Its elimination half-life was 31 h, which is longer than that of phenindione, because of the greater stability of the fluorinated derivate.


Plasma concentrations and urinary excretion of the antiarrhythmic quaternary ammonium compound QX-572 in man. A quantitative thin layer chromatographic (TLC) method has been developed for determination of the antiarrhythmic quaternary ammonium compound N,N-bis (phenylcarbamoyl methyl) dimethylammonium chloride  (QX-572) in biological materials. Prior to chromatography QX-572 was transferred into chloroform as perchlorate by ion pair extraction. Tritium-labelled QX-572 was used as the internal standard and a TLC scanning spectrophotometer equipped with a linear detector system afforded the required accuracy, specificity and simplicity. The method was used to determine QX-572 in plasma from 11 patients with various cardiac diseases who received QX-572 8 mg/kg body wt. as an intravenous infusion over 30 min. There was a rapid initial decay of the plasma levels from 11.0+/-1.1 mug/ml (mean+/-SE) at the end of infusion to 3.5+/-0.5 mug/ml after 30 min. 240 min after commencement of the infusion the plasma level was 0.7+/-0.1 mug/ml. In these patients 22+/-2% (mean+/-SE) of the total administered dose of QX-572 was excreted unchanged in urine during the 24 hours following infusion of the drug. A second group of 28 patients with acute myocardial infarction also received QX-572 8 mg/kg body wt. Their plasma levels did not differ significantly from those found in the first group of patients. There was a poor correlation between the amount of QX-572 administered and plasma level at the end of the infusion. The study has provided some preliminary data about the pharmacokinetics of QX-572, but before a detailed analysis can be done data from longer periods of observation is required. The present results suggest that in future QX-572 can be administered in a standardized dosage, what would be advantageous in practice.


Disposition of placentally transferred carbamazepine (Tegretol) in the newborn. The plasma elimination of carbamazepine (Tegretol) was studied in five newborns who had got the drug transplacentally from their epileptic mothers. The half-lives ranged from 8.2-27.7 hours which is comparable or even shorter than those found in adults after a single oral dose, but in the same range as those found in adults after multiple oral doses. This suggests that the newborns' drug metabolizing capacity has been induced during fetal life.


Delayed absorption of lithium in intoxication: a case history. A 55-year old man with lithium intoxication showed increasing serum concentrations in spite of forced diuresis and dialysis. A high lithium content was found in gastric juice three days after the compound had been taken. The serum lithium level began to fall after gastric lavage.


Mechanism of the inhibitory effect of PAS granules on the absorption of rifampicin: adsorption of rifampicin by an excipient, bentonite. The bioavailability (plasma concentrations, AUC and urinary excretion) of an oral solution of rifampicin was investigated in six healthy volunteers. Simultaneous administration of PAS granules produced a significant decrease in the absorption of RMP, whereas Na-PAS tablets had no effect. This indicated that the dosage form of the granules and not PAS itself was responsible for the interaction, and that the dissolution of RMP was not involved. The interaction could be reproduced by giving dummy granules that contained the same excipients but no PAS. The disintegration and dissolution of PAS granules in vitro correlated well with the disappearance of RMP from the solution. The major excipient of the granules, bentonite (a mineral closely related to kaolin), was found to adsorb rifampicin rapidly and strongly.


Effect of rifampicin treatment on the metabolism of oestradiol and 17alpha-ethinyloestradiol by human liver microsomes. Liver biopsies were obtained from four patients treated with rifampicin 600 mg for 6-10 days. Hepatic microsomes were incubated with an NADPH-regenerating system and the substrates [2,4,6,7-3H] oestradiol, [6,7-3H] oestradiol, [2,4,6,7-3H] ethinyloestradiol and [6,7-3H] ethinyloestradiol. The hydroxylation rates of these steroids at the labelled positions of rings A and B were determined by measuring the transformation of tritium into HTO by the microsomal enzymes. Comparison with previously published data showed that treatment with rifampicin caused a fourfold increase in the rate of hydroxylation of oestradiol and ethinyloestradiol at positions C-2/C-4 of ring A and C-6/C-7 of ring B. The acceleration of oestrogen hydroxylation by rifampicin was paralleled by an increase in microsomal cytochrome P-450, and also by microsomal reduction of rifampicin-quinone, a reactive metabolite of rifampicin. The increased aromatic hydroxylation of oestradiol and ethinyloestradiol leads to enhancement of their irreversible binding to microsomal protein. The data provide an explanation for the diminished efficacy of oestrogens in contraceptive formulations given to patients under treatment with rifampicin.


Haemodynamic effects of intravenous verapamil at rest and during exercise in subjectively healthy middle-aged men. Verapamil, 0.1 mg/kg body wt, was injected i.v. over 2 minutes in 8 subjectively healthy middle-aged men, followed by a continuous infusion of 0.007 mg/kg body wt per minute. Prior to the injection several of the subjects had raised pulmonary or systemic arterial pressures. At rest, the central pressures increased slightly, which was taken as a sign of a moderate negative inotropic effect, but there was no change in pre-ejection period or maximal dp/dt of the aortic pressure. The heart rate increased and there was a small decrease in systemic arterial pressure, probably due to a fall of systemic vascular resistance. The PQ time was prolonged. During exercise, with its positive inotropic stimulation, the moderate negative inotropic effect of verapamil disappeared, whereas the increase in heart rate and decrease in aortic pressures persisted. Some variables that reflected the oxygen demand of the heart decreased. The slight negative inotropic effect does not appear to be a particular contraindication to the use of verapamil, but it should be employed cautiously in conditions with a compensatory rise in systemic vascular resistance, or if atrioventricular conduction is impaired.


Effect of premedication on stress and plasma cortisol in patients bronchoscoped under local anaesthesia. Four groups of 8 patients undergoing bronchoscopy were premedicated with either pentobarbitone 1 mg/kg i.m. followed by i.v. saline, or diazepam 10 mg and saline i.v., or diazepam 10 mg i.m. followed by diazepam 20 mg i.v. and, diazepam 20 mg i.m. and then saline i.v. Both the patients and the bronchoscopist were asked to score the premedication as excellent, satisfactory, unsatisfactory or bad. Plasma cortisol was measured before premedication and before and after bronchoscopy. Preoperatively plasma cortisol increased in every group except that given diazepam 20 mg i.m., and during bronchoscopy it rose in all except the group who received 20 mg diazepam i.v. In patients who considered the premedication unsatisfactory, the rise in plasma cortisol from before premedication until after bronchoscopy was significantly higher than in satisfied subjects. It appears that in patients undergoing bronchoscopy higher doses of diazepam (20-30 mg) gave better suppression of stress than 10 mg diazepam, or 1 mg/kg pentobarbitone.


Plasma kinetics of carbamazepine and its epoxide metabolite in man after single and multiple doses. Carbamazepine (Tegretol) was administered orally to four patients as a single dose, and one week later three times daily for 15-21 days. The plasma half-lives of the drug were shorter in all patients after multiple doses (20.9 +/- 5.0 hours) than after the initial single dose (35.6 +/- 15.3 hours). During the multiple dose the plasma concentrations of the metabolite carbamazepine-10,11-epoxide followed those of the parent drug. The steady-state plasma concentrations expected during multiple doses were calculated from the pharmacokinetic parameters obtained in the single dose studies. The calculated levels were higher (17.2+/-7.2 mug/ml) than the observed maximal concentrations (8.4+/-1.6 mug/ml on day 4), which were obtained 3-4 days after starting the multiple doses. The levels tended to decrease further during the experimental period. The results suggest that carbamazepine induces its own metabolism in man.


Kinetics of nortriptyline in man according to a two compartment model. Plasma concentrations of nortriptyline have been assayed in four subjects after intravenous infusion of 57 mg nortriptyline hydrochloride. The data were evaluated according to a two compartment open model. The calculated best-fitting curves were in good agreement with the experimental data, better than could be expected from a simpler model. This justifies the assumption that the kinetics of nortriptyline in man may be described by this model with an appropriate input function. The data permitted estimation of all the parameters of the model. The meaning of the parameters is discussed, particularly in relation to individual variation.


Urinary excretion of amantadine by the elderly. The urinary excretion of single or multiple oral doses of amantadine hydrochloride by three elderly patients has been studied by gas chromatography. Steady state amounts in urine were about 230-240 mg per day. The half life of urinary excretion was approximately 34.17 hours. Urine collection from aged subjects is difficult.


Pharmacokinetics of chlormethiazole in humans. The pharmacokinetics of chlormethiazole have been studied in six healthy volunteers following an intravenous infusion of the drug. The log. plasma concentration-time curve of chlormethiazole after cessation of the infusion was found to be curvilinear and was fitted therefore, by a bi-exponential equation computed by non-linear least squares regression analysis. Half-lives for the initial alpha-phase (0.54+/-0.05 h) and the terminal beta-phase (4.05+/-0.60 h) were calculated together with other pharmacokinetic parameters of the two compartment open model. An explanation for the discrepancy between the presently reported plasma half-lives and those appearing in the literature has been presented. The pharmacokinetic treatment of the plasma concentration-time data obtained following intravenous infusion also enabled the prediction that the maximal systemic availability of an orally administered dose of chlormethiazole would be of the order of 15%.


Assay of the major (4-hydroxylated) metabolites of diphenylhydantoin in human urine. A modified gas chromatographic procedure for the determination of unconjugated and conjugated 4-hydroxydiphenylhydantoin (4-OH-DPH) in urine has been developed. Unconjugated 4-OH-DPH is determined after selective extraction with toluene-ether (1:1). For the assay of conjugated 4-OH-DPH, the urine is pre-extracted with isoamylalcohol before acid hydrolysis to avoid interference by the dihydrodiol metabolite of DPH. The sensitivity of the method is 0.1 mug per ml. The method has been used to determine the urinary metabolites in two adult volunteers, during steady state plasma concentrations of DPH and in the elimination phase.


Effect of particle size on the bioavailability of digoxin. The bioavailability of digoxin in three tablets prepared from materials with different particle sizes was measured in healthy volunteers in a cross-over study using an alcoholic solution of digoxin as a reference standard. Its bioavailability in tablets with particle sizes of 7 mu or 13 mu was 78-97% of that of digoxin in solution. The tablet with largest particle size (102 mu) showed markedly lower bioavailability than the reference solution, namely 39%. It is obvious that particle size is an important determinant of the dissolution rate and bioavailability of digoxin.


Plasma concentration of alpha-methyldopa and sulphate conjugate after oral administration of methyldopa and intravenous administration of methyldopa and methyldopa hydrochloride ethyl ester. The plasma concentrations of free alpha-methyldopa and methyldopa sulphate conjugate were measured in 7 hypertensive patients with normal renal function following alpha-methyldopa (1 g) orally. Five of these patients subsequently received alpha-methyldopa ethyl ester (250 mg) (methyldopate) intravenously and two further patients received 250 mg of alpha-methyldopa intravenously. After oral administration a large amount of total plasma alpha-methyldopa was present as sulphate conjugate. There were wide interindividual differences in the ratio of free: conjugated alpha-methyldopa in plasma (ratio at 4 hours ranged from 3.73-0.83) suggesting that individual differences in the extent of sulphate conjugation may occur. There was no close correlation between the degree of conjugation and the fall in arterial pressure. At all time intervals examined, plasma concentrations were higher following intravenous alpha-methyldopa than alpha-methyldopate. The plasma concentration of alpha-methyldopa (free and esterified) 60 minutes after i.v. alpha-methyldopate was 1.7+/-0.3 mug/ml while at the same time after the same dose of methyldopa by the same route the mean concentration was 5.9 mug/ml. Although small amounts of sulphate conjugate were detected after i.v. alpha-methyldopate, insignificant quantities of conjugate were found after i.v. alpha-methyldopa. The average fall in mean arterial pressure was 27 mm/Hg following i.v. alpha-methyldopa but only 2.7 mm Hg following alpha-methyldopate. These results suggest that sulphate conjugation of alpha-methyldopa occurs in the gastrointestinal tract during absorption. Hydrolysis of alpha-methyldopa ethyl ester does not appear to be instantaneous and pharmacokinetic differences between the ester and free alpha-methyldopa have been demonstrated.


Effect of diazoxide on left ventricular performance in hypertension. The effect of diazoxide on left ventricular performance during rest and isometric exercise (handgrip) was examined in 16 unselected hypertensive patients, 6 of whom had been pretreated with the beta-adrenergic blocking agent pindolol. Diazoxide regularly and promptly produced a fall in left ventricle systolic and end diastolic pressures, and an increase in heart rate and left ventricular dp/dtmax. Haemodynamic changes were maximal 2 minutes after injection of the drug and decreased little over the next 8 minutes. After beta-adrenergic blockade, diazoxide caused a more pronounced reduction in left ventricular systolic pressure and a less marked fall in end-diastolic pressure, whilst the diazoxide-induced rise in heart rate was partially and the increase of dp/dtmax was completly inhibited. The increase in systolic pressure during isometric exercise was not influenced by diazoxide, but the positive inotropic reaction was augmented. The findings appear to show that cardiac stimulation by diazoxide is due to a reflex mechanism transmitted by baroreceptors, and that improvement of cardiac performance is mainly due to a reduction of left ventricular after-load.


Cardiovascular and respiratory effects of the beta-adrenoceptive antagonist sotalol: studies in health, angina pectoris and obstructive lung disease. The cardiovascular and respiratory actions of the adrenergic beta adrenoceptive drug sotalol have been studied in an open, short term trial. Fifteen patients with angina performed standardized orthostatic and exercise tests before and after injection of 20 mg sotalol intravenously. Although there was a significant reduction of heart rate and blood pressure at the time of appearance of angina pectoris and ST-segment depression, there was only a slight and statistically insignificant increase in work before the appearance of angina pectoris, and ischaemic changes in the ECG disappeared more rapidly after work. In a different group of patients suffering from obstructive lung disease, sotalol 10 mg intravenously produced a significant increase in airway resistance. It has no such effect on normal subjects.


Initial clinical experience with a new peripheral vasodilator, PR-G-138-Cl, in hypertensive patients. PR-G-138-C1, a new antihypertensive agent with vasodilating properties, was studied in ten patients with moderate to severe hypertension. The patients were admitted to a metabolic ward and followed on a 2 gm salt diet. Placebo was given daily until blood pressure and weight were stabilized. A dose titration was then started with increasing single daily doses of 3, 5, 8, and 10 mg of PR-G-138-C1 orally. The dose at which the mean arterial pressure was reduced by 15 mm Hg was continued for a total of seven days. PR-G-138-C1 lowered sitting mean arterial pressures significantly in all subjects (133.8+/-15.1 leads to 116.0+/-12.4 mm Hg, p less than 0.001). The antihypertensive effect was first noted 30 minutes following drug administration and persisted for as long as six hours with a peak effect at one hour. All patients had a significant increase in sitting pulse rate (80.4+/-9.11 leads to 90.0+/-6.91/min, p less than 0.002). Blood pressure reduction and increase in pulse rate were dose related. The most common side effects noted were headaches in eight out of ten patients and postural dizziness in seven out of ten patients. There were no signs of fluid retention (weight gain or edema). Electrocardiogram and other laboratory parameters remained essentially unchanged.


Comparison of fixed interval and visual analogue scales for rating chronic pain. A visual analogue scale (VAS) and a 4-point scale (FPS) have been compared in patients suffering from prolonged constant pain due to chronic inflammatory or degenerative arthropathy. Each patient was treated with a constant low or high dose of paracetamol or dihydrocodeine throughout a four week period. The VAS was accurate, as reliable and more sensitive than the FPS in registering the intensity of chronic pain. Separate records of each estimate, sealed immediately on completion by the patient, resulted in omission of significantly more pain recordings on the FPS, whereas retention by the patients of their previous records did not systematically influence subsequent judgments. In this study, the VAS appeared to be more satisfactory than the FPS for patient self-rating of pain intensity.


On the pharmacokinetics of proscillaridin A in man. The plasma concentration of proscillaridin was measured by a modified 86Rb method during treatment with multiple doses of a commercial preparation of proscillaridin. Despite high doses, very low plasma levels were found, and there were only minute amounts of glycoside activity in urine and faeces. Administration of an enteric-coated proscillaridin preparation gave higher plasma levels, which raises the possibility of inactivation of the glycoside by acid gastric juice. The results suggest that proscillaridin has low biological availability when given orally, and that it is extensively metabolised in the body.


Metabolism and excretion of methylproscillaridin by man. 0.5 mg 3H-proscillaridin-4-methylether was administered orally to 5 healthy males. Maximum plasma levels of total radioactivity were reached after one to two hours. In two subjects a second peak was observed between 6 and 12 hours. The plasma half life of total radioactivity was 51 hours. 20% and 56% respectively of the dose were eliminated in urine and faeces during the following 7 days. 55% of the total radioactivity in plasma, 80% in urine and 20% in faeces consisted of CHC13-insoluble compounds. 50-60% of the latter in plasma and urine could be hydrolysed by beta-glucuronidase. More than 90% of the split products were identified as conjugates of methylproscillaridin. TLC-separation of the CHC13-soluble fractions of plasma and urine yielded two unidentified metabolites, P2 and P3, as the main compounds, besides methylproscillaridin, proscillaridin and scillarenin. In faeces more than 90% of the non-polar fraction was identified as methylproscillaridin. Shortly after administration of 3H-methylproscillaridin, the radioactivity in plasma consisted mainly of CHC13-insoluble conjugates and of the metabolite P2.


A GLC method for estimation of chlorophenoxyisobutyric acid in plasma. Pharmacokinetics of a single oral dose of clofibrate in man. A GLC method has been developed to measure chlorophenoxyisobutyric acid in plasma after benzol extraction and transformation to its methyl ester, using methyl laurate as the internal standard. Plasma free fatty acids did not interfere with the analysis, but it could not be employed in the presence of salicylates. The method has been employed to study the pharmacokinetics of chlorophenoxyisobutyric acid in man after oral ingestion of a single dose of clofibrate.


Renal function and the rate of disappearance of methotrexate from serum. The disappearance of methotrexate (MTX) from serum was studied using H3-MTX. The overall elimination half-life (MTX T1/2) was well defined from one to about six hours after i.v. administration; in 25 patients it ranged from 102 min to 750 min and was inversely related to endogenous creatinine clearance, which ranged from 6 to 140 ml/min. The corresponding apparent volume of distribution, V, obtained by extrapolation tended to decrease at lower levels of renal function. The total clearance of MTX calculated in this period varied linearly with creatinine clearance. In patients with normal serum creatinine concentration, the half-life increased with advancing age, which reflects the concurrent age-dependent decrease in creatinine production and renal function. This illustrates the need for knowledge  of renal function, not based solely on serum creatinine concentration, in patients treated with methotrexate or other drugs eliminated by the kidneys. In 9 patients the results were not affected by treatment with diuretics (furosemide, hydroflumethiazide). In four patients serum MTX concentration was measured for up to 24-72 hours. An increasing half-life of MTX with time was found, suggesting that the elimination kinetics of the drug would be most adequately described by a multi-compartment model.


Binding of amobarbital, pentobarbital and diphenylhydantoin to blood cells and plasma proteins in healthy volunteers and uraemic patients. By equilibrium dialysis of human plasma it has been shown that the binding of pentobarbital and diphenylhydantoin to plasma proteins is decreased in uraemic patients (46 and 74 per cent bound, respectively) compared to healthy volunteers (61 and 88 per cent bound). The degree of binding of pentobarbital was significantly correlated with that of diphenylhydantoin and amobarbital, which suggests similarity of their binding sites. Appreciable proportions of the drugs were found in blood cells both in healthy and uraemic subjects. As expected, the distribution of drugs in whole blood was different in the uraemics from healthy subjects, because of the decreased plasma protein binding and the lowered red cell count in uraemia. Analysis of the data showed that the ratio between the concentrations in blood cells and plasma water in uraemic patients was not significantly different from that in healthy subjects.


A comparison of triprolidine and clemastine on histamine antagonism and performance tests in man: implications for the mechanism of drug induced drowsiness. The effects of triprolidine hydrochloride 1.25, 2.5 and 5 mg, clemastine 1 and 2 mg and lactose dummy administered orally, in a balanced order, at weekly intervals to 12 healthy volunteers, on the flare and weal responses to intradermal histamine injection, and also on both subjective effects and objective psychomotor tests were examined. The histamine response was significantly larger at 09.00 h falling through the day but increasing by late afternoon. Triprolidine produced a dose-related antagonism of both flare and weal response maximal at 3 h and wearing off after the lower doses at 8 h. Clemastine by contrast produced poor antagonism of histamine at 3 h but a marked effect at 5.5 and 8 h. Auditory vigilance was significantly (p less than 0.05) impaired by all doses of triprolidine 1 to 2 h after administration, but no change followed clemastine at this time. When tested 6 to 7 h after administration significant impairment followed both doses of clemastine but only the 5 mg dose of triprolidine. Both drugs prolonged reaction time in a dose-related manner at 2.5 and 5.0 h but the effects had worn off at 7 h. Digit symbol substitution was impaired by the top doses of both antihistamines but short term memory was unaffected. Subjective effects measured using analogue lines reflected the effects in the vigilance test, in that drowsiness and mental impairment were noted early after triprolidine, while clemastine produced maximal effects at 5 h. Subjects were ranked in order of magnitude of inhibition of both flare and weal, and impairment of vigilance, prolongation of reaction time and subjective drowsiness score. There was no indication of a significant correlation, using Spearman's test, between antagonism of histamine and effects on the central nervous system.


Absorption, half-life, and toxicity of oral aprindine in patients with acute myocardial infarction. Plasma concentrations of aprindine were used to assess its absorption, toxicity and disappearance rate after oral administration to patients within 24 hours of admission to a coronary care unit. Despite high oral doses, absorption was so slow that in half the patients effective plasma levels (exceeding 0.70 mug/ml) were not found during the first 12 hours of treatment. Therefore the oral route should not be used to treat cases of acute myocardial infarction with severe ventricular dysrhythmias. Clinical tolerance was good; there was one episode of delirium tremens in a chronic alcoholic (aprindine plasma concentration: 3 mug/ml); no case of tremor or cerebellar syndrome was observed. Disappearance of aprindine from plasma was slow, by far exceeding the half-lives found in healthy volunteers, and ranging from 20 to over 100 h. The variability of biological half-life in individual patients makes plasma level determiniations necessary whenever aprindine is to be administered for a long period.


Comparative study of the cardiac and peripheral vascular effects of strophantin K and lanatoside C in coronary heart disease. The effects of intravenous strophanthin K (0.125 and 0.25 MG) and lanatoside C (0.4, 0.8 and 1.6 mg) on systolic time intervals (STI) and impedance plethysmographic (IP)P values were studied in ten patients with compensated coronary heart disease. The heart rate decreased significantly during a two-hour study in the lying position after both glycosides and placebo; the systemic blood pressure remained unchanged. Electromechanical systole (QS2), left ventricular ejection time (LVET) and preejection period (PEP), corrected for heart rate (QS2I, LVETI, PEPI), showed no change after placebo. The glycosides caused no change in LVETI. QS2I was significantly shortened only after lanatoside C 1.6 mg. PEPI and ICT were significantly shortened by both doses of strophanthin K and lanatoside C; the effects were dose-related. Taking into consideration the effects of cardiac glycosides on STI, use of the index ICT/QS1, the quotient of isovolumic contraction time and electro-mechanical delay, is proposed, because it showed quite sensitively the increase in myocardial contractility after digitalis. The effect of strophanthin K could be detected 10 minutes, and that of lanatoside C 30-40 minutes, after injection. The amplitude of the IP curve and the relative pulse volume showed positive and negative changes without any trend after administration of placebo or glycoside. The data suggests that the usual therapeutic doses of these cardiac glycosides do not cause significant changes in the peripheral circulation in patients with compensated coronary heart disease, but their action on STI is quite marked, showing a positive inotropic effect.