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Objective. To investigate the tolerance, pharmacokinetics and pharmacodynamJcs of the microparticle fonnulation of buserelin, when it wasaaministered subcutaneously.Design. A single-blind, randomised, parallel-group design was used to investigate the duration of suppression of ovarian function associated with doses of 1,8, 3,6 and 7,2 mg buserelin administered subcutaneously as microparticles.Setting. The study was carried out at the Hoechst Research Centre for Clinical Pharmacology, Department of Pharmacology, University of the Orange Free State, Bloemfontein.Patients. Thirty-two healthy premenopausal female volunteers aged between 19 and 39 years and weighing between 52 and 85 kg completed the study.Outcome measures. Serum progesterone and oestradiol concentrations were measured twice weekly until normal ovarian function resumed, i.e. when serum progesterone concentrations increased to at least 8 nmoVI (a sign of ovulation) and oestradiol concentrations increased to values above 300 pmol/l. Serum and urinary concentrations of buserelin were measured at the same times as those of progesterone and oestradiol.Results. Doses of 1,8,3,6 and 7,2 mg elicited anovulation for mean periods of 52, 77 and 113 days and suppressed ovarian production of oestrogen for 19, 38 and 69 days. Resumption of normal ovarian function occurred when serum buserelin concentrations decreased to between 0,03 and 0,05 lJg/ml. The correlation coefficient between dose and duration of anovulation was 0,75; the correlation coefficient between dose and duration of suppression of oestrogen production was 0,76.Conclusion. Apart from minor side-effects such as hot flushes, vaginal spotting and acne, the compound was tolerated well. We conclude that a good relationship exists between dose and duration of suppression of ovarian function. Doses of 3,6 - 7,2 mg buserelin should suppress oestrogen production for approximately 6 - 9 weeks and ovulation for 11 - 16 weeks.

Automated counting resulted in erroneously low numbers of platelets (pseudothrombocytopenia) in three patients. The machine-derived values (ELT-8) were initially 30 000, 8000 and 8000/microliter, respectively. Numerous agglutinates could be demonstrated in the counting chamber. Whereas counting in the first patient showed a real value with an average of 252 000/microliter both the other preparations could not be counted due to numerous agglutinates. The artificially low number of platelets in the counter can thus be explained by lack of recognition as platelets due to the size of the in vitro formation of agglutinates. Should these be of the size of white cells leukocytosis may be suggested. Formation of agglutinates was not limited to use of EDTA as anticoagulant but could also be observed with other anticoagulants such as heparin and citrate. For prevention of superfluous and potentially dangerous therapeutic steps the diagnosis of platelet deficiency should be ascertained in any case by additional determination of the platelet count in the counting chamber.

BACKGROUND: The consensus documents published to date on hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) have focused on adult patients. Many of the previous recommendations have not been adapted to pediatric patients. We intended to produce consensus recommendations for the diagnosis and management of pediatric patients with C1-INH-HAE.METHODS: During an expert panel meeting that took place during the 9th C1 Inhibitor Deficiency Workshop in Budapest, 2015 (www.haenet.hu), pediatric data were presented and discussed and a consensus was developed by voting.RESULTS: The symptoms of C1-INH-HAE often present in childhood. Differential diagnosis can be difficult as abdominal pain is common in pediatric C1-INH-HAE, but also commonly occurs in the general pediatric population. The early onset of symptoms may predict a more severe subsequent course of the disease. Before the age of 1 year, C1-INH levels may be lower than in adults; therefore, it is advisable to confirm the diagnosis after the age of one year. All neonates/infants with an affected C1-INH-HAE family member should be screened for C1-INH deficiency. Pediatric patients should always carry a C1-INH-HAE information card and medicine for emergency use. The regulatory approval status of the drugs for prophylaxis and for acute treatment is different in each country. Plasma-derived C1-INH, recombinant C1-INH, and ecallantide are the only agents licensed for the acute treatment of pediatric patients. Clinical trials are underway with additional drugs. It is recommended to follow up patients in an HAE comprehensive care center.CONCLUSIONS: The pediatric-focused international consensus for the diagnosis and management of C1-INH-HAE patients was created.

South Africa recently became the first African country where clinical pharmacology has been approved as a specialty. This article outlines the need for clinical pharmacologists, their role in advancing public health, the potential benefits to the country, and recommendations for ensuring a healthy future for the discipline.

The pharmacokinetics of the sulfonylurea, glimepiride, in risk groups of NIDDM patients are reviewed with regard to pharmacokinetic-effect relationships. A variety of factors, such as regulatory processes, glucose absorption, insulin sensitivity, might prevent the definition of a clear concentration-effect relationship for sulfonylureas. However, when these processes are minimized, as with the glucose clamp technique, such relationships can be defined. This is true for glibenclamide or glimepiride, for which saturation of effect is apparent in the upper therapeutic dose range in healthy subjects. However, pharmacokinetic-pharmacodynamic relationships are less readily defined during long-term treatment of NIDDM patients. In kidney or liver disease, the hypoglycemic effect of sulfonylureas can be increased and prolonged, mainly due to a decrease in insulin metabolism or of hepatic glucose output; the risk of hypoglycemia is increased. The pharmacokinetics of most sulfonylureas have not been well characterised in patients with kidney or liver disease. Generally, sulfonylureas are eliminated by renal excretion of metabolites, some of which have similar pharmacological activity to the parent drug e.g. glibenclamide, chlorpropamide, tolbutamide. In renal disease, elimination of these metabolites can be impaired. In 31 NIDDM patients with kidney disease, elimination of unchanged glimepiride was greater in patients with more severe renal disease, probably due to a decrease in the plasma protein-bound fraction. Elimination of the renally excreted metabolites was also impaired in the same group of patients. 12 of 16 NIDDM patients with kidney disease who continued glimepiride treatment for three months maintained fasting blood glucose levels of less than 9.99 mmol/l at a daily dose of 1-6 mg, the typical dose range for patients with normal renal function. Pharmacokinetic data on sulfonylureas are generally inconsistent in cirrhotic patients. In 11 patients with liver disease, the pharmacokinetics of glimepiride were similar to those of healthy volunteers. In conclusion, pharmacokinetics, pharmacodynamics and their relationships can be defined for glimepiride under controlled conditions. Such information is lacking for many commonly used sulfonylureas in risk group NIDDM patients. Studies described here show that the pharmacokinetics of glimepiride are altered in renal disease but may not be seriously affected in patients with liver disease.

Objective: Pharmacokinetics of 4-methyl-amino-antipyrine (MAA), the active metabolite of the nonsteroidal anti-inflammatory agent dipyrone, whose time course correlates to the therapeutic effect of the drug, are studied. Study design and setting: 153 patients hospitalized in the Department of Medicine at the Hadassah University Hospital, Jerusalem, Israel. Intervention: Patients receiving dipyrone for the treatment of fever or pain were asked to participate in the study. Pharmacokinetics and statistical analysis: Using the population approach based on a formerly developed experimental model, the relationships between pharmacokinetic parameters and demographic and physiological covariates are explored. Results: The results of the analysis show considerable variability in pharmacokinetics across the study population, and a significant decrease in clearance with age. Conclusion: A population pharmacokinetic analysis of MAA, the active product of dipyrone, reveals that age is a significant predictor of MAA disposition. Covariates that measure hepatic and renal function do not appear to be good predictors of the rate of MAA disposition.

INTRODUCTION: If a caregiver does not have access to a refrigerator, the South African National Department of Health advises that stavudine adult capsule formulations be employed using the off-label 'opened capsule' dosing method. The accuracy of this dosing method has not previously been validated. AIM: To assess the accuracy of the off-label opened capsule method for stavudine dosing in infants and children. In addition, we assessed the relative ease of dispersion of generic and original capsule preparations in water to determine which preparations, if any, are suitable for the off-label opened capsule dosing method. METHOD: We evaluated 10 Zerit (Bristol-Myers Squibb), 5 Stavudine (Aspen), and 5 Stavir (Cipla) capsules. Each capsule was dispersed in 30 ml water, creating 20 separate solutions. Timed dispersion of each generic was compared with that of the original (Zerit). Each solution was then centrifuged to remove sediment, and the concentration of active drug (mg/ml) was analysed by high-performance liquid chromatography. RESULTS: The ease of dispersion of the contents of Aspen Stavudine capsules was equivalent to that of Zerit, and resulted in a mean recovery of active drug from solution of over 97%, confirming the accuracy of this dosing method. The contents of Stavir capsules, however, were extremely difficult to disperse in water despite prolonged agitation; consequently, the recovery of active drug from the solution was reduced. CONCLUSION: The accuracy of the off-label opened capsule dosing method for stavudine is acceptable. There is no need to instruct caregivers to include sediment in the aliquot given to the infant. However, studies that confirm adequate bioavailability and efficacy are needed. In addition, it is important to avoid supplying generic capsules the contents of which do not disperse easily in water, as this may lead to a significant reduction in the amount of active drug that a child receives.

The safety, efficacy, and pharmacokinetics of glimepiride were investigated in a multiple-dose, open study in subjects with non-insulin dependent diabetes mellitus (NIDDM) and renal impairment. Glimepiride was given to 19 patients over a 3-month period. NIDDM patients were divided into two groups with creatinine clearance of 30-60 and 10-30 mL/min. The initial daily dose of 1 mg glimepiride was adjusted within the range of 1-8 mg to achieve good glucose control. Safety evaluation and tests were performed before, and 1, 2 and 3 months after start of the trial. Standard safety parameters were observed: vital signs, standard clinical biochemistry and hematology determinations, etc. Adverse events were monitored and recorded throughout the study. Glimepiride was well tolerated and there were no drug-related adverse events other than recurrent hypoglycemia episodes in one patient (she did not require further antidiabetic drug treatment thereafter). Three of 19 subjects were not eligible for efficacy and pharmacokinetic evaluation, two of them due to inadequate glycemic control and one due to his decision to withdraw from the study. The therapeutic goal of a fasting blood glucose level of