Application of Caco-2 cell line in herb-drug interaction studies: current approaches and challenges.

The Caco-2 model is employed in pre-clinical investigations to predict the likely gastrointestinal permeability of drugs because it expresses cytochrome P450 enzymes, transporters, microvilli and enterocytes of identical characteristics to the human small intestine. The FDA recommends this model as integral component of the Biopharmaceutics Classification System (BCS). Most dedicated laboratories use the Caco-2 cell line to screen new chemical entities through prediction of its solubility, bioavailability and the possibility of drug-drug or herb-drug interactions in the gut lumen. However, challenges in the inherent characteristics of Caco-2 cell and inter-laboratory protocol variations have resulted to generation of irreproducible data. These limitations affect the extrapolation of data from pre-clinical research to clinical studies involving drug-drug and herb-drug interactions. This review addresses some of these caveats and enumerates the plausible current and future approaches to reduce the anomalies associated with Caco-2 cell line investigations focusing on its application in herb-drug interactions.

The pharmacokinetics of enteral antituberculosis drugs in patients requiring intensive care.

BACKGROUND: There is a paucity of data on the pharmacokinetics of fixed-dose combination enteral antituberculosis treatment in critically ill patients. OBJECTIVES: To establish the pharmacokinetic profile of a fixed-dose combination of rifampicin, isoniazid, pyrazinamide and ethambutol given according to weight via a nasogastric tube to patients admitted to an intensive care unit (ICU). METHODS: We conducted a prospective, observational study on 10 patients (mean age 32 years, 6 male) admitted to an ICU and treated for tuberculosis (TB). Serum concentrations of the drugs were determined at eight predetermined intervals over 24 hours by means of high-performance liquid chromatography. RESULTS: The therapeutic maximum plasma concentration (Cmax) for rifampicin at time to peak concentration was achieved in only 4 patients, whereas 2 did not achieve therapeutic Cmax for isoniazid. No patient reached sub-therapeutic Cmax for pyrazinamide (6 were within and 4 above therapeutic range). Three patients reached sub-therapeutic Cmax for ethambutol, and 6 patients were within and 1 above the therapeutic range. Patients with a sub-therapeutic rifampicin level had a higher mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score (p=0.03) and a lower estimated glomerular filtration rate (GFR) (p=0.03). CONCLUSIONS: A fixed-dose combination tablet, crushed and mixed with water, given according to weight via a nasogastric tube to patients with TB admitted to an ICU resulted in sub-therapeutic rifampicin plasma concentrations in the majority of patients, whereas the other drugs had a more favourable pharmacokinetic profile. Patients with a sub-therapeutic rifampicin concentration had a higher APACHE II score and a lower estimated GFR, which may contribute to suboptimal outcomes in critically ill patients. Studies in other settings have reported similar proportions of patients with 'sub-therapeutic' rifampicin concentrations.

Clinical pharmacology becomes a specialty in South Africa.

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.

Para-aminosalicylic acid plasma concentrations in children in comparison with adults after receiving a granular slow-release preparation.

There are no paediatric data regarding slow-release para-aminosalicylic acid (PAS). We studied PAS plasma concentrations in 10 children receiving a single 150 mg/kg dose daily or 75 mg/kg twice daily and 12 adults receiving 4 g twice daily. Blood specimens pre-dose and 2, 4, 6, 8 and 12 h post-dose from the children and 2, 3, 4, 5, 6, 8 and 12 h post-dose from the adults were analysed by high performance liquid chromatography MS/MS. The mean Cmax in children receiving PAS 75 mg/kg and 150 mg/kg and adults receiving 4 g was 45.40, 56.49 and 51.3 µg/ml, respectively (p = 0.614); the AUC0-12 was 233.3, 277.9 and 368.0 µg/h/ml (p = 0.587). No parameters differed significantly between children and adults nor between the two doses in the same children. A 150 mg/kg PAS dosage given as one or two daily doses leads to plasma concentrations in children similar to those of adults receiving 4 g PAS twice daily.

Pharmacokinetics of isoniazid, rifampin, and pyrazinamide in children younger than two years of age with tuberculosis: evidence for implementation of revised World Health Organization recommendations.

The World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dosage recommendations for children. No pharmacokinetic studies for these revised dosages are available for children <2 years. The aim of the study was to document the pharmacokinetics of the first-line anti-TB agents in children <2 years of age comparing previous and revised WHO dosages of isoniazid (INH; 5 versus 10 mg/kg/day), rifampin (RMP; 10 versus 15 mg/kg/day), and pyrazinamide (PZA; 25 versus 35 mg/kg/day) and to investigate the effects of clinical covariates, including HIV coinfection, nutritional status, age, gender, and type of tuberculosis (TB), and the effect of NAT2 acetylator status. Serum INH, PZA, and RMP levels were prospectively assessed in 20 children <2 years of age treated for TB following the previous and the revised WHO dosage recommendations. Samples were taken prior to dosing and at 0.5, 1.5, 3, and 5 h following dosing. The maximum drug concentration in serum (C(max)), the time to C(max) (t(max)), and the area under the concentration-time curve (AUC) were calculated. Eleven children had pulmonary and 9 had extrapulmonary TB. Five were HIV infected. The mean C(max) (µg/ml) following the administration of previous/revised dosages were as follows: INH, 3.19/8.11; RMP, 6.36/11.69; PZA, 29.94/47.11. The mean AUC (µg·h/ml) were as follows: INH, 8.09/20.36; RMP, 17.78/36.95; PZA, 118.0/175.2. The mean C(max) and AUC differed significantly between doses. There was no difference in the t(max) values achieved. Children less than 2 years of age achieve target concentrations of first-line anti-TB agents using revised WHO dosage recommendations. Our data provided supportive evidence for the implementation of the revised WHO guidelines for first-line anti-TB therapy in young children.

Pharmacokinetics of ethionamide in children.

Ethionamide (ETH), a second-line antituberculosis drug, is frequently used in treating childhood tuberculosis. Data supporting ETH dose recommendations in children are limited. The aim of this study was to determine the pharmacokinetic parameters for ETH in children on antituberculosis treatment including ETH. ETH serum levels were prospectively assessed in 31 children in 3 age groups (0 to 2 years, 2 to 6 years, and 6 to 12 years). Within each age group, half received rifampin (RMP). Following an oral dose of ETH (15 to 20 mg/kg of body weight), blood samples were collected at 0, 1, 2, 3, 4, and 6 h following 1 and 4 months of ETH therapy. The maximum serum concentration (C(max)), time to C(max) (T(max)), and area under the time-concentration curve from 0 to 6 h (AUC(0-6)) were calculated. Younger children were exposed to lower ETH concentrations than older children at the same mg/kg body weight dose. Age correlated significantly with the AUC after both 1 month (r = 0.50, P = 0.001) and 4 months (r = 0.63, P = 0.001) of therapy. There was no difference in the AUC or C(max) between children receiving concomitant treatment with RMP and those who did not. Time on treatment did not influence the pharmacokinetic parameters of ETH following 1 and 4 months of therapy. HIV infection was associated with lower ETH exposure. In conclusion, ETH at an oral dose of 15 to 20 mg/kg results in sufficient serum concentrations compared to current adult recommended levels in the majority of children across all age groups. ETH levels were influenced by young age and HIV status but were not affected by concomitant RMP treatment and duration of therapy.

Population pharmacokinetic analysis of the active product of dipyrone.

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.

Rapid separation of elemental species by multicapillary GC.

Multicapillary gas chromatography has been applied to the speciation of organomercury compounds. Basic investigation of the fundamental properties of multicapillary columns, to evaluate their potential and limitations as a rapid separation unit, are presented. For analysis of methylated and ethylated mercury compounds a complete separation can be performed within 45 s under isothermal conditions. The adaptation of the technique for use with a purge and trap system and with an element-selective plasma-emission detector results in a compact and effective system for mercury speciation. Results from analysis of certified reference materials were in good agreement with certified values within the significance levels.

Pulp capping of carious exposures: treatment outcome after 5 and 10 years: a retrospective study.

One hundred twenty-three pulp cappings had been performed by students in 1984 to 1987 (= 10-yr group) or in 1990 to 1992 (= 5-yr group) and were followed up in 1997. Teeth were checked for sensitivity (CO2/electrical pulp testing), percussion, and palpation; radiographs were taken to assess periapical status. In addition several other factors were determined that might have an influence on the success or failure rates, such as base material, type of restoration, site of exposure, etc. Results showed 44.5% failures (18.5% questionable and 37% successful cases) in the 5-yr group and 79.7% failing, 7.3% questionable, and 13% successful cases in the 10-yr group. As a factor of influence, the placement of a definitive restoration within the first 2 days after pulp exposure was found to contribute significantly to the survival rate of these teeth.

Propentofylline in the treatment of vascular dementia and Alzheimer-type dementia: overview of phase I and phase II clinical trials.

Pathophysiologic processes common to both vascular (multi-infarct) dementia and dementia of the Alzheimer type may include microglial activation with resultant generation of inflammatory cytokines and neurotoxic free radicals, decreased secretion of nerve growth factor by astrocytes, excess release of glutamate with associated neurotoxicity, and loss of cholinergic neurons. The functional benefits and neuroprotective effects of propentofylline (PPF) stem from its interference with these overlapping pathways of neurodegeneration. The clinical pharmacology and safety of PPF were studied in a number of phase I studies in healthy young and elderly adults and in patients with renal or hepatic impairment. These studies have shown that PPF 300 mg t.i.d. is safe and well tolerated when taken on an empty stomach 1 h before meals. In a randomized, double-blind phase II study involving 190 elderly subjects with clinically and psychometrically documented mild to moderate dementia, 12 weeks of PPF therapy produced significantly greater improvements than placebo in Gottfries-Bråne-Steen (GBS) scores, Mini-Mental State Examination (MMSE) scores, and Clinical Global Impression (CGI) ratings. A subsequent phase II study using positron emission tomography (PET) revealed that cortical glucose metabolism improved significantly in patients with vascular dementia after 12 weeks of PPF treatment but deteriorated significantly with placebo. A third phase II study, which enrolled patients with Alzheimer-type dementia, demonstrated that PPF significantly enhanced functional reserve, as reflected by increases in regional cerebral glucose metabolism after stimulation with a verbal memory task. In contrast, patients randomized to placebo exhibited a significant decline in functional activation and significant worsening in their MMSE scores over the course of this 12-week study. Propentofylline proved to be safe, well tolerated, and free of severe side effects in all three of these phase II trials. Phase I trial results suggest that significant food interactions occur with PPF, indicating that the drug should be taken on an empty stomach 1 h before meals. Phase II trial results indicate that PPF yields clinically measurable improvements in the symptoms of dementia and prevents loss of stimulation-related increases in glucose metabolism over a treatment period of 3 months. Whether these results indicate that PPF can slow the progression of dementia can be determined only by long-term trials specifically designed to determine the drug's effect on disease progression.

Pharmacokinetics and safety of glimepiride at clinically effective doses in diabetic patients with renal impairment.

The pharmacokinetics, efficacy and safety of glimepiride were investigated in a single- and a multiple-dose open study in patients with non-insulin-dependent diabetes mellitus and renal impairment and an initial creatinine clearance above 10 ml/ min. Patients were divided into three groups with creatinine clearance above 50 ml/min, 20-50 ml/min and under 20 ml/min. Fifteen fasting patients received a single dose of 3 mg glimepiride and serial blood and urine samples were taken over 24 h for pharmacokinetic and efficacy analyses. A further 16 patients received glimepiride over a 3-month period, an initial dose of 1 mg glimepiride being adjusted within the range 1 to 8 mg to achieve good glucose control. Pharmacokinetic evaluation was done on day 1 and after 3 months. Mean relative total clearance and mean volume of distribution of both single (41.6 ml/ min and 8.47 litres, respectively, when creatinine clearance was above 50 ml/min) and multiple doses of glimepiride increased in proportion to the degree of renal impairment (to 91.1 ml/min and 14.98 litres, respectively, when creatinine clearance was below 20 ml/min, single dose), whereas the terminal halflife and mean time remained unchanged. Lower relative total clearance and renal clearance of both glimepiride metabolites correlated significantly with lower creatinine clearance values. Of the 16 patients 12 required between 1 and 4 mg glimepiride to stabilize their fasting blood glucose. Glimepiride was well-tolerated and there were no drug-related adverse events. In conclusion glimepiride is safe, effective and has clearly-definable pharmacokinetics in diabetic patients with renal impairment. The increased plasma elimination of glimepiride with decreasing kidney function is explainable on the basis of altered protein binding with an increase in unbound drug.

[Constipation after tilidine/naloxone and tramadol in comparison to codeine. A dose response study in human volunteers]. / Die obstipierende Wirkung der Opioide Tilidin-N und Tramadol im Vergleich zu Codein. Eine vergleichende Gegenüberstellung zweier Wirkstoffkonzentrationen bei Probanden.

Tramadol, a mixed mu-opioid agonist and a monoamine-reuptake blocking analgesic, has been supposed to have little effect on propulsive gastrointestinal motility. However, this has not been specifically studied in man. Following institutional approval, 18 human volunteers were given 50 mg of tramadol, tilidine/naloxone, and codeine, respectively, in a double-blind randomised cross-over design. Additionally, 12 further volunteers were given 100 mg of each opioid in a double-blind, randomised fashion, followed by measurement of gastrocoecal transit time. Gastrointestinal transit time was measured using the lactulose H(2)-breath test. A threefold increase in end-expiratory hydrogen when compared to the control value was considered the end point of gastrocoecal transit. At the low dose (50 mg) the three opioids did not differ significantly with regard to their effect on gastrointestinal motility. Gastrocoecal transit time was 90.8 (+/- 10.1 SEM) min for tramadol, 100.6 (+/- 9.8 SEM) min for tilidine/naloxone, and 104.2 (+/- 8.7 SEM) min for codeine. Doubling the dose of each opioid resulted in an increase in mean gastrocoecal transit, namely 97.8 (+/- 11.2 SEM) min for tramadol, 129.2 (+/- 12.2 SEM) min for tilidine/naloxone and 135.9 (+/- 9.2 SEM) min for codeine. The increase in gastrocoecal transit time was significant (P < 0.01) for high doses of tilidine/naloxone and codeine in contrast to the effect of the low doses. This lesser constipation effect may be due to the reduced affinity of tramadol to the mu-opioid receptor. Sedation was significantly higher for codeine after 50 mg (P < 0.05) and 100 mg (P < 0.005) than for tilidine/naloxone and tramadol. Vertigo was significantly higher after 50 mg (P < 0.05) and 100 mg (P < 0.005) of tilidine/naloxone and codeine than after tramadol. Perspiration was significantly higher after tramadol 100 mg (P < 0.005) than after tilidine/naloxone and codeine. Sedation is considered a typical symptom of analgesics interacting with centrally located opioid receptor sites. The higher incidence of perspiration after tramadol suggests that monominergic pathways may be involved in thermoregulation. In conclusion, the opioids tilidine/naloxone and codeine at the doses used significantly prolong gastrointestinal transit time in the high-dose range. Since tramadol does not induce a dose-related increase in gastrocoecal transit time, it may be a useful analgesic in patients who are prone to developing constipation during high-dose opioid therapy.

Pharmacokinetic basis for the safety of glimepiride in risk groups of NIDDM patients.

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.

Clinical pharmacokinetics of molsidomine.

Molsidomine is a prodrug for the formation of nitric oxide (NO). Its pharmacokinetics are characterised by rapid absorption and hydrolysis, taking a short time to achieve maximal systemic concentrations of both the parent compound and its active metabolite, SIN-1. The time to peak plasma drug concentration (tmax) is 1 to 2 hours. The bioavailability of the parent compound after oral administration in tablet form is 44 to 59%, but further metabolism to release NO and form polar metabolites is rapid; the half-life (t-1/2) of SIN-1 is 1 to 2 hours. Urinary excretion accounts for more than 90% of the part of the administered dose of molsidomine which is not excreted unchanged. Protein binding of the parent compound is very low (3 to 11%) and its volume of distribution (Vd) corresponds to the range of bodyweight. Single-dose studies (1, 2 and 4 mg) have revealed linear pharmacokinetics, and multiple dose studies in healthy individuals (2 mg 3 times daily for 7 days) and coronary artery disease (CAD) patients (4 mg 4 times daily for 4 weeks) do not show any accumulation of the drug. A study in young and elderly individuals indicated that the first-pass effect is decreased and t-1/2 prolonged with age, resulting in an increased area under the concentration-time curve (AUC) of molsidomine and SIN-1. In patients with liver disease and congestive heart failure similar changes were observed, but much less so in patients with CAD. Clearance was also impaired in patients with liver disease, but the pharmacokinetics of molsidomine were not markedly altered by impaired renal function. In general, due to a large therapeutic dose range, dosage adjustments are not required on the basis of clinical experience. In certain patients a lower starting dose may be recommended, such as in those with impaired liver or kidney function, in congestive heart failure or in the presence of concomitant treatment with other vasoactive compounds. A linear dose-effect relationship is observed with counterclockwise hysteresis, i.e. a greater effect associated with the decrease of plasma concentrations than during their increase, which may be at least partly due to the metabolic delay in the formation of NO from SIN-1. Accordingly, the duration of action of molsidomine is longer than would be expected on the basis of the elimination half-life. The pharmacokinetics of molsidomine support the recommended dosages for use in angina pectoris.

The effects of buserelin microparticles on ovarian function in healthy women.

OBJECTIVE: To investigate the tolerance, pharmacokinetics and pharmacodynamics of the microparticle formulation of buserelin, when it was administered 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 health 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 nmol/l (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 microgram/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.

Dipyrone and diclofenac do not influence creatinine-clearance, inulin-clearance or PAH-clearance in healthy male volunteers.

The effects of the non-steroidal anti-inflammatory drug diclofenac and the pyrazolone derivative dipyrone on renal function were compared with those of placebo in 12 healthy male volunteers in a randomized, controlled, triple-crossover study with a wash-out period of 4 days between each of the 3 trial periods (dipyrone, diclofenac and placebo) which lasted three days each. The volunteers received dipyrone (1 g, 3 times/day for 2 days, followed by twice 1 g on the main trial day, which was day 3 of each study period) or diclofenac (50 mg, 3 times/day for 2 days, followed by twice 50 mg on the main trial day) or placebo orally. Standardized meals (50 mEq sodium per day) were given from one week before the start until the end of the study and on the main trial days a protein-rich lunch (2 g protein/kg body weight) was taken. Renal function was assessed in each study period by measurement of creatinine-clearance, inulin-clearance and p-aminohippurate (PAH)-clearance to characterize glomerular filtration rate and renal plasma flow. High protein intake induced glomerular hyperfiltration (increased creatinine-clearance, inulin-clearance and PAH-clearance) in all 3 study periods (dipyrone, diclofenac, placebo). Dipyrone and diclofenac had no effect on renal clearance of creatinine, inulin or PAH in comparison to placebo. These results show that dipyrone and diclofenac at therapeutic dosages over 3 days do not decrease glomerular filtration and renal plasma flow in healthy individuals. Furthermore, it is unlikely that prostaglandins play a major role in protein-induced glomerular hyperfiltration.

Clinical pharmacokinetics of dipyrone and its metabolites.

The pharmacokinetics of dipyrone are characterised by rapid hydrolysis to the active moiety 4-methyl-amino-antipyrine (MAA), which has 85% bioavailability after oral administration in tablet form, and takes a short time to achieve maximal systemic concentrations (tmax of 1.2 to 2.0 hours). Absolute bioavailability after intramuscular and rectal administration is 87 and 54%, respectively. MAA is further metabolised with a mean elimination half-life (t1/2) of 2.6 to 3.5 hours to 4-formyl-amino-antipyrine (FAA), which is an end-metabolite, and to 4-amino-antipyrine (AA), which is then acetylated to 4-acetyl-amino-antipyrine (AAA) by the polymorphic N-acetyl-transferase (t1/2 of AA is 3.8 hours in rapid acetylators and 5.5 hours in slow acetylators). Urinary excretion of these 4 metabolites accounts for about 60% of the administered dose of dipyrone. Protein binding of the 4 main metabolites is less than 60%. The volume of distribution of MAA is about 1.15 L/kg of lean body mass. All 4 metabolites are excreted into breast milk. A single-dose study (0.75, 1.5 and 3g) and a multiple-dose study (1g 3 times a day for 7 days) revealed nonlinear pharmacokinetics consistent with a shift of MAA metabolism from FAA to AA. Apparent MAA clearance decreased by 22% during multiple administration. MAA clearance was reduced by 33% in the elderly. In patients with cirrhosis of the liver, the apparent clearance of all metabolites is generally reduced. In patients with renal disease, apparent clearance of MAA remains unchanged, whereas elimination of the renally excreted metabolites AAA and FAA is markedly impaired. No clinically important drug interactions have thus far been recognised. Dipyrone does not affect the pharmacodynamic response to alcohol (ethanol), glibenclamide (glyburide), oral anti-coagulants or furosemide (frusemide). The low toxicity of dipyrone and its efficacy support its use in clinical practice, despite some complex aspects of its disposition.

Single-dose pharmacokinetics of cefpirome in patients receiving hemodialysis and in patients treated by continuous ambulatory peritoneal dialysis.

Cefpirome is eliminated primarily by renal excretion, compelling dosage reduction in kidney failure. We studied the elimination kinetics after intravenous administration of 1 gm cefpirome in patients undergoing hemodialysis (n = 9) and after intravenous (n = 6) or intraperitoneal administration (n = 6) of 1 gm cefpirome in subjects treated by continuous ambulatory peritoneal dialysis (CAPD). Four hours of hemodialysis removed 48% +/- 9% of the drug present in the body at the start of hemodialysis. Consequently, a supplementary dose equal to 50% of the daily dose recommended in end stage renal disease (ESRD) should be administered after each hemodialysis treatment. In patients receiving CAPD, therapeutic levels in both serum and dialysate were reached after intravenous and intraperitoneal administration. The bioavailability after intraperitoneal administration was 84%. After systemic administration, the elimination of cefpirome in the dialysate was negligible. Consequently, systemic dosage of cefpirome in patients receiving CAPD and in patients with ESRD should be identical.

Single-dose pharmacokinetics of cefpirome in patients with renal impairment.

The pharmacokinetic parameters of cefpirome (HR 810) were examined in 22 patients with different degrees of renal impairment. HPLC was used to analyze samples of blood and urine for cefpirome; and enzymatic assay of creatinine in serum and urine was used to assess kidney function. Creatinine clearance correlated linearly with both total and renal clearance of cefpirome. The loss of kidney function resulted in a decreased renal clearance, whereas the volume of distribution remained the same. This result led to an increase in the terminal half-life of the drug, from 2 hours in healthy subjects to 14 1/2 hours in patients with uremia. This increase also resulted in a prolonged high serum concentration well above the minimum inhibitory concentration. The following dosages are thus recommended: (1) creatinine clearance greater than 50 ml/min: normal daily dose, (2) creatinine clearance from 20 to 50 ml/min: 50% of normal daily dose, and (3) creatinine clearance less than 20 ml/min: 25% of normal daily dose. An initial loading dose of 1 gm, independent of renal function, is advised. Cefpirome was safe and well tolerated.

Recombinant hirudin, a new anticoagulant, has no effect on faecal blood loss.

Hirudin is a selective thrombin inhibitor with strong anticoagulant properties which could elicit gastro-intestinal bleeding. A double-blind cross-over study of the effects of hirudin on gastro-intestinal bleeding was therefore conducted on 12 healthy, consenting males. After labelling erythrocytes with 51Cr and returning them intravenously, stools were collected for 2 days to measure radioactivity and hence baseline faecal blood loss. After injection of hirudin or placebo stools were collected for 3 days. Partial thromboplastin time was measured sequentially after medication with hirudin or placebo. This procedure was repeated after injection of the alternate medication 1 week later. Hirudin was tolerated well. Mean faecal blood loss associated with hirudin was slightly higher than with placebo (1.63 ml vs 1.15 ml over 3 days; 95% confidence interval for the difference between hirudin and placebo was -0.68 to 1.63) but these differences are clinically irrelevant. After hirudin injection PTT was elevated to about twice the baseline values but returned to baseline within 12 h after the last hirudin injection.