Central analgesic effects of aspirin-like drugs.

Aspirin-like drugs mainly include paracetamol, salicylates and other non-steroidal anti-inflammatory drugs, and metamizole. Their analgesic effect is classically ascribed to a peripheral site of action, within the pain-processing site. There is, however, convincing evidence that a central component contributes to the overall analgesia provided by these agents. Experimental and clinical studies referring to this challenging proposal are reviewed here. The exact site and mode of action of aspirin-like drugs within the central nervous system remains controversial. It is likely that supraspinal mechanisms play an important role. Some experiments lend support to the involvement of monoaminergic control systems. Other data indicate that these drugs act centrally through the inhibition of cyclo-oxygenase activity. The interactions between prostaglandins and various neurotransmitters suggest that both mechanisms may be linked.

Determination of flunitrazepam in plasma by liquid chromatography.

A reversed-phase liquid chromatographic method has been used to determine flunitrazepam in plasma. Extraction was simple and there was no need to hydrolyse the drug. Separation was achieved on a 150 x 3.9 mm i.d. column packed with 4-microns Nova Pack C18 using a mobile phase of water-acetonitrile-triethylamine (700:300:4, v/v/v) (adjusted to pH 7.5 with orthophosphoric acid). The method was shown to be rapid and reliable with a lower limit of detection of 5 ng ml-1. Results are reported of simple experiments on the effects of temperature and light on the stability of flunitrazepam in plasma kept on the laboratory bench.

Column-switching high-performance liquid chromatographic determination of vancomycin in serum.

Concentrations of vancomycin in serum were measured by an automatic high-performance liquid chromatographic (HPLC) micromethod. Vancomycin is a glycopeptide antibiotic with broad application in the therapy of gram-positive infections. As this drug is potentially nephro- and ototoxic, a method to maximize its therapeutic benefit while minimizing the risk of toxicity is desirable. This fully automated HPLC method did not involve a sample pretreatment step. The configuration of the apparatus permitted a solid phase extraction of the serum sample on two precolumns filled with a reversed-phase material, followed by a chromatographic separation of the sample constituents on an analytical column. The reversed phase analytical column (muBondapak C18) was flushed with a mobile phase of water-acetonitrile-triethylamine, 870: 130: 4 (vol/vol/vol); the pH was adjusted to 3.0 with orthophosphoric acid. Precision was expressed as the coefficient of variation (CV), which was always < or = 4.13% for intra- and inter-assays (n = 10) in the range 2-50 micrograms/ml. We compared this specific HPLC determination to an enzyme-multiplied immunoassay (EMIT). Fifty clinical samples obtained from patients under vancomycin therapy were assayed by each method and results compared using a linear regression analysis. There was a significant correlation between results from HPLC and EMIT: EMIT = 0.51 + 1 x HPLC (r = 0.963; p < 0.0001). The rapidity and specificity of this HPLC micromethod make it suitable for use in the monitoring of serum levels of vancomycin and for use in pharmacokinetic studies of this antibiotic.

[Side-effects during treatment of rheumatoid arthritis with methotrexate]. / Effets indésirables observés au cours du traitement de la polyarthrite rhumatoïde par le méthotrexate.

Methotrexate is the drug with the highest long-term continuation rate in rheumatoid arthritis patients. However, toxicity is the main reason for methotrexate withdrawal. Most adverse effects are mild abnormalities, such as digestive symptoms, stomatitis, elevations in transaminase levels, and moderate decreases in peripheral blood cell counts. Potentially life-threatening effects include hypersensitivity pneumonitis and pancytopenia. Cirrhosis is less common than in patients with psoriasis. Opportunistic infections and Epstein-Barr virus-related lymphomas have been reported. Neurological disorders, cutaneous reactions and renal lesions have been ascribed to low-dose methotrexate. Prior renal dysfunction and concomitant administration of a number of drugs, including cotrimoxazole, have been shown to increase methotrexate toxicity. However, susceptibility to the toxic effects of methotrexate varies widely across individuals. The effectiveness of folate supplementation in preventing methotrexate toxicity remains controversial.

Influence of food and body weight on the pharmacokinetics of penticainide.

The pharmacokinetics of penticainide, a class Ic antiarrhythmic drug, was studied in 16 healthy adults (eight males and eight females) after a single 300-mg oral dose in fasting conditions and with a standard meal. Penticainide concentrations in plasma and urine were measured by hplc. The pharmacokinetic parameters of penticainide including Cmax, tmax, AUC and t1/2 were not significantly altered in the presence of food. AUC values (mean +/- sd) were 50.68 +/- 10.8 mg.h.l-1 and 49.52 +/- 9.87 mg.h.l-1 in the absence and presence of food, respectively. However, a significant difference was observed between males and females in both fasting and fed conditions with a higher value of the apparent oral clearance in the second group. The values of apparent oral clearance, expressed in weight-normalized units were 1.33 +/- 0.35 ml.mn-1.kg-1 (male) and 1.93 +/- 0.34 ml.mn-1.kg-1 (female) in fast conditions (P < 0.01) and 1.38 +/- 0.28 ml.mn-1.kg-1 (male) and 1.93 +/- 0.49 ml.mn-1.kg-1 (female) in fed conditions (P < 0.02), respectively. The pharmacokinetics of penticainide is not modified by the presence of food, but an influence of body weight may be considered.

[Tissue and systemic diffusion of idrocilamide after cutaneous administration]. / Diffusion tissulaire et systémique de l'idrocilamide après application cutanée.

Experimental findings have demonstrated that idrocilamide exhibits antiinflammatory and muscle relaxant properties due at least in part to tissular effects. Percutaneous diffusion of a 10% glycero-alcoholic idrocilamide solution was studied in ten patients scheduled to undergo total knee replacement. Four 200-mg doses of idrocilamide were applied to the suprapatellar area at 12-hour intervals before surgery. Pain was evaluated using a visual analog scale before and after treatment. Surgery was performed 1.75 to 3.5 hours after the last idrocilamide dose. Idrocilamide was assayed using high performance liquid chromatography in tissue, plasma, and joint fluid specimens taken during the surgical procedure. Topical administration of idrocilamide on healthy skin produced significant concentrations of the drug in all the tissue specimens, including subcutaneous fat, muscle, tendon, synovium, and knee capsule. Tissue levels were consistently higher than synovial fluid and plasma levels, indicating that little systemic diffusion occurred. Idrocilamide levels in potential target tissues might influence clinical effects.

The determination of bromazepam in plasma by reversed-phase high-performance liquid chromatography.

A reversed-phase high-performance liquid chromatographic method has been developed for the determination of bromazepam, an anxiolytic benzodiazepine, in plasma. After a single-step extraction from alkalinized plasma with diethyl-ether in the presence of an internal standard (alpha-hydroxy-triazolam), the residues were chromatographed on a reversed-phase Nova Pak 5 microns C18 column, with a mobile phase of acetonitrile-water-triethylamine (700:300:4, v/v/v) adjusted to pH 7.4 with orthophosphoric acid. The limit of detection was 50 ng ml-1, using a 20 microliters injection with UV detection at 240 nm. Between-day and within-day relative standard deviations were lower than 6%. Studies of drug stability during sample storage at -20 degrees C and at +4 degrees C showed no degradation of bromazepam. However, bromazepam seemed to be degraded at ambient temperature, without any influence of light. This method is applied to the determination of bromazepam plasma levels in analytical toxicology.

Pharmacokinetics of intravenous and intraperitoneal ceftazidime in chronic ambulatory peritoneal dialysis.

The pharmacokinetics of ceftazidime have been investigated in eight patients with chronic renal failure undergoing continuous ambulatory peritoneal dialysis. Each subject was given ceftazidime 1 g intravenously and 1 g intraperitoneally at an interval of 1 week. Ceftazidime was assayed by high-pressure liquid chromatography. After intravenous administration, the pharmacokinetic parameters of ceftazidime were: elimination plasma half-life (t1/2 beta) = 24.6 +/- 4.6 hours; apparent volume of distribution (V(area)): 0.37 +/- 0.09 1/kg, total plasma clearance (CL): 11.9 +/- 3.3 mL/minute, peritoneal clearance (CLp): 1.7 +/- 0.3 mL/minute. Over 72 hours, only 15.6 +/- 4.7% of the dose was eliminated by the peritoneal route. After intraperitoneal administration, ceftazidime appeared in the plasma rapidly, and the peak plasma concentration of 24.5 +/- 5.2 mg/L was achieved at the fourth hour; the elimination half-life (t1/2ke) was 20.8 +/- 1.7 hours. The absorption of ceftazidime from the peritoneal space was 74.1 +/- 7.4%. These data suggest that ceftazidime has bidirectional exchange characteristics through the peritoneal membrane. A single 1-g intraperitoneal dose led to serum and dialysate concentrations of ceftazidime above the minimum concentrations for susceptible pathogen germs for 24 hours.

Pharmacokinetics and pharmacodynamics of non steroidal anti-inflammatory drugs in synovial fluid.

Since the joint is the target organ of non steroidal anti-inflammatory drugs (NSAIDs) in rheumatic diseases, the concentration in the synovial fluid (SF) is an important determinant of clinical response to these agents. Present data indicate that in the SF pharmacokinetic behaviour of NSAIDs depends on their plasma elimination half-life. Moreover, some chiral drugs exhibit stereoselective distribution properties. Finally, pharmacodynamic investigations suggest that inhibition of prostaglandin synthesis in the synovial compartment is the dominant mechanism of action for most, if not all, NSAIDs.

Plasma levels of piperacillin and vancomycin used as prophylaxis in liver transplant patients.

The pharmacokinetics of piperacillin and vancomycin used intravenously as antibioprophylaxis were measured in the plasma and bile during orthotopic liver transplantation. Piperacillin (4 g and then 2 g every 4 h) and vancomycin (1 g and then 0.5 g every 6 h) were infused in 10 patients. During vascular clamping without venovenous bypass, clearance of both antibiotics decreased in relation to renal insufficiency. During the surgical procedure, volume of distribution of both drugs increased because of fluid redistribution. The peaks of piperacillin after first, second and third administrations were respectively 314, 265 and 210 mg.l-1, while trough levels were 46.5, 55.2 and 54.5 mg.l-1. The peaks of vancomycin were 54.4, 49.6 and 40.9 mg.l-1, while first and second trough levels were 9.5 and 12 mg.l-1. These plasma concentrations were quite similar to levels reported in healthy subjects despite large blood loss and fluid replacement. However, piperacillin trough concentrations (< 64 mg/l) were too low in relation to its concentration-dependent antibacterial activity and vancomycin peak concentrations (> or = 40 mg/l) were slightly too high in relation to its toxicity.

2-Amino-2-oxazolines, V: Synthesis of some 5-dialkylaminomethyl-2-amino-2-oxazolines and evaluation of their diuretic activity.

A series of 5-dialkylaminomethyl-2-amino-2-oxazolines was prepared and screened for diuretic activity. These compounds were previously examined for their lipophilic behaviour using a reversed-phase HPLC technique. The capacity factors, expressed as log k'w, were correlated with the partition coefficient log P. A QSAR analysis of the diuretic activity in relation with the lipophilicity was attempted for these structurally related compounds.

Pharmacokinetics of famotidine in patients with cirrhosis and ascites.

The pharmacokinetics of famotidine has been investigated in ascitic cirrhotic patients. 10 decompensated cirrhotic patients were studied (9m, 1f), who had normal renal function, and six healthy control subjects (4m, 2f), matched for age, sex and weight. Each subject received on two occasions, at least four days apart, a single oral (40 mg) or intravenous dose (20 mg) of famotidine, at 21.00 h in a randomised manner. Serial blood samples were collected and famotidine in plasma was determined by a HPLC/UV method. Plasma data were subjected to non compartmental pharmacokinetic analysis. There were no statistically significant differences in pharmacokinetic parameters between the two groups after either the intravenous or oral administration of famotidine. The findings suggest that the dose of famotidine may not require any adjustment in ascitic patients without renal failure.

[Does glycemic level influence the pharmacokinetics of an antibiotic (cefoperazone)?]. / Existe-t-il une influence du niveau glycémique sur la pharmacocinétique d'un antibiotique (la céforpérazone)?

Hyperglycemia may modify pharmacokinetics of some antibiotics as shown in the literature. We studied the influence of glycaemic levels on pharmacokinetics properties of cefoperazone in 12 type 1 insulin dependent diabetic patients. Hyperglycaemia was obtained by a reduction of one quarter of their usual insulin dosage and normoglycaemia by an artificial pancreas (Biostator GCIIS). Cefoperazone had a high protein affinity and a high biliary elimination. Pharmacokinetic study was performed during a 8 hour period following one gram intravenous bolus. We did not found any influence of glycaemic level (normoglycaemia or hyperglycaemia) on the pharmacokinetic parameters of cefoperazone.

Pharmacokinetics and protein binding of cefpiramide in patients with alcoholic cirrhosis.

The pharmacokinetics of cefpiramide, a new cephalosporin, were investigated after a single 1 gm intravenous injection in 11 patients with alcoholic cirrhosis and compared with those of 11 healthy subjects. In patients with cirrhosis the plasma elimination half-life was three times longer than that in normal subjects. The total plasma clearance was decreased significantly (p less than 0.001): 12.3 +/- 6.5 ml/min in patients and 25.6 +/- 4.6 ml/min in healthy volunteers, respectively. The urinary excretion of unchanged drug (percent of intravenous dose) for patients (69.8% +/- 29.9%) was statistically higher (p less than 0.01) than that for subjects (16.2% +/- 3.9%). The renal elimination became increasingly important with hepatic impairment. Protein binding of cefpiramide was reduced significantly in the group with cirrhosis. The average unbound fraction was 10.4% +/- 9.5% in patients with cirrhosis and 1.9% +/- 0.3% in normal subjects (p less than 0.01). Because the rate of elimination from plasma in patients is slower, the dosage regimen of cefpiramide would probably be modified in cirrhosis.

Pharmacokinetics of the antidepressant tianeptine at steady state in the elderly.

The pharmacokinetics of tianeptine, an antidepressant with an original serotoninergic neurochemical action, was investigated in elderly patients. Kinetic profiles were developed in 12 elderly patients (age range: 72-81 yr) after single (12.5 mg) dose and multiple oral dosages (12.5 mg tid for 17 days). Multiple dosing of tianeptine was well tolerated; no accumulation of the unchanged drug was observed. Tianeptine and its MC5 metabolite (C5 acid analogue of tianeptine) reached maximum plasma levels after 1.81 +/- .99 and 2.96 +/- 1.44 hr, respectively, with values of 353 +/- 198 and 81 +/- 20 ng/mL, respectively, after a single dose and of 405 +/- 202 and 175 +/- 85 ng/mL, respectively, after multiple dosing. Minimum plasma concentrations of tianeptine were about half those of its MC5 metabolite (68 +/- 41 and 121 +/- 64 ng/mL-1 on day 5), and for each compound, they were not statistically different from day 5 to day 18 of the chronic administration. This finding is compatible with the terminal half-lives that were observed after the single dose that was 2.8 +/- .9 hr for tianeptine and 12.3 +/- 7 hr for the MC5 metabolite. For both compounds, the area-under-the-plasma levels time curve at steady state was as predicted from the initial single dose that showed no deviation from linearity with time. The kinetics of tianeptine in elderly patients were similar to those reported for young adults. However, MC5 metabolite plasma levels were higher in elderly patients than in younger patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Micro-method for the determination of piperacillin in plasma by high-performance liquid chromatography.

A simple and sensitive high-performance liquid chromatographic method for the determination of piperacillin in plasma is described. A C8 reversed-phase column was used with a mobile phase consisting of methanol-water-triethylamine (550:450:4, v/v/v) adjusted to pH = 3 with orthophosphoric acid and UV detection at 270 nm. Cephalothin was used as internal standard. The method involves a plasma protein precipitation with acetonitrile followed by extraction of endogenous compound with chloroform and injection of the upper aqueous phase into the chromatograph. Within-day and between-day assays give relative standard deviations less than or equal to 5.7%. The detection limit is 0.2 microgram ml-1. Stability studies show that piperacillin degradation starts at -4 degrees C. Therefore, samples have to be processed promptly and stored at -20 degrees C. The method described is convenient for clinical monitoring and for pharmacokinetic studies.

[Pharmacokinetics of propofol injected after deliberate preoperative hemodilution]. / Pharmacocinétique du propofol injecté après hémodilution intentionnelle préopératoire.

The effects of acute isovolaemic haemodilution (AIH) on propofol pharmacokinetics were studied in 16 male patients scheduled for prostatectomy. They were all ranked ASA 1, and were randomly allocated to two groups, group I (n = 8), who did not undergo any haemodilution, and group II (n = 8), in whom AIH was carried out. Anaesthesia was induced with a single 2.5 mg.kg-1 propofol bolus given in 30 s; maintenance was achieved with fentanyl 2 micrograms.kg-1, atracurium 1 mg.kg-1, and a ventilation with a mixture of nitrous oxide in oxygen 50 %, with enflurane 1 %. Those patients due to be haemodiluted had blood withdrawn before surgery (1,387.5 +/- 423.3 ml), at the same time as they were given the same volume of modified fluid gelatin (Plasmion). The volume of blood to be withdrawn was calculated according to the initial haematocrit, and that required. Haematocrit was decreased to 32.3 +/- 3.9 % (extremes 27 and 37 %). Thereafter blood samples were then collected over a 24 h period, which included surgery. Propofol was assayed in whole blood using high performance liquid chromatography. Analysis with a three-compartment model was carried out. The AIH only altered the central compartment volume (65.5 +/- 15.6 l in the control group vs 83.6 +/- 13.3 l in group II, p less than 0.01). Initial concentrations were not significantly different in the two groups (2,892 +/- 762 ng.ml-1 in controls vs 2,373 +/- 589 ng.ml-1 in the others). Clinically, anaesthesia and recovery were uneventful. It is concluded that the induction dose of propofol in patients scheduled for haemodilution does not require any alteration.

[Pharmacokinetics of chlormezanone in healthy volunteers]. / Pharmacocinétique de la chlormézanone chez le volontaire sain.

The kinetics of chlormezanone were determined after oral administration of single (400 mg) and multiple doses (400 mg/day during 8 days) in eight young healthy male subjects. Plasma levels determination had been carried out by HPLC. After single dose administration, Cmax concentrations 4.62 +/- 0.75 mg/l were obtained (Tmax) 2.18 +/- 1.49 h after drug intake. Area under plasma concentrations time curve was 224.93 +/- 27.79 mg.h/l and terminal half-life 40.50 +/- 4.19 h. On chronic regimen, chlormezanone accumulates in the body: trough plasma concentrations are significantly increased from Day 7 (2.97 +/- 0.45 mg/l) to Day 9 (5.41 +/- 0.90 mg/l) and reach the steady state faster than it can be expected from half-life (40 hours) and dosing interval (24 hours). Elimination is faster (T1/2 beta = 37.14 +/- 3.18 h) after chronic regimen. Area under curve during dosing interval at steady state (164.19 +/- 21.70 mg.h/l) is significantly lower than the area under curve between zero and infinity in the single dose sequence (224.93 +/- 27.79 mg.h/l). These results agree with probable induction effect of chlormezanone on its own metabolism.