Clinical pharmacology of timentin (ticarcillin and clavulanic acid).

Ticarcillin (4 gm) and clavulanic acid (0.1 gm) were simultaneously administered as timentin to patients with cancer as therapy for infections. The pharmacokinetics of both ticarcillin and clavulanic acid were studied in 15 patients after 30-minute and 2-hour intravenous infusions. The mean (+/- SD) ticarcillin plasma peak concentrations after the two infusions were 341 +/- 76 and 210 +/- 60 micrograms/ml. The plasma terminal t1/2 values of ticarcillin were 80 +/- 32 and 56 +/- 12 minutes. The AUCs were 631 +/- 189 and 601 +/- 230 mg/L X hr. The volumes of distribution of the area were 15 +/- 5 and 21 +/- 7 L and total clearances were 115 +/- 36 and 127 +/- 54 ml/min. The corresponding values for clavulanic acid after the infusions are as follows: mean peak concentrations, 5 +/- 1 and 4 +/- 1 micrograms/ml; plasma terminal t1/2 values, 84 +/- 24 and 74 +/- 36 minutes; AUCs, 11 +/- 3 and 11 +/- 6 mg/L X hr; volumes of distribution of the area, 22 +/- 3 and 32 +/- 6 L; and total clearances, 170 +/- 58 and 175 +/- 68 ml/min.

Controlled release levodopa-carbidopa (CR-5) in the management of parkinsonian motor fluctuations.

Parkinsonian patients receiving long-term levodopa-carbidopa (Sinemet) therapy often develop fluctuations in motor performance. Although maintenance of stable levels of plasma levodopa by means of its continuous intravenous infusion diminishes these fluctuations, practical limitations attending this therapeutic approach have prompted continuing attempts to develop oral controlled release levodopa-carbidopa formulations. In a double-blind, crossover clinical trial, one such preparation, CR-5 (Merck, Sharp & Dohme), produced significantly less plasma levodopa variations and substantially improved motor performance over Sinemet in 15 patients with mild to moderate fluctuations, all but one of whom chose to continue on CR-5 therapy after the study. Eight patients with severe motor fluctuations could not adjust to this preparation during the open phase and consequently withdrew from the study. Subjectively, most patients noted the convenience of less frequent dosing, improved sleep, and the amelioration of early morning akinesia and dystonia.

Platelet aggregability in rats with early atherosclerotic changes induced by parenterally-administered lipid emulsions.

The present study is the first work to evaluate thrombin-, ADP-, and collagen-induced platelet aggregation in laboratory rats receiving alimentation with the parenterally-administered lipid emulsion, Lipofundin-S, in doses sufficient to induce early atherosclerotic changes in the aorta. The aggregometry parameters of percent maximum aggregation, slope, and b2 or b20 almost uniformly indicate that such lipid treatments result in a statistically significant increased sensitivity of the platelets to ADP and collagen, while no change is noted with thrombin as the aggregating agent. By varying the amounts of ADP and collagen during aggregometry, we also demonstrate that the concentrations of these reagents necessary for equivalent platelet aggregation is substantially lower in lipid-infused rats than in controls. We conclude from this study that such lipid infusions can cause increased platelet aggregation, and that these lipids probably act in a synergistic fashion by affecting a variety of components which comprise the atherogenic process and its clinical endpoint. In addition, we believe that this experimental approach is of interest in that infusions of clinically-useful lipid emulsions are easily controlled, while alterations in platelet physiology and aortic structure occur concurrently and rapidly.

Clinical experience with a new combination formulation of triamterene and hydrochlorothiazide (Maxzide) in patients with mild to moderate hypertension.

The results of an investigation to assess the clinical responses of patients with mild to moderate hypertension to a new combination formulation containing 75 mg triamterene and 50 mg hydrochlorothiazide are reported. One hundred fifty-six subjects entered the investigation. Subjects were divided into three groups, depending on whether they took two (group 1) or four capsules per day of a currently available formulation of triamterene and hydrochlorothiazide (Dyazide), or no antihypertensive medication prior to the start of the study. These medications were continued for an additional two weeks to generate baseline data. Thereafter, subjects received one tablet of the new combination formulation for four weeks. Seventy of the 156 participants received the new formulation for an additional period of at least 20 weeks. Observations during the study included sitting and standing pulse and blood pressure, weight, and serum electrolytes, uric acid, creatinine, and blood urea nitrogen levels. The results of the investigation indicated that subjects transferred to the new combination drug maintained normal serum electrolyte values, including potassium, with no or minor changes in the levels of uric acid, creatinine, and blood urea nitrogen. Reductions in systolic and diastolic blood pressure were observed in all three study groups, including subjects receiving two or four capsules of Dyazide per day in the two-week baseline period. We conclude that mild to moderately hypertensive subjects taking no medication or either two or four capsules of Dyazide per day may be transferred safely to the new combination product of triamterene and hydrochlothiazide.

Treatment of idiopathic parkinsonism with L-dopa in the absence and presence of decarboxylase inhibitors: effects on plasma levels of L-dopa, dopa decarboxylase, catecholamines and 3-O-methyl-dopa.

The effect of levodopa (L-dopa), alone or in combination with a peripheral decarboxylase inhibitor (PDI), on plasma levels of aromatic-L-amino acid decarboxylase (ALAAD, = dopa decarboxylase), L-dopa, 3-O-methyl-dopa (3-OMD), dopamine (DA), noradrenaline, adrenaline and dopamine beta-hydroxylase has been studied. In healthy subjects and in patients with parkinsonism plasma ALAAD level fell after administration of L-dopa + benserazide, but returned to previous levels within 90 min. In a cross-sectional study blood was obtained, 2 h after dosing, from 104 patients with idiopathic parkinsonism, divided into four groups: no L-dopa treatment (group 1), L-dopa alone (group 2), L-dopa + benserazide (Madopar) (group 3) and L-dopa + carbidopa (Sinemet) (group 4). Plasma ALAAD, which was normal in groups 1 and 2, was increased 3-fold in groups 3 and 4, indicating that there was induction of ALAAD by the co-administration of PDI. Despite this induction of ALAAD, in groups 3 and 4, with half the daily L-dopa dose compared with group 2, plasma L-dopa and 3-OMD levels were 5 times higher, while plasma DA levels were not different. The DA/L-dopa ratio was decreased 5-fold in group 2 and 16-fold in groups 3 and 4 as compared with group 1. Neither 3-OMD levels nor 3-OMD/L-dopa ratios correlated with the occurrence of on-off fluctuations. In a longitudinal study of three patients started on Madopar treatment the induction of plasma ALAAD was found to occur gradually over 3-4 weeks. Further detailed pharmacokinetic studies in plasma and cerebrospinal fluid are required in order to elucidate whether the ALAAD induction by PDI may be related to the loss of clinical efficacy of combination therapy in some patients and how it is related to end-of-dose deterioration and on-off phenomena.

The pharmacokinetics of the individual constituents of an aspirin-metoclopramide combination ('Migravess').

A study was carried out in 10 healthy volunteers, aged between 22 and 28 years, to investigate the pharmacokinetics of an aspirin-metoclopramide combined preparation compared with those of the individual components given alone. Blood levels were determined before and after administration of a single dose of the three medications given at weekly intervals. No significant difference was found in the bioavailability of either the aspirin or metoclopramide from the combination as compared to the individual components.

Ocular bioavailability and tissue distribution of [14C]ketorolac tromethamine in rabbits.

The ocular bioavailability of 0.5% [14C]ketorolac tromethamine administered topically (50 microL) to the eye was determined. The ocular bioavailability of ketorolac was 4% in anesthetized rabbits and was determined by comparing drug concentrations in the aqueous humor after topical application with those obtained after intracameral injection of an equivalent dose of 0.25 mg of ketorolac tromethamine per eye. Although ketorolac administered to the eye was completely absorbed systemically, concentrations of ketorolac (AUC) were, on the average, 13 times higher in the aqueous humor than in plasma after topical administration. In a separate ocular distribution study, peak concentrations of radioactivity were achieved in the ocular tissues and in plasma within 1 h post instillation. Concentrations of total radioactivity were highest in the cornea and sclera and lowest in the lens.

Elimination kinetics of Lipofundin MCT: bolus injection and infusion compared.

Fifteen healthy young probands (nine males, six females) underwent an intravenous fat tolerance test (IVFTT) and, on the following day, a fat infusion lasting 6 hr. The emulsion tested was Lipofundin MCT 10%. One half of its triglyceride mass contains medium chain fatty acids. The IVFTT was started by injection of 0.1 g lipid per kg body weight into the fasting proband. Lipid elimination was estimated by measurement of light-scattering intensity of serum samples collected during a 60-min period. Individual fraction elimination rate constants covered a considerable range (K2 = 8.84 +/- 3.45%/min). The infusion test was performed at a rate of 0.1 g lipid per kg body weight and hr and lasted 6 hr. Serum triglyceride concentrations were determined enzymatically. They increased from 0.941 +/- 0.285 mmol/liter at the fasting state to a plateau level of 1.753 +/- 0.306 mmol/liter during infusion, and returned to initial levels 1 to 2 hr after the infusion was terminated. Individual triglyceride increments during infusion were significantly correlated with half-life periods of lipid elimination during IVFTT (r = 0.792, p less than 0.001). This relationship was derived using a model of the stationary state during infusion. We conclude that elimination kinetics of exogenous fat given either as bolus or infusion are ruled by the same fractional elimination rate constant K2. The IVFTT provides an estimate of the stationary triglyceride increment during a lipid infusion lasting several hr.

Death through injection of barbiturates.

The authors report two cases of lethal intoxication due to barbiturates in two male individuals, respectively 24 and 35 years old. They stress the comparatively rare mode of administration of such drugs in the absence of another party, i.e. the parenteral way.

Serum and synovial fluid steady-state concentrations of trimethoprim and sulfadiazine in horses with experimentally induced infectious arthritis.

The tarsocrural joints of 11 horses were inoculated with 1.2 to 2.16 x 10(6) viable Staphylococcus aureus organisms susceptible to a trimethoprim-sulfadiazine (TMP-SDZ) combination with minimal inhibitory concentration (MIC) of 0.25 micrograms of TMP/ml and 4.75 micrograms of SDZ/ml. Antimicrobial treatment consisted of oral administration of a TMP-SDZ combination--30 mg/kg of body weight given once daily (group-1 horses) or 60 mg/kg given as 30 mg/kg every 12 hours (group-2 horses). Paired serum and synovial fluid samples were obtained before intra-articular inoculation with the S aureus, after inoculation with S aureus but before antimicrobial treatment, and after inoculation at various hourly intervals after oral administration of the TMP-SDZ combination. The TMP-SDZ combination was administered daily in the 2 dosages for 21 days. Samples were collected after day 3 of repetitive drug administration so that drug steady-state concentration would have been achieved. Serum and synovial fluid samples were analyzed for TMP and SDZ concentrations. Administration of the TMP-SDZ combination at a dosage of 30 mg/kg once daily was not effective in maintaining TMP or SDZ concentrations above the MIC of TMP-SDZ for the S aureus (0.25 and 4.75 micrograms/ml for TMP and SDZ, respectively) in the infected synovial fluid or in maintaining adequate TMP concentration in the serum. The alternative use of the TMP-SDZ combination at a dosage of 60 mg/kg given as 30 mg/kg every 12 hours was effective in maintaining serum and synovial fluid concentrations of TMP and SDZ that were greater than the MIC for the infective organism.(ABSTRACT TRUNCATED AT 250 WORDS)

The fate of drotaverine-acephyllinate in rat and man. II. Human pharmacokinetics of drotaverine-14C-acephyllinate.

Pharmacokinetics of Drotaverine-Acephyllinate, Chinoin was investigated in seven male volunteers using 14C labelled drug. Drotaverine-Acephyllinate was administered at a 100 mg single oral dose. Measurements of total radioactivity showed that the drug was absorbed completely and was eliminated by renal and biliary routes. Within 72 hours 39.9 +/- 9.9% and 47.1 +/- 4.9% of the dose were recovered in the urine and faeces respectively. Experimental results were interpreted on the basis of a complex linear compartment model. The structural identifiability of the model was proved by computer analysis, and the pharmacokinetic parameters were determined.

[Experimental and clinical studies of BRL 25000 (clavulanic acid-amoxicillin) granules in the field of pediatrics].

BRL 25000 granules, a formulation consisting of amoxicillin (AMPC) and clavulanic acid (CVA), was evaluated in the field of pediatrics. In a pharmacokinetic study, serum concentrations were determined in a patient after oral administration of BRL 25000 granules in the non-fasting state at a dose of 11.76 mg/kg. The serum levels of amoxicillin (AMPC) and clavulanic acid (CVA) 1 hour after administration were 7.76 micrograms/ml and 6.64 micrograms/ml, with biological half-lives of 0.86 hour and 0.88 hour respectively. The serum concentration profile at a dose of 31.58 mg/kg showed almost the same tendency as at 11.76 mg/kg, although the peak level and biological half-life of the serum concentrations were not obtained. These serum levels and their peak levels were considered reasonable compared with those obtained in adults at similar dose levels. In clinical studies, 34 patients were evaluated including 8 patients with acute pharyngitis or acute tonsillitis, 1 patient with acute bronchitis, 1 patient with bronchopneumonia, 23 patients with scarlet fever and 1 patient with pertussis. BRL 25000 granules were administered orally 3-4 times per day for 4-8 days to 2 patients at doses of 20 approximately less than 30 mg/kg/day, to 18 patients at doses of 30 approximately less than 40 mg/kg/day, to 11 patients at doses of 40 less than approximately 50 mg/kg/day, and to 3 patients at doses of 50-60 mg/kg/day. The clinical response was assessed excellent in 13 cases and good in 21 cases giving an overall clinical efficacy rate of 100% (34/34). The causative organisms were isolated in 17 cases and included 12 strains of Streptococcus group A, 2 S. pneumoniae, 3 H. influenzae and 1 H. parainfluenzae.(ABSTRACT TRUNCATED AT 250 WORDS)

[Nocardial brain abscess: case report].

A 25-year-old man, who was slightly immunosuppressed, presented headache and right motor weakness due to multiple brain abscesses disseminated from lung abscess. They were diagnosed, by bacteriological examination, as nocardial brain abscesses (nocardia asteroides) 4 weeks after the first operation. In spite of delay in the diagnosis, he was relieved by operations (three times) and chemotherapy including high doses of Sulfamethoxazole-Trimethoprim. He was eventually discharged. We stress the necessity of early diagnosis and the efficacy of Sulfamethoxazole-Trimethoprim for nocardial brain abscess.

Pharmacokinetic studies on clavulanate potentiated ticarcillin in normal subjects and patients with renal insufficiency.

Pharmacokinetics of the novel combination of ticarcillin with the beta-lactamase inhibitor clavulanic acid (BRL 28500, Timentin, Betabactyl) was investigated in order to calculate the dose reduction factor (DRF) and elaborate dosage recommendations for patients with varying degrees of renal impairment. Serum and urine levels of ticarcillin and clavulanic acid have been determined following the i.v. application of 3.2 g and 5.2 g BRL 28500 consisting of 3.0 g and 5.0 g ticarcillin, respectively, and 0.2 g of clavulanic acid each. 10 healthy volunteers and 9 patients received the 5.2 g formulation, and 6 normal subjects and 9 patients the 3.2 g formulation. The pharmacokinetics of both components of BRL 28500 behave fairly similarly and provides the combination with a logic basis. The dose reduction factor, being 1 by definition in normal renal function, rises in final renal failure to 2-3 for clavulanic acid and to 4-5 for ticarcillin. A dosis reduction to 1/2-1/4 will roughly produce the same AUC in a patient with terminal renal insufficiency as the normal dosage in a healthy subject. The distribution volume of ticarcillin and clavulanic acid was found to be enlarged probably due to overhydration in this group of patients. The recovery of both BRL 28500 components decreased with impaired renal function. The recovery 6 h after administration of 0.2 g clavulanic acid in the 5.2 g (3.2 g) BRL 28500 formulation fell from 58 +/- 12% (52 +/- 6) in healthy subjects to 25 +/- 14% (25 +/- 13) in patients with renal insufficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of sulfadoxine and pyrimethamine after Fansidar administration in man.

The pharmacokinetics of sulfadoxine (SULF) and pyrimethamine (PYR) were studied in 7 healthy volunteers after a single oral dose of Fansidar. A comparison was made between the pharmacokinetics of the components of Fansidar calculated from whole blood and plasma data. The mean whole blood to plasma concentration ratios of SULF and PYR were 0.62 and 0.87, respectively. The elimination half-lives of SULF and PYR were similar in whole blood and plasma. The apparent volume of distribution and clearance of SULF and PYR in whole blood were significantly higher (p less than 0.01) than the corresponding plasma values. Because malaria-infected erythrocytes appear to concentrate SULF, it may be more relevant to measure drug concentrations in whole blood rather than in plasma in assessing the antimalarial efficacy of Fansidar.

[Metabolic interaction between cimetidine, ranitidine and amitriptyline/chlordiazepoxide]. / Metabolische Interaktion zwischen Cimetidin, Ranitidin und Amitriptylin/Chlordiazepoxid.

The effects of cimetidine and ranitidine on plasma levels of amitriptyline and chlordiazepoxide were examined in a biphasic study with 12 young male volunteers. During the first phase all subjects received a fixed combination of 2 X amitriptyline (25 mg) and chlordiazepoxide (10 mg) daily for one week. After the last dose blood samples were drawn up to 72 hours in order to detect plasma levels of the drugs and their main metabolites. Following a wash-out-period of 7 days two groups of 6 subjects, each were formed in a randomized order. In addition to the mentioned medication 3 X 200 mg plus 1 X 400 mg of cimetidine daily or 2 X 150 mg of ranitidine daily were administered for one week. After discontinuation of amitriptyline/chlordiazepoxide the medication with H2-blockers was kept and blood samples were collected again for plasma analysis. Plasma level detections were carried out employing HPLC. The change of the area under the plasma level-time curve (AUC), total clearance and terminal half-life served as parameters indicating interaction. Under treatment with cimetidine plasma levels of amitriptyline and chlordiazepoxide were significantly (5%) increased, whereas such effects could not be observed with ranitidine. Due to these interactions under the conditions of coadministration of H2-blockers and amitriptyline and/or chlordiazepoxide the use of ranitidine is recommended.

Pharmacokinetics of trimethoprim and sulfamethoxazole in serum and cerebrospinal fluid of adult patients with normal meninges.

The pharmacokinetics of trimethoprim (TMP) and sulfamethoxazole (SMX) in cerebrospinal fluid (CSF) and serum after a single intravenous infusion of 5 mg of TMP and 25 mg of SMX per kg of body weight over approximately 120 min were studied i nine patients who had uninflamed meninges and were undergoing elective myelography. Peak concentrations of TMP and SMX in CSF were 1 microgram/ml and 13.8 micrograms/ml, respectively. The peak TMP concentration in CSF occurred significantly earlier than the peak SMX concentration (60 versus 480 min postinfusion). At 15 h, there was no detectable TMP in the CSF, and there was 4.7 micrograms of SMX per ml of CSF. In the postdistribution phase (in CSF), simultaneous CSF-to-serum concentration ratios ranged from 0.23 to 0.53 for TMP and from 0.20 to 0.36 for SMX. CSF penetration (measured by comparison of the area under the curve of the composite CSF and serum concentration-time curves) was 18% for TMP and 12% for SMX. A loading dose of TMP-SMX (bases on TMP) of 10 to 12 mg/kg and a maintenance dose of 6 mg/kg every 8 h or 8 mg/kg every 12 h (with a 2-h infusion) should yield steady-state peak concentrations of at least 5 micrograms of TMP per ml of serum and 160 micrograms of SMX per ml of serum. Further studies of TMP-SMX administered in these doses in the treatment of serious bacterial infection, including meningitis, are warranted.