International journal of clinical pharmacology, therapy, and toxicology (Int J Clin Pharmacol Ther Toxicol )

Publisher: International Symposia on Clinical Pharmacology


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    International journal of clinical pharmacology, therapy, and toxicology (International Symposia on Clinical Pharmacology: 1980), International journal of clinical pharmacology, therapy and toxicology
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Publications in this journal

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    ABSTRACT: Given the mortality and morbidity associated with acute iron intoxication, effective iron chelation which is easily administered in an emergency situation would be ideal. The pharmacokinetics of L1 were examined in 5 healthy adult male volunteers to assess its potential for use in acute iron overload. Ferrous sulfate (600 mg), L1 (900 mg), and ferrous sulfate and L1 were administered on three separate days, each one week apart. On each test day, blood samples were collected at regular intervals for the measurement of plasma L1 and total iron. Pharmacokinetic values were calculated. The data were also compared to that obtained in 10 patients with beta-thalassemia and chronic iron overload. In the normal volunteers, a 20% decrease in the area under the concentration time curve of plasma iron and of plasma L1 was demonstrated when they were co-administered. There was no change in urinary iron excretion when L1 was given with iron (p = 0.414). The elimination half-life of L1 in the thalassemia patients (137.65 +/- 48.65 min) was significantly longer than that in the healthy volunteers (77.56 +/- 13.0) (p = 0.0047) due to larger apparent volume of distribution. In all of the iron-overloaded individuals L1 resulted in increased urinary iron excretion. None of the other pharmacokinetic variables compared were significantly different between these two groups. These studies indicate that at levels below saturation, transferrin does not allow L1 to remove absorbed iron in healthy volunteers, whereas in thalassemia patients, who are beyond saturation of their iron binding capacity, the drug binds iron and promotes its excretion.
    International journal of clinical pharmacology, therapy, and toxicology 01/1994; 31(12):602-5.
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    ABSTRACT: Pharmacokinetic data obtained from healthy subjects after a single i.v. infusion over 30 min of either astromicin (AST) or isepamicin (ISP), the newly developed aminoglycoside antibiotics, were analyzed by a computer program, NONMEM, together with those in patients having impaired renal functions of various degrees, which were cited from the literature. A two-compartment open model was utilized for the analysis, assuming that the total body clearance of drug (ClB) is linearly correlated with endogeneous creatinine clearance (Clcr). By the analysis, it was found that the body weight explains some part of interindividual variability in ClB of ISP, although it did not hold true in the case of AST. For each drug, the means and variances of ClB and the distribution volume of central compartment, and only the means of two intercompartmental constants (K12 and K21), all of which were obtained by the NONMEM analysis, were implemented in a Bayesian prediction program for a microcomputer. This, thus, clarified a point as to when blood sample should be collected in order to get the best prediction of individual ClB with the use of the above Bayesian program and the measurement of drug concentration in the sampled blood as a feedback information. For this purpose, the drug concentrations in plasma obtained in the multiple-dose study of each drug, in which the drug was administered in healthy subjects as i.v. infusion over 1 h every 12 h for 4.5 days, were used.(ABSTRACT TRUNCATED AT 250 WORDS)
    International journal of clinical pharmacology, therapy, and toxicology 01/1994; 31(12):606-10.
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    ABSTRACT: While on therapy for acute myeloid leukemia, a 15-year-old girl developed extensive punctate keratitis of both eyes following high-dose cytarabine therapy (HD-Ara-C). Pharmacokinetic monitoring showed an increase of the Ara-C plasma levels up to twice the steady-state level within 10 minutes after discontinuation of the Ara-C infusion. Calculations of Ara-C plasma half-life, plasma clearance and volume of distribution were within the expected range. Owing to the short half-life of Ara-C in blood due to rapid deamination, varying infusion velocities will result in markedly varying plasma levels. Higher peak plasma levels lead to proportionally higher diffusion into compartments like tears, aqueous humor and cerebrospinal fluid. In compartments which lack noteworthy deaminase activity, dose intensity will be much more enhanced than in plasma. Peak plasma levels, therefore, may be associated with multifold local toxicity without concurrent increase of hematological toxicity. Especially when the drug is given in small volumes of infusion, these considerations should be taken into account. Precise control of infusion parameters and application of artificial tears for dilution of the Ara-C concentration on the corneal surface should be part of keratitis prophylaxis.
    International journal of clinical pharmacology, therapy, and toxicology 01/1994; 31(12):593-6.
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    ABSTRACT: To investigate whether or not DL-sodium lactate inhibits the renal excretion of purine bases and oxypurinol, we administered physiological saline containing 0.2 mol DL-sodium lactate to 7 normal subjects intravenously. DL-sodium lactate infusion decreased the urinary excretion and the fractional clearance of uric acid, xanthine and oxypurinol, but the fractional clearance of hypoxanthine was not affected. These results suggested that the implications of DL-sodium lactate-induced hyperuricemia must be considered in patients with gout on its long term and high dose administration, and that the implications of DL-sodium lactate-induced prolongation of half-life of oxypurinol must be considered in hyperuricemic patients treated with allopurinol. However, since the high dose and long term administration of DL-sodium lactate is clinically rare, the effect of DL-sodium lactate infusion on the urinary excretion of uric acid, xanthine and oxypurinol may not be clinically important.
    International journal of clinical pharmacology, therapy, and toxicology 01/1994; 31(12):588-92.
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    ABSTRACT: The distribution of lidocaine and digoxin in myocardial and aorta tissues of open chest anesthetized dogs was studied, following the administration of 30 ml phosphate buffer solution of the drugs in the pericardial cavity where it was kept for increasing time intervals. Transfer of lidocaine (15 or 30 mg) from the solution to myocardium was almost complete within 60 min, while only 50% of digoxin (2 or 50 micrograms) was removed, and this occurred during the first 30 min. Accordingly, the absorption rate of lidocaine by heart tissues increased with time up to 60 min while that of digoxin decreased with time. Absorption of digoxin by the atria and absorption of both drugs by intrapericardial aorta were higher than that of other heart tissues, between 20 and 60 min. At 30 and 60 min, lidocaine was evenly distributed across the LV wall while digoxin 50 micrograms was mainly concentrated subepicardially. On the contrary, i.v. administration of digoxin resulted in even distribution in the LV wall without preferential concentration in the atria. The uptake of both drugs by aorta was several times lower compared to heart tissues after i.v. administration. Drug concentrations in LV wall almost at therapeutic level, were derived from solution of low concentration of the drug in the pericardial cavity. It is concluded that intrapericardial administration of the drugs may be used when increased concentration of them is desired in specific areas of the heart and the aorta.
    International journal of clinical pharmacology, therapy, and toxicology 01/1994; 31(12):611-5.
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    ABSTRACT: Cocaine abuse today has reached greater heights than it did during the first cocaine epidemic in the late nineteenth century. It is estimated that one out of every four Americans has used cocaine and some six million people in the US use it regularly. Although cocaine affects all systems in the body, the central nervous system (CNS) is the primary target. Cocaine blocks the reuptake of neurotransmitters in the neuronal synapses. Almost all CNS effects of cocaine can be attributed to this mechanism. Euphoria, pharmacological pleasure and intense cocaine craving share basis in this system. The effects of cocaine on other organ systems, in addition to its effects on the CNS, account for the majority of the complications associated with cocaine abuse. In this paper, the CNS effects following cocaine administration and their treatment are discussed.
    International journal of clinical pharmacology, therapy, and toxicology 01/1994; 31(12):575-81.
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    ABSTRACT: Alfuzosin is a new alpha 1-adrenoceptor antagonist particularly effective in the symptomatic treatment of benign prostatic hypertrophy (BPH). The elimination of alfuzosin being almost entirely metabolic, the potential pharmacokinetic interaction with cimetidine (H2-receptor antagonist) was investigated in 10 healthy young subjects. Pharmacokinetics of alfuzosin were appraised as a 5 mg oral dose before, after one day and after 20 days of cimetidine (1 g/d) administration. An inhibition of the hepatic mixed function oxidase system by cimetidine was established by the oral antipyrine clearance test. Under these conditions, alfuzosin pharmacokinetics were only marginally affected by concomitant cimetidine administration. Surprisingly, a significantly shorter elimination half-life was found after 20 days on cimetidine (from 5.1 +/- 0.4 h to 4.4 +/- 0.5 h). This fact must be attributed to the large inter-individual variation in pharmacokinetic parameters reported for alfuzosin. Cmax and AUC increased up to 20% after cimetidine but without statistical significance. No side-effects on the association cimetidine-alfuzosin were reported. In conclusion, there is a lack of pharmacokinetic interaction on cimetidine-alfuzosin co-administration.
    International journal of clinical pharmacology, therapy, and toxicology 12/1993; 31(11):568-71.
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    ABSTRACT: Plasma kinetics of netilmicin, an aminoglycoside antibiotic was studied in 62 patients undergoing urologic surgery. Despite the use of a standard 100 mg-dose, no toxic levels were achieved except in one patient. A poor correlation was found between netilmicin plasma elimination constant and creatinine clearance (r = 0.34, p = NS). We can conclude that the prediction of netilmicin plasma concentrations is not possible using only demographic patient's data. The monitoring of netilmicin levels should be performed in long-term treatments but not in 4-dose regimes such as in urologic prophylaxis.
    International journal of clinical pharmacology, therapy, and toxicology 12/1993; 31(11):557-60.
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    ABSTRACT: A parallel, double-blind, placebo controlled and randomized study in a single center was done with ketoprofen 2.5% gel to treat acute soft tissue injuries. Patients applied the gel twice a day for seven days, corresponding to 250 mg of ketoprofen per day. Assessments were made on the third and seventh day by VAS, subjective evaluation and pain threshold algometry. The study group consisted of 29 patients and the control group 27 patients. Pain at rest was significantly relieved in the ketoprofen group, whereas in the placebo group the difference was not significant. In terms of side-effects, no difference between the groups was noticed. In both groups, local dermal irritation was found. Our results suggested that ketoprofen 2.5% gel was safe and superior to placebo in the treatment of soft tissue injuries.
    International journal of clinical pharmacology, therapy, and toxicology 12/1993; 31(11):561-3.
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    ABSTRACT: Pharmacokinetic measurements were performed in two groups of patients with coronary heart disease (CHD) after single and multiple dosing of 2 mg linsidomine (SIN 1). The drug was administered by intravenous short time infusion in 12 CHD-patients with renal insufficiency (RI group, Clcr: 11 +/- 6 ml/min) and in 12 CHD-patients with normal kidney function (control group, Clcr: 88 +/- 22 ml/min). The measurement of plasma concentration time courses of total SIN 1C (SIN 1 + SIN 1C) was found to be suitable for an estimation of the SIN 1C related half-life of the terminal phase (t50% = 1.5 +/- 0.5 h), as SIN 1 was eliminated from plasma rapidly (t50% = 12 to 20 min). Furthermore, the mean total SIN 1C plasma profiles were equal after single and multiple administration of the drug giving evidence that SIN 1C is not accumulating during repetitive dosing of SIN 1 in patients with renal disease. The mean maximum renal fraction of total SIN 1C excretion of RI-subjects (fe = 0.8 +/- 0.8% of dose) was significantly different from the corresponding mean value of the control group (fe(N) = 5.8 +/- 5.1% of dose). No differences were found for fe and fe(N) between day 1 and day 4. As SIN 1 is degraded in plasma very rapidly and as SIN 1C is cleared mainly extrarenally, any restrictions concerning repetitive SIN 1 dosage regimen should not be considered for CHD-patients with renal failure.
    International journal of clinical pharmacology, therapy, and toxicology 12/1993; 31(11):533-41.
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    ABSTRACT: Two new bioavailability parameters were recently suggested [Koeleman et al. 1991] to define (i) the time that the concentration in the blood stays above a defined minimum effective concentration, te and (ii) the onset of the effect, to. In addition to conventional bioequivalence parameters, the new bioavailabilty parameters (to and te) were calculated in this study and statistically compared for penicillin, chloroquine, oxytetracycline, amoxycillin and flucloxacillin from available bioequivalence data. For oxytetracycline, flucloxacillin and amoxycillin, the conventional bioavailability parameters indicated partial equivalence whereas using the te and to parameters, more realistic indications of the possible extent of the performance of a drug from dosage forms were obtained than with the conventional bioequivalence parameters. The new parameters gave additional information for a better evaluation of the performance of a drug from a dosage form.
    International journal of clinical pharmacology, therapy, and toxicology 12/1993; 31(11):542-6.
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    ABSTRACT: We studied 16 mild to moderate essential hypertensive patients (14 male, 2 female; mean age 45 years, range 34-55 years) in order to investigate the effects of an ACE inhibitor, cilazapril (5 mg o.d.) and a selective beta-blocker, atenolol (100 mg o.d.) on the hemodynamics of the brachial and carotid arteries after an isometric stress test with a handgrip. Both drugs caused a statistically significant decrease in blood pressure after three months' treatment, but only cilazapril reduced it after the first dose. Heart rate was reduced only by atenolol (61 +/- 3 vs 71 +/- 3 bpm; p < 0.01). Changes in forearm compliance and characteristic impedance showed a difference statistically significant both for acute test and after three months of treatment. The increase in blood pressure during handgrip did not differ appreciably between the two treatment groups. On the contrary, after handgrip only cilazapril caused a significant increase of the reactive hyperemia.
    International journal of clinical pharmacology, therapy, and toxicology 12/1993; 31(12):582-7.
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    ABSTRACT: Since immunosuppressed patients are at higher risk of serious influenza virus infection than healthy subjects, we decided to study the serological effectiveness of influenza vaccination on renal transplant patients, despite the theoretical aspect that such treatment could induce glomerular lesions through an immunological process. Forty transplant patients aged from 20 to 50 years with well functioning renal graft and no febrile episode were studied. Blood samples were collected before the intramuscular injection of 0.5 ml of multivalent influenza vaccine (PASTEUR MERIEUX SERUM VACCINS), at one and at two months after the vaccination. Before vaccination, the antibody titers to influenza virus ranged from 0 to 1/20 and after vaccination from 1/20 to 1/320. One month after vaccination 17/40 (42.5%), 18/31 (58%) and 16/33 (48%) patients showed a four-fold or greater increase of serum influenza antibody titers to antigens A/H3N2, A/H1N1 and B, respectively. A similar response at two months in relation to the first month response rate after vaccination was found in 15/17 (88%), 18/18 (100%), and 15/16 (93%) of transplant patients for the above mentioned three antigens. Side-effects were observed in two of the studied patients. Serum creatinine and urine protein were not changed. Also acute graft rejection episodes were not observed. It is suggested that influenza vaccination is safe and serologically effective on renal transplant patients.
    International journal of clinical pharmacology, therapy, and toxicology 12/1993; 31(11):553-6.
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    ABSTRACT: In the previous study, we determined the in vivo binding parameters of valproic acid to serum proteins in seven healthy young adults at steady-state. In this study, we determined the effects of serum protein binding on hepatic elimination with the use of observed data obtained from our previous study of valproic acid. A regression analysis between the binding parameters and the pharmacokinetic parameters was performed. In addition, the relationship between each pharmacokinetic parameter was also analyzed. The order of association constant (K) for valproic acid-serum protein was 10(-2) l/mumol. No significant correlation was found between the binding parameters and the rate of elimination. On the other hand, the average unbound serum concentration was found to be a significantly negative correlation with the unbound (intrinsic) clearance (p = 0.0082). The product of association constant and concentration of free protein (P) correlated positively with the unbound clearance (p = 0.0233) and negatively with the average unbound and total serum concentrations (p = 0.0021 and p = 0.0029, respectively). The results indicate that the membrane permeability of valproic acid is high and that the increase of unbound clearance accompanies directly the decrease of the average unbound and total serum concentrations. Consequently, the KP values are proportional to the unbound clearance due to the rapid changes of the concentration of free protein. Therefore, the dissociation of the valproic acid-serum protein complex is not a rate-limiting factor for hepatic elimination and hence the serum protein binding cannot limit the ability of the liver to extract drug from blood.
    International journal of clinical pharmacology, therapy, and toxicology 12/1993; 31(11):529-32.
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    ABSTRACT: Cocaine abuse is widespread in North America. It is estimated that almost one in every four Americans has used cocaine at least once in his/her lifetime. In the past two decades, cocaine related cardiovascular complications have mushroomed because cocaine has become cheaper and more readily available. The fundamental effects of cocaine on cardiovascular system are similar to those observed following an intense, sympathetic stimulation. Cocaine intake results in marked increase in blood pressure, myocardial oxygen demand and heart rate. Coronary blood flow, which increases in response to exercise (endogenous sympathetic stimulation) however, is decreased by cocaine intake. Increased demand of oxygen by the myocardium in the face of decreased supply in subjects with cocaine use, leads to myocardial ischemia, which in turn forms a substrate for most of the cardiovascular complications, namely, myocardial infarction, cardiac arrhythmias and acute pulmonary edema. Hypertension related complications, dissection and rupture of aortic aneurysm, hemorrhagic stroke, in addition to infective endocarditis, myocarditis, cardiomyopathy all occur more frequently in cocaine addicts. In this review, pertinent clinical pharmacology and cardiovascular risks associated with cocaine abuse are presented.
    International journal of clinical pharmacology, therapy, and toxicology 12/1993; 31(11):521-8.
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    ABSTRACT: Food-induced changes on the bioavailability of a sustained-release theophylline tablet, which uses acrylic resins Eudragit as sustaining agent, were studied in 12 healthy male volunteers. The tablet was developed in our laboratory using conventional technology. It presented a good bioavailability pattern and maintained plasmatic concentrations within the therapeutic range for 12 hours under conditions of steady-state. The study design was a 4 x 4 latin square involving 12 subjects who received a single dose of the tablet while fasting or with a standardized normal, high fat or high fat/high protein meal. The results showed no differences in AUC, K, tmax, ka and MRT. Statistical differences were found in Cmax comparing the fasting condition with high fat/high protein diet. A delay was also observed in the detection of the drug in plasma when the tablet was administered with high fat and high fat/high protein food, but clinically the changes seem to be irrelevant.
    International journal of clinical pharmacology, therapy, and toxicology 12/1993; 31(11):547-52.
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    ABSTRACT: Current methods for the treatment of glucose intolerance first discovered in pregnancy are reviewed and a systematic data-based approach is introduced. Gestational diabetes mellitus (GDM) is a leading cause of adverse perinatal outcome in 5% of all pregnancies in the United States. Early detection and initiation of treatment meant to restore euglycemia will prevent many of the major complications associated with hyperglycemia. Staged Diabetes Management (SDM) is introduced in this paper as an innovative approach for the detection and treatment of GDM and glucose intolerance in pregnancy. Relying on self-monitored blood glucose data, SDM guides the primary care physician through increasingly more complex regimens until euglycemia is reached. Computer-based technologies assist the clinical decision-making by producing Ambulatory Glucose Profiles (AGP), which are graphic representations of glycemic control. SDM combined with AGP technology are meant to significantly reduce the threefold greater risk of adverse outcome in pregnancy experienced by women with GDM.
    International journal of clinical pharmacology, therapy, and toxicology 11/1993; 31(10):497-505.
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    ABSTRACT: Plasma concentration and PR-interval prolongation were correlated after a single dose of 80 mg verapamil (trial A) and at steady-state during one dose interval (80 mg verapamil t.i.d.) on day 7 (trial B) and day 14 (trial C) and the subsequent dose interval at the afternoon on day 14 (trial D). The pharmacokinetic parameters of verapamil indicated a two-fold increase in AUC and Cmax at trial B and C when compared with the single dose application, but AUC and Cmax were considerably lesser during the afternoon dosing interval (trial D). For each subject, concentration/effect analysis was established: according to a linear and a sigmoidal model, and using a plasma concentration vs effect approach (1) and a semiparametric effect-site concentration vs effect approach (2). The comparison of the two different approaches and models showed that in general, the concentration/effect analysis based on the linear model and with approach 2 gave the best description of the dromotropic response to verapamil for the majority of the individuals. However, approach 1 accounts for 30 to 50% of the concentration/effect curve established in the data subsets of trial A to D, and about 40% of all curves in trial A, B and C can be more precisely described with the Emax-model, whereas almost all curves obtained in trial D were best described by a linear model. A decrease in the responsiveness to verapamil at steady-state was indicated by both models, but more precisely described by the parameters of the Emax-model.
    International journal of clinical pharmacology, therapy, and toxicology 11/1993; 31(10):469-75.
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    ABSTRACT: The program TopFit was developed and validated within the European pharmaceutical industry. It provides both pharmacokinetic data analysis support for international regulatory submissions of new drugs, and sophisticated techniques for model-based kinetic/dynamic evaluation during drug development. TopFit features are: (1) non-compartmental methods; (2) standard compartment models assembled from input and disposition modules; (3) a potentially unlimited number of linear user-defined models that accommodate metabolites, effects, and absorption profiles; (4) a library of 24 non-linear models. No user programming is required. A well-defined file structure allows ready exchange of data with other programs such as SAS. TopFit version 2.0 is now commercially available, with comprehensive documentation, in the form of an MS-DOS application for the PC.
    International journal of clinical pharmacology, therapy, and toxicology 11/1993; 31(10):514-20.

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