- [Show abstract] [Hide abstract] ABSTRACT: Digoxin serum levels are measured after intravenous infusion of a 2 mg dose. The pharmacokinetic parameters for a two and three-compartment open-body model are calculated by compartmental analysis using a digital computer; the three-compartment open-body model gives the superior fit. The behaviour of digoxin during multiple administration is predicted and compared to the experimental results obtained after eleven intravenous injections of 0·5 mg digoxin. For pharmacokinetic and pharmacodynamic purposes the behaviour of digoxin in man is best described by a three-compartment open body model. For clinical purposes, such as determining the optimum dosage regimen for individual patients, a simpler moder might be adequate and easier to use.
- [Show abstract] [Hide abstract] ABSTRACT: Approximately one half of the patients takes prescribed medications irregularly or omits these altogether. On the basis of our own observations and published reports we analyze the factors influencing compliance. The motivation of the patients plays a decisive role, it is rooted in the meaning the patient gives to his existence, to where the strength of his family bonds and the confidence in the care-taking persons lays as well as the possibility to express himself which is most important. The better guidance and training of the doctors in the difficult task of strengthening such motivation may contribute to substantially improve this situation.
- [Show abstract] [Hide abstract] ABSTRACT: Examined the feasibility and accuracy of the Brief Psychiatric Rating Scale (BPRS) as an evaluative tool. 80 psychiatric inpatients (aged 17–63 yrs) were evaluated with the BPRS on the day of admission and every subsequent 10th day. Results indicate that the BPRS shows a factor structure that is consistent with previous studies (e.g., J. E. Overall; 1974). The BPRS represents a level of abstraction that is compatible with the way clinicians think and communicate about manifest psychopathology. Finally, the BPRS is sensitive to changes in the patient's condition during pharmacological treatment. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
- [Show abstract] [Hide abstract] ABSTRACT: The aim of this study was to investigate the effect of chronic renal insufficiency on absorption, distribution and elimination of D-xylose which was chosen as a "test substance". Pharmacokinetic analysis was based on eighteen D-xylose tests carried out either by the enteral or parenteral route in a randomized fashion on nine patients suffering from chronic renal insufficiency. These results were compared with those obtained in healthy volunteers. The renal clearance was simultaneously measured with the 51Cr-EDTA test. In the experimental conditions the intestinal absorption of D-xylose was not modified qualitatively (absorption rate) nor quantitatively (systemic availability). Inspite of this, the maximal concentration of the D-xylose was higher in these patients and was reached later than in healthy volunteers. This fact should be taken into consideration when interpreting the results of a D-xylose test in patients suffering from chronic renal insufficiency.
- [Show abstract] [Hide abstract] ABSTRACT: Antipsychotic drugs (neuroleptics) are candidates for plasma concentration monitoring, but not all agents have the same potential in this respect. The present review analyses the available data on the kinetics and metabolism of fluphenazine, perphenazine, thiothixene, flupenthixol, clopenthixol, haloperidol, pimozide, penfluridol, sulpiride and clozapine. Although some of the drugs described in this review have been in use for many years, knowledge of their pharmacokinetics is still only approximate. This is primarily because determination in biological fluids is not always feasible. Accordingly, analytical methods useful for pharmacokinetic studies or plasma concentration monitoring of these antipsychotic drugs are discussed. With the exception of sulpiride, all the neuroleptics reviewed share some basic pharmacokinetic properties: good gastrointestinal absorption but reduced systemic availability because of hepatic first-pass metabolism, high hepatic clearance and a large apparent volume of distribution leading to an apparent elimination half-life of about 24 hours for most of these compounds. The renal elimination is negligible and it seems that these drugs do not possess active metabolites. The pharmacokinetic properties of antipsychotic drugs are important for the inclusion of a set of drugs in a psychiatric institution where there is a possibility of drug concentration monitoring. In addition, the availability of a depot preparation is of importance. These factors are discussed in view of the experience made during the last years in the University Psychiatric Institutions of Geneva.
Article: Antipsychotic Drugs[Show abstract] [Hide abstract] ABSTRACT: Antipsychotic drugs (neuroleptics) are candidates for plasma concentration monitoring, but not all agents have the same potential in this respect. The present review analyses the available data on the kinetics and metabolism of fluphenazine, perphenazine, thiothixene, flupenthixol, clopenthixol, haloperidol, pimozide, penfluridol, sulpiride and clozapine. Although some of the drugs described in this review have been in use for many years, knowledge of their pharmacokinetics is still only approximate. This is primarily because determination in biological fluids is not always feasible. Accordingly, analytical methods useful for pharmacokinetic studies or plasma concentration monitoring of these antipsychotic drugs are discussed. With the exception of sulpiride, all the neuroleptics reviewed share some basic pharmacokinetic properties: good gastrointestinal absorption but reduced systemic availability because of hepatic first-pass metabolism, high hepatic clearance and a large apparent volume of distribution leading to an apparent elimination half life of about 24 hours for most of these compounds. The renal elimination is negligible and it seems that these drugs do not possess active metabolites. The pharmacokinetic properties of antipsychotic drugs are important for the inclusion of a set of drugs in a psychiatric institution where there is a possibility of drug concentration monitoring. In addition, the availability of a depot preparation is of importance. These factors are discussed in view of the experience made during the last years in the University Psychiatric Institutions of Geneva.
- [Show abstract] [Hide abstract] ABSTRACT: A patient showed excessive concentrations of desmethylclomipramine after receiving normal daily doses of clomipramine (Anafranil) and the elimination kinetics of the desmethylated metabolite was zero-order/saturable. Investigation showed that she was a poor metabolizer of debrisoquine and that, in addition, she had been treated with allopurinol, an inhibitor of hepatic drug metabolism.
- [Show abstract] [Hide abstract] ABSTRACT: In man, unabsorbed disaccharide lactitol is fermented by colonic flora with an H2 breath production proportional to the absorbed quantity. The osmolality of the ingested solution is without effect either on the oro-cecal transit time and the time of H2 peak, or on the output and peak value of H2 expired. The intestinal symptoms seemed less prominent with slighter osmolality. The beginning of H2 production and the amount of H2 recorded varied widely between different subjects and in the same subject. It is thus important to consider this variability when measuring transit time and evaluating the amount of unabsorbed sugar. The comparison between two analogous doses of lactitol and lactulose (Duphalac) shows lower H2 production with lactulose, but clinical symptoms are slightly more pronounced. The glycemic peak was significantly higher for lactulose than for lactitol.
- [Show abstract] [Hide abstract] ABSTRACT: The clinical classification of depressive states has undergone considerable modification in the past few years. More particularly, the various clinical forms described earlier in relation to age or dubious etiological hypotheses have been reorganized within the framework of general categories of depression established according to clinical criteria. This development has been largely due to the work accomplished by the American Psychiatric Association Task Force and its Diagnostic and Statistical Manual of Mental Disorders, which has become a standard reference work worldwide. With its precise criteria, this classification enables clinicians to adjust therapeutic indications more readily to each particular case. Monotherapy is the rule of thumb for the pharmacological treatment of depression, particularly in the elderly. Combination of medications in the treatment of agitated or melancholic depressive states must be limited to situations in which it is absolutely necessary, and in such cases it is even more important to monitor blood levels than in monotherapy. When there is a significant psychotic component to major depression (hallucinations, delusions), it is advisable to undertake specific antipsychotic treatment before initiating antidepressant medication. In the majority of cases it is possible to treat depressive states in the elderly by appropriate selection of both medication and dosage, and by careful clinical attention to the patients' physical and psychological well-being.
- [Show abstract] [Hide abstract] ABSTRACT: At the present time, the third generation cephalosporins that are already on the market or close to this point include cefsulodin, cefotaxime, cefoperazone, latamoxef, ceftriaxone, ceftazidime, ceftizoxime and cefotetan. Other newer compounds are also under development but have not been included in this review. None of the third generation compounds is suitable for oral administration and, accordingly, their pharmacokinetics have been studied only after intravenous and intramuscular administration. Microbiological assays and HPLC methods have been used for the measurement of plasma/serum, urine, bile and cerebrospinal fluid (CSF) concentrations. As found with cefotaxime, microbiological assays should only be used when the full metabolite spectrum of a particular drug is known, as otherwise, the presence of microbiologically active metabolites may lead to erroneous conclusions. Under normal conditions, the major route of elimination is via the kidneys for cefsulodin, latamoxef, ceftazidime, ceftizoxime and cefotetan. In contrast, cefoperazone is mainly eliminated in the bile, whereas cefotaxime and ceftriaxone depend both on the liver and the kidneys for their elimination. With the exception of ceftriaxone, which has a longer elimination half-life (i.e. around 8 hours), all the other third generation cephalosporins have a t1/2 ranging between 1.5 and 2.5 hours. Plasma protein binding is variable from one compound to another. However, the clinical relevance of this parameter is not clearly established since tissue penetration also depends on the relative affinity of the drug for tissue components. Third generation cephalosporins seem to penetrate adequately into the CSF and, thus pharmacokinetically appear to be appropriate agents for the treatment of meningitis. The degree of modification of pharmacokinetic parameters by renal insufficiency or hepatic diseases depends, as for other drugs, on the extent to which the compound is excreted via the kidneys or the liver. The third generation cephalosporins have been extensively studied under these conditions and recommendations for dosage modification in special circumstances are available for most of them. The pharmacokinetics of some third generation cephalosporins may be modified in neonates and elderly patients. Accordingly, their use at the extremes of age must be accompanied by a closer than usual clinical monitoring of the patient. From a clinical point of view, the third generation cephalosporins possess reliable pharmacokinetic properties.(ABSTRACT TRUNCATED AT 400 WORDS)
- [Show abstract] [Hide abstract] ABSTRACT: Bufuralol is a beta-adrenoceptor blocking drug whose oxidative metabolism is under the same genetic control as debrisoquine and sparteine. The pharmacokinetics of bufuralol were studied in 10 healthy subjects (7 extensive and 3 poor metabolizers of debrisoquine) after oral and intravenous administration. In extensive metabolizers the systemic availability of bufuralol was 43%. Poor metabolizers were characterized by a considerable increase in systemic availability due to a corresponding decrease in hepatic first-pass metabolism. After oral administration of bufuralol non-linear kinetics may occur.
- [Show abstract] [Hide abstract] ABSTRACT: In an open study, 18 patients suffering from an acute episode of schizophrenia and 18 patients with severe mania were given haloperidol at different dosage levels. Haloperidol plasma concentrations were measured and the status of the patients was evaluated at intervals using the Brief Psychiatric Rating Scale (BPRS). No correlation was found between the oral dose and the plasma concentrations in the schizophrenic group, but there was a low correlation for manic patients. In both groups, however, there was a correlation between these two parameters when the drug was given intramuscularly. There was no correlation between haloperidol plasma concentrations and the BPRS scores. Of the 36 patients 28 responded well to the treatment and were discharged from hospital. A good relationship between the clinical status as observed by the clinicians and the BPRS score was found. Plasma haloperidol concentration measurement was found to be a useful tool for the detection of non-compliance or excessive plasma levels. Accordingly, the present study indicates the value of drug level monitoring as a means to improve therapy.
- [Show abstract] [Hide abstract] ABSTRACT: Many patients do not take their medication according to the instructions of their physician. Patient compliance is particularly poor in the long-term treatment of diseases, which produce only minor symptoms in the patient. The aim of the present study was to quantitate patient compliance in diabetics treated with tolbutamide. The amount of tolbutamide taken by the patient was estimated on the basis of its 24 hours urinary excretion. The collection of the 24 hours urine is a standard procedure in our outpatient clinic for the measurement of glycosuria. The study involved 33 diabetics followed over several months. In those reliable patients, who conscientiously took their medication, we found a good correlation between the prescribed dose and the 24 hours urinary excretion. In contrast, when the data from the entire group of 33 out-patients was evaluated, the correlation between these two parameters of prescribed dose and urinary excretion was poor. The correlation between urinary excretion and the dose admitted by the patient was just as poor. According to our results, only one out of two diabetics took the prescribed dose. After our initial observations, we informed the outpatients about their inclusion in this study. In spite of the fact that the patients knew that they were under observation for compliance, we found large interindividual differences in the urinary excretion of tolbutamide over several months. In contrast, the intraindividual variability was low. We found that interviews with patients are a poor means to detect non-compliance, whereas urinary excretion measurements appear to be more reliable.(ABSTRACT TRUNCATED AT 250 WORDS)
- [Show abstract] [Hide abstract] ABSTRACT: Oxprenolol is a non-selective β-adrenoceptor blocking drug extensively metabolized in the liver. Forty milligrams of Oxprenolol were given p.o. to 6 hemodialyzed patients and 7 healthy subjects. Blood concentration profiles of Oxprenolol and of the glucuronide of Oxprenolol, the main blood derivative, were determined. Simultaneously the effect of the drug on exercise tachycardia was recorded. In patients with renal failure, both the area under the curve of blood concentration versus time and the peak blood concentrations were higher than in healthy subjects. Blood concentrations of Oxprenolol decreased rapidly (mean half-life for patient 1.02±SD 0.40 h and for healthy subjects 1.26±0.46 h). During the interdializis interval, there is, in practice, no elimination of glucuronide derivatives. Despite very high blood concentrations of Oxprenolol glucuronide, no back transformation into active Oxprenolol could be measured. A 40 mg dose of Oxprenolol produced higher blood concentrations of Oxprenolol in the patients than in the healthy subjects. In spite of this, this dose did not result in any major difference in cardiac effect between patients and healthy subjects. Thus, administration of Oxprenolol does not require dosage adjustement in patients with severe renal failure.
- [Show abstract] [Hide abstract] ABSTRACT: Bufuralol is a beta-adrenoceptor blocking drug whose metabolism is under the same genetic control as debrisoquine. Bufuralol appears to be a sensitive tool for characterization of this pharmacogenetic variation. After test drug absorption, one single blood collection allows separation between extensive and poor metabolizers. In Switzerland, the poor metabolizer status has a prevalence of 8%. In poor metabolizers bufuralol plasma concentrations are very high, an observation of interest when considering the occurrence of side effects of the drug. In addition to disease-induced variability in drug response, oxidation polymorphism is a major source of interindividual variations in drug effect. As the metabolism of numerous drugs is affected by this pharmacogenetic variation, the question arises whether systematic screening should not be considered.
University of GenevaGenève, Geneva, Switzerland