Clozapine may partially compensate for task-related brain perfusion abnormalities in risperidone-resistant schizophrenia patients.

BACKGROUND: Previous reports show different cerebral activity patterns during treatment with clozapine and typical neuroleptics. However, to date no study has directly compared the brain activity patterns while subjects are undergoing treatment with clozapine and other atypical antipsychotics. This comparison is of interest, given the probably different mechanism of action of clozapine in comparison with other atypicals. OBJECTIVE: To assess the effect of clozapine on perfusion deviations still evident during treatment with risperidone. METHODS: Here we used hexamethylene-propylenaminoxime single photon emission computed tomography to compare the perfusion patterns observed during the performance of a Stroop test in 10 patients sequentially treated with risperidone and clozapine, owing to a lack of response to the former, and in 10 healthy controls. RESULTS: Patients on risperidone showed decreased perfusion as compared to controls in the medial prefrontal, middle cingulate and insular regions, as well as increased activities in brain stem and the posterior hippocampus. After receiving clozapine, the same patients showed an even wider prefrontal perfusion deficit and the brain stem was still hyperactive, but the abnormalities in the cingulate cortex, insula and hippocampus had disappeared. Clinical improvement was directly related to an increase in thalamic perfusion. CONCLUSION: Clozapine may alleviate hyperactivity in the limbic system in schizophrenia and may facilitate activation of the regions involved in cognitive tasks to a greater degree than risperidone, as well as eliciting greater inhibition of the PF region.

Cost-effectiveness analysis of serum vancomycin concentration monitoring in patients with hematologic malignancies.

OBJECTIVE: This study evaluates the cost-effectiveness of vancomycin serum concentration monitoring in patients with hematologic malignancies. METHODS: The study was designed as a prospective randomized study. Seventy immunocompromised febrile patients with hematologic malignancies were randomly assigned to either a vancomycin therapeutic drug monitoring group (TDM group; n = 37) or to a control group (n = 33). Intervention in the TDM group involved patient follow-up by a clinical pharmacist to obtain and pharmacokinetically interpret serum vancomycin concentrations for dosage individualization. RESULTS: Evaluation of all patients included global clinical response and nephrotoxicity, as well as the economic costs and effectiveness derived from the vancomycin monitoring program. There were no significant differences between the TDM and control groups in the outcome measures, except for the incidence of nephrotoxicity: the rates of minor nephrotoxicity were 33.3% and 13.5% in the control and TDM groups, respectively. The corresponding figures for moderate nephrotoxicity were 9.1% and 0%. Logistic regression analysis confirmed that TDM independently reduced the incidence of nephrotoxicity in this patient population. On the basis of this reduced nephrotoxicity, a incremental cost of $435 per case of nephrotoxicity prevented was found for vancomycin serum concentration monitoring. CONCLUSIONS: A decreased incidence of nephrotoxicity provides evidence of a real clinical benefit to patient management in patients with hematologic malignancies. The TDM for vancomycin therapy in this high-risk population has been shown to be a cost-effective procedure.

Drug dosage in end-stage renal disease (ESRD) patients undergoing haemodialysis. A predictive study based on a microcomputer program.

Drug dosage in end-stage renal disease (ESRD) patients undergoing haemodialysis is a very complex problem because of numerous variables relating to the patient, the type of drug administered and the type of dialysis and dialyser. We carried out a multifactorial study of these parameters using a microcomputer program written in BASIC. Three sets of data were fed into the computer: those relating to the biophysical characteristics of the patient, the type of dialysis and dialyser to be used, and others relating to the chemical and pharmacokinetic characteristics of the drug. From these, a predictive intravenous dosage regimen (bolus and infusion) was compiled for each ESRD patient. To check the program we used 2 drugs (tobramycin and vancomycin) and several types of dialyser. The findings were that, with tobramycin, an ESRD patient should be given different postdialytic doses, depending on the type of dialyser used. The maintenance doses calculated by the program were similar to those usually administered to patients receiving clinical treatment with this drug. In the case of vancomycin, the program calculated the clearance value in vivo through the 'Hemoflow F60' dialyser with a polysulphone membrane. The computer program calculated the maintenance dosage of vancomycin that should be given after each dialysis cycle so that its concentration did not fall below its minimum therapeutic concentration.

Bayesian forecasting in paediatric populations.

Bayesian forecasting offers several important advantages for dosage individualisation in children, although, unlike for adults, its use in this population is much lower. Indeed, currently Bayesian methods are underused in this patient population. The paucity of paediatric population pharmacokinetic parameters, and the unavailability of specific clinical pharmacokinetic software for the whole paediatric population, are the main limitations to the application of Bayesian methods in these patients. When these problems have been overcome, this approach will allow clinicians to achieve therapeutic concentrations more readily, faster and more precisely, thus making the methodology highly attractive in the paediatric setting.

The influence of adrenalin on the pharmacokinetics of interpleurally administered lidocaine in patients with pancreatic neoplasia.

The influence of adrenalin on the pharmacokinetics of lidocaine given interpleurally to 10 patients with pancreatic neoplasia was studied. Five patients received an interpleural dose of lidocaine (200 mg; control group), and 5 patients received an interpleural dose of lidocaine (200 mg) plus adrenalin (1:200,000). Plasma and cerebrospinal fluid (CSF) levels of lidocaine were measured before and at specified times (up to 8 hours) after the dose. The analytical technique was radioimmunoassay; and plasma and CSF data were assessed using noncompartmental analysis. The drug was quickly absorbed into the plasma in the control group (Cmax = 2.76 +/- 0.10 microgram/mL at 0.33 +/- 0.14 hours after administration); whereas drug access to CSF was decreased and occurred slowly (Cmax = 0.32 +/- 0.07 microgram/mL at 1.66 +/- 1.35 hours). The drug was eliminated more quickly from plasma than from CSF, with half-lives of 1.71 +/- 0.43 hours and 3.86 +/- 1.27 hours, respectively. The simultaneous administration of adrenalin delayed absorption (tmax = 0.91 +/- 0.52 hours). The drug elimination half-lives in plasma and CSF of this group increased to 3.22 +/- 1.22 hours and 8.71 +/- 3.28 hours, respectively. The duration of the analgesia, evaluated as the time until the patient needed another dose, increased from 8.2 +/- 1.5 hours in the control group to 9.7 +/- 1.3 hours in the group that received adrenalin. From these results the levels that would be reached on a multiple-dose regimen (D = 200 mg, tau = 8 hours) were predicted.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of acute renal impairment in the penetration of cefoxitin into interstitial tissue fluid in rabbits.

The pharmacokinetics of cefoxitin were studied after the administration of a single intravenous dose of 40 mg/kg to rabbits with normal renal function and rabbits with varying degrees of renal impairment. The plasma and interstitial fluid concentrations of the antibiotic were determined by a microbiologic plate diffusion method. The antibiotic follows a two-compartment open kinetic model. The plasma half-life of slow disposition phase t1/2 beta, increases from 0.26 hour in rabbits with normal renal function to 5.41 hours in rabbits with severe renal impairment. In the interstitial fluid the elimination half-life increases from 1.18 hours in rabbits with normal renal function to 99.00 hours in rabbits with renal impairment. A linear relationship is established between the values that define the elimination of the antibiotic and the serum creatinine concentrations. The constant of the incorporation into the interstitial fluid decreases significantly in rabbits with renal impairment.

Disposition of cefoxitin in patients with pleural effusion.

The pharmacokinetics of cefoxitin were studied in nine patients with pleural effusion of varied etiologies. All patients received a single intravenous bolus of 30 mg/kg. Cefoxitin levels were determined simultaneously in plasma and pleural fluid by means of a microbiologic plate diffusion method. The antibiotic follows a two-compartment open kinetic model. In the pleural fluid, maximum concentrations of cefoxitin of 19.72 +/- 9.72 microgram/ml were reached two hours after administration. The fraction of the antibiotic that reaches the pleural fluid represents 0.22% to 4.03% of the dose administered. The disappearance constant of the antibiotic from the pleural fluid is significantly smaller (Kd = 0.15 +/- 0.03 hours-1) than the elimination constant determined from the plasma levels (K13 = 2.27 +/- 0.90 hours-1). Cefoxitin was always found in antibacterial concentration in the pleural fluid for a considerable period of time.

Individualizing vancomycin dosing regimens: an evaluation of two pharmacokinetic dosing programs in critically ill patients.

We evaluated the predictive performance of two commercial computer programs (Abbott and Simkin) for pharmacokinetic dosing of vancomycin in 50 critically ill patients, 40 with hematologic malignancies and 10 in intensive care. Predictive performance was assessed for both pharmacokinetics and forecasting vancomycin serum levels by using a set of peak and trough drug levels per patient. The effect of renal function and serum sampling (steady state, nonsteady state) on predictive performance of both programs was also analyzed. No statistically significant differences were found between the programs for predicting either pharmacokinetics or serum levels, regardless of a patient's renal function or serum sampling. The Abbott and Simkin programs were similar for individualizing vancomycin dosage regimens.

IR and X-ray diffraction study of chlorpheniramine maleate-montmorillonite interaction.

As a contribution to studies on the adsorption of drugs by clay minerals aimed at achieving sustained action in the oral administration of antihistamines, the adsorption of chlorpheniramine maleate by sodium montmorillonite was studied by X-ray diffraction and IR spectroscopy. The results indicated that the chlorphenirammonium ion penetrated into the interlayer space of montmorillonite, producing an increase in the basal spacing, d001, of the silicate. This increase was influenced, as was the amount adsorbed, by the pH and the concentration of the chlorpheniramine maleate solution. At pH 7.0, the amount adsorbed was close to the exchange capacity, and the complex formed had a basal spacing of 17.14 A (delta = 7.54 A). The only mechanism responsible for the interaction was cation exchange. The complex at 17.14 A must be a monolayer with the benzene rings positioned perpendicular to the surface of the oxygen atoms.

Determination of the thermodynamic ionization constants of cefroxadine.

The values of the thermodynamic ionization constants of the carboxylic (pK = 3.30 +/- 0.02) and amine (pK = 7.00 +/- 0.06) groups of cefroxadine were determined at 35.0 degrees C using potentiometric data. The apparent ionization constants of these groups were also determined at 35.0 degrees C, and at different values of ionic strength.

Evaluation of thermodynamic ionization constants by computation of spectrophotometric and potentiometric experimental data obtained simultaneously from a flow system.

A method is proposed for the direct and simultaneous determination of the thermodynamic ionization constants of bifunctional substances, with (microscopic) and without overlap in the ionizations, with computational treatment of spectrophotometric and potentiometric experimental data obtained simultaneously in a flow system. For monofunctional substances, potentiometric data are enough. The data are obtained at very low values of ionic strength, which is variable throughout the experiment because no inert electrolyte is added. The MICROTER program, written in FORTRAN 77, is based on an algorithm of mathematical optimization with a controlled-descent movement. The ionization constants of the following substances of pharmacological interest were determined: cysteine, penicillamine, ofloxacin, and norfloxacin (bifunctional with overlap); cephalexin and cephapirin (bifunctional without overlap); and tolazoline, naphazoline, and oximetazoline (monofunctional).

Pharmacokinetics of cefamandole in rabbits with experimentally induced renal impairment.

The pharmacokinetics of cefamandole have been studied in rabbits with normal renal function and varying degrees of renal impairment caused experimentally, by uranyl nitrate, after i.v. administration of a single dose of 30 mg/kg of the antibiotic. The plasma concentrations of cefamandole 80 minutes after administration were 3 micrograms/ml in normal rabbits reaching 90 micrograms/ml at 9 hours in the case of terminal renal impairment. With respect to the pharmacokinetic parameters established in rabbits with normal renal function, the following modifications may be observed in the case of rabbits with renal impairment: alpha, beta, K12, K21, K13, Vc and Vp are decreased, while there is an increase in t 1/2 alpha, t 1/2 beta and (AUC)infinity 0. Linear relationships have been established between log alpha and log beta, respectively, and serum creatinine. Biliary excretion of cefamandole is increased parallel to the increase in the degree of renal impairment, there being a linear relationship between the percentage excreted of the antibiotic and serum creatinine. The values of KB fall from 0.57 h-1 in rabbits with normal renal function, to 0.26 h-1 in rabbits with severe renal impairment.

Effect of infusion time on the pharmacokinetics of dibekacin in rabbits.

A study was made of the serum levels and of the pharmacokinetic parameters of dibekacin after administration by intravenous infusion at a dose of 2 mg/kg of the drug to rabbits using different infusion times. The peak serum level (Cmax) was seen to decrease progressively on increasing infusion time. The maximum value of Cmax was obtained after administration of the antibiotic by single bolus injection with an average value of 18.297 +/- 9.694 micrograms/ml, while the minimum value was obtained after intravenous infusion over 1 hour, with an average value of 6.597 +/- 1.250 micrograms/ml. A series of linear relationships was established between different pharmacokinetic parameters and the infusion time and a decrease was observed in the pharmacokinetic parameters alpha, K12, K21 and K13 when the infusion time was increased. Changes were also observed in the distribution kinetics of dibekacin in the rabbit on varying the infusion conditions, suggesting alterations in the access and permanence of the antibiotic in tissues.

Pharmacokinetic study of a new semisynthetic cephalosporin (AL-226) in rabbits.

The pharmacokinetics of AL-226, a new semi-synthetic cephalosporin, were studied after i.v. and i.m. administrations to rabbits at doses of 10, 20, 30 and 40 mg/kg. The average values of the pharmacokinetic parameters after bolus i.v. administration of the antibiotic expressed by an open two-compartment kinetic model were: alpha = 0.131 min.-1, beta = 0.0341 min-1, K12 = 0.0287 min.-1, K21 = 0.0552 min.-1, K13 = 0.081 min.-1 a linear relationship between C0 and dose was found. The urinary excretion constants after i.v. administration were: 0.0266 min.-1, 0.0294 min-1, 0.0289 min.-1, 0.0306 min.-1, for doses of 10, 20, 30 and 40 mg/kg, respectively. The pharmacokinetic parameters after i.v. administration were used to determine the absorption constant: 0.0525 min.-1, 0.057 min.-1, 0.0596 min.-1, 0.0511 min.-1, after i.m. administration for doses of 10, 20, 30 and 40 mg/kg, respectively.

[Pharmacoeconomic analysis of community-acquired pneumonia treatment with telithromycin or clarithromycin]. / Analisis farmacoeconomico del tratamiento de la neumonia adquirida en la comunidad con telitromicina o claritromicina.

A pharmacoeconomic analysis was carried out comparing the efficacy of two treatment options for community-acquired pneumonia (CAP): telithromycin and clarithromycin. It was a retrospective analysis using a decision tree model. The efficacy of the two treatment options was estimated from a randomized, double-blind clinical trial, in which 800 mg/day oral telithromycin for 10 days was compared to 1000 mg/day oral clarithromycin for 10 days in patients with CAP (162 and 156 respectively). The use of resources was estimated based on the clinical trial and Spanish sources, and the unit costs from a Spanish health costs database. Costs were evaluated for the acquisition of antibiotic treatments, change of antibiotic due to therapeutic failure, hospital admissions, adverse reactions to treatment, primary care visits, tests and indirect costs (working days lost). The model was validated by a panel of Spanish clinical experts. As the clinical trial was designed to show equivalence, there were no significant differences in efficacy between the treatment options (clinical cure rate 88.3% and 88.5%, respectively), and a cost minimization analysis was performed. In the base case, the average cost of the disease per patient was 308.29 euros with telithromycin and 331.5 euros with clarithromycin (a difference of 23.21 euros). The results were stable in the susceptibility analysis, with differences favorable to telithromycin ranging between 5.50 and 45.45 euros. Telithromycin results in a cost savings of up to 45.45 euros per CAP patient compared to clarithromycin.

Study on pharmacokinetics and nephrotoxicity of netilmicin in rabbits using a new dosage regimen.

The potential nephrotoxicity and pharmacokinetic parameters of netilmicin were investigated in rabbits after single and multiple dosage regimens (7 mg/kg/12 h) allometrically equivalent to a once-daily regimen of 5 mg/kg/24 h in man. Netilmicin was determined in plasma and renal tissue by a high-performance liquid chromatography (HPLC) technique with fluorescence detection and precolumn derivatization. The renal toxicity was determined by electron microscopy. Statistical comparison between animals that received a single dose and those that received a multiple dosage regimen showed that the only parameter significantly different was the elimination constant K10. The histological study revealed a high interindividual variability in the nephrotoxicity induced by prolonged treatment with netilmicin: 50% of the animals experienced tubular necrosis and the remaining did not. Although plasma concentration time curves did not show significant differences between both groups of animals, the concentrations of netilmicin in renal cortex were higher in the group with tubular necrosis. In conclusion, even though netilmicin was administered in a dosage regimen equivalent to once-daily administration in man, it induced tubular necrosis which was probably related to the duration of treatment. The results also showed that there was no correlation between plasma concentrations of the drug and its potential nephrotoxicity.

Multicriteria decision analysis for determining drug therapy for intermittent claudication.

Drugs of various classes are prescribed for intermittent claudication. However, there is some discrepancy between medical practice and the scientific basis for drug selection. We have developed a quantitative criteria-based decision analysis to evaluate all implications of drug treatment choices for intermittent claudication. Pentoxifylline, buflomedil, naftidrofuryl and ticlopidine were the drugs selected for analysis. The evaluation criteria were 1) therapeutic efficacy, 2) safety, 3) patient acceptance and 4) cost. A review panel of experts determined the relative importance of each criterion by assigning points (or utility values) to each one. The points were 48, 20, 14 and 18, respectively, for criteria 1, 2, 3 and 4. A probability value, or numerical estimate of how well a drug meets a criterion, was assigned to each drug for each of the 4 criteria. The probability value was multiplied by the utility value to determine the score for each drug and criterion. The criteria points for each drug were added for a total score for the drug. The drug with the highest overall score was pentoxifylline, with 69 points out of an ideal score of 100. The rank order for the other drugs was buflomedil, ticlopidine and naftidrofuryl. A sensitive analysis showed that the relative ranking of the drugs remained unchanged over a series of data modifications.

Influence of clinical diagnosis in the population pharmacokinetics of amikacin in intensive care unit patients.

The aim of the present study was to analyse the pharmacokinetic behaviour of amikacin in intensive care unit (ICU) patients using a mixed-effect model and sparse data collected during routine clinical care. The patient population comprised 158 medical ICU patients divided into two groups: one for computing the population model (n = 120) and the other for validation (n = 38). A 1-compartment model was used and the following covariates were tested for their influence on clearance (CL) and volume of distribution (Vd): age, gender, weight, parenteral nutrition, creatinine clearance, duration of therapy and clinical diagnosis. The nonlinear mixed-effect model (NONMEM) was used to assess the population pharmacokinetic model of amikacin in this patient population. In this study, the final population model accounting for amikacin pharmacokinetics in ICU patients was: CL = 0.93 CL(CR) (1 + 0.22 Trauma), Vd = 0.39 TBW (1 + 0.24 Sepsis), where CL(CR) and TBW corresponded to the patients' creatinine clearance and total bodyweight, respectively. The 'Trauma' and 'Sepsis' variables referred to the clinical diagnosis of the patients. This model was subsequently used to predict amikacin serum levels obtained in the validation population by a priori and Bayesian methods. The predictive performance was adequate for clinical purposes, pointing to the feasibility of our population model to provide reference values for a priori prediction as well as the Bayesian approach for individualisation of amikacin therapy in ICU patients.

Contribution of biopharmaceutics and pharmacokinetics to improve drug therapy.

Efficacy, safety and costs are the elements defining the quality of pharmacological therapy. Several clinical studies have shown the contribution of pharmacokinetics and biopharmaceutics to different treatment responses. During the past few years, new drugs with very interesting properties, such as good oral bioavailability, wide tissue distribution and slow elimination rate, have been introduced. It has allowed improvement in the patient's treatment, and has introduced new therapeutic possibilities. The development of new drug delivery systems has facilitated achieving certain pharmacodynamic effects and overcoming some pharmacokinetic disadvantages of conventional formulations. This achievement has been a biopharmaceutical challenge in answer to a clinical need. Therapeutic drug monitoring in wide populations has permitted improvements in the design of new dosage regimens in order to ameliorate the therapeutic efficacy for different groups of drugs: antibiotics, antineoplastics, cardiovascular agents etc. Pharmacokinetic criteria have to be considered as a clinical strategy to increase the accuracy when making decisions about dosage individualization. Individual patients, other patient populations, and also the use of usually unmonitored drugs, take advantage of therapeutic monitoring benefits. The contribution of biopharmaceutics and pharmacokinetics has been important for obtaining maximum efficacy with minimal side-effects and cost optimization.