Andrea Messori

Clinical Pharmacokinetics of Valproic Acid - 1988

SummarySodium valproate (valproic acid) has been widely used in the last decade and is now considered a relatively safe and effective anticonvulsant agent. Recently, several investigators have proposed its use in the treatment of anxiety, alcoholism and mood disorders, although these indications require further clinical studies.Valproic acid is available in different oral formulations such as solutions, tablets, enteric-coated capsules and slow-release preparations. For most of these formulations bioavailability approaches 100%, while the absorption half-life varies from less than 30 minutes to 3 or 4 hours depending on the type of preparation used. Once absorbed, valproic acid is largely bound to plasma proteins and has a relatively small volume of distribution (0.1 to 0.4 L/kg). Its concentration in CSF is approximately one-tenth that in plasma and is directly correlated with the concentration found in tears. At therapeutic doses, valproic acid half-life varies from 10 to 20 hours in adults, while it is significantly shorter (6 to 9 hours) in children.Valproic acid undergoes extensive liver metabolism. Numerous metabolites have been positively identified and there is reasonable evidence that several of them contribute to its pharmacological and toxic actions. In fact, several valproic acid metabolites have anti-convulsant properties, while many of the side effects it may cause (e.g. those related to hyperammonaemia or liver damage) are most often observed in patients previously treated with phenobarbitone. This could indicate that induction of liver enzymes is responsible for the formation of toxic valproic acid metabolites.

Bleeding and pneumonia in intensive care patients given ranitidine and sucralfate for prevention of stress ulcer: meta-analysis of randomised controlled trials

Abstract Objectives: To determine the effectiveness of ranitidine and sucralfate in the prevention of stress ulcer in critical patients and to assess if these treatments affect the risk of nosocomial pneumonia. Design: Published studies retrieved through Medline and other databases. Five meta-analyses evaluated effectiveness in terms of bleeding rates (A: ranitidine v placebo; B: sucralfate v placebo) and infectious complications in terms of incidence of nosocomial pneumonia (C: ranitidine v placebo; D: sucralfate v placebo; E: ranitidine v sucralfate). Trial quality was determined with an empirical ad hoc procedure. Main outcome measures: Rates of clinically important gastrointestinal bleeding and nosocomial pneumonia (compared between the two study arms and expressed with odds ratios specific for individual studies and meta-analytic summary odds ratios). Results: Meta-analysis A (five studies) comprised 398 patients; meta-analysis C (three studies) comprised 311 patients; meta-analysis D (two studies) comprised 226 patients: and meta-analysis E (eight studies) comprised 1825 patients. Meta-analysis B was not carried out as the literature search selected only one clinical trial. In meta-analysis A ranitidine was found to have the same effectiveness as placebo (odds ratio of bleeding 0.72, 95% confidence interval 0.30 to 1.70, P=0.46). In placebo controlled studies (meta-analyses C and D) ranitidine and sucralfate had no influence on the incidence of nosocomial pneumonia. In comparison with sucralfate, ranitidine significantly increased the incidence of nosocomial pneumonia (meta-analysis E: 1.35, 1.07 to 1.70, P=0.012). The mean quality score in the four analyses (on a 0 to 10 scale) ranged from 5.6 in meta-analysis E to 6.6 in meta-analysis A. Conclusions: Ranitidine is ineffective in the prevention of gastrointestinal bleeding in patients in intensive care and might increase the risk of pneumonia. Studies on sucralfate do not provide conclusive results. These findings are based on small numbers of patients, and firm conclusions cannot presently be proposed.

Quality of Life and Utility in Patients with Non-Small Cell Lung Cancer

AbstractBackground: Although several studies have determined quality of life in patients with lung cancer, there is still little information about the use of generic questionnaires [e.g. the 36-item Short Form health survey (SF-36)] and utility questionnaires [e.g. the EuroQOL instrument (EQ-5D)] in this disease. Objectives: To (i) measure quality of life and utility in patients with non-small cell lung cancer (NSCLC) using the SF-36 and the EuroQOL questionnaires; (ii) to evaluate the impact of some clinical variables on quality of life and utility; (iii) to assess the correlation between the measurements produced by the 2 questionnaires. Study design: Cross-sectional study. Participants: 95 patients from15 Italian hospitals with NSCLC (93% male, mean age 62 years) completed both questionnaires. Results: The mean scores for the 8 domains of the SF-36 ranged from 20.8 (physical role) to 63.0 (social functioning). The mean physical and mental summed scores of the SF-36 were 36.8 [standard deviation (SD) 9.8] and 43.0 (SD 11.5), respectively. The EuroQOL mean score was 0.58 (SD 0.32) in the self-classifier (SC) version and 0.58 (SD 0.20) in the visual analogue scale (VAS) version. Among the clinical variables that affected quality of life and utility, the presence of metastasis had the greatest impact: patients with metastasis had statistically significantly lower scores for 2 domains of the SF-36 (physical functioning, p = 0.009; bodily pain, p = 0.016), for the physical component summed score of the SF-36 (p = 0.015) and for both utility estimates (EuroQOL-SC, p = 0.027; EuroQOL-VAS, p = 0.038) than patients without metastasis. Both the SC and VAS EuroQOL scores showed a statistically significant correlation with each of the 8 domains of the SF-36. The scores for both the SF-36 and the EuroQOL in patients with NSCLC were considerably worse (relative differences ranging from −8 to −73%) than the corresponding values (normative data) previously reported for healthy individuals. Conclusions: Our study quantified the degree to which quality of life is impaired in patients with NSCLC, showed that the presence of metastasis had an important role, and indicated a strong correlation between the measurements produced by the 2 questionnaires. The EuroQOL measurements obtained from these patients will aid evaluation of the cost-utility ratio for NSCLC therapies.

Immediate and late outcome of patients aged 80 years and older undergoing isolated aortic valve replacement: A systematic review and meta-analysis of 48 studies

OBJECTIVE This study was planned to evaluate the outcome of patients ≥80 years old undergoing isolated conventional aortic valve replacement (AVR). METHODS Systematic review of the literature and meta-analysis of data on octogenarians and nonagenarians who underwent isolated AVR were performed. RESULTS The literature search yielded 48 observational studies reporting on 13 216 patients ≥80 years old. Pooled proportion of immediate postoperative mortality was 6.7 % (95% CI 5.8-7.5, 47 studies, 13,092 patients), and it was 5.8% (95% CI 4.8-6.9) in 18 studies with a mid-date from 2000 to 2006 and 7.5% (95% CI 6.8-8.2) in 30 studies with a mid-date from 1982 to 1999 (P = .004). Pooled proportion of postoperative stroke was 2.4% (95% CI 2.1-2.7, 21 studies, 8,436 patients), that of postoperative dialysis was 2.6% (95% CI 1.6-3.8, 10 studies, 1,945 patients), and that of postoperative implantation of a pacemaker was 4.6% (95% CI 3.6-5.8, 6 studies, 1,470 patients). Pooled survival rates at 1, 3, 5, and 10 years after isolated AVR were 87.6%, 78.7%, 65.4%, and 29.7%, respectively. CONCLUSIONS Immediate postoperative mortality and morbidity after isolated AVR in patients ≥80 years old are rather low. Postoperatively mortality decreased even further in the most recent series. Importantly, isolated AVR in these high-risk patients was associated with good late survival. These findings suggest that advanced age alone cannot be considered as a contraindication to conventional isolated AVR and that any new valve prosthesis implanted in these patients should be durable enough to guarantee the results so far offered by conventional surgery.

Clinical Features, Pathogenesis and Management of Drug-Induced Seizures

SummaryMany classes of pharmacological agents have been implicated in cases of drug-induced seizures. The list includes antidepressant drugs, lithium salts, neuroleptics, antihistamines (H1-receptor antagonists), anticonvulsants, central nervous system stimulants, general and local anaesthetics, antiarrhythmic drugs, narcotic and non-narcotic analgesics, non-steroidal anti-inflammatory drugs, antimicrobial agents, antifungal agents, antimalarial drugs, antineoplastic drugs, immunosuppressive drugs, radiological contrast agents and vaccines. For each of these classes of drugs, this article offers a revision of the literature and emphasises in particular the frequency of the adverse reaction, its clinical presentation, its presumed epileptogenic mechanism and the therapeutic strategy for the management of drug-induced seizures. An attempt is also made to distinguish seizures induced by standard dosages from those provoked by accidental or self-induced intoxication. For some classes of drugs such as antidepressants, neuroleptics, central nervous system stimulants (e.g. theophylline, cocaine, amphetamines) and β-lactam antibiotics, seizures are a well recognised adverse reaction, and a large body of literature has been published discussing exhaustively the major aspects of the issue; sufficient data are available also for the other classes of pharmacological agents mentioned above. In contrast, several other drugs [e.g. allopurinol, digoxin, cimetidine, protirelin (thyrotrophin releasing hormone), bromocriptine, domperidone, insulin, fenformin, penicillamine, probenecid, verapamil, methyldopa] have not been studied thoroughly under this aspect, and the only source of information is the occasional case report. This review does not address the issue of seizures induced by drug withdrawal.

Clinical Pharmacokinetics of Factor VIII in Patients with Classic Haemophilia

SummaryStudies of Factor VIII pharmacokinetics in haemophiliacs can be classified into 2 groups depending on whether single-dose or multiple-dose Factor VIII curves are used. This review analyses information published so far in both these areas, with particular emphasis on the choice of appropriate models for pharmacokinetic analysis.Single-dose studies of Factor VIII kinetics have previously used a wide variety of methods for pharmacokinetic analysis (empirical methods of Factor VIII level prediction, graphical techniques for semilog analysis, 1-compartment and 2-compartment models). However, Factor VIII poses unique problems to the pharmacokineticist because decay curves can be either monophasic (monoexponential) or biphasic (biexponential) for unknown reasons, and because Factor VIII concentrations are generally subject to significant assay error. Problems of compartmental analysis that occurred in previous studies are highlighted, and a model-independent non-compartmental approach for analysing Factor VIII curves is proposed.To date, fewer data have been published on multiple-dose kinetics of Factor VIII. From a clinical point of view, repeated-dose regimens are most commonly required in patients undergoing surgery and in patients with severe bleeding. A fairly well defined ‘therapeutic window’ of optimal Factor VIII plasma concentrations has been identified, particularly in surgical patients. This fact has spurred research aimed at applying to haemophilia patients the pharmacokinetic dosing methods commonly used for therapeutic monitoring of drugs (e.g. Bayesian method for dosage individualisation). A few papers have already been published in this field, and this review summarises problems encountered by previous investigators, and evaluates comparatively the pharmacokinetic methods used.

Adjunctive lamotrigine therapy in patients with refractory seizures: a lifetime cost–utility analysis

AbstractObjective: Lamotrigine as add-on treatment (500 mg per day) is effective in patients with refractory epilepsy, but its high cost requires a pharmacoeconomic analysis. We conducted a retrospective lifetime cost–utility study in which clinical data were derived from a recent placebo-controlled clinical trial, cost-of-illness data were drawn from a previous ad-hoc study, and quality-of-life values were obtained by prospectively interviewing a separate group of 81 patients referred to our institution with epilepsy. Results: Our analysis showed that chronic lamotrigine treatment implies an incremental lifetime cost of about

G-CSF for the prophylaxis of neutropenic fever in patients with small cell lung cancer receiving myelosuppressive antineoplastic chemotherapy: meta-analysis and pharmacoeconomic evaluation.

1 600 000 for every 100 patients. Incremental lifetime utility was around 40 quality-adjusted life-years (QALYs) for every 100 patients. On the basis of these data, adjunctive lamotrigine was estimated to cost approximately

Pharmacokinetics of a new heat-treated concentrate of factor VIII estimated by model-independent methods

41 000 per QALY gained. Sensitivity testing suggested a range of

Combined surgery and chemotherapy for the treatment of primary gastrointestinal intermediate- or high-grade non-Hodgkin's lymphomas.

25 000–