Betahistine in the treatment of vertiginous syndromes: a meta-analysis.

Vertigo is a very frequent disorder, associated with highly disabling symptomatology. Since the aetiology cannot always be easily identified, treatment is often addressed to the symptoms. Betahistine, a drug characterized by a multi-factorial mode of action of the modulatory type, has been widely employed in the management of various vertiginous syndromes. Its use in Italy is, currently, authorized to treat the vertiginous symptoms related to Ménière's disease. A meta-analysis has, therefore, been carried out to assess, the efficacy of betahistine in the treatment of other vertiginous syndromes, such as positional paroxysmal vertigo (cupulo-canalolithiasis) and vertigo secondary to arterial deficiency of the vertebrobasilar area, regardless of the specific cause. A review has been made of the literature concerning clinical trials performed with betahistine versus placebo in a randomised double-blind, parallel-group or cross-over design. Only studies evaluating betahistine in patients with vertiginous symptomatology not related to Ménière's disease were selected. Of the 104 publications, obtained from an analysis of "Medline", "EMBASE" and "CINAHL" databases, 7 clinical studies, which met the selection criteria, for a total of 367 patients, were extrapolated and analysed. The meta-analysis was conducted using the "Cochrane Collaboration's Review Manager" software in all the case series and in the sub-groups identified by the experimental design (parallel or crossover design), range of dosages (32-48 mg/day) and range of treatment duration (from 3 weeks to 4 months). The various parameters used to evaluate efficacy, adopted in the trials, and taken into account in the metaanalysis, as overall judgement of the patient or physician, number of vertiginous episodes and their duration, were classified according to the binary classification of "improved" and "not improved". The results of the meta-analysis confirm the therapeutic benefit of betahistine versus placebo. In particular, the investigation carried out on the overall sample shows an odds ratio of 3.52 (95% confidence interval 2.40-5.18) and a relative risk of 1.78 (95% confidence interval 1.48-2.13), while the analysis of the sub-groups denotes a maximum efficacy after doses of 32 to 36 mg and with a period of treatment of 3-8 weeks. The present meta-analysis confirms the benefit of drug treatment with betahistine for the vertiginous symptomatology related to cupulo-canalolithiasis and vertebro-basilar arterial insufficiency.

Updated cost-effectiveness analysis of supplemental glutamine for parenteral nutrition of intensive-care patients.

BACKGROUND/OBJECTIVES: Intravenous (i.v.) glutamine supplementation of parenteral nutrition (PN) can improve clinical outcomes, reduce mortality and infection rates and shorten the length of hospital and/or intensive care unit (ICU) stays compared with standard PN. This study is a pharmacoeconomic analysis to determine whether i.v. glutamine supplementation of PN remains both a highly favourable and cost-effective option for Italian ICU patients. SUBJECTS/METHODS: A previously published discrete event simulation model was updated by incorporating the most up-to-date and clinically relevant efficacy data (a clinically realistic subgroup analysis from a published meta-analysis), recent cost data from the Italian health-care system and the latest epidemiology data from a large Italian ICU database (covering 230 Italian ICUs and more than 77,000 patients). Sensitivity analyses were performed to test the robustness of the results. RESULTS: Parenteral glutamine supplementation can significantly improve ICU efficiency in Italy, as the additional cost of supplemented treatment is more than completely offset by cost savings in hospital care. Supplementation was more cost-effective (cost-effectiveness ratio (CER)=[euro ]35,165 per patient discharged alive) than standard, non-supplemented PN (CER=[euro ]40,156 per patient discharged alive), and it resulted in mean cost savings of [euro ]4991 per patient discharged alive or [euro ]1047 per patient admitted to the hospital. Sensitivity analyses confirmed the robustness of these results. CONCLUSIONS: Alanyl-glutamine supplementation of PN is a clinically and economically attractive strategy for ICU patients in Italy and may be applicable to selected ICU patient populations in other countries.

Congenital deficiency of alpha-2-adrenoceptors on human platelets: description of two cases.

The biochemistry and functionality of platelets from two related subjects (mother and son) with alpha-2-adrenoceptor-deficient platelets has been evaluated. Radioligand binding experiments with the specific alpha-2-adrenergic-receptor antagonist, 3H-yohimbine, showed a drastic reduction of alpha-2-adrenoceptors in platelets from both subjects in comparison with the control values. Electron microscopy studies revealed a normal morphology and a normal number of alpha granules and dense bodies. Levels of adenine nucleotides; 5-hydroxytryptamine; B-thromboglobulin; platelet-factor-4 and thromboxane A2 production were within normal limits. Platelet aggregation and 5-hydroxytryptamine production in response to adrenalin (at concentrations up to 50 microM) were absent, whereas ADP, AA, PAF, collagen and thrombin-induced aggregation, secretion, Ca++ flux and thromboxane A2 production were normal. The inhibitory effect caused by different concentrations of prostacyclin on Ca++ flux, aggregation, secretion and thromboxane A2 production of platelet functionally lacking of alpha-2-adrenoceptor was not distinguishable from control platelets and platelets preincubated with yohimbine.

[3H]imipramine binding sites are decreased in platelets of chronic pain patients.

Tritiated imipramine binding to whole platelets was measured in 16 chronic pain patients not suffering from major depression and in a control group. Maximum binding was significantly lower in chronic pain patients than in the control group, whereas the binding affinity was not significantly different.

Determination of disodium clodronate in human plasma and urine using gas-chromatography-nitrogen-phosphorous detections: validation and application in pharmacokinetic study.

We present a specific method for the determination of disodium clodronate in human plasma and urine using a gas-chromatographic system with nitrogen phosphorus detector (NPD). The compound was extracted from plasma and urine samples by an anion-exchange resin and derivatizated with bistrimethylsilyltrifluoroacetamide (BSTFA). Sodium bromobisphosphonate was used as internal standard. The calibration curves were linear in both plasma and urine, with a regression coefficient r > 0.9975 in plasma and r > 0.9977 in urine. The limit of quantitation was 0.3 microg/ml in plasma and 0.5 microg/ml in urine. The method was validated by intra-day assays at three concentration levels. During the study we carried out inter-day assays to confirm the feasibility of the method. The precision in plasma at 0.5, 15, and 45 microg/ml was 12.4, 0.2, and 6.5% (n = 40), respectively; in urine at 0.8, 8, and 40 microg/ml it was 8.6, 6.4, and 9.3% (n = 40), respectively. The method was accurate and reproducible, and was successfully applied to determine the pharmacokinetic parameters of clodronate in healthy volunteers after intravenous infusion and intramuscular injection of 200 mg of the compound. The Cmax after intravenous infusion and intramuscular injection was 16.1 and 12.8 microg/ml, respectively. AUC(0-48 h) after infusion administration and intramuscular injection was 44.2 +/- 18.0 and 47.5 +/- 12.4 h microg/ml, respectively. The elimination half-life in both administrations was 6.31 +/- 2.7 h.

Cytotoxicity of anticancer drugs incorporated in solid lipid nanoparticles on HT-29 colorectal cancer cell line.

Solid lipid nanoparticles (SLN) carrying cholesteryl butyrate (chol-but), doxorubicin and paclitaxel had previously been developed, and the antiproliferative effect of SLN formulations versus conventional drug formulations was here evaluated on HT-29 cells. The 50% inhibitory concentration (IC(50) values were interpolated from growth curves obtained by trypan blue exclusion assay. In vitro cytotoxicity of SLN carrying chol-but (IC(50 72 h) 0.3 +/- 0.03 mM vs >0.6 mM) and doxorubicin (IC(50 72 h) 81.87 +/- 4.11 vs 126.57 +/- 0.72 nM) was higher than that of conventional drug formulations. Intracellular doxorubicin was double after 24 h exposure to loaded SLN versus the conventional drug formulation, at the highest concentration evaluated by flow cytometry. In vitro cytotoxicities of paclitaxel-loaded SLN and conventional drug formulation (IC(50 72 h) 37.36 +/- 6.41 vs 33.43 +/-1.17 nM) were similar. Moreover, the combination of low concentrations of chol-but SLN (0.1-0.2 mM) and doxorubicin (1.72 nM) or paclitaxel (1.17 nM) exerted a greater-than-additive antiproliferative effect at 24 h exposure, while the combination of Na-but and doxorubicin or paclitaxel did not. These preliminary in vitro results suggest that SLN could be proposed as alternative drug delivery system.

The influence of bile salts on the absorption in vitro and in vivo of propranolol.

The lipophilicity of propranolol is increased by some bile salts which form ion-pairs. In the presence of taurodeoxycholate, the logarithm of the apparent partition coefficient (log P) of propranolol is increased. Moreover, the apparent diffusion constants in vitro of propranolol as ion-pairs at pH 3.0-6.0 are about 5-6 times higher than those of propranolol alone. The area under the curve values of plasma concentration-time profiles of propranolol, following its oral administration to rabbits together with taurodeoxycholate, are about 1.4 times higher than those after administration of propranolol alone. Moreover, after the administration of propranolol with taurodeoxycholate the plasma concentration rises more rapidly, with a point of inflection between 0.5 and 1.5 h, than after administration of propranolol alone. Taurodeoxycholate does not modify the first-pass effect of propranolol in rabbits following intravenous and intraportal administration. The absorption of an oral dose of propranolol in the presence of taurodeoxycholate increases from 70% to 100%, due to the higher lipophilicity of the ion-pair. The plasma concentration-time curves suggest the hypothesis that greater absorption of the ion-pair occurs mainly in the upper region of the gastrointestinal tract.

Pharmacoeconomic aspects of antibacterial treatment with cefotaxime.

Pharmacoeconomics is a relatively new discipline, which is becoming increasingly useful in the current climate of medical advances that continue despite limited access to healthcare resources. Pharmacoeconomics may be used as a tool, assisting healthcare decision makers to select clinically beneficial therapies and weigh clinical gain against expenditure. Cefotaxime has been shown in many studies to be a cost-effective antibiotic agent, its monetary value being augmented by its use in low dose, low frequency regimens. This cost-effectiveness, combined with a maintained broad spectrum of antibiotic activity, low propensity for selecting resistant bacterial strains and high therapeutic index, makes cefotaxime a suitable antibiotic agent in many indications involving mild-to-moderate infections by susceptible organisms.

Pharmacokinetics, endocrine and antitumour effects of leuprolide depot (TAP-144-SR) in advanced prostatic cancer: a dose-response evaluation.

Twenty-two patients with advanced prostatic cancer and one with benign prostatic hypertrophy were given the GnRH analogue leuprolide in the form of a slow-release depot formulation by subcutaneous injection at doses of 3.75, 7.5, 15 or 30 mg. Following the first dose, drug levels were measured by a double-antibody RIA over an observation period of 5 weeks. Thereafter patients continued long-term subcutaneous treatment at the same dose every 4 weeks. Serum levels of leuprolide showed a rapid increase immediately after injection, reaching a peak proportional to dose within 3 h (range of mean values 13.1-54.5 ng/ml). Subsequently, mean drug levels declined to a plateau proportional to dose (0.49-1.99 ng/ml at 5 weeks). A significant dose-dependent increase in the area under the serum concentration-time curve from zero to 35 days (AUC0-35 days) from 541.7 to 1653.9 ng/ml.h was also noted (p less than 0.01). With all doses there was an initial rise in serum LH and FSH, followed by a rise in testosterone and dihydrotestosterone, then a sharp decrease within 3 weeks. FSH inhibition was achieved in all the 20 evaluable patients and was maintained in 17 of them (85%) over 5 weeks. Fifteen subjects (75%) had marked suppression of LH levels. In 13 of them (65%) this condition continued for the entire observation time. Castration levels of serum testosterone and dihydrotestosterone, however, were maintained in all patients for up to 5 weeks. Two of the 21 evaluable patients (10%) had a complete response; 15 a partial response (71%) and 3 stable disease (14%). No significant differences were observed in relation to dose. Clinical improvement and serum hormonal changes support this as a new and superior method of administration of leuprolide at a dose as low as 3.75 mg.

Changes of lymphocyte beta-adrenergic receptors after surgical stress.

In this study the authors' purpose was to observe the effects of surgical stress on the number of lymphocyte beta-adrenergic receptors in hypertensive and normotensive subjects. It was noticed that after surgery a significant reduction occurred in the number of binding sites of lymphocytes of both hypertensive and normotensive subjects. The time course of recovery to the pre-operative values of binding sites varied between the two groups, being slower in normotensive than in hypertensive patients. This might suggest a different pattern of regulation of the beta-adrenergic receptor between hypertensive and normotensive subjects.

Pharmacokinetics of some cephalosporins in normal and nephrectomized rabbits.

We made a pharmacokinetic study of the cephalosporins cephazolin, cephaloridine, cefoperazone, and cefuroxime in the rabbit. We computed the pharmacokinetic parameters of a two-compartment open model from the plasma concentration time curves obtained at different increasing doses. Cephazolin, cephaloridine and cefoperazone demonstrated a dose dependent kinetics since the constants of apparent rate of elimination and apparent volume of distribution varied with the doses. In order to evaluate the extra-renal of elimination, we performed pharmacokinetic analysis on the same animals after nephrectomy. While cephazolin, cephaloridine and cefuroxime were eliminated primarily through the kidneys, cefoperazone was largely eliminated by extrarenal pathways.

[Antitubercular agents]. / I farmaci antitubercolari.

Author resume the most important stages of the antitubercular struggle. Then they consider the action mechanisms of single drugs, often not well known, such the action mechanism of pyrazinamide. At present, the criteria of effectiveness, tolerance, availability and economy allow to use rationally and not arbitrarily the antitubercular drugs and these criteria also assure the best therapeutic results.

[Pharmacokinetics of a new aminoglycoside: kanendomycin]. / Farmacocinetica di un nuovo aminoglicoside: kanendomicina.

The pharmacokinetics of kanendomycin, a new aminoglycoside derived from kanamycin, has been assessed in 15 volunteers after i.m. administration of 100 and 300 mg and i.v. administration of 100 mg. Analysis of the tricompartmental model adopted for the pharmacokinetic study showed that kanendomycin half-life is similar and perhaps superior to that of gentamycin. The antibiotic's bioavailability is of the order of 70-80% of the dose used.

[Clinical study on a new cephalosporin: CGP 9000 (cefroxadine)]. / Ricerca clinica su una nuova cefalosporina: CGP 9000 (cefroxadina).

CGP 9000 (cefroxadine), a new cephalosporine derived from N-acyl-3-alkoxy-7-amino-3-cefem-4-carboxylic acid for exclusively oral use, has been experimented on 67 patients, 41 adults and 20 children. CGP 9000 appeared to possess good therapeutic activity, even in low doses: its rapid absorption and moderate sero-protein bond are a guarantee of an immediate and almost total bioavailability.

[Cefoperazone: microbiological, kinetic and clinical studies]. / Cefoperazone: ricerca microbiologica, cinetica e clinica.

In vitro cefoperazone proved more active against the tested gram-negative bacteria than either piperacillin or mezlocillin. When administered in 1 g venous bolus the antibiotic achieved high plasmatic concentrations that were still adequate after 8 hours. 33.2% was excreted by the kidneys and a considerable amount by the biliary way. Cefoperazone produced a clinical cure in 35/36 patients (97.22%). A disulfiram-like effect was noted in 18.18%.

[Pharmacokinetics and clinical studies of a new cephalosporin: cefamandole nafate]. / Farmacocinetica e clinica di una nuova cefalosporina: cefamandolo nafato.

The results of a pharmacokinetic and clinical study of cephamandol naphate indicated that the drug quickly reaches high plasma concentration after both i.m. and i.v. bolus administration. Urinary excretion of the biologically active form is as much as 84--90% of the total dose and mostly takes place in the first 6 hr. The therapeutic response was good: clinical cure in 90%, marked improvement in 6.6%, no change in 3.3%.

[Pharmacokinetic and clinical evaluation of cefoxitin]. / Valutazione farmacocinetica e clinica della cefoxitina.

An investigation conducted on healthy volunteers showed that cefoxitin quickly reaches high plasma concentrations, and is almost completely excreted via the urine within 6 hours. In a series of 21 cases treated with 2 g i.v. in 100 ml of a 5% glucose solution two or three times a day, a clinical cure was achieved in 20, and marked improvement in the remaining patient.

[Pharmacokinetics of intravenous rifampicin (RMP) and its clinical evaluation in purulent bacterial meningitis]. / Farmacocinetica della rifampicina (RMP) per via venosa e sua valutazione clinica in corso di menmingite purulenta batterica.

A combined kinetic and clinical study showed that rifampicin displays good tissue diffusibility, though it may have a tendency to accumulate. A liquor transfer sufficient for the bacteria most commonly responsible for meningeal inflammation was observed; 15/18 cases of purulent bacterial meningitis treated were clinically cured without sequelae, while 1 displayed considerable improvement. Two patients died from unforseen, uncontrollable complications that were not related to administration of the drug.

[Kinetic and clinical study of bacampicillin]. / Ricerca cinetica e clinica sulla bacampicillina.

A mean plasma concentration curve, with peaks within the first hour and moderate individual variations, was obtained after a single administration of 800 mg of bacampicillin to 5 healthy volunteers. An adequate antibiotic transfer from the circulation to the bronchial apparatus was demonstrated. Treatment of 34 patients suffering from ampicillin-sensitive bacterial diseases permitted clinical cure of all patients, without onset of side-effects. It is concluded that bacampicillin is preferable to oral ampicillin because of its kinetic and tolerance features.

[Ceftriaxone, a long-acting cephalosporin. Microbiological, kinetic and clinical study]. / Ceftriaxone, cefalosporina "long acting". Ricerca microbiologica, cinetica e clinica.

Ceftriaxone effectively inhibited 332 out of 452 (73.45%) bacterial strains in vitro tests. 291 out of 365 (79.69%) gram negative and 41 out of 87 (47.12%) gram positive strains were inhibited. The tests showed ceftriaxone to be more effective than cephalothin, cephotaxime, cephuroxime, cephamandol and cephoxitin. Kinetic tests showed that cephtriaxone has a plasmatic half life of 7.25 hrs. 24 hours after administration of a 1000 mg venous bolus the drug was still present in the blood. Urinary elimination over a 24 hr. period amounted to means 486.8 mg (48.68%). The drug has liquor transfer capacity. 37 of the 38 patients treated showed complete clinical or clinicobacteriological cure. Improvement was noted in the 38th.