Effect of moderate or severe liver dysfunction on the pharmacokinetics of gamma-hydroxybutyric acid.

OBJECTIVES: To assess the effect of moderate or severe liver dysfunction on the pharmacokinetics of gamma-hydroxybutyric acid (GHB). METHODS: The absorption and disposition kinetics of GHB were studied in eight cirrhotic patients without ascites (Child's class A) and eight cirrhotic patients with ascites (Child's class C), after administration of a single oral dose of 25 mg.kg-1. The liver metabolic function of each patient was evaluated by measuring antipyrine clearance and the formation rate of the lidocaine metabolite monoethylglycinexylidide (MEGX). RESULTS: Compared to those previously determined in eight healthy control subjects given the same GHB dose, mean AUC values were double or greater in the cirrhotic patients. Accordingly, apparent oral clearance was markedly reduced (from 9.1 to 4.5 and 4.1 ml.min-1.kg-1 in nonascitic and ascitic patients, respectively). Terminal half-life (t1/2), was significantly longer in nonascitic patients than in control subjects (32 vs 22 min). A further significant prolongation of t1/2, most likely due to an increased distribution volume, was observed in patients with ascites (56 min). Nonetheless, GHB plasma concentrations fell to either undetectable or negligible levels by the end of the usual dosing intervals (6-8 h). More limited changes were noted in the absorption parameters. The peak level (Cmax) increased only in nonascitic patients, but not proportionally to the increase in AUC. The time to Cmax increased from 30 to 45 min in both cirrhotic groups. These findings are consistent with a slowed rate of GHB absorption in cirrhotic patients. Adverse effects were similar, for intensity and duration, to those recorded in healthy volunteers, i.e., mild and transient. CONCLUSIONS: Although liver cirrhosis causes significant modifications of GHB disposition kinetics, the increase in t1/2 is not such as to cause drug accumulation on repetitive dosing. However, in consideration of the higher mean plasma levels observed in cirrhotic patients, it appears wise to keep the initial GHB daily dose at the lower end of the therapeutic range and to carefully monitor the patients if upward dose adjustments are required.

The pharmacokinetics of teniloxazine in healthy subjects and patients with hepatic cirrhosis.

The single-dose and steady-state pharmacokinetics of teniloxazine, an investigational drug with antidepressant and anti-anoxic properties, were compared in 12 healthy volunteers and 12 cirrhotic patients, following oral administration of 80 mg teniloxazine maleate every 12 h for 7 days. In healthy volunteers, an increase in oral clearance, CLo (from a mean (s.d.) value of 14.6 (3.9) to 18.0 (6.6) ml min-1 kg-1; mean % ratio between the two values (95% CI), 123 (94-151)) and a significant shortening of t 1/2 (from 6.2 (2.7) to 4.8 (1.4) h; mean % ratio (95% CI), 78 (58-98)) were observed upon repeated administration, suggesting autoinduction of teniloxazine metabolism. In cirrhotic patients, the pharmacokinetic parameters of teniloxazine remained essentially invariant with time. Compared with normal subjects, CLo was about halved in cirrhotic patients, whereas t 1/2 was more than doubled. As a consequence of these modifications, the multiple-dose regimen resulted in a two-fold mean drug accumulation in cirrhotic patients, compared with virtually no accumulation in healthy volunteers. Although no adverse events were noted in either study group, it is suggested that maintenance doses for patients with liver dysfunction should initially be at the lower end of the therapeutic range.

Morphologic changes of Doxorubicin-sensitive and resistant lovo cells treated in-vitro by calcium channels blockers.

A morphological analysis by scanning electron microscopy (SEM) of the effect of two Ca++ channel blockers (verapamil and dilazep) on LoVo S (doxorubicin sensitive) and LoVo R (doxorubicin resistant) plated together with 3T3 in order to cause an experimental ground of metastasis was performed. Ca++ channel blockers have been previously tested alone and combined with doxorubicin. The increasing effect on the sensitivity of inherently antiblastic drug resistance and their possible role as antimetastatic agent according to the experiments of Tsuruo et al (Cancer Chemother Pharmacol 14: 30-33, 1985) is reported.

Study on the bactericidal activity and synergistic effect of neutropenic rat serum with gentamicin.

It is well known that normal rat serum (NRS) shows an antibacterial activity because of the presence of endogenous substances that are able to express a defence against pathogenic microorganisms. Moreover, in former studies, we observed that NRS presents a synergistic activity with some antibiotics (thus able to lower minimum inhibitory concentration values). The aim of this research was to study the antibacterial activity and synergistic effect of neutropenic rat sera (NPRS) with gentamicin. The animals were made neutropenic by the i.p. injection of cyclophosphamide (100 mg/kg on day 0 and 75 mg on day 4). At all tested concentrations (from 0.25% to 5%) NPRS showed lower antibacterial activity than NRS with differences which were always statistically significant. The synergistic activity of NPRS with gentamicin was still present and quite similar to that of NRS, in spite of many altered blood parameters showing evident immunodepression. Some possible interpretations of these results are discussed.

Effect of dipyridamole, 5'-(N-ethyl)-carboxamidoadenosine and 1,3-dipropyl-8-(2-amino-4-chlorophenyl)-xanthine on LOVO cell growth and morphology.

The effects of stable compounds acting on adenosine receptors, 5'-(N-ethyl)-carboxamidoadenosine (NECA: A2 and A1 adenosine receptor agonist) and 1,3-dipropyl-8-(2-amino-4-chlorophenyl)-xanthine (PACPX: selective A1 adenosine receptor antagonist) were evaluated in vitro on doxorubicin-resistant LoVo (LoVo-R) and doxorubicin-sensitive LoVo (LoVo-S) human metastatic cell lines by using the neutral red test for cell growth. The effect of dipyridamole, an adenosine uptake inhibitor, was also evaluated. The drugs had an inhibitory effect on LoVo cell growth. The association of the drugs with doxorubicin enhanced the inhibition of cell growth, particularly for NECA and PACPX on LoVo-R cells. Morphological observation with scanning electron microscopy indicated cytotoxicity of the tested compounds, alone or in association with doxorubicin both in LoVo-R or LoVo-S cells, supporting the hypothesis of inhibitory effect on tumor cell growth.

The effect of cis-DDP and Pt mercaptopyridine complexes on cell lines in vitro.

The effect of Platinum (II) complexes with mercaptopyridines on cell lines (fibroblasts 3T3 and the tumour ones F10, Föhn, Lovo) were studied. Synthesis and characterization of the compounds are reported together with the preliminary in vitro tests. Data obtained on cytopathogenic effect (CPE), cell growth and colony forming ability demonstrated that all the platinum mercaptopyridines tested are more active than cisplatin in the same conditions.

Biocompatibility and biodegradation of different hyaluronan derivatives (Hyaff) implanted in rats.

Hyaluronan (HL), a naturally occurring glycosaminoglycan, has been chemically modified through the esterification of its carboxylic groups with different types of alcohol. The physico-chemical properties of these new biopolymers allow the preparation of many biomaterials which may be used in several medical applications. In the present study both the biocompatibility and biodegradation of some water-insoluble HL esters have been evaluated, either as raw material or as manufactured devices after subcutaneous and intraperitoneal implantation in male rats. The inflammatory response and the degree of resorption for each tested material are reported. The relationships between the degree of esterification and the type of alcohol used with the above parameters are also investigated.

Comparison of the antibacterial activity and synergistic activity towards antibiotics of different mammalian sera.

The antibacterial activity against Escherichia coli ATCC 10798 and Staphylococcus aureus Mag 90 of normal sera from nine species of mammals was investigated by Avantage (Abbott). Human and rat sera showed the highest antibacterial activity against E. coli ATCC 10798, while all investigated sera did not exhibit, till the maximum concentration tested (20%), spontaneous antibacterial activity against S. aureus Mag 90. Heat inactivated sera (56 degrees C for 30 min) of all investigated species lost their antibacterial activity, but maintained their synergistic effect with sub-MICs of some antibacterial drugs, principally against E. coli ATCC 10798.

Possible influence of assay methods in studies of the pharmacokinetics of antibiotics.

In the present research, levels of gentamicin (GM) in serum and carrageenan pleural exudate from the rat have been compared, using three evaluation methods: microbiological assay (MA), enzyme-immunoassay (EMIT) and fluorescence-immunoassay (TDX). In a first study, the evaluations carried out by MA and EMIT have furnished comparable data in serum, while statistically significant differences were verified at all times in pleural exudate. On the contrary, in a second study, while the evaluations carried out by MA and EMIT, at all times and in both biological fluids, have produced similar data, the evaluation carried out by TDX consistently supplied higher results, with statistically significant differences at some times (5 min and 60 min for serum, 30 min and 60 min for exudate). Some possible interpretations of these results are discussed.

Increased spontaneous cell detachment of F10 cells induced in vitro by some calcium-channel blockers.

We investigated the action of some Ca(++)-channel blockers such as flunarizine, nifedipine and verapamil on F10 cells in vitro. Cell adhesion to the growth substratum, evaluated by the technique of spontaneous detachment in culture medium, is reduced in Ca(++)-channel blocker treated cells by comparison with controls. In our opinion such an event could also explain the inhibitory effect on cell growth and colony forming ability.

The effect of Dilazep on F10 cells in vitro.

Experiments on F10 cell growth, colony ability, cell adhesion and ultramorphology at SEM have been performed. The effect of Dilazep (DIL) has been compared with that of well known modulating agents such as Flunarizine (FLU) and Verapamil (VER) on cells cultured in high Ca++ medium (HCM) and in low calcium medium (LCM). While in HCM there is no difference among the three drugs, FLU and VER had a stronger effect on cell growth inhibition in LCM. Cell adhesion to the growth substratum, evaluated by the technique of spontaneous detachment in culture medium, is reduced in DIL treated cells in comparison to the controls.