Cefepime versus ceftazidime in the treatment of lower respiratory tract infections.

The objective of the study was to compare the safety and efficacy of cefepime and ceftazidime in the treatment of community acquired lower respiratory tract infections of moderate intensity. Eighty-six patients were randomized at a 2:1 ratio to receive respectively cefepime 1 g b.i.d. or ceftazidime 1 g t.i.d. The drugs were well tolerated and the occurrence of adverse events in each group was comparable. The rates of satisfactory clinical response were 96% (49/51) for cefepime and 89% (24/27) for ceftazidime. A total of 73 pathogens were isolated and pathogen eradication rates were 98% and 96% respectively for the cefepime and ceftazidime treatment groups. In conclusion, the data confirmed that cefepime could be a good alternative to ceftazidime.

Italian multicentre study of didanosine compassionate use in advanced HIV infection. Italian BMS-906 Study Group.

The aim of the present study, a multicentre trial of didanosine (ddI) compassionate use, was to identify factors associated with a better outcome in patients given ddI monotherapy. Enrolled were 1047 HIV-positive patients intolerant of and/or unresponsive to zidovudine (ZDV) therapy, with CD4+ cell counts of < 200/microliter or AIDS. Didanosine was given at a dose of 250 mg b.i.d. (patients > or = 60 kg) or 167 mg b.i.d. (patients < 60 kg). Clinical examinations and laboratory tests were performed every two months. Endpoints included death, the occurrence of a new AIDS-defining disease, or permanent discontinuation of ddI for a severe adverse event. At entry, the median CD41 cell count was 47/microliter and the median duration of prior ZDV treatment 19 months; 446 patients (43%) were classified as having AIDS. Severe toxicity occurred in 143 subjects (14%); the frequency of pancreatitis was very low (0.2%). The benefit in terms of CD4+ cell counts was greater for patients whose counts exceeded 100/microliter at entry and remained at this level until month 12 in those patients still receiving treatment. Death and/or new AIDS-defining events were observed in 374 cases (36%) over a median follow-up of eight months. AIDS dementia was observed in 11 patients (1%). Multivariate analysis of survival without disease progression showed that the factors associated with a worse outcome include the severity of immunodepression, a diagnosis of AIDS at entry, and a history of both intolerance of and clinical resistance to ZDV. Surprisingly, the patients who had received previous prolonged treatment with ZDV had a better outcome. In conclusion, severely immunodepressed patients previously administered long-term monotherapy may receive a short-term benefit from being switched to another antiretroviral drug.

Once versus twice daily administration of didanosine in children with symptomatic HIV-associated disease who were intolerant to or clinically deteriorated on zidovudine. The Italian Pediatric Collaborative Study Group on Didanosine.

The objective of this study was to compare the safety, tolerability and clinical response of once- versus twice-daily administration of didanosine given at a dosage of 270 mg/m2/day in children with symptomatic HIV-associated disease who were intolerant to or clinically deteriorated on zidovudine monotherapy. We carried out a randomized, open-label multicentre trial. Didanosine was supplied in buffered tablets, which could be chewed or dispersed in liquid. The children were recruited from 16 paediatric departments participating in the Italian Register for HIV Infection in Children. A total of 53 children (median age 5.5 years) started trial treatment; 26 were given didanosine twice daily and 27 once daily; 85% had AIDS and 98% had clinically deteriorated while on zidovudine therapy. Similar safety and tolerability results were demonstrated for the two schemes of therapy. A total of 11 children (20.7%) required discontinuation of didanosine for severe adverse events (five children (19.2%) in the twice-daily group; six children (22.2%) in the once-daily group, log-rank P = 0.81). Severe hepatic toxicity was uncommon (5.6%) while mild to moderate hepatic dysfunction was demonstrated in about 17% of the participants, without any difference between the two groups. Haematological toxicity was common (about 40% of the children, 11 in the twice- and 19 in the once-daily group) but never severe. Clinical pancreatitis and retinal lesions were never demonstrated. There was no significant difference in progression to death or to a new opportunistic infection between the two treatment regimens (log-rank P = 0.54). The modification of surrogate efficacy parameters during the study period was similar in the two groups. However, weight gain was poorer in children treated once daily. This study suggests that the safety and tolerability of 270 mg/m2/day of didanosine given once daily is substantially similar to that of the traditionally recommended schedule of two divided doses. Owing to the small sample and to the severity of the clinical condition of the children enrolled, no definite conclusions on the comparative efficacy of the two regimens can be drawn.

Binding capacities and affinities at mu-, delta- and kappa-opioid sites in membrane suspensions from guinea-pig brain regions.

Binding capacities and affinities (KD) of ligands at mu-, delta- and kappa-opioid binding sites were determined by selective labelling techniques together with analysis of saturation curves in seven regions of the guinea-pig brain. The kappa-sites predominated over the other sites in most regions and were 90% of the total in the cerebellum; binding capacities at kappa-sites were highest in the cortex, intermediate in the cerebellum, striatum and mesencephalon and lowest in the diencephalon, hippocampus and pons-medulla. At the mu-sites, binding capacities were highest in the diencephalon and mesencephalon, with intermediate levels in the pons-medulla, cortex and striatum, and low levels in the hippocampus and cerebellum. The highest binding capacity at the delta-sites was in the striatum, intermediate in the cortex, diencephalon and hippocampus, low in the mesencephalon and pons-medulla and not detectable in the cerebellum. No regional differences in binding affinities were found at mu-, delta- and kappa-sites with [3H]-[D-Ala2,MePhe4,Gly-ol5]enkephalin (KD = 1.10-2,61 nM), [3H]-[D-Ala2,D-Leu5]enkephalin (KD = 0.81-1.94 nM) and [3H]-(-)-bremazocine (KD = 0.083-0.185 nM). Thus in guinea-pig brain there are regional differences in opioid binding capacity and in the distribution of mu-, delta- and kappa-sites, but not in binding affinities.

In vitro binding profile and in vivo pharmacological properties of the K-opioid compound PD 117302.

The in vitro binding profile and some in vivo pharmacological properties of (+/-)trans-N-Methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzo[b]-thiophene- 4-acetamide (PD 117302) were tested in rats. In rat brain membrane preparation, PD 117302 was selective for the k-binding sites, its KI (3.51 nM) being respectively about 200 and 1300 times lower at k- than at mu- and delta-sites. In vivo, PD 117302 injected intravenously (i.v.) showed dose-related analgesic effects in the 55 degrees C hot-plate test (peak-time 5 min) and in the paw pressure test. In both tests high doses of naloxone were required for full antagonism. PD 117302, injected i.v., produced dose-related diuresis in normally hydrated rats, which was prevented by 2 mg/kg of subcutaneous naloxone or diprenorphine. PD 117302 at doses between 0.125 and 2 mg/kg i.v. did not delay the gastrointestinal transit of a charcoal meal and did not antagonize morphine-induced constipation. Thus PD 117302 has good selectivity for k-binding sites in vitro and induces analgesia and diuresis, but does not slow gastrointestinal transit in vivo, supporting its k-agonist activity.

Role of peripheral mu, delta and kappa opioid receptors in opioid-induced inhibition of gastrointestinal transit in rats.

The roles of various types of opioid receptors in opioid-induced local inhibition of gastrointestinal transit were studied in rats 5 min after a charcoal meal, injecting i.p. relatively selective agonists and antagonists. The proposed mu agonists, morphine and [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO), and the nonselective delta agonist, [D-Ala2,D-Leu5]enkephalin (DADLE), produced a dose-related inhibition of gastrointestinal transit at the peak time and the i.p. doses producing a 50% reduction of the control values (A50) were 0.015, 0.006 and 0.023 mg/kg, respectively, for morphine, DAMGO and DADLE. The effect of the other nonselective delta agonist, [D-Ser2,L-Leu5]enkephalyl-Thr (DSLET), was not linearly related with the dose. The proposed selective delta agonist, [D-Pen2,D-Pen5]enkephalin (DPDPE), and the selective kappa agonist, U-69,593, up to 2 and 15 mg/kg i.p., respectively, did not delay gastrointestinal transit. Naloxone (0.05 mg/kg i.p.) injected 1 min before each agonist produced a significant parallel shift to the right of the dose-response curves for morphine and DAMGO, but only partly antagonized the effects of DADLE and DSLET. The selective delta antagonist ICI 174,864 (1 mg/kg i.p., injected 1 min before each agonist) shifted the dose-response curve of DADLE, but not of the mu agonists, slightly, but significantly to the right, and had an inconsistent effect on DSLET. Naloxone prevented DADLE's effect on the gut with a nonlinear dose-response curve and much higher doses of naloxone were required to prevent fully DADLE-induced effects than to antagonize doses of morphine equiactive to DADLE on the gut.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of dopaminergic drugs for the chronic treatment of congestive heart failure.

1. The search of orally active dopaminergic drugs for the chronic treatment of congestive heart failure has followed two different approaches. 2. On the one hand, a selective DA-1 receptor agonist, such as fenoldopam, has been investigated as an agent developed for the stimulation of vascular and tubular DA-1 receptors in the kidney. On the other hand, orally active prodrugs were synthetized with the aim of mimicking the full pattern of dopaminergic and adrenergic actions of intravenous dopamine. 3. Ibopamine, the diisobutyric ester of N-methyldopamine, has shown effects comparable to those of dopamine in various animal models and in clinical investigations. Furthermore, patients suffering from mild or severe congestive heart failure were shown to benefit from ibopamine treatment in a number of therapeutic trials. 4. Limited experience is currently available on other prodrugs, such as docarpamine and Sim 2055, i.e. the 4-0-phosphate ester of N-methyldopamine. The latter is an analogue of ibopamine designed for a preferential delivery of N-methyldopamine in the kidney. 5. Based upon some additional studies with levodopa, the results suggest that a combination of DA-1 and DA-2 agonistic activity is a desirable feature of a new drug, since it appears suitable to provide vasodilation while counteracting the neurohumoral abnormality of congestive heart failure.

Regional variations in binding capacities at mu-, delta- and kappa-opioid sites in membrane suspensions from rabbit brain.

The highest maximum binding capacities at the mu-sites of rabbit brain are in the striatum, with intermediate levels in the diencephalon, mesencephalon, cerebellum and cortex and low levels in the pons-medulla and hippocampus. For the delta-site the highest maximum binding capacity is also in the striatum; there are almost equally low levels in the other brain regions. At the kappa-sites the maximum binding capacities are highest in the diencephalon; there are intermediate levels in the cortex and striatum, and low levels in the mesencephalon, cerebellum, hippocampus and pons-medulla. The KD values lack reproducibility; there are no regional variations at the kappa-site as estimated with [3H](-)-bremazocine, but the possibility cannot be excluded that there are regional variations in the KD values for [3H][D-Ala2,MePhe4,Gly-ol5]enkephalin at the mu-site or for [3H][D-Ala2,D-Leu5]enkephalin at the delta-site. It may be important to use saturation analysis in future investigations of the distributions of the binding sites.

Antagonism by N-methyl levallorphan-methane sulphonate (SR 58002 C) of morphine-elicited acute and chronic central and peripheral effects.

The peripheral activity of the quaternary narcotic antagonist N-methyl levallorphan-methane sulphonate (SR 58002 C) at opioid sites located in the periphery and in the central nervous system (CNS), was studied by different approaches in rats after subcutaneous injection (s.c.). Pretreatment with SR 58002 C 2,8 or 32 mg/kg s.c. 10, 50 or 110 min before buprenorphine consistently reduced buprenorphine in vivo binding only in the small intestinal longitudinal muscle with attached myenteric plexus (MP), whereas naloxone (1 mg/kg s.c.) 10 min before buprenorphine lowered buprenorphine binding in MP and brain (without cerebellum). Plasma levels were not altered by SR 58002 C or naloxone. The same doses of SR 58002 C injected 10, 50 or 110 min before morphine selectively antagonized the inhibition of transit of a charcoal meal along the small intestine (mainly a peripheral effect) induced by the agonist, but did not antagonize morphine-elicited analgesia in the hot-plate test (central effect). Naloxone (1 mg/kg s.c.) injected 10 min before morphine antagonized both agonist effects simultaneously. In morphine-dependent rats SR 58002 C (0.25, 1, 4 and 32 mg/kg s.c.) induced diarrhea, dose-dependently, in most animals within the first 30 min, while jumping, measured in the same rats, occurred in some animals, not dose-dependently, from 60 min on. Naloxone (1 mg/kg s.c.) induced both effects in most rats. These findings suggest that, although SR 58002 C probably penetrates the blood-brain barrier in some morphine-dependent rats, it discriminates peripheral and CNS opioid effects.

Interaction of U-69,593 with mu-, alpha- and kappa-opioid binding sites and its analgesic and intestinal effects in rats.

The kappa-opioid compound U-69,593 was studied in rats in vitro in binding assays to assess its selectivity at the single types of opioid sites and in vivo to assess its analgesic activity and effect on intestinal propulsion. In vitro the U-69,593 inhibition curve of [3H]-(-)-bremazocine binding suppressed at mu- and alpha-sites was biphasic and the inhibition constant (Kl) at the high-affinity site (10-18 nM) was two orders of magnitude smaller than the Kl at the low-affinity site. The Kl at mu- and alpha-sites were respectively 3.3 and 8.5 microM. Thus [3H]-(-)-bremazocine, suppressed at mu- and alpha-sites, may still bind more than one site, which U-69,593 might distinguish. In vivo U-69,593 i.p. prolonged the reaction time of rats on a 55 degrees C hot-plate and the dose of naloxone required to antagonize this effect was 40 times the dose that antagonized morphine-induced antinociception, suggesting the involvement of the kappa-receptor. In the intestinal transit test U-69,593 at doses between 0.5 and 15 mg/kg i.p. only slightly slowed intestinal transit of a charcoal meal in rats with no dose-relation; it partly but significantly antagonized morphine-induced constipation. These results suggest that the kappa-type of opioid receptor, with which U-69,593 interacts may induce analgesia, but has no appreciable role in the mechanisms of opioid-induced inhibition of intestinal transit in rats.

D-optimal design applied to binding saturation curves of an enkephalin analog in rat brain.

The D-optimal design, a minimal sample design that minimizes the volume of the joint confidence region for the parameters, was used to evaluate binding parameters in a saturation curve with a view to reducing the number of experimental points without loosing accuracy in binding parameter estimates. Binding saturation experiments were performed in rat brain crude membrane preparations with the opioid mu-selective ligand [3H]-[D-Ala2,MePhe4,Gly-ol5]enkephalin (DAGO), using a sequential procedure. The first experiment consisted of a wide-range saturation curve, which confirmed that [3H]-DAGO binds only one class of specific sites and non-specific sites, and gave information on the experimental range and a first estimate of binding affinity (Ka), capacity (Bmax) and non-specific constant (k). On this basis the D-optimal design was computed and sequential experiments were performed each covering a wide-range traditional saturation curve, the D-optimal design and a splitting of the D-optimal design with the addition of 2 points (+/- 15% of the central point). No appreciable differences were obtained with these designs in parameter estimates and their accuracy. Thus sequential experiments based on D-optimal design seem a valid method for accurate determination of binding parameters, using far fewer points with no loss in parameter estimation accuracy.

The role of mu- and delta- opioid receptors on the intestinal propulsion in rats.

The agonist effects on intestinal transit of relatively selective mu- and delta- ligands, administered intraperitoneally, and their antagonism by the preferentially mu- and delta- antagonists naloxone and ICI 174,864 were studied in rats 5 min after a charcoal meal. The dose-response curves of the preferential mu- ligands morphine and [D-Ala2, MePhe4, Gly-ol5] enkephalin (DAGO) were shifted by naloxone at low doses but not by ICI 174,864. The preferential delta-peptide [D-Pen2, D-Pen5] enkephalin (DPDPE) had no significant agonist activity. [D-Ala2, D-Leu5] enkephalin (DADLE) induced dose-related effects that were weakly antagonized by ICI 174,864 and partly by low-dose naloxone. Thus the inhibition of intestinal transit induced by opioids may depend mainly on the interaction of the agonists at the mu-receptors, while the delta- receptors may play only a secondary role. DADLE agonist effects probably depend on interaction at mu-, delta- and at non-opioid receptors.