Pedro Zapater

Tobramycin penetration into epithelial lining fluid of patients with pneumonia

To study the penetration of tobramycin in lung tissue evaluated as the concentration in epithelial lining fluid and to characterize the time course of the drug in the treatment of patients with pneumonia.

Neuroprotection by the novel calcium antagonist PCA50938, nimodipine and flunarizine, in gerbil global brain ischemia

Calcium is involved in the physiopathology of cerebral ischemia. Calcium antagonists might prevent the calcium overload and death of cells from ischemically compromised tissue. We compare the neuroprotective effect of various doses (0.2, 0.5 and 1 mg/kg) of two dihydropyridines, nimodipine and the novel 1,4-dihydropyridine derivative PCA50938, and flunarizine in the gerbil model of global ischemia. Improvements in morbidity were observed 2 h after the end of carotid occlusion (McGraws scale) with 0.5 mg/kg of flunarizine, all doses of PCA50938 and 0.2 mg/kg nimodipine. Neuronal loss in the CA1 sector of the hippocampus was examined. The animals treated with 0.5 mg/kg flunarizine and those treated with 1 mg/kg PCA50938 showed a significant reduction in the percentage of damaged neurons in the hippocampal CA1 area, 72 h after transient ischemia. None of the animals treated with 0.5 mg/kg flunarizine had more than 80% of the evaluated neurons altered. We conclude that PCA50938 and flunarizine may act as neuroprotective drugs with different patterns of dose-response and neuroprotective-morbidity-mortality relationships, in the model of global cerebral ischemia in the gerbil. Flunarizine has a narrow therapeutic range.

Gender differences in angiotensin-converting enzyme (ACE) activity and inhibition by enalaprilat in healthy volunteers.

Abstract: This bioequivalence study was supported by Laboratorios Vita S.A (Barcelona). To study the existence of differences between sexes in the pharmacokinetic and pharmacodynamic of enalapril. A bioequivalence phase 1 clinical trial to compare two formulations of enalapril was carried out in twenty-four healthy volunteers (12 men and 12 women). Enalaprilat concentrations, plasma activity of ACE, and systolic and diastolic arterial pressure were determined. Basal activity of ACE and the maximum ACE inhibition were significantly smaller in women. No significant differences in the drug concentration required to produce 50% of Emax were observed. Women had lower systolic arterial pressures and ACE activities than men at any time, even when the maximum inhibition of the ACE activity was attained. Women at the follicular phase had a minimum activity of ACE significantly inferior than men. Healthy women had lower systolic arterial pressures and ACE activities than men.

Anticonvulsant effects of nimodipine and two novel dihydropyridines (PCA 50922 and PCA 50941) against seizures elicited by pentylenetetrazole and electroconvulsive shock in mice

In animal models of epilepsy, calcium entry blockers have shown anticonvulsant properties. We studied the antiepileptic effects of nimodipine and two novel dihydropyridines, a calcium antagonist (PCA 50922) and a calcium agonist (PCA 50941), on pentylenetetrazole seizure and maximal electroshock seizure (MES) in mice. Anticonvulsant profile of nimodipine and PCA 50922 was similar to that of clonazepam, but markedly different from that of phenytoin. None of the doses of the PCA 50941 showed anticonvulsant effect.

Effects of dotarizine and flunarizine on chromaffin cell viability and cytosolic Ca2

Dotarizine (a novel piperazine derivative with antimigraine properties) and flunarizine (a Ca2+ channel antagonist) were compared concerning: first, their ability to cause chromaffin cell damage in vitro; second, the possible correlation of their octanol/water partition coefficients and those of another 28 compounds (i.e., Ca2+ channel antagonists, blockers of histamine H1 receptors, antimycotics, beta-adrenoceptor antagonists, neuroleptics), with their ability to cause cell damage; third, their capacity to protect the cells against the damaging effects of veratridine; and fourth, their capabilities to enhance the basal cytosolic Ca2+ concentration in fura-2-loaded single chromaffin cells, or to modify the pattern of [Ca2+]i oscillations elicited by veratridine. After 24-h exposure to 1-30 microM dotarizine, the viability of bovine adrenal chromaffin cells (measured under phase contrast or as lactate dehydrogenase, released into the medium) was similar to that of control, untreated cells; at 100 microM, 80% lactate dehydrogenase release was produced. At 1-3 microM flunarizine caused no cell damage; however 10 microM caused 20% lactate dehydrogenase release and 30 and 100 microM over 90% lactate dehydrogenase release. The time course of cell damage was considerably faster for flunarizine, in comparison to dotarizine. Out of 30 molecules tested (at 10 microM), having different octanol/water partition coefficients (log P), dotarizine was among the molecules causing no cell damage; flunarizine caused 20% cell loss, lidoflazine and verapamil over 50% cell loss, and penfluridol, draflazine, astemizole or nifedipine over 80% cell loss. No correlation was found between log P and cytotoxicity. Both dotarizine (10-30 microM) and flunarizine (3-10 microM) provided protection against veratridine-induced cell death; however, at 30 microM dotarizine afforded a pronounced protection while flunarizine enhanced the cytotoxic effects of veratridine. Dotarizine (30 microM) (but not flunarizine) caused a prompt transient elevation of the basal [Ca2+]i. Both compounds abolished the K+-induced increases of [Ca2+]i as well as the oscillations of [Ca2+]i induced by veratridine. The blocking effects of dotarizine were readily reversed after washout, while those of flunarizine were long-lasting. These differences might be relevant to the clinical use of dotarizine as an antimigraine drug.

Contribution of SK and BK channels in the control of catecholamine release by electrical stimulation of the cat adrenal gland.

1. Transmural electrical stimulation (10 Hz, 1 ms, 40 V for 10 s) of cat adrenal glands perfused at room temperature with Krebs‐Hepes solution produced catecholamine secretory responses which were reproducible when stimulations were applied at 5 min intervals. Such responses were inhibited about 20% by atropine (1 microM) and 80% by hexamethonium (30 microM). Apamin (100 nM) increased the secretory response 2.5‐fold in the presence of atropine and 8‐fold in the presence of hexamethonium. 2. Potentiation by apamin of secretory responses evoked by 100‐pulse trains was similar at 5, 10 and 20 Hz (about 2‐fold). When glands were continuously stimulated at 3 Hz, apamin increased 4‐fold the initial secretion plateau. Continuous stimulation at a higher frequency (20 Hz) produced a sharp secretory peak followed by a small, sustained plateau; apamin did not alter this plateau. Apamin also enhanced the secretory responses obtained with sustained stimulation with acetylcholine (10 or 200 microM). 3. Secretion peaks induced by brief acetylcholine pulses (10 microM for 10 s) applied to isolated and superfused cat adrenal chromaffin cells were enhanced more than 3‐fold by 100 nM apamin. Charybdotoxin (10 nM) did not enhance these secretory peaks. 4. In perfused cat adrenal glands, charybdotoxin (10 nM) affected neither the secretion evoked by trains of electrical stimulation applied at different frequencies nor the secretion evoked by acetylcholine pulses. 5. In 0.5 mM [Ca2+]o, apamin enhanced 3‐fold the secretion evoked by electrical stimulation trains of 100 pulses (10 Hz, 10 s) and almost 6‐fold the acetylcholine (10 microM for 10 s)‐induced secretion. In 5 mM Ca2+, apamin enhanced the secretory responses to electrical stimulation and acetylcholine 2‐ and 10‐fold, respectively. Charybdotoxin enhanced 2.5‐fold the secretory response to electrical stimulation in 0.5 mM Ca2+, although this effect was not statistically significant. A synergistic interaction between the two toxins on catecholamine release induced by electrical stimulation was observed at low but not at high [Ca2+]o. 6. Simultaneous release of acetylcholine and catecholamines upon electrical stimulation was achieved in glands in which the endogenous acetylcholine stores in the splanchnic nerve terminals had been prelabelled by perfusion with [3H]choline. While apamin enhanced more than 2‐fold the postsynaptic release of catecholamines, the presynaptic release of acetylcholine remained unaffected. 7. The results are compatible with the hypothesis that, under physiological conditions, Ca(2+)‐activated SK channels present in chromaffin cells control the firing patterns of action potentials induced by the acetylcholine released from splanchnic nerves during stress.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of ω-conotoxin MVIIC on veratridine-induced cytotoxicity and cytosolic Ca2+ oscillations

Abstract External Ca 2+ entry through various Ca t+-channel subtypes is responsible for the large oscillations of the cytosolic Ca 2+ concentrations, [Ca 2+ ] i , and cell death induced by veratridine in primary cultures of bovine chromaffin cells. Blockade by ω-conotoxin GVIA (GVIA) of N-type Ca 2+ channels, by ω-agatoxin GIVA (IVA) of P-type Ca 2+ channels, or by furnidipine of L-type Ca 2+ channels did not afford cytoprotection. However, ω-conotoxin MVIIC (MVIIC), a wide-spectrum blocker of N-, P- and Q-type Ca 2+ channels greatly protected the cells against the cytotoxic effects of veratridine. Furnidipine further enhanced the cytoprotecting effects of MVIIC. MVIIC but not fumidipine, markedly reduced the oscillations of [Ca 2+ ] i induced by veratridine in single fura-2-loaded chromaffin cells. The results suggest that Ca 2+ entry through any of the different Ca 2+ channel subtypes present in bovine chromaffin cells might be cytotoxic. They also support two ideas: (i) that wide-spectrum neuronal Ca 2+ channel blockers (i.e. MVIIC) might be better cytoprotecting agents than more specific neuronal Ca 2+ channel blockers (i.e., GVIA, IVA, furnidipine); and (ii) that combined Ca 2+ channel blockers may provide greater cytoprotection than single compounds.

Do Muscarinic Receptors Play a Role in Acute Pancreatitis

AbstractObjective: In a previous clinical trial, we reported the potential usefulness of pirenzepine, a selective muscarinic M1 cholinergic receptor antagonist, in the treatment of acute pancreatitis. The aim of this study is to extend these results to determine the comparative efficacy and tolerability of pirenzepine and nasogastric suction in the treatment of acute pancreatitis.n Design: Prospective, randomised, comparative clinical trial.n Setting: University hospital.n Patients: 50 consecutive patients admitted to the emergency room with acute pancreatitis diagnosed by abdominal pain and serum amylase levels higher than 700 IU/L or urine amylase levels higher than 1800 IU/L.n Interventions: Patients received treatment with nasogastric suction or pirenzepine (10mg every 12 hours intravenously followed by 50mg every 12 hours orally once oral intake had resumed).n Main Outcome Measures: Serum and urine amylase levels and clinical symptoms.n Results: Basal clinical and biochemical parameters were similar between the two treatment groups. Pirenzepine significantly decreased the duration of hyperamylasaemia and hyperamylasuria, and the time to resumption of bowel sounds, passage of first faeces and clinical recovery compared with nasogastric suction. Pirenzepine was well tolerated and there were no differences between the two groups in the incidence of complications associated with acute pancreatitis.n Conclusions: The use of pirenzepine in acute pancreatitis has proved to be more beneficial in shortening the recovery period than nasogastric suction and thus may be a more beneficial alternative in these patients. The results of this trial reinforce our thinking that selective muscarinic M1-receptor antagonists warrant evaluation in further studies to define their efficacy and tolerability in patients with acute pancreatitis.

Effects of the neuroprotectant lubeluzole on the cytotoxic actions of veratridine, barium, ouabain and 6‐hydroxydopamine in chromaffin cells

1 Incubation of bovine adrenal chromaffin cells with veratridine (10–100 μm) during 24 h, caused a concentration‐dependent release of the cytosolic lactate dehydrogenase (LDH) into the bathing medium, an indicator of cell death. Lubeluzole or its R(−) enantiomer, R91154, did not enhance LDH release. Both lubeluzole and R91154 (0.3–10 μm) decreased the veratridine‐induced LDH release. 2 Penfluridol did not increase LDH release at concentrations 0.003–1 μm; 3–10 μm increased LDH release to 50–60%, after 24 h exposure. Penfluridol (0.03–0.3 μm) did not protect against the cytotoxic effects of veratridine; at 1 μm, 15% protection was produced. Higher concentrations (3–10 μm) enhanced the cytotoxic effects of veratridine. 3 Ba2+ ions caused a concentration‐dependent increase of LDH release. This cytotoxic effect was partially prevented by 3 μm lubeluzole and fully counteracted by 1 μm penfluridol. R91154 was less potent than lubeluzole and only protected against the lesion induced by 0.5 mm Ba2+. 4 Ouabain (10 μm during 24 h) increased LDH release to about 30%. Both lubeluzole (0.3–10 μm) and the lower concentrations of penfluridol (0.003–0.3 μm) prevented the ouabain cytotoxic effects. At higher concentrations (3 μm), penfluridol increased drastically the ouabain cytotoxic effects. 5 6‐Hydroxydopamine (6‐OHDA) caused significant cytotoxic effects at 30 and 100 μm. Lubeluzole (3–10 μm) or penfluridol (0.03–0.3 μm) had no cytoprotective effects against 6‐OHDA. 6 Lubeluzole (3 μm), R91154 (3 μm) and penfluridol (1 μm) blocked the current through Na+ channels in voltage‐clamped chromaffin cells (INa) by around 20–30%. Ca2+ current through Ca2+ channels (ICa) was inhibited 57% by lubeluzole and R91154 and 50% by penfluridol. The effects of penfluridol were not washed out, but those of lubeluzole and R91154 were readily reversible. 7 Lubeluzole (3 μm) induced reversible blockade of the oscillations of the cytosolic Ca2+, [Ca2+]i, in fura‐2‐loaded cells exposed to 30 or 100 μm veratridine. Penfluridol (1 μm) inhibited those oscillations in an irreversible manner. 8 The results suggest that lubeluzole and its R‐isomer caused cytoprotection against veratridine cell damage, by blocking the veratridine stimulated Na+ and Ca2+ entry, as well as the [Ca2+]i oscillations. The Ba2+ and ouabain cytotoxic effects were prevented more efficiently by penfluridol, likely by blocking the plasmalemmal Na+/Ca2+ exchanger. It remains dubious whether these findings are relevant to the reported neuroprotective action of lubeluzole in stroke; the doubt rests in the stereoselective protecting effects of lubeluzole in in vivo stroke models, as opposed to its lack of stereoselectivity in the in vitro model reported here.

Comparative pharmacoeconomic study of vancomycin and teicoplanin in intensive care patients

Randomized clinical trials and meta-analyses have not demonstrated any statistically significant differences between teicoplanin and vancomycin with regard to efficacy. A cost-minimization analysis was conducted to compare the economical impact of the treatment with vancomycin and teicoplanin in intensive care patients. Information on resource utilization was retrospectively collected from 100 consecutive clinical histories of patients hospitalized in a Spanish Intensive Care Unit, who had been given a glycopeptide antibiotic (50 teicoplanin and 50 vancomycin) for the treatment of a suspected or proven infection. Although personnel, material, and monitoring costs were higher in the vancomycin group, the acquisition costs and the total costs were much lower in this group, so the resulting total costs per day were 5508 ptas (33 euros) for vancomycin-treated patients and 9893 ptas (59.5 euros) for teicoplanin-treated patients. The savings with vancomycin for a 10-day course of treatment would be approximately 40697 ptas (244.5 euros) per patient. Results were consistent for a variety of conditions that were included in the sensitivity analysis.