New chemotherapy regimens for advanced bladder cancer.

Because of demonstrated superiority in multiple randomized trials, MVAC has become the standard therapy for metastatic or unresectable bladder cancer. However, the disappointing long-term results with this regimen have prompted the development of newer agents and regimens for this disease. These include novel antifolates, gemcitabine, taxanes, ifosfamide, and gallium nitrate. Each of these agents leads to objective responses, including complete responses in both untreated and previously treated patients. More recent reports of combination regimens using these agents suggest that response rates are equivalent to those seen with MVAC but that there is significantly less toxicity. These observations, if confirmed in randomized trials, would signify an important advance in the therapy of metastatic bladder cancer.

Computerized tomographic findings in adolescent and adult Nigerian epileptics.

We evaluated CT findings in 75 Nigerians who suffer from epilepsy aged 12 years and over to determine factors associated with positive yield for judicious utilisation of CT. There were 48 males and 27 females with a mean age of 36 +/- 15 years. CT was normal in 41 subjects (54.7%). The commonest CT abnormality was cortical atrophy encountered in 16 subjects. The other abnormalities were occupying lesions (13) comprising 11 neoplasms and 2 subdural haematoma, vascular lesions (4) and poroencephaly (1). The presence of CT abnormality was statistically significantly associated with neurologic deficit, partial seizure type and EEG abnormalities (P < 0.05). The decision on when to request CT scan in epileptics could therefore be influenced by our findings.

Phorbol ester-induced ventricular fibrillation in the Langendorff-perfused rabbit heart: antagonism by staurosporine and glibenclamide.

Using a paced Lagendorff-perfused rabbit heart paradigm, we investigated the role of protein kinase C (PKC) in the development of ventricular fibrillation (VF) in hearts subjected to hypoxia (12 min) and re-oxygenation (40 min). We studied the effect of putative activators and inhibitors of PKC on the incidence of VF. Hearts exposed to 4 beta-phorbol,12,13-dibutyrate (PDBu), isophorbol or the membrane permeant diacylglycerol analog, 1-oleoyl-2-acetyl-rac-glycerol (OAG), during the prehypoxic phase had an increased incidence of VF during the hypoxic and reoxygenation periods. The incidence of VF was 90%, 83% and 75% in hearts exposed to PDBu, isophorbol and OAG, respectively (P < 0.05 vs control). Perfusion of hearts with PDBu was associated with a significant increase in the membrane fraction of cardiac PKC activity. In the presence of the inactive phorbol ester 4 alpha-phorbol didecanoate, the incidence of VF was 17% (P > 0.05 vs control). PKC activators were profibrillatory at concentrations that did not affect cardiac function: neither left ventricular developed pressure nor coronary perfusion pressure were affected. The effect of PDBu was antagonized by staurosporine: the incidence of VF was 17% in PDBu+staurosporine treated hearts (P < 0.05 vs control). To further study the profibrillatory effect of PDBu, hearts were exposed to PDBu in the presence of the ATP-dependent potassium channel antagonist glibenclamide. The latter prevented PDBu-induced VF. The results show that under the conditions employed, PDBu-induced activation of PKC induces redistribution of PKC activity and is associated with the development of VF.

Antifibrillatory and profibrillatory actions of selected class I antiarrhythmic agents.

We wished to examine selected class I antiarrhythmic agents for their potential to exhibit proarrhythmic or antifibrillatory actions. Quinidine, lidocaine, aprindine, and flecainide were evaluated in an experimental model that made use of rabbit isolated perfused heart. Hearts were stabilized with oxygenated buffer (95% O2/5% CO2) with or without pinacidil (1.25 microM) and then were subjected to hypoxia (95% N2/5% CO2) for 12 min, followed by 40-min normoxic perfusion (95% O2/5% CO2). Test drugs were added to the perfusion medium 5 min before hypoxia was induced. Prevention of spontaneous ventricular fibrillation (VF) was determined. To characterize the electrophysiologic effects of the selected antiarrhythmic agents, we determined the changes in threshold current and effective refractory period (ERP) before and after drug treatment. Addition of the potassium channel agonist, pinacidil, to the perfusion medium invariably resulted in VF during the hypoxic interval or shortly after reoxygenation. Pretreatment of the heart with glibenclamide prevented pinacidil-induced VF. Quinidine, aprindine, lidocaine, and flecainide each were studied at a single concentration. The respective drug concentrations were selected to produce comparable changes in ventricular refractory period. Of the class I agents selected for study, only quinidine prolonged the ventricular ERP and provided significant protection against pinacidil-induced VF. In contrast, aprindine and lidocaine decreased ventricular ERP and did not prevent VF induced by the combination of pinacidil and hypoxia. Quinidine, aprindine, and lidocaine did not exhibit proarrhythmic effects in the presence of hypoxia when pinacidil was not added to the perfusion medium. Flecainide, when added to the perfusion medium without pinacidil elicited proarrhythmic activity leading to VF when the hearts were made hypoxic. Flecainide-induced VF was antagonized by glibenclamide. The data suggest that VF can be provoked by the potassium channel agonist pinacidil or by flecainide under conditions that reduce intracellular ATP concentration. Glibenclamide, a selective antagonist of the KATP channel prevented the profibrillatory actions of pinacidil and flecainide. Quinidine, but not lidocaine and aprindine, prevented VF induced by pinacidil and hypoxia.

Actions of pinacidil at a reduced potassium concentration: a direct cardiac effect possibly involving the ATP-dependent potassium channel.

We investigated the effects of the ATP-dependent K+ channel antagonist glyburide and the ATP-dependent K+ channel agonist pinacidil in a Langendorff-perfused rabbit isolated heart subjected to a period of global hypoxia. A class III antiarrhythmic drug, E-4031, also was studied in this model. These studies aimed to define the mechanism of action of putative profibrillatory actions of pinacidil and the mechanism for the antifibrillatory effect of the class III antiarrhythmic drug, E-4031, in the hypoxic heart. After stabilization and determination of baseline functional parameters under normoxic perfusion conditions (95% O2/5% CO2), hearts were subjected to global hypoxia by switching to a 95% N2/5% CO2 saturated perfusion medium for a period of 12 min. After the hypoxic period, normoxia was re-established by switching to the oxygen-carbon dioxide saturated buffer medium for a period of 40 min. The oxygen tension of the perfusion buffer was reduced from approximately 400 mm Hg to below 50 mm Hg during the hypoxic period. All hearts subjected to hypoxia had reduced function: the left ventricular developed pressure and +/- dP/dt were reduced significantly. Myocardial tissue ATP concentrations were reduced (> 50%) in hearts subjected to hypoxia. Under conditions of hypoxic/reoxygenation and in the presence of a low (2.5 mM) potassium concentration ([K+]0), pinacidil (1.25 microM) facilitated the induction of ventricular fibrillation (80% fibrillation in the presence of pinacidil vs. 20% in the absence of pinacidil). Glyburide (10 microM) and E-4031 (1 and 10 microM) significantly reduced the incidence of ventricular fibrillation associated with pinacidil (20% fibrillation in the presence of hypoxia, pinacidil, and glyburide or 10 microM E-4031). Opening of the ATP-dependent K+ channel by pinacidil under normoxia and low K+ also facilitated the induction of ventricular fibrillation (60% ventricular fibrillation). Pinacidil failed to induce ventricular fibrillation under either normoxic or conditions of hypoxic/reoxygenation when the [K+]0 was increased to 5.1 mM. The results of this study demonstrate that K+ channel activators facilitate the induction of ventricular fibrillation under both normoxic conditions and conditions of hypoxic/reoxygenation when the perfusion buffer K+ concentration is reduced.

Enzymes in normally perfused and ischaemic dog hearts which release a substance with kinin like activity.

The presence of amidases cleaving the tripeptide VAL.LEU.ARG.pNA, and liberating from human plasma kininogen substance(s) able to contract uterine smooth muscle and to lower blood pressure (uterus contracting and hypotensive activity), has been demonstrated in vascular and muscle tissues from normally perfused and ischaemic areas of dog hearts. Studies were carried out on blood free preparations of coronary arteries and veins and normally perfused and ischaemic ventricle. All the tissues were found to contain both acid optimum (pH 6) and alkaline optimum (pH greater than 9) enzymes forming uterus contracting substance (UCS, bioassayed on isolated uterus of rats in oestrus), the highest levels of both activities being found in arterial tissues and the least in ventricle. Enzyme levels in ischaemic or normally perfused ventricle did not differ significantly. Gel filtration (Sephacryl, S-300) of coronary artery extracts gave one peak each of acid optimum enzyme with a molecular weight of 38,300 +/- 800 daltons and alkaline optimum enzyme with a molecular weight of 92,100 +/- 4000 daltons. Both acid and alkaline enzyme fractions cleaved the tripeptide substrate with pH optima identical to those for UCS formation. The acid optimum activity, both of UCS formation and tripeptide cleavage, was inhibited by pepstatin but not by aprotinin or soybean trypsin inhibitor (SBTI). The alkaline optimum activity was inhibited by aprotinin and SBTI but not pepstatin. Both acid and alkaline optimum enzymes released a hypotensive agent from a plasma protein substrate. The molecular weight and response to inhibitors of the acid optimum enzyme were similar to a cathepsin, and those of the alkaline optimum enzyme were similar to plasma kallikrein.

The effect of aspirin, indomethacin and sodium meclofenamate on coronary artery ligation arrhythmias in anaesthetized rats.

The intravenous administration of either aspirin, (in doses of 1 and 3 mg/kg) sodium meclofenamate (1 and 3 mg/kg) or indomethacin (1 and 3 mg/kg) markedly reduced ventricular arrhythmias (VT and VF) induced by coronary artery ligation in anaesthetised rats. Their effect were very pronounced on ventricular ectopic activity occurring between the sixteenth and thirtieth min. These effects suggest the desirability of combining the non steroidal anti-inflammatory drugs with beta-adrenergic blockers in the treatment of ventricular arrhythmias following acute myocardial infarction.

The effects of prazosin, phentolamine and phenoxybenzamine on inhibitory alpha-adrenoceptors in the guniea-pig isolated ileum.

1 The relaxant effect of noradrenaline on strips of guinea-pig isolated terminal ileum was blocked by pretreatment with prazosin, phentolamine, yohimbine and phenoxybenzamine. 2 The presence of a very high concentration of noradrenaline (50 micrometers) during exposure to the blocking agent protected against the blocking effect of the drugs. 3 Yohimbine, prazosin and phentolamine partially protected against irreversible blockade by phenoxybenzamine. 4 Spontaneous release of acetylcholine in the unstimulated ileum was blocked by noradrenaline (0.05-5.9 micrometers) this effect of noradrenaline was antagonized by phentolamine (0.13-26 micrometers) and yohimbine (0.051-0.51 micrometers) but not prazosin (0.53-5.3 micrometers) or phenoxybenzamine (4.2-42 nm). All four antagonists reversed the noradrenaline-induced relaxation of the ileum. 5 Acetylcholine output in the transmurally stimulated ileum was inhibited by noradrenaline. This effect of noradrenaline was antagonized by phentolamine and yohimbine but not by prazosin or phenoxybenzamine. The first two antagonists blocked the noradrenaline-induced inhibition of evoked twitches of the ileum while the last two had no effect. 6 The results show (a) that prazosin has no effect on presynaptic alpha-adrenoceptor located on cholinergic nerve endings in the guinea-pig ileum and (b) that prazosin, phentolamine and phenoxybenzamine act on the same subgroup of postsynaptic alpha-adrenoceptors on the smooth muscle of the guniea-pig ileum.

The effect of prazosin on the guinea-pig ileum.

1 The alpha-adrenoceptor blocking activity of prazosin was compared with that of phentolamine, yohimbine and phenoxybenzamine in the guinea-pig isolated ileum. 2 Phentolamine (2.56 X 10(-8) to 2.56 X 10(-6) M) and yohimbine (5.12 X 10(-8) to 5.12 X 10(-6) M) antagonized the sympathetic inhibition of twitches induced by transmural stimulation, whereas prazosin (5.28 X 10(-8) to 5.28 X 10(-6) M) and phenoxybenzamine (4.2 X 10(-9) to 4.2 X 10(-7) M) had no effect. 3 Phentolamine, yohimbine, prazosin and phenoxybenzamine antagonized the relaxant response of the ileum to periarterial nerve stimulation and to exogenous noradrenaline in the absence of transmural stimulation. 4 The pA2 value for phentolamine against noradrenaline in the transmurally-stimulated gut (presynaptic alpha-adrenoceptor site; 8.17 +/- 0.04) was significantly different from that in the non-stimulated gut (postsynaptic alpha-adrenoceptor site; 6.88 +/- 0.12). 5 Phentolamine and prazosin probably block noradrenaline responses at the same alpha-adrenoceptor site on the postsynaptic membrane.