Does the unfavorable pharmacokinetic and pharmacodynamic profile of the iNOS inhibitor GW273629 lead to inefficacy in acute migraine?

The objective of this study was to investigate the pharmacodynamics and pharmacokinetics of a single dose of GW273629, a selective iNOS inhibitor, given during and outside a migraine attack. GW273629 1500 mg was administered to 15 migraine patients both ictally and interictally. Nasal and exhaled nitric oxide (NO), plasma 3-nitrotyrosine, and nitrates were measured to assess systemic NO production. In addition, pharmacokinetics and treatment response were assessed. Data are mean (95% confidence interval [CI]). Plasma 3-nitrotyrosine was higher ictally: 11.96 (8.22, 15.71) ictally versus 2.74 (2.24, 3.24) ng/10 mg interictally (P < .0001). Exhaled and nasal NO showed a similar trend: 12.5 (6.5, 18.6) and 62.2 (41.5, 82.8) ppb ictally versus 9.9 (6.3, 13.4) ppb and 52.5 (38.5, 66.0) ppb interictally, respectively. Early absorption of GW273629 (AUC(0-2) [90% CI]) was reduced by 41 (22, 55)% during an attack. There was no improvement of headache or associated symptoms. Migraine headache is associated with reduced early absorption of GW273629 and excess NO production. In this open-label study, GW273629 was ineffective in the treatment of acute migraine.

Atorvastatin affects leukocyte gene expression in dyslipidemia patients: in vivo regulation of hemostasis, inflammation and apoptosis.

BACKGROUND: The beneficial effect of HMG-CoA reductase inhibitors (statins) on coronary artery disease has been linked to mechanisms beyond their lipid-lowering effect. However the existence of direct, lipid-independent effects of statin in humans is still controversial. OBJECTIVE: To investigate the early effect of atorvastatin on peripheral blood mononuclear cells (PBMC) in dyslipidemic patients using gene arrays. PATIENTS AND METHODS: Eleven male patients with primary hyperlipidemia received 20 mg atorvastatin daily for 4 weeks. Blood was collected at baseline, 12 h, 36 h, 1 and 4 weeks after the start of treatment. RESULTS: Human microarrays containing 12 650 genes were used to study the effect of atorvastatin on PBMC gene expression at all time-points. Two hundred and forty genes were significantly regulated by atorvastatin treatment, several of which are involved in hemostasis, inflammation and other processes critical to atherosclerosis. Different patterns of response over time suggested both lipid-dependent and independent effects of atorvastatin on gene expression. CONCLUSIONS: This study demonstrates for the first time that atorvastatin regulates gene expression in PBMC in man before changes in the lipid profile are detectable in serum. Using blood leukocytes as a pharmacogenomic surrogate, we have identified new in vivo targets of atorvastatin treatment.

The current status of antihypertensive treatments: into the new millennium.

In this short review, we present a historical perspective of the treatment of hypertension, highlight some current issues and look to the possible future of antihypertensive therapy. The distribution of blood pressure within the population adopts a continuous, albeit somewhat skewed, distribution, so what constitutes hypertension? Conventionally, the disease has been defined as a level of blood pressure >> 140/90 mmHg. Accepting this 'arbitrary' definition infers that approximately one quarter of the adult population in the US are hypertensive [1]. This has significant implications in terms of the impact upon public health. We know that treatment of hypertension can prevent the serious consequences of cardiovascular disease: stroke, myocardial infarction (MI), heart failure and renal disease. Thus, it is important that raised blood pressure is both detected and effectively lowered. To what level should blood pressure be reduced. Conventionally, a level of 120/80 mmHg has been used to define normotension but there are indications that under certain circumstances this should not be the target. The question also arises as to whether it matters how blood pressure is treated. The choice of agent may ultimately depend upon the presence of any concomitant condition and risk factors. Recent trial evidence has concluded that therapy selected to treat raised blood pressure should take into account the overall cardiovascular risk profile of the patient [2].

Report on the Royal Society of Medicine one day meeting on coronary artery disease--'Bench to Bedside'. 29th June 2000, London, UK.

A one day meeting was organised by the Royal Society of Medicine during the summer. This was a meeting of high value with excellent speakers and provided several snapshot views on the progress which has been made in understanding and treating coronary artery disease (CAD) from the perspective of the lab scientist to that of the practising clinician. It basically provided updates for three areas: pathophysiology/inflammation gene therapy imaging coronary arteries.

72nd Meeting of the American Heart Association. November 1999, Atlanta, Georgia, USA.

The American Heart Association annual meeting must be one of the largest scientific gatherings, attracting over 30,000 delegates. The meeting at the end of last year was held in Atlanta, USA, the 2000 meeting will be in New Orleans, USA. The following highlights represent my own interests.

Safety and tolerability of 619C89 after acute stroke.

BACKGROUND: 619C89 is a use-dependent sodium channel blocker which reduces hemispheric infarction volume by up to 60% after permanent middle cerebral artery occlusion in rats. Intravenous doses of up to 1 mg/kg have been well tolerated by healthy young and elderly volunteers. This study sought to assess safety and tolerability of 619C89 in the treatment of acute stroke. METHODS: Patients were randomised within 12 h of onset of stroke to receive 619C89 or placebo as an intravenous loading dose, followed by maintenance doses given 8 hourly for 64 h in a double-blind, ascending-dose tolerance study. Dosing commenced at 0.5 mg/kg loading plus 0.25 mg/kg/8 h maintenance for the first group and increased in increments of 0.5 mg/kg loading +0.25 mg/kg/8 h maintenance thereafter. Safety evaluation was continued for 3 months. RESULTS: 48 patients were recruited. 12 received placebo and 36 received 619C89 in doses up to 2.5 mg/kg loading plus 1.25 mg/kg/8 h. Dose escalation was stopped after the occurrence of hallucinations in 5 of 18 patients who received 2 mg/kg/8 h or more. Gastro-intestinal upset and confusion were also possibly drug related. No drug-related effects on cardiovascular function were found. CONCLUSIONS: 619C89 was associated with significant central nervous system side-effects at doses of 2 mg/kg + 1 mg/kg/8 h or greater as discrete intravenous infusions within 12 h of stroke onset. It may also cause gastro-intestinal side-effects. Doses below this are well tolerated in patients. No adverse cardiovascular effects were seen.

Pharmacokinetics of 619C89, a novel neuronal sodium channel inhibitor, in acute stroke patients after loading and discrete maintenance infusions.

1. This was a multi-centre, placebo controlled, randomized, dose-escalating design study in which five dosing regimens of 619C89/placebo were evaluated in 48 stroke patients. Loading infusions of 0.5, 1, 1.5, 2 and 2.5 mg kg-1 over 1 h were followed by respective maintenance infusions of 0.25, 0.5, 0.75, 1 and 1.25 mg kg-1 over 30 min at 8 hourly intervals for 3 days. 2. Plasma concentrations of 619C89 and its N-oxide, 341C90, and N-demethylated, 78C90, metabolites were assayed using an LC-MS-MS method. Plasma concentration-time profiles after the final maintenance infusion were subjected to conventional noncompartmental pharmacokinetic analysis. 3. For 619C89, geometric CL means ranged between 0.71 and 0.99 1 h-1 kg-1 for maintenance infusions up to 1.25 mg kg-1 over 30 min, with an overall mean of 0.85 l h-1 kg-1 (95% CI: 0.70-1.04 l h-1 kg-1). Geometric Vss means ranged between 13.2 and 27.9 l kg-1 for the same doses, with an overall mean of 22.5 l kg-1 (95% CI: 16.4-30.9 l kg-1). The ANOVA results revealed that neither CL, Vss nor t1/2 were significantly different across the five dosing regimens (P values: 0.82, 0.54 and 0.61, respectively). 4. Average AUC for 341C90 was 270% and that for 78C90 was 62% of the AUC for 619C89. The AUCm/AUCp-ratios were similar at all dose levels for each metabolite. Values of t 1/2 for 341C90 were similar to those of 619C89 whereas t1/2 for 78C90 was about three-fold longer than that of parent drug. 5. In conclusion, the pharmacokinetics of 619C89 are independent of dose in acute stroke patients. The pharmacokinetics of 341C90 are probably formation rate-limited and those of 78C90 are elimination rate-limited and are also dose-independent.

Comparison of isradipine with nitroprusside for control of blood pressure following myocardial revascularization: effects on hemodynamics, cardiac metabolism, and coronary blood flow.

The effects of isradipine (ISR) on cardiac performance, myocardial metabolism, and coronary blood flow were compared with those of sodium nitroprusside (SNP) when used to control blood pressure following myocardial revascularization. Twenty patients were randomized to receive either intravenous ISR or SNP if arterial blood pressure increased above 130 mm Hg systolic. Hemodynamic and metabolic parameters were studied using radial, pulmonary arterial, and coronary sinus catheters. Cardiac output and coronary blood flows were measured by thermodilution and blood was taken for calculation of myocardial oxygen consumption and lactate extraction. Electrocardiographic changes were recorded by Holter monitoring throughout the study. ISR and SNP both produced a satisfactory reduction in blood pressure accompanied by a decreased systemic vascular resistance (P less than 0.001). ISR infusion was associated with increases in cardiac output and stroke index (P less than 0.01), which were not apparent in the SNP group. Tachycardia occurred with SNP (P less than 0.01) but not with ISR therapy. Right and left ventricular stroke work indices and myocardial oxygen consumption were reduced with SNP. The ISR group showed unchanged myocardial oxygen consumption with increased right ventricular stroke work index. Coronary vascular resistance decreased (P less than 0.01) during ISR infusion but decreased only slightly in the SNP group. Great cardiac vein blood flow was significantly increased with ISR but not with SNP, resulting in a significant difference between the groups (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the inotrope DPI 201-106 on cardiac performance following cardiac surgery.

The haemodynamic, cardiac metabolic and electrocardiographic effects of the intravenous inotropic agent DPI 201-106, in 20 and 40 milligram doses, were studied in patients after coronary arterial bypass grafting. The patients were randomly allocated to receive placebo or DPI 201-106. Those receiving the active drug received either the 20 or the 40 milligram dosages of DPI 201-106. Both the placebo and the active drug were infused over 20 minute periods. Two baseline readings confirmed haemodynamic stability, and readings were taken immediately following the infusions and then at 20 minutes and at 40 minutes afterwards. Comparison of all the haemodynamic and metabolic data did not reveal any significant intra or inter group differences. Comparison of the electrocardiographic data revealed some differences. Patients receiving DPI 201-106 showed prolongation of the QTc interval immediately following the infusions. Changes in ST segments and T waves were observed. Independent analysis of the affected electrocardiographs reported that the changes were suggestive of, but not pathognomonic of, myocardial ischaemia. The metabolic data showed that the electrocardiographic changes were not associated with any evidence of anaerobic metabolism. The indication for DPI 201-106 as a positive inotropic agent in patients following coronary revascularization surgery was not established.

Use of isradipine in hypertension following coronary artery bypass surgery.

A dose-finding pilot study including six patients concluded that isradipine at an initial rate of 0.6 microgram/kg/minute, decreasing to 0.3 microgram/kg/minute with further adjustments as necessary, was safe for the treatment of post-aortocoronary bypass graft hypertension. A comparative study followed, comprising 20 patients randomly assigned to receive isradipine (starting at 0.6 microgram/kg/minute) or nitroprusside (initially 1 microgram/kg/minute) for the treatment of post-aortocoronary bypass graft hypertension. Both drugs produced a satisfactory reduction in arterial blood pressure accompanied by a decrease in systemic vascular resistance. Central venous pressure and mean pulmonary artery pressure decreased with nitroprusside, but both increased with isradipine. Pulmonary capillary wedge pressure was reduced, heart rate increased, and cardiac output was minimally changed with nitroprusside. However, wedge pressure was maintained with isradipine and there was no tachycardia. An increase in cardiac output was seen, associated with an increase in stroke index. Isradipine is a more specific treatment for post-aortocoronary bypass graft hypertension than nitroprusside because its systemic arterial dilating effect is associated with a minimum of other circulatory changes.

Clinical cardiac electrophysiologic evaluation of the positive inotropic agent, DPI 201-106.

DPI201-106 is a new positive inotropic agent. The cardiac electrophysiology of 16 patients was studied before and during DPI 201-106 administration (loading dose of intravenous DPI 201-106, 1.8 mg kg-1 h-1 administered over 10 min, followed by a maintenance dose of 0.2 mg kg-1 h-1). DPI 201-106 had no effect on the sinus node. The AH interval during fixed-rate atrial pacing became prolonged during DPI 201-106 infusion. There was a significant prolongation of the QT interval [QT (corrected), 417 +/- 22 to 502 +/- 35 ms, P less than 0.05; QT (atrial pacing at 600 ms), 374 +/- 17 to 419 +/- 23 ms, P less than 0.05; QT (ventricular pacing at 600 ms), 409 +/- 37 to 449 +/- 30 ms, P less than 0.05]. The ventricular effective refractory period significantly prolonged during DPI 201-106 administration (242 +/- 21 to 287 +/- 56 ms, P less than 0.05), but the supernormal-period duration decreased. The atrial effective refractory period was shortened in four patients and prolonged in one (261 +/- 67 to 240 +/- 53 ms, NS). The corrected atrial repolarization time (PTac) shortened significantly during DPI 210-106 infusion (479 +/- 26 to 445 +/- 22 ms at 20 min of the maintenance dose, P less than 0.05). Atrial fibrillation was initiated in five patients during DPI infusion, but no ventricular arrhythmia was provoked. These findings suggest that DPI 201-106 has novel differential electrophysiological effects on atria and ventricles.

Haemodynamic effects of DPI 201-106, following single intravenous dose administration to patients with moderate cardiac failure.

DPI 201-106 is a novel compound unrelated to other cardioactive agents and has been shown to have an inotropic effect in animal preparations. The drug was given by intravenous infusion (20 mg over 10 min) to 10 patients with moderate cardiac failure and the haemodynamic effects measured at intervals up to 1 h following infusion. Maximal effects were seen immediately following the infusion of DPI 201-106. Cardiac index showed an increase from baseline 2.72 (0.16) 1 min-1 m-2 to 3.18 (0.21) 1 min-1 m-2 at the end of infusion (P less than 0.001). Subsequent values were not significantly raised. Pulmonary capillary wedge pressure and pulmonary artery pressure fell from 27.6 (3.2) and 36.9 (4.4) to 15.3 (3.6) and 24.2 (4.9) mmHg, respectively (P less than 0.001 in both cases). A statistically significant effect on cardiac index was not seen at 1 h. However, pulmonary pressures remained reduced at this point. Radionuclide ejection fraction showed a significant increase from 15.4 (1.5) to 21.9 (2.2)% (P less than 0.005) at the end of infusion, and maintained a significant increase at 1 h. Having demonstrated beneficial, acute haemodynamic effects in this study, further work should be undertaken with DPI 201-106 to investigate the effect of chronic treatment in patients with cardiac failure.