Colin A. Campbell

Profile of SB-204269, a mechanistically novel anticonvulsant drug, in rat models of focal and generalized epileptic seizures

1 Earlier optimization of structure‐activity relationships in a novel series of 4‐(benzoylamino)‐benzopyrans, led to the discovery of SB‐204269 (trans‐(+)‐6‐acetyl‐4S‐(4‐fluorobenzoylamino)‐3,4‐dihydro‐2,2‐dimethyl‐2H‐benzo[b]pyran‐3R‐ol, hemihydrate), a potent orally‐active anticonvulsant in the mouse maximal electroshock seizure threshold (MEST) test. 2 Studies have now been undertaken to determine the effects of SB‐204269 in a range of seizure models and tests of neurological deficits in rats. In addition, the compound has been evaluated in a series of in vitro mechanistic assays. 3 SB‐204269 proved to be an orally‐effective anticonvulsant agent, at doses (0.1–30 mg kg−1) devoid of overt behavioural depressant properties, in models of both electrically (MEST and maximal electroshock (MES)) and chemically (i.v. pentylenetetrazol (PTZ) infusion)‐evoked tonic extension seizures. However, the compound did not inhibit PTZ‐induced myoclonic seizures at doses up to 30 mg kg−1, p.o. 4 SB‐204269 also selectively reduced focal electrographic seizure activity in an in vitro elevated K+ rat hippocampal slice model at concentrations (0.1–10 μM) that had no effect on normal synaptic activity and neuronal excitability. 5 In all of these seizure models, SB‐204269 was equivalent or better than the clinically established antiepileptic drugs carbamazepine and lamotrigine, in terms of anticonvulsant potency and efficacy. 6 Unlike SB‐204269, the corresponding trans 3S,4R enantiomer, SB‐204268, did not produce marked anticonvulsant effects, an observation in accord with previous findings for other related pairs of trans enantiomers in the benzopyran series. 7 In the rat accelerating rotarod test, a sensitive paradigm for the detection of neurological deficits such as sedation and motor incoordination, SB‐204269 was inactive even at doses as high as 200 mg kg−1, p.o. This was reflected in the excellent therapeutic index (minimum significantly effective dose in the rotarod test/ED50 in the MES test) for SB‐204269 of >31, as compared to equivalent values of only 7 and 13 for carbamazepine and lamotrigine, respectively. 8 At concentrations (10 μM) well above those required to produce anticonvulsant activity in vivo (i.e. 0.1 μM in brain), SB‐204269 did not interact with many of the well known mechanistic targets for established antiepileptic drugs (e.g. Na+ channels or GABAergic neurotransmission). Subsequent studies have shown that the anticonvulsant properties of SB‐204269 are likely to be mediated by a novel stereospecific binding site present in the CNS. 9 The overall efficacy profile in rodent seizure models, together with a minimal liability for inducing neurological impairment and an apparently unique mechanism of action, highlight the therapeutic potential of SB‐204269 for the treatment of refractory partial and generalized tonic‐clonic seizures.

Effect of verapamil on infarct size in dogs subjected to coronary artery occlusion with transient reperfusion

Reocclusion after successful coronary reperfusion occurs in 15 to 35% of patients receiving thrombolytic therapy for acute myocardial infarction. The present study was designed to simulate the clinical situation of reocclusion and determine whether verapamil might be effective in reducing myocardial necrosis and preserving high energy phosphates in this setting. Pentobarbital-anesthetized, open chest dogs underwent occlusion of the left anterior descending coronary artery for 2 hours followed by 1 hour of reperfusion and a further 4 hours of coronary artery occlusion. Treatment with verapamil (intravenous bolus dose of 0.2 mg/kg body weight followed by infusion of 0.56 +/- 0.14 mg/kg per h) was begun 1 hour after occlusion and infusion was continued for the remainder of the experiment. The dose of verapamil was adjusted to lower mean arterial pressure to approximately 90 mm Hg. The area at risk was determined by intraatrial injection of monastral blue dye and the area of necrosis was assessed by triphenyltetrazolium chloride staining. In vivo myocardial needle biopsy for determination of adenosine triphosphate and creatine phosphate was performed at the end of the experiment. The area of the left ventricle at risk was similar in both groups (control [n = 8], 20.2 +/- 1.6% versus verapamil-treated [n = 9], 23.1 +/- 2.9%; p = NS). The area of necrosis expressed as a percent of the area at risk was reduced in the verapamil-treated group compared with the control group (43.3 +/- 5.0% versus 63.1 +/- 6.8%, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Infarct size reduction: a review of the clinical trials

The most important finding to emerge from this review of experimental and clinical studies is that the earlier therapy is begun after the onset of symptoms of acute MI, the greater the potential for reduction of infarct size and possibly mortality. It is difficult to define a precise time after which therapy would not have an effect, since the clinical trials for each drug group vary significantly in respect to time of therapy initiation. In experimental studies, major salvage of ischemic myocardium occurs when the drug is given within two hours of coronary artery occlusion. If drug therapy is begun four to six hours postocclusion, then only minor or no reductions in infarct size will occur. The ability of any drug or intervention to reduce infarct size in humans would be optimized if therapy were begun less than four hours of onset of symptoms. With the realization of the wavefront phenomenon and the potential salvage of myocardium at risk with reperfusion, the introduction of reperfusion in the clinical setting with thrombolytic agents or other procedures becomes highly desirable. Clot-selective thrombolytic agents, such as tissue plasminogen activator, diminish the adverse effects and high costs of intracoronary thrombolytic therapy or PTCA. Consequently, it is probable that the initial procedure of choice would be the use of clot-selective thrombolytic therapy. Thrombolytic therapy only lyses thrombi and does not affect the underlying causes of the coronary artery occlusion. Therefore, therapy to reduce the chances of reinfarction and death must also be initiated. Percutaneous transluminal coronary angioplasty, in selected patients, should reduce the reocclusion rate. Beta-adrenoceptor blocking agents appear to be an excellent therapy for reducing mortality when administered chronically; these agents reduce myocardial oxygen consumption and reverse the imbalance between oxygen supply and oxygen demand caused by activation of the sympathetic nervous system and actions of catecholamines. Since thrombus formation has occurred at least once in patients who survive an MI, it is probable that the conditions for thrombus formation still exist. Therefore, institution of antiplatelet aggregating drugs, such as aspirin, would seem to be an appropriate prophylactic regimen. Beta blockers and possibly nitroglycerin have desirable effects when thrombolysis is unavailable. The efficacy of calcium-channel blocking agents on reduction of infarct size appears to be limited, although in the setting of stable and unstable angina postinfarction, these agents can play an important role.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of nitroglycerin-induced reduction of left ventricular filling pressure on diastolic filling in acute dilated heart failure.

Recent information has suggested that early diastolic filling may be influenced by the left ventricular filling pressure, especially in the failing left ventricle. Acute severe left ventricular dysfunction was induced in 14 dogs by severe left ventricular global ischemia produced by left main coronary artery microsphere embolization until the left ventricular end-diastolic pressure was greater than or equal to 20 mm Hg. To assess the importance of left ventricular filling pressure on left ventricular diastolic filling, nitroglycerin was infused and titrated to reduce left ventricular end-diastolic pressure to less than 15 mm Hg in seven dogs, whereas the remaining seven dogs were observed for 1 h after acute severe left ventricular dysfunction. In both groups of dogs, severe left ventricular dysfunction resulted in left ventricular dilation and elevation of end-diastolic pressure, reduction in area ejection fraction (echocardiographically determined) and an early redistribution of diastolic filling (increased filling fractions at one-third and one-half diastole) despite prolongation of the time constant of left ventricular pressure decline. Pressure-area plots shifted upward and rightward with severe left ventricular dysfunction and were unchanged at 1 h as were all other variables. Nitroglycerin infusion reduced left ventricular size and filling pressure, redistributed diastolic filling to later in diastole as characterized by reduced filling fraction at one-third diastole (left ventricular dysfunction 48.8 +/- 9.7%, nitroglycerin 17.9 +/- 7.9%, p less than 0.001) and shifted downward left ventricular pressure-area plots. Nitroglycerin also improved the time constant of relaxation (left ventricular dysfunction 83 +/- 15 ms, nitroglycerin 52 +/- 15 ms, p less than 0.001) and lengthened the diastolic filling period.(ABSTRACT TRUNCATED AT 250 WORDS)

The autoperfusion balloon angioplasty catheter limits myocardial ischemia and necrosis during prolonged balloon inflation

A new balloon angioplasty catheter with multiple proximal and distal side holes has previously been shown to allow significant protection from ischemia during a 3 min balloon inflation in a coronary artery. Because of the potential benefits of very long periods of inflation, 21 anesthetized thoracotomized dogs were randomized to left circumflex coronary artery occlusion with either a standard or an autoperfusion balloon catheter for 90 min. Nine dogs sustained ventricular fibrillation before completing the study, eight after standard balloon inflation and one after autoperfusion balloon inflation (p = 0.04). ST segment elevation was 0.45 +/- 0.13 mV after 15 min of standard balloon inflation versus -0.03 +/- 0.03 mV after autoperfusion balloon inflation (p less than 0.001). Regional myocardial blood flow was 0.02 +/- 0.01 ml/min per g after 30 min of standard balloon inflation compared with 0.78 +/- 0.23 ml/min per g in the group subjected to autoperfusion balloon inflation (p = 0.01). The area of necrosis/area at risk in the standard catheter group was 40.4 +/- 19.3% versus 1.2 +/- 1.2% for the autoperfusion catheter group (p = 0.01). Thus, the autoperfusion catheter preserves blood flow and limits myocardial ischemia and necrosis despite 90 min of balloon inflation.

Amelioration of ischemia during angioplasty of the left anterior descending coronary artery with an autoperfusion catheter

A new autoperfusion balloon angioplasty catheter with sideholes proximal and distal to the balloon--facilitating distal blood flow during inflation--was compared with standard angioplasty catheters in a prospective, randomized study with blinded data analysis. Hemodynamic and electrocardiographic markers of ischemia after 1 minute of standard or autoperfusion catheter inflations were compared with ischemia after control inflation with standard balloons. In the patient group randomized to standard balloon inflation only, ST-segment elevation after control inflation with a standard balloon catheter was 0.37 +/- 0.04 mV; ST-segment elevation after final balloon inflation with a standard catheter was unchanged at 0.35 +/- 0.04 mV (difference not significant). In the group randomized to the autoperfusion catheter, control inflation with a standard catheter resulted in 0.48 +/- 0.1 mV ST elevation; final inflation with the autoperfusion catheter demonstrated 0.16 +/- 0.09 mV ST elevation (p less than 0.005). Autoperfusion catheter inflation was continued for 2 minutes without change in electrocardiographic findings: ST segments remained at 0.08 +/- 0.03 mV, unchanged from 0.07 +/- 0.03 mV before angioplasty (difference not significant). Thus, while coronary angioplasty performed with standard catheters resulted in marked ST-segment elevation, in patients undergoing angioplasty with the autoperfusion catheter, ischemia was generally not seen, despite sustained balloon inflation for 2 minutes.

Effect of inotropic and vasodilator therapy on left ventricular diastolic filling in dogs with severe left ventricular dysfunction

Inotropic and vasodilator therapy for congestive heart failure improve left ventricular systolic performance by different mechanisms. However, the nature and extent to which diastolic filling is altered have not been well described. Acute severe left ventricular dysfunction was induced in 21 dogs by severe left ventricular global ischemia produced by left main coronary artery microsphere embolization until left ventricular end-diastolic pressure was greater than or equal to 18 mm Hg. Dobutamine was infused in seven dogs until the peak positive first derivative of left ventricular pressure (dP/dt) increased by greater than or equal to 33%. Nitroprusside was infused in seven dogs until left ventricular end-diastolic pressure was less than 15 mm Hg. Seven dogs were observed for 1 h after the induction of acute severe left ventricular dysfunction and served as the control group. In all groups of dogs, severe left ventricular dysfunction resulted in left ventricular dilation, reduction in area ejection fraction, elevation of left ventricular end-diastolic pressure and an early redistribution of diastolic filling (increased 1/3 and 1/2 filling fractions) despite a markedly abnormal time constant of relaxation. No changes were noted in any variable after 1 h of observation in the seven control dogs. Nitroprusside reduced left ventricular size and filling pressure, increased cardiac output, improved relaxation and redistributed diastolic filling to later in diastole as characterized by a reduced 1/3 filling fraction (19.4 +/- 7.4% versus 51.4 +/- 10%, p less than 0.001). The pressure-area curve was shifted downward and leftward.(ABSTRACT TRUNCATED AT 250 WORDS)

The cardiotonic agent amrinone does not increase anatomic infarct size.

The effect of the positive inotropic agent amrinone on anatomic infarct size induced by coronary artery occlusion and reperfusion in dogs is unknown, although previous studies have shown that amrinone increases indices of myocardial ischemia during very brief coronary artery occlusions. Thus, this study was performed to determine if amrinone changes anatomic infarct size and improves hemodynamics induced by 3 h of coronary occlusion and 3 h of reperfusion in anesthetized, open-chest dogs. Amrinone (1-mg/kg bolus followed by 6 mg/kg/h) or an equivalent volume of saline was administered intravenously for 3 h beginning 30 min postocclusion. The area at risk was 19.7 +/- 2.6% in the control group (n = 9) and 20.2 +/- 1.8% in the amrinone-treated group (n = 9; p = NS). The amount of the area at risk that developed infarction was 60.6 +/- 6.1% in the control group and 54.6 +/- 5.6% in the amrinone-treated group (p = NS). Pretreatment left ventricular end-diastolic pressure increased from 11.4 +/- 1.8 to 20.1 +/- 3.0 mm Hg (p less than 0.05) in the control group and from 10.8 +/- 1.3 to 17.3 +/- 1.3 mm Hg (p less than 0.05) in the amrinone-treated group following coronary artery occlusion. During coronary occlusion, amrinone administration significantly increased left ventricular maximum +dP/dt [+483 +/- 85 vs. -11 +/- 53 mm Hg/s (p less than 0.01) in amrinone vs. control group, respectively] and heart rate (+27 +/- 6 vs. -4 +/- 2 beats/min; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary Reperfusion Following Experimental Myocardial Infarction

Numerous studies have shown that early coronary reperfusion is feasible in the setting of evolving acute myocardial infarction in man. While early reperfusion reduces myocardial infarct size, there are potentially deleterious consequences of reperfusion. The concept of “reperfusion injury”, oxygen‐free radical damage, no reflow phenomenon, and stunned myocardium are discussed.

Effect of milrinone on acute myocardial infarct size

Abstract Milrinone has been reported to possess positive inotropic activity in normal anesthetized and conscious dogs, in anesthetized dogs with drug-induced heart failure, 1 and in patients with severe congestive heart failure. 2 Previous studies have suggested that inotropic stimulation of the infarcting heart could extend the amount of necrosis. 3 Whether milrinone has such an effect is unknown. Thus, the aim of this report was to investigate the effect of milrinone on acute myocardial infarct size and hemodynamics in an anesthetized canine model of acute myocardial infarction.