Secondary prevention in a cardiology group practice and hospital setting after a heart-care initiative.

The American Heart Association (AHA) Consensus Panel Statement for Preventing Heart Attack and Death in Patients with Coronary Disease provides recommendations for the secondary prevention of heart disease in at-risk patients. Blackstone Cardiology Associates of Pawtucket, Rhode Island, undertook an initiative in their practice implementing secondary-prevention guidelines in patients with coronary artery disease. This retrospective study evaluates practice patterns for the management of hyperlipidemia for a cardiology group in an ambulatory and hospital setting after the institution of a physician-supervised, nurse-based disease management program. Practice patterns in patients with established coronary heart disease treated in a lipid center compared with non-lipid-center settings were evaluated. Parameters evaluated included documenting low-density lipoprotein (LDL) cholesterol, presence of lipid-lowering therapy, and achieving the National Cholesterol Education Program II (NCEP II) goal of LDL-cholesterol levels < or =100 mg/dL in patients with preexisting coronary artery disease. A total of 352 patients met inclusion criteria in the lipid-center setting and were compared with 289 non-lipid-center consecutively chosen patients. Age and gender differences were also evaluated. Inpatient medical records from a 254-bed Brown University-affiliated teaching hospital were also evaluated for lipid profile, achievement of NCEP II goal, and use of lipid-lowering medication on admission and discharge. The most recent LDL-cholesterol values of patients followed in the lipid-center and in the non-lipid-center setting of the Blackstone Cardiology Associates were compared. Blackstone Cardiology Associates consists of 4 cardiologists and 4 advanced-practice nurses. Achievement of LDL-cholesterol goal was higher in both the lipid-center and non-lipid-center settings compared with baseline. A smaller percentage of patients at goal in the lipid setting is likely due to referral bias resulting in patients with more difficult-to-manage mixed dyslipidemias and behavior-management issues ending up in the lipid center. There were no apparent sex differences at goal, and more elderly (age > or =65 years) achieved goal in the lipid clinic center. In the non-lipid-center setting, more males were at goal and had a lower mean LDL-cholesterol level.

Economic and health state utility determinations for schizophrenic patients treated with risperidone or haloperidol.

The current study uses utility analysis to assess economic and quality-of-life benefits of risperidone in patients with chronic schizophrenia. A retrospective analysis was performed on Positive and Negative Syndrome Symptoms (PANSS) data obtained from the published Canadian multicenter risperidone trial (part of the North American trial). Cluster analysis applied to endpoint PANSS scores, including all patients (N = 135), identified three clusters representing 130 patients with mild, moderate, and severe symptomatology. A narrative health state profile was written for each cluster, and 100 psychiatric nurses from Washington, DC, were asked to assign preference ratings to each one using linear analog and standard gamble (SG) methods. Mean utility values (confidence interval 95%) obtained from the SG ratings for the three health state profiles were 0.61 +/- 0.069 (mild); 0.36 +/- 0.073 (moderate); and 0.29 +/- 0.071 (severe). The mild health state (including the majority of risperidone 6 mg-treated patients) was rated by nurses to have a 0.25 +/- 0.0501 greater utility than the moderate health state (composed of the majority of haloperidol-treated patients). The results of these utility evaluations (SG) by the nurses were related to the clinical outcome for three of the six drug treatment groups (N = 65) by multiplying the percentage of patients in each of the three clusters, both at baseline and end-point, who were receiving risperidone 6 mg/day, haloperidol, or placebo, by the utility value for the health state assigned to that cluster. The gain in utility for risperidone-treated patients was 2.6 times higher (0.125) compared with haloperidol-treated patients (0.049), and 7 times higher compared with placebo (-0.021). After multiplying the gain in utility of each treatment by the remaining expected life span for men and women, it was found that risperidone-treated patients obtained more than twice as many quality-adjusted years as haloperidol patients. The incremental drug treatment cost divided by the incremental benefit of risperidone versus haloperidol was found to yield a favorable, generally accepted cost-utility ratio.

Effects of phenytoin, carbamazepine, and clonazepam on cortex- and amygdala-evoked potentials in partially kindled rats.

The kindling technique has been reported to produce a long-lasting enhancement in both the early and late phases of evoked potentials triggered from the kindled focus. It also alters paired-pulse facilitation and depression in the pathways which support these phenomena. The present experiment was designed to determine whether the drugs which antagonize secondary generalization in the kindling model also antagonize kindling-enhanced excitation in the pathways leading out of the focus. Multiple doses of phenytoin, carbamazepine, and clonazepam were therefore tested against single- and double-pulse evoked potentials triggered from the focus in rats that had been subjected to parital kindling from either the amygdala or the cortex. Responses were recorded in monosynaptic sites and in the mesencephalic reticular formation--a polysynaptic site thought to play an important role in secondary generalization. No drug-related effects were found on early evoked potential components, either in the single-pulse or the double-pulse paradigm. Kindling-enhanced late components ("late waves"), however, were clearly and selectively antagonized by clonazepam.

Valproic acid disposition in rabbits during chronic treatment with Escherichia coli endotoxin.

The disposition of valproic acid (VPA) in rabbits was studied after chronic treatment with Escherichia coli endotoxin. Endotoxin (1-2 micrograms/kg) was administered daily to 10 male New Zealand white rabbits for 5 days. On day 5, 50 mg/kg of VPA was given iv during the time of the peak febrile response. Blood samples were drawn at appropriate time intervals and analyzed for free and total VPA levels as well as plasma proteins and free fatty acids. The data were compared with similar control experiments performed 2 weeks before and after endotoxin treatment. Pharmacokinetic analysis indicated that the changes in free VPA clearance after endotoxin were related to the change in the febrile response during chronic treatment (r = 0.77; p less than 0.05); that is, animals which developed tolerance to the febrile response showed elevated drug clearance, whereas nontolerant animals showed decreased clearance of VPA.

Effects of carbamazepine and its epoxide metabolite on amygdala-kindled seizures in rats.

Fourteen animals with stable generalized kindled seizures received three doses of carbamazepine and its epoxide (12.5 to 50 mg/kg IP) in a crossover design. Both compounds suppressed the secondarily generalized convulsion but only affected the partial seizure from the amygdala to a limited extent. The parent drug and the metabolite were equipotent against both seizure types. The results confirm the belief that carbamazepine epoxide has anticonvulsant properties and suggest that it may exert a major therapeutic effect in humans.

Pharmacokinetic interactions of antiepileptic drugs.

The problem of antiepileptic drug interactions is significant in that many epileptic patients are treated with multiple drug therapy. Moreover, patients may also be receiving additional medication for other concurrent disorders. Most drug interactions are pharmacokinetic, involving changes in absorption, protein binding, metabolism, or excretion. As a result, plasma levels of the antiepileptic drug may decrease leading to exacerbation of seizures. Alternatively, plasma levels may rise resulting in toxic side effects. Similar changes may also occur with drugs given for other disorders. In this paper, possible mechanisms of drug interactions are discussed. This is followed by a description of clinically significant interactions involving phenytoin, carbamazepine, barbiturates, valproic acid, benzodiazepines, and succinimides. Potentially serious drug interactions may be minimized by using as few medications as possible and by regularly monitoring plasma levels of antiepileptic drugs.

Pharmacokinetics of enteric-coated valproic acid.

Five adult epileptic patients received 1,000 mg of valproic acid (Depakene) in both the regular and the enteric-coated form. Serum valproic acid levels were determined at suitable intervals after drug administration. Pharmacokinetic parameters were equivalent for both preparations except for an absorption lag with the enteric-coated form. The relative bioavailability of the two compounds was similar across the group of patients, although there were marked differences between individual subjects. Close supervision of valproic acid serum levels is suggested after a change in drug formulation.

Effects of phenytoin, carbamazepine, and clonazepam on cortex- and amygdala-evoked potentials.

Multiple doses of phenytoin, carbamazepine, and clonazepam were tested against single- and double-pulse evoked potentials. Evoked responses were triggered from either the amygdala or the cortex and were recorded in both monosynaptic sites and the mesencephalic reticular formation (MRF). In accordance with previous studies of spinal potentials, it was expected that all three drugs would display a depressant action. Contrary to expectation, only clonazepam had any significant effect, and this drug was effective only against potentials triggered in the amygdala and recorded in the MRF. These data appear inconsistent with the traditional belief that anticonvulsants block seizure spread by antagonizing transmission in neural pathways.

Effects of carbamazepine, clonazepam, and phenytoin on seizure threshold in amygdala and cortex.

This experiment was designed to determine whether or not the stronger effect of anticonvulsants on cortex than on amygdala focal seizures was due to a greater elevation of cortex seizure threshold. The effects of several doses of carbamazepine, clonazepam, and phenytoin were examined on the threshold for electrically induced afterdischarge in amygdala and cortex in 71 rats. All three drugs were found to be effective in increasing the seizure threshold with greater effects being produced in the cortex than in the amygdala. Carbamazepine produced the largest threshold increase in both foci, and clonazepam produced the weakest effects. These data are comparable to previous data on drug action against focal or partial seizures, and suggest that anticonvulsants may control partial attacks through their action on the local seizure threshold. This theory of anticonvulsant drug action adds to the common belief that carbamazepine and phenytoin act primarily by blocking seizure spread.

Development of a new pharmacological seizure model: effects of anticonvulsants on cortical- and amygdala-kindled seizures in the rat.

The potency of eight standard anticonvulsants was tested in dose-response studies on kindled rats. Animals with either amygdala- or cortical-generalized seizures were used, and the effects of drugs were assessed on: (1) amygdala focal activity; (2) cortical focal activity; and (3) the generalized convulsion triggered from either focus. Ethosuximide, which is used against absence attacks, was not effective at subtoxic levels against any type of kindled seizure. The seven other drugs, all of which are effective against tonic-clonic seizures, were found to be: (a) most potent against generalized convulsive seizures; (b) slightly less potent against cortical focal activity; and (c) only partially effective against amygdala focal activity even at high (toxic) doses. The effect of these drugs on kindled seizures closely parallels their known clinical effects against (respectively) tonic-clonic, simple partial, and complex partial attacks. It is concluded that the kindling preparation could provide new pharmacological models for several different types of clinical seizure. Its most important use, however, is likely to be as a model for complex partial seizures, since there is at present no satisfactory pharmacological model for these common and drug-resistant attacks.