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.

Reduction of hospital days in chronic schizophrenic patients treated with risperidone: a retrospective study.

Hospital costs for chronic schizophrenic patients consume a major share of the cost of mental health care. Despite the success of numerous community mental health programs, repeated hospital admission of schizophrenic patients is a significant problem. Effective therapy and compliance with that therapy are two important factors in reducing hospitalization. Adverse effects of antipsychotic agents, particularly extrapyramidal symptoms (EPS), negatively influence compliance. A new antipsychotic agent, risperidone, has demonstrated efficacy against both positive and negative symptoms of schizophrenia and has been associated with a low incidence of EPS. To assess the potential of risperidone therapy to reduce the number of days in the hospital, a retrospective analysis was undertaken of data from a year-long clinical trial of risperidone. For 27 patients who had completed 365 days of open-label therapy with risperidone, the number of hospital days during this period was compared with the number of hospital days in the preceding 365-day period, when the patients were receiving conventional antipsychotic medication. The mean number of hospital days was reduced from 106 to 85 days, for a 20% reduction (P = 0.003) after the initiation of risperidone. Three subgroups of patients were apparent: (1) those who had spent no time in the hospital in the pre-risperidone year, (2) those who had been continuously hospitalized in the pre-risperidone year, and (3) those who had spent part of the pre-risperidone year (3 to 165 days) in the hospital. A 73% reduction (P = 0.0009) in mean hospital days (from 49 to 13 days) was achieved in the third subgroup (n = 14). These findings suggest that risperidone may have a role in reducing hospital days for the chronic schizophrenic population.

Breast self-examination for visually impaired women.

Regularly practiced breast self-examination (BSE) has been demonstrated to be an effective method in the early detection of breast abnormalities. Women are becoming increasingly aware of the importance of BSE as a means of self-health care and are seeking instruction on how to perform such examinations properly. Unfortunately, not all women have equal access to BSE instruction. This project addresses the need for BSE instruction specifically tailored to meet the needs of visually impaired women. A review of existing sources revealed that no formal methods of BSE instruction are being used to meet the needs of this population. The participants in this study included 20 women between the ages of 30 and 75 years, all of whom are partially sighted or legally blind. The women participate in life skills classes on a regular basis at a county association for the blind. The authors conducted an instructional seminar demonstrating BSE and used methods which focus on the senses of touch and hearing. According to the authors, the instructional seminar can result in an increased self-awareness of the importance of BSE and help to meet the unique needs of the visually impaired women.

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.

Reduction of polypharmacy in epileptic patients.

An attempt was made to reduce polypharmacy in 90 epileptic patients. All patients received their original drug regimen for at least six months and were followed up for a minimum of 16 months after reduction of polypharmacy. In 72 patients (80%), the average number of drugs administered was reduced from 2.75 to 1.49. In 39 of these (54%), a reduction was made to single drug therapy. Either no change or an improvement in seizure control was observed, and side effects decreased in many patients. In 18 patients (20%), medications could not be withdrawn. In nine of these, another drug was required for seizure control. In the remaining nine, more frequent seizures necessitated a return to the previous regimen. The critical variable predicting unsuccessful reduction of polypharmacy was the presence of multiple concurrent seizure types.

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.

Inhibition of beta-amino acid transport by diamide does not involve the brush border membrane surface.

Diamide (dicarboxylic acid bis-(N,N-dimethylamide) has been shown in previous studies to block the uptake of the beta-amino acid taurine at its high affinity transport site in rat renal cortex slices. Diamide may act by increasing the efflux of taurine from the slice. Studies performed in rat slices again indicate enhanced efflux over 8-12 minutes. The time course of reduced glutathione (GSH) depletion from renal cortex is similar, indicating a potential interaction between GSH depletion and inhibition of taurine accumulation. Diamide further blocks the uptake of taurine by collagenase-isolated renal tubules in a dose-dependent fashion with greater inhibition at 20 minutes than at 5 minutes. The effect of 9 mM diamide on the Na+ -dependent accumulation of taurine (10 and 250 microM) by brush border membrane vesicles was examined, and the taurine uptake value both initially and at equilibrium was the same in the presence and absence of diamide. That the effect in tubules is greater at 20 minutes than at 5 minutes is consistent with the idea that diamide enhances efflux of taurine immediately after exposure of tubules to taurine, or that diamide influences some intracellular process, requiring a time interval before this action is observed. Isolation of the brush border surface and subsequent transport studies of taurine are not influenced by diamide. Thus, diamide inhibition of taurine uptake does not involve physiochemical alteration of the membrane surface where active amino acid transport occurs, despite the thiol-oxidizing properties of this agent. Further, these studies suggest that diamide either acts at the basolateral surface, rather than the brush border surface of rat renal cortex or requires the presence of an intact tubule, capable of metabolism, prior to its inhibitory action.

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.

Renal adaptation to alteration in dietary amino acid intake.

The nonessential beta-amino acid taurine, which is inert in renal tissue, was used to study the renal adaptation to dietary taurine change. Three isoproteinic diets were employed: HTD--high in taurine, NTD--normal taurine, and LTD--deficient in the taurine precursors cysteine and methionine. When compared with NTD, HTD resulted in an increase in the urinary excretion and fractional excretion of taurine, whereas LTD led to a decrease in urinary excretion and fractional excretion of taurine. In vitro studies demonstrated an increase in the Vmax of the high-affinity, low-capacity uptake system with no change in "apparent" Km following LTD. Complete adaptation developed within days after the diet was changed (NTD to HTD = 3 days; NTD to LTD = 3-6 days). These studies demonstrate that the renal response to altered dietary amino acid can be evaluated and that adaptation occurs for the beta-amino acid taurine. The renal response serves to conserve taurine during periods of deprivation and to dispose of taurine during periods of excess. The renal adaptation to restricted taurine intake seems to occur through an increase in transport sites (increased Vmax) or change in flux at the transport sites, with no change in transport affinity (unaltered apparent Km).

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.

Valproic acid therapy for complex partial seizures. Its efficacy and toxic effects.

Twenty-four adult outpatients with poorly controlled complex partial seizures were treated with valproic acid. Previous therapy with antiepileptic agents was continued to maintain stable plasma drug levels. Initially 12 patients experienced greater than 50% seizure reduction. Only five patients maintained longterm benefit. In the other seven patients a tolerance developed to valproic acid's efficacy. Duration of seizure control seemed to be a function of initial seizure frequency. Toxic effects were generally mild. No hepatotoxic effect was noted and no hematological abnormalities developed. Weight changes occurred in 17 patients (14 gained weight) and five patients experienced a postural tremor. Eighteen patients experienced nausea.

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.