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Bile acid sequestrants, fibric acid derivatives (fibrates), hydroxy-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors ("statins"), and niacin are able to increase HDL-C serum concentrations to varying degrees. Bile acid sequestrants are the least effective, whereas niacin is the most powerful agent for increasing HDL-C levels. Because of 2 alternate metabolic pathways of niacin breakdown, flushing or hepatotoxicity can occur in patients taking niacin. These effects can be mediated in a carefully designed formulation of niacin that releases the drug at a predictable rate. Niacin has few drug interactions and is a relatively inexpensive means of increasing HDL-C. A combination formulation that combines niacin plus a statin has shown promise in ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Over the past two decades methamphetamine (MA) abuse has seen a dramatic increase. The abuse of MA is particularly high in groups that are at higher risk for HIV-1 infection, especially men who have sex with men (MSM). This review is focused on MA toxicity in the CNS as well as in the periphery. In the CNS, MA toxicity is comprised of numerous effects, including, but not limited to, oxidative stress produced by dysregulation of the dopaminergic system, hyperthermia, apoptosis, and neuroinflammation. Multiple lines of evidence demonstrate that these effects exacerbate the neurodegenerative damage caused by CNS infection of HIV perhaps because both MA and HIV target the frontostriatal regions of the brain. MA has also been demonstrated to increase viral load in the CNS of SIV-infected macaques. Using transgenic animal models, as well as cultured cells, the HIV proteins Tat and gp120 have been demonstrated to have neurotoxic properties that are aggravated by MA. In addition, MA has been shown to exhibit detrimental effects on the blood-brain barrier (BBB) that have the potential to increase the probability of CNS infection by HIV. Although the effects of MA in the periphery have not been as extensively studied as have the effects on the CNS, recent reports demonstrate the potential effects of MA on HIV infection in the periphery including increased expression of HIV co-receptors and increased expression of inflammatory cytokines.

Objective: To estimate differences in direct costs attributable to avoided hospitalizations and procedures during the years of the HOPE (Heart Outcomes Prevention Evaluation) study after the cost of treatment with ramipril or alternative angiotensin-converting enzyme inhibitor therapy was taken into account., Methods: A decision analytical model was developed to estimate the economic impact of reductions in hospitalizations and/or procedures both at annual increments and over the first 4 years of the HOPE study. The analysis compared the number of cardiovascular events per endpoint per year in the intervention and placebo group with hospitalization and procedural costs. Cost data were derived from the literature and inflated to the appropriate index year using the consumer price index., Results: For approximately 9000 patients studied, the gross estimated savings in direct costs for 297 events avoided were more than $5 million over 4 years. After the cost of treatment was deducted for both groups, the net estimated savings were $871 000 over 4 years., Conclusions: The results demonstrate that the use of ramipril provides cost-effective treatment for high-risk cardiovascular patients with an ejection fraction >40%.

The need to implement improved teaching methods in clinical pharmacology is critically important for health care globally. This need is driven by the overwhelming amount of information currently available on appropriate drug usage, by a proliferation of new biotechnology-derived pharmacologic agents, and by an expanded prescribing authority that is being granted to health professionals who have not traditionally had this responsibility and training. This discussion emphasizes the points that (a) the technology is available to share the best teaching materials for clinical pharmacology over the Internet, (b) clinical pharmacology organizations are best positioned to facilitate this exchange of educational materials, and that (c) continued discourse about problem-based learning and other curricular approaches to teaching clinical pharmacology is essential. The currently available information on the Internet includes case studies, slide sharing for lectures, educational programs and educational software. Clinical pharmacology organizations are not only starting to organize this information, but also to review the content of these programs and continuously add new material. These organizations have also developed a powerful tool through their journals in which to present educational series on rational therapeutics and to discuss educational approaches to instruction. Teaching forums, such as those presented annually at the American College of Clinical Pharmacology Annual Meeting, are essential to encourage discussion about teaching clinical pharmacology in the broadest context of the therapeutics, the economics and the legal aspects of clinical drug use.

Many antipsychotics are used to treat disorders other than schizophrenia, such as bipolar disorder. However, some of these agents are associated with cardiovascular side effects that can have serious or fatal implications for the patient. One dangerous side effect is QT prolongation, which can lead to torsades de pointes and ventricular arrhythmia. The group of drugs labeled as antipsychotics is diverse, making it challenging for the clinician to keep track of which agents cause which effects and important for the clinician to learn to identify signs of cardiovascular side effects and manage those events when they occur.

The pharmacology of angiotensin-converting-enzyme (ACE) inhibitors and their role in the renin-angiotensin system (RAS) are described, and pharmacokinetic properties and common adverse events are presented. ACE inhibitors play a vital role in the RAS by regulating the potent vasoconstrictor angiotensin II. All ACE inhibitors share the same basic structure; however, they can be separated on the basis of their functional (binding) group: carboxyl, sulfhydryl, or phosphinyl. These functional groups are, in part, responsible for differences in the pharmacokinetic and safety profiles of these agents. Captopril and lisinopril are the only ACE inhibitors that are not prodrugs requiring activation through hepatic biotransformation. Differences among the ACE inhibitors in lipophilicity are described; fosinopril has the greatest lipophilicity and lisinopril the least. ACE is found in numerous tissues, and there is increasing evidence of differences among ACE inhibitors in their ability to inhibit tissue ACE. Most ACE inhibitors are eliminated mainly by the kidneys and to a lesser extent through the liver. Lisinopril is the only ACE inhibitor that does not require hepatic metabolism. In the selection of an ACE inhibitor for once-daily use to treat hypertension, differences in trough-peak ratios are clinically relevant. Fosinopril, ramipril, and trandolapril have minimum trough-peak ratios of 50% or greater. ACE inhibitors are generally well tolerated, with hypotension, cough, and hyperkalemia being the most frequently reported adverse effects for the entire class. Drug interactions across the ACE inhibitor class as well as agent-specific interactions are described. Factors to be considered in the selection of an ACE inhibitor include differences in potency, affinity for ACE, pharmacokinetics, and toxicity that are related to structural properties of the drug; whether the trough-peak ratio enables use of a once-daily dose; and potential adverse effects related to a drug's functional (binding) group.

The presence of hypertension in individual patients confers significant risk in terms of coronary artery disease, myocardial infarction, stroke and congestive heart failure. However, it is also a modifiable risk factor, as risk may be decreased through either lifestyle changes or pharmacotherapy to reduce the elevated blood pressure. Over the past 3 decades, there has been strenuous debate among clinical scientists regarding the role played by racial background in both the pathogenesis and response to pharmacotherapy. A number of studies, such as the third National Health and Nutrition Examination Survey (NHANES III) have demonstrated a higher prevalence of hypertension in black populations. The Hispanic Health and Nutrition Examination Survey (HHANES) suggested that the prevalence of hypertension in Hispanics of Caribbean descent was similar to that of African Americans, while Mexican Americans had lower rates of the disease. It appears that the pathophysiological consequences of elevated blood pressure may also be more severe in black patients. Thus, these patients will have a worse prognosis than their white counterparts at any given blood pressure level. The incidence of end-stage renal disease has been reported to be as much as 17 times more common in African American patients. A number of individual factors have been postulated for these differences including increased sodium intake, differences in sodium handling, decreased potassium intake, decreased calcium intake, elevated fasting insulin levels, lower levels of plasma renin activity and urinary kallikrein excretion. These differences in prevalence and pathophysiology have resulted in recommendations for differential therapeutic approaches in the treatment of hypertension. A major trial conducted in the Veteran Affairs Medical Centers in the USA noted that African Americans are generally more responsive to diuretics and calcium channel blockers than to ACE inhibitors or beta-blockers. However, it has been reported that this resistance may be overcome by increasing the dose of these agents. It has been postulated that these differences may be related to lower plasma renin activity noted in the black population, since diuretics and calcium channel blockers appear to be better suited to this population. These differential therapeutic recommendations will be reviewed in light of our current knowledge of the disease.

The educational value of case reports and the four main categories of information they include are described. Checklists and directions for effective spoken presentations are detailed, so the presenter knows not only the information the audience is likely to expect, but the techniques that will help convey the information. A typical case as it might be presented during rounds is shown with questions for discussion. Guidelines for writing case reports for publication also are included, such as journal selection, descriptions of the standard and nonstandard case formats, the content of the three main sections of the typical case report, and the directions that journal editors typically ask reviewers to follow.

Calcium antagonists continue to be used to treat congestive heart failure (CHF), despite clinical evidence that they may exacerbate the disease. The systemic vasodilatory actions of these drugs make them potentially attractive for use as afterload reducing agents in patients with CHF. Newer calcium antagonists of the 1,4-dihydropyridine class, with claims of little or no negative inotropic properties and minimal effects on the sympathetic nervous system, seem a promising treatment of this disease. All calcium antagonists, however, consistent with their ability to block transmembrane calcium transport in cardiac muscle cells, are intrinsically negative inotropes. Moreover, clinical trial data are inconclusive about the ability of these newer calcium antagonists to activate the sympathetic nervous system. The relatively small numbers of patients with CHF, the differing degrees of CHF in different patient groups, and the variation in route of administration, dosage, and schedule of hemodynamic measurements make analyses of published data difficult. Although some patients with CHF respond positively to treatment with calcium antagonists, there is great individual variability of response, and the majority of patients show deterioration of myocardial function when taking calcium antagonists. Until conclusive clinical evidence of the safety and effectiveness of calcium antagonists in the treatment CHF is available, they should not be used to treat this disease unless individual patient characteristics clearly indicate a positive benefit/risk ratio.

The prevalence of hypertension increases with age. Multiple physiologic factors are involved in the development of hypertension in the elderly. Alpha1-adrenergic blocking agents lower blood pressure through a reduction in total peripheral resistance. Prazosin, terazosin, and doxazosin have been shown to be equally effective in reducing blood pressure in older persons. The bioavailability, terminal elimination half-life, and volume of distribution of prazosin is increased in the elderly. Hybrid drugs, such as ketanserin, urapidil, and indoramin are also effective in lowering blood pressure. Ketanserin seems to have a greater effect on blood pressure reduction in persons older than 60 years of age. Alpha1-adrenergic blockers may be used safely in patients with diabetes, asthma, and hyperlipidemia.

The incidence of both systolic and diastolic hypertension is increased in elderly patients, therefore antihypertensive drugs are commonly used in this population. In addition to changes in blood pressure, the aging process also causes numerous changes in other physiological parameters, resulting in altered pharmacokinetic and pharmacodynamic responses to the drugs. The dosage regimens for thiazide diuretics and amiloride must be individually titrated in the elderly patient, since the elimination of these agents decreases concurrently with decreased renal function, as indicated by compromised creatinine clearance. The initial doses of the calcium antagonists should be decreased in elderly patients, since representative compounds from all 3 chemically heterogeneous classes have been shown to have decreased clearance in these patients which appears to be primarily due to the status of hepatic function in the patient. However, with verapamil, the dosage should be further decreased in association with compromised renal function. The dosage of the angiotensin converting enzyme (ACE) inhibitors should be adjusted according to renal function rather than age. Lisinopril, which is primarily eliminated unchanged, is usually given in lower doses in the elderly, and doses of both captopril and enalapril may need to be reduced, depending on renal function. While there is no need to adjust the dosage regimen for the alpha-adrenoceptor blocking drugs (prazosin, terazosin), caution should be used with the beta-adrenergic blockers, particularly the hydrophilic agents, since they are renally eliminated. Labetalol may be a suitable alternative beta-blocker for the elderly patient, since its pharmacodynamic properties of decreased systemic vascular resistance without changes in heart rate or stroke volume are preferential for the elderly patient, and its pharmacokinetics are relatively unchanged in this population. Drugs that act primarily through the central nervous system, such as clonidine, methyldopa and guanfacine, require smaller doses in the presence of renal dysfunction. In contrast, guanabenz is metabolised primarily by the liver, so it would appear to be useful in elderly patients with renal dysfunction despite the lack of studies in this population. Guanadrel, an adrenergic neuron blocking drug, also requires a dosage reduction in patients with impaired renal function. In addition to the pharmacokinetic changes that occur in the elderly patient, pharmacodynamic changes may also be anticipated due to receptor modifications. Older patients have a decrease in beta-receptor sensitivity, while alpha-receptor sensitivity does not change. When designing the dosage regimen for a senior patient with hypertension, the combination of all these variables must be considered.

The attitudes and knowledge of pharmacists in Nebraska regarding children's learning disabilities were surveyed by questionnaire. One hundred thirty-three pharmacists responded. The results were analyzed according to type of practice (community, chain and hospital) and age (20--30 years, 31--40 years, 41--50 years, and 51 years and over). The results indicate that pharmacists are being asked about learning disabilities. Overall, 53% of the pharmacists responding had been asked about learning disabilities by parents, physicians, teachers or others. No significant interactions were found between the type of practice and age, and no significant main effect for type of practice was found in the ANOVA results for knowledge scores or attitude scores. Even though there were no differences owing to age in pharmacists' knowledge of learning disabilities, age was found to have a significant effect on attitudes toward increased pharmacist involvement in monitoring behaviors of learning-disabled children; the younger groups had a more positive attitude. The pharmacist seems to have the knowledge and attitudes required to become more actively involved in monitoring the medications and behaviors of children with learning disabilities.

Diltiazem binding was measured by equilibrium dialysis in the serum of five healthy male subjects, aged 22 to 34 years, at seven serum diltiazem concentrations ranging from 0.03 to 2.06 micrograms/ml. The percentage of unbound diltiazem ranged from 19.6 +/- 3.1 to 22.6 +/- 4.1 (mean +/- S.D.) and was independent of serum diltiazem concentration. Serum diltiazem binding was also examined in the presence of six drugs that might be used concurrently with diltiazem in patients being treated for cardiac disease. The percentage of unbound diltiazem was not influenced by digoxin, hydrochlorothiazide, phenylbutazone, propranolol, salicylic acid, or warfarin at therapeutic concentrations of these drugs over the therapeutic range of diltiazem.

Animal and clinical studies have demonstrated the efficacy of calcium channel blockers in reducing blood pressure, especially in older patients whose hypertension is characterized by increased peripheral vascular resistance. Their chemical heterogeneity, which permits targeted therapy, as well as their minimal side effects, drug interactions, and clinical utility in numerous pathophysiologic states common to the elderly, enhance the suitability of calcium channel blockers in treating mild to moderate hypertension in this subgroup. This is particularly relevant for those patients who have concomitant conditions, such as diabetes, chronic obstructive pulmonary disease, or peripheral vascular disease, and for whom many of the more traditional antihypertensive drugs are either contraindicated or might cause a worsening of the disease.

The calcium entry blockers are used in a wide variety of clinical situations. Coexisting disease states, such as renal or hepatic dysfunction, may require individualized dosing of these agents. The physiologic changes associated with aging may also affect the pharmacokinetic properties of the drugs. If calcium entry blockers are used concurrently with other medications, dosage adjustment or selection of an alternative drug may be needed. Drug interactions between calcium entry blockers and cimetidine, digoxin and quinidine appear to be clinically significant. Individualized dosing in patients who have coexisting disease or who are using other medications is essential to achieve an adequate therapeutic response and avoid adverse effects. Considerations to attain an optimal response in such situations are presented.

In a randomized, double-blind, dose-ranging trial, the acute antihypertensive effects of 7.5, 15, 30, 45, 60, 90, and 120 mg single daily doses of urapidil were compared with those of placebo in 10 patients with essential hypertension. Patients were randomized to either urapidil or placebo, such that each active drug day was followed by a placebo washout day. Blood pressure and heart rate responses were measured in the supine position, immediately upon standing, and after 3 to 5 minutes of standing for each dose. A variable but significant reduction in systolic and diastolic blood pressures that lasted from 4.5 to 8 hours was observed primarily at the 60, 90, and 120 mg doses (P less than 0.05). The maximum reduction in diastolic blood pressure occurred in the standing position at 3 to 5 hours after dosing. When urapidil was compared with placebo, a change from the supine to the standing positions produced a significantly larger reduction in systolic and diastolic blood pressures (P less than 0.05) but no significant change in heart rate. This suggests an acute blood pressure lowering effect of urapidil that occurs predominantly in the standing position and that does not significantly increase heart rate.

The increasing use of the calcium-entry blockers has led to an enhanced potential for drug interactions with a variety of different drugs. Interactions with cardiovascular agents are of great concern because of the consequences of synergistic negative dromotropism or inotropism. We therefore assessed the concomitant use of calcium-entry blockers and cardiac glycosides, beta-blockers, antiarrhythmic agents, and other chemical types of calcium-entry blockers from a standpoint of clinical relevance. We also evaluated reported drug interactions with H2-receptor antagonists, anticonvulsants, lithium carbonate, general anesthetics, cytostatic drugs, rifampin, and sulfinpyrazone with regard to clinical implications, along with the modification of calcium-entry blocker dose for concurrent social drug use, such as cigarette smoking and ethanol intake. Although a myriad of potential drug interactions exists for these agents, combination therapy is still a reasonable alternative if doses are adjusted appropriately.

GABA levels were measured in various areas of rat brain at 3 or 6 hour intervals for a period of 24 hours in animals adapted for 3 weeks to a programmed-lighting schedule. On the normal cycle rats were illuminated from 08 to 20 hours; on the reverse cycle, from 20 to 08 hours. The cerebellar pattern is unimodal with a peak in the dark at 06 hours and a trough in the light at 18 hours which coincides with maxima and minima of motor activity in the nocturnal rat. The cortical pattern also peaks in the dark at 06 hours but is less well-defined. On the reverse illumination cycle both patterns peak significantly in the dark at 18 hours. Only the cerebellum displays significant differences when averaged GABA levels for light and dark phases are compared. A circadian pattern peaking in the dark described for GABA levels of the corpora quadrigemina which is partly-reversed by reversing the photoperiod. The rhythm in thalamus-hypothalamus which peaks in the dark is complex, consisting of an ultradian rhythm super-imposed on a circadian one. The former rhythm appears to be endogenous and unaltered by a change in the illumination cycle; the latter exogenous since it varies with the illumination cycle. Lower GABA levels in rat brain were found after photoperiod reversal.

We conducted a double-blind, placebo-controlled crossover study of verapamil HCl in the prophylaxis of chronic migraine headaches. Verapamil significantly reduced both headache frequency and duration with few side effects. The drug may be useful for a segment of the migraine population refractory to other prophylactic agents or for those who cannot tolerate the side effects of other drugs.

Dopamine levels were measured in the corpus striatum, upper and lower brainstem at 6 hour intervals for a period of 24 hours in rats adapted for 3 weeks to either of two concomitantly-conducted lighting programs. On the normal cycle the animals were illuminated from 08(00)--20(00); on the reverse cycle, from 20(00)--08(00). In the corpus striatum dopamine levels peaked during the dark phase of both illumination cycles indicating that 24 hour rhythm is exogenous. On the other hand, in the upper and lower brainstem, dopamine peaks occurred in both light cycles at 00(00) or 06(00) indicating that these 24 hour rhythms are endogenous in nature. Photoperiod reversal resulted in significantly elevated dopamine levels in the corpus striatum and lower brainstem. The existence of a stress as well as a seasonal factor which affects striatal dopamine is suggested.

Intraperitoneal administration of allylglycine resulted in a hypothermic response in rats. At a dosage of 90 mg/kg, a significant decrease in temperature was noted at 4 and 8 hr after administration, but no significant difference was noted at 12 hr. The same dose administered intraperitoneally to decapitated rats did not result in a hypothermic response, and intraventricular administration resulted in a rapid onset of hypothermia after 1 hr. These findings are indicative of a central site of action for the allylglycine-induced hypothermia. Quantitative assay of hypothalamic monoamines (norepinephrine, serotonin, and dopamine) did not show any significant changes at 4, 8, and 12 hr postadministration when compared to controls. A significant decrease in hypothalamic gamma-aminobutyric acid was noted at each of these time points when compared to controls. These data suggest an important role for gamma-aminobutyric acid in mammalian thermoregulatory control.

The absorption, distribution and elimination of diltiazem hydrochloride in rodent and canine species are reviewed. The drug is well absorbed but undergoes first pass metabolism after oral administration. Diltiazem is extensively distributed, and 52 to 81 percent is bound to serum protein, depending on the species studied. Diltiazem is metabolized in the liver by several pathways; deacetylation, N-demethylation, and O-demethylation are the primary degradative steps. The metabolites are excreted in urine and feces, indicating that biliary excretion occurs. There is some evidence for enterohepatic cycling. Diltiazem is rapidly eliminated (t 1/2 = 2.24 hours) in beagle dogs, and the relatively short half-life appears to be a result of the high level of plasma clearance (46.1 +/- 4.8 ml/min/per kg body weight). A comparison of the plasma diltiazem clearance with hepatic blood flow in the dog indicates that the drug is eliminated at a rate dependent on hepatic blood flow.

The effects of equal doses of three sedative-hypnotics, phenobarbital, methaqualone, and methyprylon, on the hepatic mixed function oxidase enzymes of the rat were investigated and compared. After 5 days of pretreatment, phenobarbital and methyprylon significantly increased aminopyrine demethylation, aniline hydroxylation, and cytochrome P-450 content in hepatic microsomes. Methaqualone pretreatment only increased hepatic aminopyrine demethylase activity and wet liver weights. After 29 days of pretreatment, phenobarbital significantly increases aminopyrine demethylase, aniline hydroxylase activity, liver weight and cytochrome P-450 content. Methaqualone only produced a significant increase in wet liver weight.