Issues surrounding tight glycemic control in people with type 2 diabetes mellitus.

OBJECTIVE: To review the prospective evidence surrounding the issue of tight glycemic control in people with type 2 diabetes mellitus and resultant long-term complications. DATA SOURCE: Conference proceedings and a MEDLINE search (1966-February 1998) identified pertinent English-language publications on type 2 diabetes in humans. Key search terms included insulin resistance, diabetes mellitus, non-insulin-dependent, macrovascular complications, microvascular complications, and intensive glycemic control. STUDY SELECTION: Selection of prospective epidemiologic and clinical studies were limited to those focusing on the management of type 2 diabetes. All articles with pertinent information relevant to the scope of this article were reviewed. DATA SYNTHESIS: The pathophysiology of type 1 and type 2 diabetes differ; however, both share chronic complications that significantly affect morbidity and mortality. People with type 1 diabetes have an absolute deficiency of insulin, whereas people with type 2 diabetes have varying degrees of insulin resistance and an inadequate compensatory insulin secretory response. The Diabetes Control and Complications Trial (DCCT) has clearly indicated that intense control of blood glucose in type 1 diabetes prevents and slows the progression of microvascular (i.e., retinopathy, nephropathy) and neuropathic complications. The Kumamoto study showed similar results in nonobese patients with type 2 diabetes. Intense insulin therapy in both populations has proven advantageous, thus supporting a common pathophysiologic process for the microvascular and neuropathic complications. Trends were seen toward fewer macrovascular (atherosclerotic disease) complications in the intensive insulin arm of the DCCT. Conversely, trends were seen toward an increase in macrovascular complications in the VA Cooperative study in people with type 2 diabetes using intensive insulin therapy. This may suggest a discordance in the pathophysiology of macrovascular disease between type 1 and type 2 diabetes. Additionally, it remains uncertain whether tight glycemic control prevents the onset or slows the progression of macrovascular disease. Two studies (the University Group Diabetes Program and the Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes) to date have examined pharmacotherapy options for patients with type 2 diabetes and resultant macrovascular complications. It has yet to be determined whether any therapeutic intervention will decrease the morbidity and mortality of macrovascular disease in this population. CONCLUSIONS: In type 2 diabetes, limited prospective evidence does support tight glycemic control to help prevent or slow the progression of microvascular and neuropathic complications. It is uncertain whether tight glycemic control decreases macrovascular complications and which pharmacotherapeutic agent(s) is/are the best options. However, therapy that improves glucose control in combination with aggressive risk factor management should be initiated and enforced in patients with type 2 diabetes in an effort to reduce long-term complications.

Insulin and coronary artery disease: is syndrome X the unifying hypothesis?

OBJECTIVE: To review data supporting the hypothesis that syndrome X plays a major role in the pathogenesis of coronary artery disease (CAD), and the effects of lifestyle factors and pharmacologic interventions on insulin, other metabolic parameters, and outcomes. DATA SOURCES: MEDLINE (January 1966-August 1997) and Current Contents database searches identified applicable English-language experimental trials, epidemiologic studies, reviews, and editorials. STUDY SELECTION AND DATA EXTRACTION: Studies that were included addressed the role of insulin resistance and hyperinsulinemia in the pathogenesis of CAD or the effects of lifestyle factors and pharmacologic interventions on metabolic parameters and outcomes. DATA SYNTHESIS: The main characteristics of syndrome X are hyperinsulinemia and insulin resistance. These result in secondary syndrome X features, including hyperglycemia, increased very-low-density lipoprotein concentrations, decreased high-density lipoprotein cholesterol, and hypertension. Insulin resistance is worsened by obesity, and insulin has been shown to contribute to the development of hypertension. Other studies demonstrate that smoking adversely affects glucose and insulin concentrations. Animal studies have linked hyperinsulinemia and atherogenesis. These animal data have been confirmed by several large prospective and population studies that have identified associations between hyperinsulinemia and CAD. CONCLUSIONS: Strong evidence links insulin resistance and hyperinsulinemia to CAD. Lifestyle modifications play an important role in decreasing cardiovascular risk, and clinicians should strongly encourage such changes. Clinicians must also carefully consider the effects of antihypertensive, antihyperglycemic, and antidyslipidemic agents on patients' metabolic profiles when choosing appropriate therapeutic regimens. However, outcome data on many potentially beneficial agents, including calcium antagonists, alpha 1-adrenergic antagonists, angiotensin-converting enzyme inhibitors, metformin, acarbose, and troglitazone, are not yet available.

Prevention and regression of atherosclerosis: effects of HMG-CoA reductase inhibitors.

OBJECTIVE: To review the current literature on the effects of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors in secondary prevention and regression of atherosclerosis. DATA SOURCES: A MEDLINE and journal search of recent studies evaluating the effects of lipid lowering with HMG-CoA reductase inhibitors on serum cholesterol as well as progression and regression of atherosclerotic coronary or carotid disease in patients with established atherosclerotic disease was conducted. Articles addressing the pathophysiology of atherosclerotic disease were identified by using the same sources. STUDY SELECTION: All available studies evaluating the use of HMG-CoA reductase inhibitors in the progression and regression of coronary and carotid atherosclerosis were reviewed. DATA SYNTHESIS: Lowering of total serum cholesterol, low-density lipoprotein cholesterol, and triglycerides, as well as increasing high-density lipoprotein cholesterol can be achieved with HMG-CoA reductase inhibitors. Aggressive lipid lowering has been demonstrated to alter progression of established atherosclerotic disease and, in some patients, actually induce regression of the atheroma. An unexpected finding of several trials was the early and significant reduction in clinical cardiac events. Other mechanisms by which clinical event reduction may be explained include plaque stabilization and restoration of endothelium vasodilation. CONCLUSIONS: Aggressive lipid-lowering therapy using HMG-CoA reductase inhibitors appears to alter the natural progression and promote regression of atherosclerosis in selected patients with established coronary or carotid atherosclerosis. However, it is unlikely that regression of atherosclerosis alone is responsible for the marked reduction in clinical cardiac events seen in these trials.

Clinical implications of white coat hypertension.

"White coat" or "office" hypertension is often defined as the transient rise or elevation of blood pressure that occurs in the medical setting. Patients with these elevated readings have normal ambulatory pressures as determined by individual home blood pressure measurements or continuous 24-hour blood pressure monitoring. This clinical finding is present in 20 to 40 percent of patients with hypertension. Although continuous blood pressure monitoring has several research implications, its use adds little to the diagnosis, prognosis and treatment options. Treatment decisions should be based on office blood pressure measurements evaluated in accordance with the recommended guidelines for the diagnosis of hypertension. The detection and confirmation of hypertension, as delineated in the fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure, is based on multiple office measurements. Ambulatory blood pressure monitoring should not be used for the routine diagnosis or management of most patients.

Calcium channel blocker-induced gingival hyperplasia: case report and review of this iatrogenic disease.

Gingival hyperplasia is a common disorder associated with phenytoin and cyclosporine therapy. However, induction of this condition by calcium channel blockers is less well known. Inflammation of the gingival tissue from bacterial plaque and the subsequent development of gingival crevicular fluid may allow sequestration of the calcium channel blocker, thus predisposing the tissue to a localized toxic effect and the development of gingival hyperplasia. Calcium channel blockers have cellular effects similar to those of phenytoin and cyclosporine, including the production of a localized folic acid deficiency. All of the available calcium channel blockers have been reported to cause gingival hyperplasia. Treatment options include meticulous plaque control, and in severe cases, gingivectomy. Gingival hyperplasia can be prevented with meticulous plaque control or avoidance of the offending medication.

Update on childhood immunizations.

OBJECTIVE: To provide an overview of childhood immunizations with emphasis in new recommendations, as well as recent vaccine developments and special populations. DATA SOURCES: English language literature identified via a MEDLINE search. Additional references were obtained from cited references. STUDY SELECTION AND DATA EXTRACTION: Original articles, reviews, and official publications were used to obtain the most accurate data on safety and efficacy of available pediatric vaccines, as well as current recommendations for their use. DATA SYNTHESIS: Immunizations have been an area of vigorous research for several years. New vaccines have been developed by improving older products to maximize immunogenicity and minimize adverse effects. Some of these novel vaccines, like the Haemophilus influenzae type b conjugate vaccines (HibCV), have already contributed significantly to the prevention of diseases in childhood. New recommendations have been issued to help speed this process. Adverse effects of routine immunizations are generally mild and transient. CONCLUSIONS: The development of new effective and safe vaccines for children is an important step in the global eradication of contagious diseases. A new generation of combination vaccines has started with the combination of the diphtheria-tetanus-pertussis vaccine and HibCV. Some other combined products are yet to come that would eventually make immunization schedules more cost-effective and improve compliance rates. Our colleagues in the community and in the ambulatory care setting must actively participate in the implementation of vaccination programs and provide education to parents regarding all aspects of the immunization process.

Hypertension: are beta-blockers and diuretics appropriate first-line therapies?

OBJECTIVE: To review the existing data on the use of diuretics or beta-blockers as first-line therapy for the treatment of mild to moderate hypertension, and to examine the issues surrounding the impact of these classes as well as the angiotensin-converting enzyme (ACE) inhibitors, calcium-channel blockers (CCBs), alpha-blockers, and alpha-beta-blockers on cardiovascular risk factors and cardiovascular morbidity and mortality. DATA SOURCES: A MEDLINE search of applicable articles on antihypertensive therapies and their impact on morbidity and mortality. In addition, a MEDLINE search of relevant articles regarding cardiovascular risk factors and the influence of the various antihypertensive therapies on these parameters. DATA SYNTHESIS: The literature was evaluated with regard to outcome. Trials examining the impact of antihypertensive pharmacotherapy, primarily with diuretics and beta-blockers, have shown them to decrease the incidence of stroke by 33-50 percent. However, their effect on coronary heart disease has been disappointing, showing only a 14 +/- 5 (mean +/- SD) percent decrease. Examination of numerous clinical trials assessing the impact of the various antihypertensive therapies on cardiovascular risk factors, including blood pressure, plasma lipids, diabetic control/insulin sensitivity, and left ventricular hypertrophy was done. The classes included beta-blockers, diuretics, alpha-blockers, ACE inhibitors, and CCBs; the results show a diversity of effect. Diuretics and beta-blockers tend to worsen cardiovascular risk status, whereas the alpha-blockers, ACE inhibitors, and CCBs all show a beneficial effect. CONCLUSIONS: Diuretics and beta-blockers can effectively reduce cerebrovascular morbidity and mortality, but have a limited effect on reducing cardiovascular disease, especially myocardial infarction. This may be explained, at least in part, by the negative, or lack of positive, effect on individual patients' overall cardiovascular risk status.

Amlodipine: a new calcium antagonist.

The chemistry, pharmacology, pharmacokinetics, efficacy, and adverse effects of amlodipine are reviewed. Amlodipine belongs to the dihydropyridine subclass of calcium antagonists. Amlodipine is a potent peripheral and coronary vasodilator with high selectivity for vascular smooth muscle and minimal effect on myocardial contractility or cardiac conduction. Absorption after oral administration is slow, and the duration of action is long, with a half-life of 36-45 hours. Amlodipine has FDA-approved labeling for use in the treatment of hypertension, chronic stable angina, and vasospastic angina. The agent is also indicated for use in hypertensive or anginal patients who also have congestive heart failure due to systolic dysfunction (New York Heart Association classes II and III). Clinical trials suggest that effective 24-hour control of hypertension and angina is provided by once-daily administration of amlodipine 5-10 mg alone or in combination with other drugs. No clinically important drug interactions have been observed to date. Amlodipine has not shown any unfavorable effects on serum glucose or lipid levels. The most common adverse effect is peripheral edema. Amlodipine is effective and well tolerated when given alone or in combination with other drugs for the treatment of hypertension and angina. Amlodipine may offer advantages over verapamil, diltiazem, and nifedipine in patients with hypertension or angina with associated congestive heart failure due to systolic dysfunction.

Intravenous streptomycin use in a patient infected with high-level, gentamicin-resistant Streptococcus faecalis.

OBJECTIVE: To report a case of intravenous streptomycin sulfate use in a patient infected with high-level, gentamicin-resistant Streptococcus faecalis. CASE SUMMARY: A 37-year-old woman with a history of schizoaffective disorder, diabetes insipidus possibly induced by lithium, chronic renal insufficiency, and anemia presented with a two-day history of decreased responsiveness, decreased verbalization, and tremulousness. Her hospital course was complicated by polymicrobial sepsis (S. faecalis, coagulase-negative staphylococci, Citrobacter diversus, Enterobacter aerogenes, and unidentified gram-negative bacilli #2) requiring vancomycin and gentamicin therapy. Gentamicin was discontinued after two doses because she developed acute-on-chronic renal insufficiency. Subsequent susceptibility data showed the enterococcus to be highly resistant to gentamicin. The patient deteriorated clinically when treated only with vancomycin. She remained septic with a blood pressure of 80/40 mm Hg; streptomycin was added to her regimen. We were concerned that streptomycin concentrations obtained following intramuscular administration would not be adequate because of possible hypoperfusion. Based on limited published literature, streptomycin was administered intravenously via a central intravenous catheter. DISCUSSION: A review of high-level aminoglycoside-resistant S. faecalis and treatment with intravenous streptomycin therapy are discussed. The availability and monitoring of streptomycin therapy are also described. CONCLUSIONS: Streptomycin is an antimicrobial agent that must be used with vancomycin in serious infections to eradicate high-level, gentamicin-resistant S. faecalis. Its unique administration and monitoring concerns require individual patient assessment.

The triglyceride connection in atherosclerosis.

OBJECTIVE: To examine the proposed mechanism of triglyceride-induced atherogenesis, to address the controversy surrounding serum triglycerides as a coronary heart disease (CHD) risk factor, and to recommend an appropriate therapeutic approach to hypertriglyceridemia. DATA SOURCES: Studies, review articles, and editorials published since 1976. A MEDLINE search of English-language literature was conducted using the terms triglyceride and hypertriglyceridemia. STUDY SELECTION: Studies, review articles, and editorials were selected for detailed review if they addressed the pathogenesis of triglyceride-induced atherosclerosis, the controversy associated with elevated serum triglyceride as a CHD risk factor, and hypertriglyceridemia treatment options. DATA EXTRACTION: Data were reviewed that described the atherogenicity of chylomicron and very low-density lipoprotein (VLDL) remnants, the inverse relationship that exists between high-density lipoprotein (HDL) and serum triglyceride, the hypertriglyceridemia treatment controversy, and the treatment options of diet, exercise, weight control, alcohol restriction, and medication. DATA SYNTHESIS: Hypertriglyceridemia is a well-known risk factor for pancreatitis. However, its role in atherogenesis is less well defined. Several proposed connections appear to exist between hypertriglyceridemia and atherosclerosis, including the inverse correlation between triglycerides and HDL, the presumed atherogenicity of triglyceride-rich lipoprotein remnant particles, the potential resultant increase in the serum concentration and atherogenicity of low-density lipoprotein (LDL), and the proposed interaction between serum triglyceride and the fibrinolytic/coagulation system. Clinical trials addressing this issue offer mixed results that are subject to interpretation. Diet, exercise, weight control, alcohol restriction, and certain lipid-lowering medications are effective at reducing serum triglyceride. CONCLUSIONS: Hypertriglyceridemia is a theoretical risk factor for CHD because of the increased production of atherogenic chylomicron and VLDL remnants, the inverse relationship present between serum triglyceride and HDL, the possible resultant increase in LDL attributable to remnant-reduced hepatic LDL-receptors as well as the formation of more dense and, therefore, more atherogenic LDL, and to the interaction between serum triglyceride and the fibrinolytic/coagulation system. However, most clinical trials that have found hypertriglyceridemia to be a risk factor for CHD do not include other CHD risk factors in their analyses. Therapeutic intervention to lower serum triglyceride with diet, exercise, and/or drugs is definitely recommended in the treatment and/or prevention of pancreatitis; however, the role of triglyceride-lowering to reduce CHD risk remains controversial.

New considerations for Haemophilus influenzae type b vaccination.

The immunogenicity, efficacy, adverse effects, dosage recommendations, and cost of the three commercially available Haemophilus influenzae type b (Hib) conjugate vaccines are discussed. Three Hib conjugate vaccines are licensed for use in children 15 months of age or older: ProHIBiT (Connaught), HibTITER (Praxis), and PedvaxHIB (Merck). HibTITER and PedvaxHIB were recently approved for use in infants as young as two months of age; both have demonstrated efficacy in preventing Hib disease in this age group, whereas ProHIBIT has not been shown to afford adequate protection in young infants. Because the three vaccines induce markedly different immunologic responses, they cannot be considered interchangeable and the recommended dosage schedules differ. The Centers for Disease Control Immunization Practices Advisory Committee (ACIP) and the American Academy of Pediatrics (AAP) both recommend that all infants be immunized with a complete series of either HibTITER or PedvaxHIB beginning routinely at two months or as soon as possible thereafter. The cost of a single dose is similar for the three Hib conjugate vaccines; full immunization with HibTITER is more expensive than with ProHIBiT or PedvaxHIB because four doses are required for completion of the series. Selection of the appropriate Hib vaccine for infants should be based on availability, cost, and the clinician's interpretation of existing data.

Study of antipsychotic drug use in long-term care facilities.

We chose to conduct this study because neuroleptic use has not been well defined in nursing homes. To our knowledge, it represents the only attempt at implementing the AIMS procedure in a group of nursing homes. We have provided evidence for what appears to be reasonably typical use of antipsychotic medication in skilled and intermediate care facilities. Senility and dementia were the most common diagnoses noted for neuroleptic recipients. Inservice education had little, if any, impact on antipsychotic drug use. Efforts to reduce the incidence of inappropriate use of neuroleptics should be aimed at physicians. We do feel that nursing and administrative staff are now more aware than previously of the dangers of indiscriminate use of these drugs. We feel that, because of our efforts, nursing staffs are better able to detect the presence of TD in their geriatric residents. If our sample of patients is representative of the entire population of institutionalized elderly, the overall rate of neuroleptic-induced TD may be lower than once thought. Similarly, the use of regularly scheduled neuroleptics in this population may be lower.

Quality of life considerations in the treatment of hypertension.

Only recently have practitioners recognized the potential effects of antihypertensive agents on quality of life. Unfortunately, few studies have been conducted to assess the effects of the newer antihypertensive agents. The introduction of four first-line antihypertensive agents permits further individualization in the selection of therapy, which will minimize adverse effects and increase the potential for prescribing a better tolerated drug regimen. Until large, well-controlled, randomized studies are conducted evaluating the effect of these antihypertensive agents on quality of life, practitioners must continue to rely on factors such as mechanism and duration of action, efficacy, side-effect profile, and cost to maximize antihypertensive efficacy and patient acceptance of therapy. A practitioner's heightened awareness for the side effects of antihypertensive agents, and the subtle quality-of-life changes that they may elicit will enable them to monitor more effectively and adjust therapy as necessary. This may increase the possibility of patients' compliance with their long-term treatment and ultimately improve patient outcome.

Effects of magnesium oxide on the lipid profile of healthy volunteers.

Elevated serum cholesterol is a risk factor in the development of coronary artery disease. Magnesium has been reported to decrease total serum cholesterol, low density lipoprotein, and very low density lipoprotein, and increase high density lipoprotein. A randomized, double-blind, placebo-controlled, crossover study was completed to determine if supplemented magnesium, in the form of magnesium oxide, would produce changes in the lipid profile. Fifty normal volunteers received placebo or magnesium oxide, 400 mg capsules, twice a day for 60 days, then switched to the alternate treatment. Weight, height, blood pressure, serum potassium, serum magnesium, and a lipid profile were determined initially and after each treatment. Analysis of variance (ANOVA), comparing the mean of each component of the lipid profile at baseline and after each treatment, showed no significant difference. In conclusion, supplemental magnesium oxide did not produce statistically significant changes in the lipid profile in this group of healthy volunteers.

Pyrethrins combined with piperonyl butoxide (RID) vs 1% permethrin (NIX) in the treatment of head lice.

In a randomized controlled trial, 58 subjects were treated for Pediculus humanus var capitis with either pyrethrins combined with piperonyl butoxide (RID, Pfizer Inc, New York) or 1% permethrin (NIX, Burroughs Wellcome Co, Research Triangle Park, NC); 31 subjects received RID and 27 subjects received NIX. Both products were applied according to manufacturer's directions so that NIX was applied only on the first visit and RID was applied on the first visit and again seven days later. After each treatment with a pediculicide, the comb supplied by the manufacturer was used to remove nits. Seven days after the initial visit, NIX was determined to be significantly better than RID for eradicating the lice infestation. Of the 27 subjects receiving NIX, 26 were live free vs 14 of the 31 RID-treated subjects. At day 14, there was no statistically significant difference in the treatments (27 of 27 NIX-treated vs 29 of 31 RID-treated subjects were lice free). The RID comb was superior to the NIX comb for nit removal. Both treatments were effective and well tolerated, and no subject experienced adverse reactions.