Melatonin Pathway and Atenolol-Related Glucose Dysregulation: Is There a Correlation?

Lower melatonin level, melatonin receptor gene variations, and atenolol treatment are associated with glucose dysregulation. We investigated whether atenolol-related glucose and melatonin changes are correlated, and whether single nucleotide polymorphisms (SNPs) in melatonin candidate genes contribute to interindividual variation in glucose change. Hypertensive Caucasians (n = 232) from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study treated with atenolol for 9 weeks were studied. Urinary 6-sulfatoxymelatonin (aMT6s) was measured pre- and posttreatment and normalized to urinary creatinine. Pharmacogenetic effects on glucose change of 160 SNPs in 16 melatonin candidate genes were assessed with multiple linear regression. Atenolol was associated with increased glucose (1.8 ± 10.1mg/dl, P = 0.02) and decreased aMT6s (-4.5 ± 10.1 ng/mg, P < 0.0001). However, the aMT6s change was not correlated with post-atenolol glucose change. SNP rs11649514 in PRKCB was associated with glucose change (P = 1.0×10(-4)). PRKCB is involved in the melatonin-insulin regulatory pathway, and may be important in mediating clinically meaningful atenolol-related hyperglycemia.

Transethnic meta-analysis suggests genetic variation in the HEME pathway influences potassium response in patients treated with hydrochlorothiazide.

Hypokalemia is a recognized adverse effect of thiazide diuretic treatment. This phenomenon, which may impair insulin secretion, has been suggested to be a reason for the adverse effects on glucose metabolism associated with thiazide diuretic treatment of hypertension. However, the mechanisms underlying thiazide diuretic-induced hypokalemia are not well understood. In an effort to identify genes or genomic regions associated with potassium response to hydrochlorothiazide, without a priori knowledge of biologic effects, we performed a genome-wide association study and a multiethnic meta-analysis in 718 European- and African-American hypertensive participants from two different pharmacogenetic studies. Single-nucleotide polymorphisms rs10845697 (Bayes factor=5.560) on chromosome 12, near to the HEME binding protein 1 gene, and rs11135740 (Bayes factor=5.258) on chromosome 8, near to the Mitoferrin-1 gene, reached genome-wide association study significance (Bayes factor >5). These results, if replicated, suggest a novel mechanism involving effects of genes in the HEME pathway influencing hydrochlorothiazide-induced renal potassium loss.

Hydrochlorothiazide-induced hyperuricaemia in the pharmacogenomic evaluation of antihypertensive responses study.

OBJECTIVE: Elevations in uric acid (UA) and the associated hyperuricaemia are commonly observed secondary to treatment with thiazide diuretics. We sought to identify novel single nucleotide polymorphisms (SNPs) associated with hydrochlorothiazide (HCTZ)-induced elevations in UA and hyperuricaemia. METHODS: A genome-wide association study of HCTZ-induced changes in UA was performed in Caucasian and African American participants from the pharmacogenomic evaluation of antihypertensive responses (PEAR) study who were treated with HCTZ monotherapy. Suggestive SNPs were replicated in Caucasians and African Americans from the PEAR study who were treated with HCTZ add-on therapy. Replicated regions were followed up through expression and pathway analysis. RESULTS: Five unique gene regions were identified in African Americans (LUC7L2, ANKRD17/COX18, FTO, PADI4 and PARD3B), and one region was identified in Caucasians (GRIN3A). Increases in UA of up to 1.8 mg dL(-1) were observed following HCTZ therapy in individuals homozygous for risk alleles, with heterozygotes displaying an intermediate phenotype. Several risk alleles were also associated with an increased risk of HCTZ-induced clinical hyperuricaemia. A composite risk score, constructed in African Americans using the 'top' SNP from each gene region, was strongly associated with HCTZ-induced UA elevations (P = 1.79 × 10(-7) ) and explained 11% of the variability in UA response. Expression studies in RNA from whole blood revealed significant differences in expression of FTO by rs4784333 genotype. Pathway analysis showed putative connections between many of the genes identified through common microRNAs. CONCLUSION: Several novel gene regions were associated with HCTZ-induced UA elevations in African Americans (LUC7L2, COX18/ANKRD17, FTO, PADI4 and PARD3B), and one region was associated with these elevations in Caucasians (GRIN3A).

Impact of CYP2D6 polymorphisms on clinical efficacy and tolerability of metoprolol tartrate.

Metoprolol is a selective ß-1 adrenergic receptor blocker that undergoes extensive metabolism by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). Our objective was to investigate the influence of CYP2D6 polymorphisms on the efficacy and tolerability of metoprolol tartrate. Two hundred and eighty-one participants with uncomplicated hypertension received 50 mg of metoprolol twice daily followed by response-guided titration to 100 mg twice daily. Phenotypes were assigned based on results of CYP2D6 genotyping and copy number variation assays. Clinical response to metoprolol and adverse effect rates were analyzed in relation to CYP2D6 phenotypes using appropriate statistical tests. Heart rate response differed significantly by CYP2D6 phenotype (P < 0.0001), with poor and intermediate metabolizers showing greater reduction. However, blood pressure response and adverse effect rates were not significantly different by CYP2D6 phenotype. Other than a significant difference in heart rate response, CYP2D6 polymorphisms were not determinants of variability in metoprolol response or tolerability.

Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans.

Hydrochlorothiazide (HCTZ) is one of the most widely prescribed antihypertensive medications. Although it is well known that HCTZ is associated with hyperglycemia and hypertriglyceridemia, the mechanisms underlying these adverse effects are not well understood. We performed a genome-wide association study and meta-analysis of the change in fasting plasma glucose and triglycerides in response to HCTZ from two different clinical trials: the Pharmacogenomic Evaluation of Antihypertensive Responses and the Genetic Epidemiology of Responses to Antihypertensive studies. Two single-nucleotide polymorphisms (rs12279250 and rs4319515 (r(2)=0.73)), located at 11p15.1 in the NELL1 gene, achieved genome-wide significance for association with change in fasting plasma triglycerides in African Americans, whereby each variant allele was associated with a 28 mg dl(-1) increase in the change in triglycerides. NELL1 encodes a cytoplasmic protein that contains epidermal growth factor-like repeats and has been shown to represses adipogenic differentiation. These findings may represent a novel mechanism underlying HCTZ-induced adverse metabolic effects.

Association of chromosome 12 locus with antihypertensive response to hydrochlorothiazide may involve differential YEATS4 expression.

A recent genome-wide analysis discovered an association between a haplotype (from rs317689/rs315135/rs7297610) on Chromosome 12q15 and blood pressure response to hydrochlorothiazide (HCTZ) in African-Americans. Our aim was to replicate this association and investigate possible functional mechanisms. We observed similar associations between this haplotype and HCTZ response in an independent sample of 746 Caucasians and African-Americans randomized to HCTZ or atenolol treatment. The haplotype association was driven by variation at rs7297610, where C/C genotypes were associated with greater mean (systolic: 3.4 mmHg, P=0.0275; diastolic: 2.5 mmHg, P=0.0196) responses to HCTZ vs T-allele carriers. Such an association was absent in atenolol-treated participants, supporting this as HCTZ specific. Expression analyses in HCTZ-treated African-Americans showed differential pre-treatment leukocyte YEATS4 expression between rs7297610 genotype groups (P=0.024), and reduced post-treatment expression in C/C genotypes (P=0.009), but not in T-carriers. Our data confirm previous genome-wide findings at 12q15 and suggest differential YEATS4 expression could underpin rs7297610-associated HCTZ response variability, which may have future implications for guiding thiazide treatment.

Association of KCNJ1 variation with change in fasting glucose and new onset diabetes during HCTZ treatment.

Thiazide-induced potassium loss may contribute to new onset diabetes (NOD). KCNJ1 encodes a potassium channel and one study observed that a KCNJ1 single-nucleotide polymorphism (SNP) was associated with changes in fasting glucose (FG) during hydrochlorothiazide (HCTZ) treatment. We used linear regression to test association of KCNJ1 SNPs and haplotypes with FG changes during HCTZ treatment in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study. We used logistic regression to test association of KCNJ1 variation with NOD in HCTZ-treated patients from the International Verapamil SR Trandolapril Study (INVEST). Multivariate regression analyses were performed by race/ethnicity with false discovery rate (FDR) correction. In PEAR blacks, a KCNJ1 SNP was associated with increased FG during HCTZ treatment (beta=8.47, P(FDR)=0.009). KCNJ1 SNPs and haplotypes were associated with NOD risk in all INVEST race/ethnic groups (strongest association: odds ratio 2.14 (1.31-3.53), P(FDR)=0.03). Our findings support that KCNJ1 variation is associated with HCTZ-induced dysglycemia and NOD.

Hydrochlorothiazide and atenolol combination antihypertensive therapy: effects of drug initiation order.

For combination antihypertensive therapy with thiazide diuretics and beta-blockers, the effect of the order of initiation of the drugs on the outcome has not been tested. Patients with uncomplicated hypertension were randomized to receive either hydrochlorothiazide (HCTZ) or atenolol monotherapy, followed by addition of the alternative drug. Blood pressure (BP) responses were evaluated by race and order of drug initiation. A total of 368 participants received combination therapy. Among the participants, blacks showed a greater BP-lowering effect than whites did with HCTZ monotherapy (-13.0/-7.4 mm Hg vs. -8.0/-4.2 mm Hg, P < 0.001) but a smaller BP-lowering effect than did whites with atenolol monotherapy (-1.1/-2.9 mm Hg vs. -9.9/-9.2 mm Hg, P < 0.0001). These differences were not evident during combination therapy. However, both groups showed greater response to HCTZ + atenolol than to atenolol + HCTZ (-19.1/-14.2 mm Hg vs. -15.6/-11.3 mm Hg, P < 0.0001). Despite optimal dosing of HCTZ + atenolol, only two-thirds of the participants achieved BP control. In HCTZ/atenolol combination antihypertensive therapy, the order in which the drugs are initiated affects total BP lowering during the first 4-6 months of therapy.

Antimicrobial resistance in 11 hospitals in Puerto Rico: results of an antimicrobial resistance management (ARM) program

PURPOSE: The Antimicrobial Resistance Management Program (ARMP) was established in 1997 at the University of Florida as an ongoing project to document trends in antimicrobial susceptibility patterns in inpatient/outpatient isolates and track resistance that may occur with specific antibiotic use. METHODS: Institutions are enrolled at no charge and provide a minimum of 3 years of antibiogram/sensitivity report data, which are reviewed to create a customized analysis of antimicrobial susceptibility trends benchmarked against national/regional comparators. The data, in a HIPAA-compliant non-identifying format, comprise a national aggregate database of 28.4 million isolates from 358 institutions. This database was interrogated to determine resistance rates for eleven hospitals in Puerto Rico from 1998-2003 and, as comparators, those in the database from the State of Florida and all U.S. institutions. RESULTS: Between 1996-2003, data on 328,837 isolates collected from 11 hospitals throughout Puerto Rico, 5,388,897 isolates from 46 institutions in Florida, and 24,951,098 isolates from 358 U.S. institutions for the following organisms (number of antibiotics tested against) were reviewed for susceptibility: coagulase-negative staphylococci (14)/Staphylococcus epidermidis (18), Enterococcus faecalis (7), Enterococcus faecium (5), Enterococcus species (4), Escherichia coli (24), Klebsiella pneumoniae (24), Proteus mirabilis (22), Pseudomonas aeruginosa (14), Serratia marcescens (22), Staphylococcus aureus (23), and Streptococcus pneumoniae (9). Antimicrobial resistance in Puerto Rico varied organism to organism from that observed in Florida and nationally. CONCLUSIONS: This first broad analysis of antimicrobial resistance in Puerto Rico provides important baseline data, both for sentinel surveillance programs and for determining strategies for intervention.

Relief of fibromyalgia symptoms following discontinuation of dietary excitotoxins.

BACKGROUND: Fibromyalgia is a common rheumatologic disorder that is often difficult to treat effectively. CASE SUMMARY: Four patients diagnosed with fibromyalgia syndrome for two to 17 years are described. All had undergone multiple treatment modalities with limited success. All had complete, or nearly complete, resolution of their symptoms within months after eliminating monosodium glutamate (MSG) or MSG plus aspartame from their diet. All patients were women with multiple comorbidities prior to elimination of MSG. All have had recurrence of symptoms whenever MSG is ingested. DISCUSSION: Excitotoxins are molecules, such as MSG and aspartate, that act as excitatory neurotransmitters, and can lead to neurotoxicity when used in excess. We propose that these four patients may represent a subset of fibromyalgia syndrome that is induced or exacerbated by excitotoxins or, alternatively, may comprise an excitotoxin syndrome that is similar to fibromyalgia. We suggest that identification of similar patients and research with larger numbers of patients must be performed before definitive conclusions can be made. CONCLUSIONS: The elimination of MSG and other excitotoxins from the diets of patients with fibromyalgia offers a benign treatment option that has the potential for dramatic results in a subset of patients.

Extended-release nifedipine bezoar identified one year after discontinuation.

OBJECTIVE: To report a case of tablet impaction of nifedipine extended-release tablets (Procardia XL) discovered one year after discontinuation of the drug in a patient with peptic stricture. DATA SOURCES: English-language references identified via a MEDLINE search from 1966 through September 1998 and bibliographic review of pertinent articles. DATA SYNTHESIS: Extended-release nifedipine has been associated with the formation of medication bezoars in case reports. Bezoars are concretions of undigested material within the gastrointestinal (GI) tract. Although they can occur throughout the GI tract, bezoars are most frequently located in the stomach and, rarely, in the duodenum. We report an unusual case of tablet impaction with a gastric outlet obstruction in the duodenal area discovered one year after the patient stopped taking extended-release nifedipine. CONCLUSIONS: Extended-release nifedipine is associated with tablet impaction, even long after discontinuing administration. Although rare, clinicians should be aware of this potential problem when prescribing extended-release medications to patients at risk, and should consider this possible etiology when refractory epigastric pain and weight loss occur.

A randomized, prospective study measuring outcomes after antibiotic therapy intervention by a multidisciplinary consult team.

Our aim was to identify financial and outcome benefits of therapeutic intervention by a multidisciplinary antimicrobial treatment team composed of pharmacists, a clinical microbiologist, and an infectious disease specialist. Of 252 consecutive inpatients receiving suboptimal intravenous antibiotics identified by the clinical pharmacist, 127 were prospectively randomized to intervention and 125 to a control group. The groups were similar with regard to severity of illness, infection type, and time from admission to randomization. Physicians received timely, detailed reviews of relevant microbiologic and clinical data with recommendations of possible optimal antibiotic choices, dosages, and rationales. Median length of stay after randomization for control and intervention groups was 9.0 days and 5.7 days, respectively (3.3-day difference, p=0.0001). Fifteen (12.0%) and eight patients (6.3%), respectively, died, although the time-specific mortality risk was not significantly different when length of postrandomization follow-up and time to death were taken into account. Physician acceptance of suggestions was 89%. Median patient charges for radiology, laboratory, pharmacy, and room were reduced by $4404/intervention, and median hospital costs were reduced by $2642/intervention. A multidisciplinary antimicrobial therapy team can be a useful information source for physicians, improve outcomes in hospitalized patients receiving intravenous antimicrobials, and result in substantial cost savings.

Levofloxacin-induced bilateral Achilles tendonitis.

OBJECTIVE: To report a case of possible levofloxacin-induced bilateral Achilles tendonitis. CASE SUMMARY: An 83-year-old white woman presented to her physician with five days of hemoptysis. She was diagnosed with right lower-lobe pneumonia based on chest X-ray, and levofloxacin 500 mg/d po for 10 days was prescribed. Three days into treatment she began having a variety of adverse effects, including severe nausea, constipation, stomach cramps, and dizziness. Signs of tendonitis began three days after treatment and peaked four days after completion of therapy. Two weeks later, she was treated by her podiatrist with an ankle immobilizer and rest. At her three-week follow-up, she had marked improvement in her pain and bruising; however, her symptoms had not completely resolved. DISCUSSION: Tendonitis and tendon rupture are rare adverse effects of fluoroquinolone antibiotics; there are no reports in the literature of levofloxacin-induced tendonitis. As newer fluoroquinolones become available, the postmarketing studies will become increasingly important to capture the data on rare but serious adverse effects not discovered in the premarketing trials. CONCLUSIONS: To our knowledge, this is the first reported case of tendonitis caused by levofloxacin reported in the literature. Reports have been made, however, to the manufacturer via postmarketing surveillance. As more people are treated with newer fluoroquinolones, the clinical incidence of tendon rupture with these agents may become clearer.

Management of essential hypertension.

Hypertension, in spite of a very high prevalence, remains undertreated. This is not due to a lack of effective therapeutic modalities. Non-pharmacological treatments can be effective in many patients. If those treatments fail to reduce blood pressure sufficiently, the physician can choose between numerous classes of antihypertensive agents. However, interpatient variability in response to these agents is high, and use of multiple agents is frequently necessary. Thus, no single class has proven to be superior for the majority of patients. This article will review the different non-pharmacological and pharmacological methods available to treat hypertension, as well as the guidelines that are available to aid in proper selection of a treatment regimen.

Possible lansoprazole-induced eosinophilic syndrome.

OBJECTIVE: To report a case of myalgia with eosinophilia related to lansoprazole administration. CASE SUMMARY: A 50-year-old white woman developed severe myalgia 1 week after starting lansoprazole. During the treatment course, the patient was also found to have eosinophilia. The myalgia and eosinophilia resolved 40 days after lansoprazole was stopped and 18 days after prednisone therapy was begun. The patient was not rechallenged with lansoprazole. DISCUSSION: To our knowledge, this is the first reported case of lansoprazole-induced eosinophilic syndrome. Clinically, it is difficult to distinguish between eosinophilia-myalgia syndrome and eosinophilic fasciitis, which are probably part of a continuum of eosinophilic disorders. This patient presented with symptoms of both syndromes. Although other causes cannot be completely ruled out, the time course strongly suggests that lansoprazole was the causative agent. CONCLUSIONS: It is important to consider medications when diagnosing patients with hypereosinophilia and/or myalgia.

The serum digoxin concentration: ten questions to ask.

Although the role of digoxin therapy has been the subject of debate, the drug is generally accepted as effective in the treatment of heart failure due to systolic dysfunction and as therapy for atrial fibrillation and supraventricular tachyarrhythmias. Serum digoxin concentrations are commonly used to gauge patient response to digoxin. Digoxin pharmacokinetics are complex, and many factors can confound the interpretation of digoxin concentrations. The exact therapeutic range of serum digoxin varies in the literature but should be considered to be from 0.8 to 2.0 ng per mL, on the basis of population data regarding therapeutic response and toxicity. Renal function plays a major role in digoxin pharmacokinetics and is an important factor in determining digoxin doses. Many medications, including quinidine, amiodarone and verapamil, alter digoxin pharmacokinetics and can result in two- to three-fold increases in the serum digoxin concentration. Effective interpretation of the digoxin concentration requires consideration of the patient's renal function and clinical status, possible drug interactions, time of the assay and other variables.

"Isolated" low high-density lipoprotein cholesterol.

OBJECTIVE: To present information on the function, structure, and importance of high-density lipoprotein cholesterol (HDL-C) and to evaluate the current literature regarding the controversy of managing patients with an "isolated" low HDL-C concentration. DATA SOURCE: A MEDLINE search was performed (1966-June 1996) to identify English-language clinical and review articles pertaining to HDL-C. Some articles were identified through the bibliography of selected articles. STUDY SECTION: All articles were considered for possible inclusion in the review. Pertinent information, as judged by the authors, was selected for discussion. DATA EXTRACTION: Important historical lipid studies, recent review articles, and clinical trials involving therapy for HDL-C were evaluated. DATA SYNTHESIS: The structure, function, and measurement of HDL-C and the state of an isolated low HDL-C are discussed for background. Lifestyle modification measures to increase HDL-C, medications to avoid, estrogen replacement, and lipid-altering agents used to raise an isolated low HDL-C are presented. CONCLUSIONS: An isolated low HDL-C concentration poses a risk for coronary heart disease. The management of this state is controversial. The first step in management is in agreement with experts and includes lifestyle modification (e.g., weight reduction, diet, smoking cessation, aerobic exercise). Estrogen replacement therapy and discontinuance of drugs that secondarily lower HDL-C are additional treatment options. The use of lipid-altering agents has been used in some patients. Nicotinic acid appears to be an effective agent for an isolated low HDL-C. A large clinical trial evaluating the effect of treating an isolated low HDL-C for primary and secondary prevention of coronary events is needed.

Alpha blockers: a reassessment of their role in therapy.

Intended for the treatment of hypertension, alpha blockers offer advantages in treating patients who also have other risk factors for coronary artery disease. Alpha blockers lower blood pressure by decreasing vascular resistance and are effective for the treatment of mild to moderate hypertension. In addition, alpha blockers have beneficial effects on lipid levels; they increase high-density lipoprotein levels and decrease total cholesterol, low-density lipoprotein and triglyceride levels. Alpha blockers do not induce glucose intolerance or hyperinsulinemia. Although they appear to decrease left ventricular mass, the clinical significance of this action is unknown. Alpha blockers are also effective for improving the symptoms of benign prostatic hypertrophy, although surgery is recommended for patients with severe symptoms.

Outcome analysis of a pharmacist-managed anticoagulation service.

The primary objective of this study was to determine if a pharmacist-managed anticoagulation monitoring service (AMS) improved the outcomes of patients receiving warfarin in a family practice setting and was cost effective in treating and preventing thromboembolic disorders. A retrospective chart review was performed on all patients at the University of Florida's Family Practice Residency Program who received warfarin pharmacotherapy between October 1, 1988, and December 15, 1993. The outcomes of patients followed by AMS were compared with those of a control group consisting of patients receiving warfarin but followed only by their physician. Outcomes were evaluated based on the number of thromboembolic and hemorrhagic events, as well as unplanned clinic visits, emergency room visits, and hospital admissions. Cost of hospital admissions, emergency room visits, and participation in the AMS were analyzed. During 28 person-years of treatment, control subjects sustained 12 thromboembolic events (2 pulmonary embolisms, 1 cerebrovascular accident, and 9 deep venous thromboses) and 2 minor and 5 major hemorrhagic events. The study group reported two minor hemorrhagic events during a total of 60 person-years. The control group was 20 times more likely than the study group to experience any event (rate ratio 20, 95% CI 5-87). In addition, hospitalization and emergency room charges indicated an actual cost of $119,074.95 for the control group's events. The cost to this group for 28 person-years of participation in the AMS would have been $5040.00. A potential cost avoidance of $4072.68 per person-year of follow-up may have been possible if these patients had been followed by the AMS. A pharmacist-managed AMS in a family practice setting can result in improved outcomes for patients receiving warfarin and is cost effective.

Recent advances: ambulatory care and family medicine.

Recent advances in primary care have been and continue to be exciting and innovative. The evolution of pharmaceutical care has the potential to have an immediate impact in the primary care arena. A major focus of primary care research will center on the evaluation of pharmaceutical care and the consequences of implementing pharmaceutical care, such as reimbursement for clinical services, quality of life, and improved clinical outcomes. With an increasing emphasis being placed on the provision of health care through primary care providers, advances in primary care/family medicine pharmacotherapy promise to remain exciting and innovative.