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Biomedical subjects

Issam Zineh

Publications and source records attributed to Issam Zineh.

18 recordsLinked to original sources
PubMed2006

Relation of beta(2)-adrenoceptor haplotype to risk of death and heart transplantation in patients with heart failure.

Heart failure (HF) is characterized by neurohormonal activation of the sympathetic nervous and renin-angiotensin systems. Genetic polymorphisms in these systems could alter the prognosis in HF. We hypothesized the genetic polymorphisms in the sympathetic nervous and renin-angiotensin systems are associated with adverse outcomes, defined as death or heart transplantation in patients with HF. A total of 227 patients with HF were enrolled from a tertiary care clinic and followed for outcomes for < or =4 years. Eight polymorphisms in 6 genes were genotyped: beta(1)-adrenergic receptor (ADRB1, S49G, R389G), beta(2)-adrenergic receptor (ADRB2, G16R, Q27E), alpha(2c)-adrenergic receptor (ADRA2C, insertion/deletion 322-325), angiotensinogen (AGT, M235T), angiotensin receptor type 1 (AGTR1, 1166A>C), and angiotensin-converting enzyme (ACE, insertion/deletion in intron 16). Most patients were treated according to consensus guidelines. Male gender (hazard ratio 2.24, 95% confidence interval 1.27 to 3.94), higher New York Heart Association functional class (hazard ratio 2.54, 95% confidence interval 1.84 to 3.52), and 2 copies of ADRB2 Arg16Gln27 haplotype (hazard ratio 1.91, 95% confidence interval 1.09 to 3.36) increased the risk of adverse outcomes. In contrast, a higher serum sodium level (hazard ratio 0.91, 95% confidence interval 0.86 to 0.97) and higher creatinine clearance (hazard ratio 0.99, 95% confidence interval 0.98 to 0.99) decreased the risk of adverse outcomes. None of the other genotypes/haplotypes were associated with adverse outcomes. In conclusion, ADRB2 Arg16Gln27 haplotype may significantly increase the risk of adverse outcomes in patients with HF receiving contemporary HF pharmacotherapy.

DNA↗
PubMed2006

Common laboratory methods in pharmacogenomics studies.

PURPOSE: Common laboratory methods used in pharmacogenomics studies are described. SUMMARY: The reliable and accurate determination of a person's genetic makeup at a particular locus in the DNA molecule, or genotype, is fundamental to pharmacogenomics. Whole blood cells and buccal cells are commonly collected to obtain a DNA sample. Once DNA is collected, the genomic DNA must be isolated from other cellular material. Next, a specific region of interest must be identified and amplified, performed via polymerase chain reaction (PCR). Gel electrophoresis is often performed after PCR to verify that PCR was successful and that the amplified target sequence is the correct size. Numerous methods are available to determine a person's genotype and differ based on allele discrimination and detection. PCR coupled with restriction fragment length polymorphism (RFLP) analysis, a conventional genotyping method, does not rely on automated technology and is practical for laboratories that genotype a limited number of samples. Pyrosequencing is an automated genotyping method in which the principal allele discrimination method is a primer extension reaction coupled with a luciferase-based enzyme reaction. TaqMan relies on the use of fluorescencelabeled probes, in addition to PCR primers, in the reaction mixture, enabling PCR amplification and allele discrimination in the same step. Mass spectrometry differentiates DNA molecules using a defined mass. Denaturing high-performance liquid chromatography (DHPLC) uses a reverse-phase ion-pair column to discriminate between variant and nonvariant alleles. CONCLUSION: An understanding of the common genotyping methods used in pharmacogenomics studies, including PCR-RFLP analysis, pyrosequencing, TaqMan, mass spectrometry, and DHPLC, will aid pharmacy practitioners and students when interpreting the methods sections of such studies.

Clinical Laboratory Techniques↗
PubMed2006

Doxycycline alters the expression of inflammatory and immune-related cytokines and chemokines in human endometrial cells: implication in irregular uterine bleeding.

BACKGROUND: Increased production of pro-inflammatory mediators is considered central in the manifestation of events leading to irregular uterine bleeding in progestin-only contraceptive users. Evidence suggests that in addition to its antimicrobial property, doxycycline (Dox) acts as an anti-inflammatory agent mainly through the suppression of pro-inflammatory mediators. METHODS: We tested this hypothesis in the endometrial environment using an in vitro model consisting of isolated human endometrial glandular epithelial and stromal cells and a human endometrial surface (HES) epithelial cell line cultured under defined conditions. RESULTS: We found that Dox at doses ranging from 1 to 100 microg/ml had a limited growth-inhibitory effect on these cells, whereas Dox in a dose-dependent manner inhibited the production of tumour necrosis factor-alpha (TNF-alpha). Using multiplex cytokine/chemokine protein analysis to test a broader range of Dox activity, we found that Dox at 25 microg/ml either alone or in the presence of 17beta-estradiol (E2), medroxyprogesterone acetate (MPA) and E2+MPA (10(-8) M) as well as TNF-alpha (25 ng/ml), representing the endometrial environment exposed to contraceptives as well as inflammatory conditions, respectively, altered the production of multiple cytokines and chemokines as compared with untreated controls. These actions of Dox occurred in cell-, ovarian steroid- and cytokine/chemokine-dependent manners. Although Dox reduced the regulatory action of steroids on the production of these cytokines/chemokines, it was less effective on TNF-alpha-treated cells. CONCLUSIONS: The results support the hypothesis that Dox, by modulating the endometrial expression of multiple inflammatory-related cytokines/chemokines in a cell- and cytokine/chemokine-dependent manner, may have a therapeutic potential in patients experiencing irregular uterine bleeding, in particular in progestin-dominant contraceptive users.

Adult↗
PubMed2006

Multiplex PCR-pyrosequencing assay for genotyping CYP3A5 polymorphisms.

BACKGROUND: The cytochrome P450 (CYP) 3A5 enzyme contributes to the metabolism of many drugs. Single nucleotide polymorphisms in the CYP3A5 gene (CYP3A5(*)3C and CYP3A5(*)6) are associated with decreased CYP3A5 expression in the liver. We designed a multiplex genotyping assay to detect the CYP3A5(*)3C and CYP3A5(*)6 polymorphisms in a single polymerase chain reaction (PCR) and a single pyrosequencing reaction. METHODS: A multiplex PCR assay was designed to simultaneously amplify 2 fragments, one containing the CYP3A5(*)3C polymorphism and the other containing the CYP3A5(*)6 polymorphism. Following PCR, multiplex genotyping was performed with pyrosequencing analysis. RESULTS: Patient samples (n=69) were analyzed for the CYP3A5(*)3C and CYP3A5(*)6 polymorphisms using the multiplex PCR-pyrosequencing assay. Genotypes obtained by the multiplex reaction were in 100% concordance with genotypes obtained using simplex PCR-pyrosequencing (n=69) and direct DNA sequencing (n=29). CONCLUSIONS: The advantage of this method is that the CYP3A5(*)3C and CYP3A5(*)6 polymorphism can be amplified in a single PCR reaction and genotyped in a single pyrosequencing reaction. This combined approach improves the time-efficiency and decreases the cost of CYP3A5 genotyping.

Alleles↗
PubMed2006

Development and cross-validation of sequencing-based assays for genotyping common polymorphisms of the CXCL5 gene.

BACKGROUND: Epithelial neutrophil activating peptide (ENA-78) is encoded by the polymorphic CXCL5 gene and is a recruiter and activator of neutrophils. Furthermore, ENA-78 may be involved in pathological inflammatory processes and variable drug responses. METHODS: To facilitate future disease-gene and pharmacogenetic investigation of ENA-78, we developed and cross-validated medium- to high-throughput genotyping assays for 2 commonly occurring CXCL5 polymorphisms (rs352046 and rs425535). Furthermore, we compared allele and genotype frequencies in a U.S. population with those of a previously studied European population. RESULTS: There was 100% genotype concordance between the 2 methods used (Pyrosequencing and TaqMan). Variant allele frequencies for rs352046 were consistent between the U.S. (16%) and European (16%) populations, while the rs425535 variant allele was more than twice as high in the European cohort (38% vs. 16%). There was complete linkage of genotypes at both loci in our population. CONCLUSIONS: The distribution of variant alleles for the 2 polymorphisms studied should be further evaluated in other populations. In addition, our data highlight the importance of assay validation using multiple platforms.

Alleles↗
PubMed2006

CXCL5 gene polymorphisms are related to systemic concentrations and leukocyte production of epithelial neutrophil-activating peptide (ENA-78).

Data exist linking elevated epithelial neutrophil activating peptide (ENA-78) concentrations with myriad inflammatory conditions. ENA-78 is encoded by the CXCL5 gene which has recently been shown to be polymorphic in nature (rs352046 and rs425535). No functional data on these polymorphisms exist. We investigated whether CXCL5 polymorphisms are associated with differences in plasma ENA-78 concentrations or leukocyte production of ENA-78 from cultured leukocytes in relatively healthy adults. We genotyped 114 adults for the above polymorphisms. Variant alleles at both loci were highly linked (D'=1, r2=0.94). The rs352046 variant allele was associated with significantly higher ENA-78 plasma concentrations. A genotype effect was also demonstrated for this polymorphism and leukocyte production of ENA-78. Both polymorphisms were predicted to have functional consequences by in silico analyses, with the rs352046 polymorphism found to occur at a transcription factor binding site for myeloid zinc finger proteins and the rs425535 polymorphism found to be located in an exon splicing enhancer site. Our findings add to the strength of CXCL5 as candidate gene in future disease-gene and pharmacogenetic association studies.

Adult↗
PubMed2006

Discordance between availability of pharmacogenetics studies and pharmacogenetics-based prescribing information for the top 200 drugs.

BACKGROUND: Despite growing numbers of pharmacogenetics studies, little pharmacogenetics-based prescribing information is available to practitioners. It is possible that the lack of prescribing data for commonly used drugs is due to a paucity of evidence-based pharmacogenetics literature for these agents. OBJECTIVE: To investigate the relationship between pharmacogenetics prescribing data in drug package inserts (PIs) and pharmacogenetics research literature for agents represented in the top 200 prescribed drugs for 2003. METHODS: A PubMed search (to August 7, 2004) was performed to identify pharmacogenetics studies relevant to the top 200 drugs. These data were compared with PIs for drugs in the top 200 list that contained pharmacogenetics prescribing information. RESULTS: Pharmacogenetics data in the literature were available for 71.3% of the top 200 drugs. The gene involved coded for a drug-metabolizing enzyme in 34.5% of the literature sampled. The remaining 65.5% of the pharmacogenetics studies contained information largely related to genetic variability in target proteins and drug transporters. Three drugs with PIs containing pharmacogenetics prescribing information deemed to be useful to guide therapy were in the top 200 list (celecoxib, fluoxetine, pantoprazole). There was no consensus on the strength of association between genetic variability and drug response for these agents. CONCLUSIONS: The lack of specific pharmacogenetics-based prescribing information in PIs for commonly used drugs does not seem to be related to a paucity of pharmacogenetics data in the research literature. Rather, other factors including, but not limited to, the uncertain clinical relevance of genetic associations may make practical prescribing recommendations difficult.

Drug Prescriptions↗
PubMed2006

Pharmacogenetics of chronic cardiovascular drugs: applications and implications.

Cardiovascular disease continues to be a tremendous worldwide problem, and drug therapy is a major modality to attenuate its burden. At present, conditions such as hypertension, dyslipidaemia and heart failure are pharmacologically managed with an empirical trial-and-error approach. However, it has been suggested that this approach fails to adequately address the therapeutic needs of many patients, and pharmacogenetics has been offered as a tool to enhance patient-specific drug therapy. This review outlines pharmacogenetic studies of common cardiovascular drugs, such as diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins and warfarin, ultimately highlighting considerations for future research and practice.

Anticoagulants↗
PubMed2006

Pharmacoeconomic modeling of nesiritide versus dobutamine for decompensated heart failure.

STUDY OBJECTIVE: To model the cost-effectiveness of nesiritide compared with dobutamine in patients with decompensated heart failure. DESIGN: Cost-effectiveness analysis. MEASUREMENTS AND MAIN RESULTS: A decision tree model was derived from randomized clinical trial data and data from a previously published economic study. Four cost-effectiveness analyses were performed: analysis 1 -- full probabilistic analysis, repeatedly sampled probabilities for 6-month mortality and hospital readmission from distributions based on 95% confidence intervals (CIs); analysis 2 -- best-case nesiritide analysis, used the limiting values of the 95% CI favorable to nesiritide; analysis 3 -- best-case dobutamine analysis, used the limiting values of the 95% CI favorable to dobutamine; and analysis 4 -- replicated the previously published cost-effectiveness study and served as a methodologic control. Fifty-one consecutive Monte Carlo simulations for cohorts of 1000 hypothetical patients were performed for each analysis. Incremental cost, incremental effectiveness, and incremental cost-effectiveness ratios (ICERs) were calculated for nesiritide versus dobutamine. Analysis 1 showed a mean ICER of 767 US dollars/life-year gained for nesiritide versus dobutamine (incremental cost 251 US dollars +/- 290 US dollars, incremental effectiveness 0.33 +/- 0.22 yr). The 95% confidence region surrounding this point estimate spanned all four quadrants of the incremental cost-effectiveness scatterplot, suggesting inconclusive results. Nesiritide was the dominant treatment strategy in analysis 2 (incremental cost -734 US dollars+/- 106 US dollars, incremental effectiveness 1.19 +/- 0.07 yrs), whereas dobutamine was dominant in analysis 3 (incremental cost 1242 +/- 73 US dollars, incremental effectiveness -0.57 +/- 0.05 yr). Analysis 4 was comparable to the previously published cost-effectiveness analysis (incremental cost -77 +/- 87 US dollars, incremental effectiveness 0.48 +/- 0.05 yr). CONCLUSIONS: Based on available randomized clinical trial data, nesiritide did not exhibit robust economic superiority over dobutamine. When incorporating the uncertainty (i.e., 95% CIs) in clinical effectiveness as reported in available clinical trial data into the economic analysis, either nesiritide or dobutamine may be the dominant treatment (i.e., more effective at lower cost) for the studied population. Economic analyses of nesiritide and any comparator must account for uncertainty in estimates of cost as well as in clinical effectiveness.

Cardiotonic Agents↗
PubMed2006

Atorvastatin effect on circulating and leukocyte-produced CD40 ligand concentrations in people with normal cholesterol levels: a pilot study.

STUDY OBJECTIVES: To investigate whether atorvastatin decreases serum or leukocyte-produced CD40 ligand (CD40L) levels and whether these effects are dependent on reduction in low-density lipoprotein cholesterol (LDL) levels in people without overt dyslipidemia. DESIGN: Prospective pilot study. SETTING: University research center. SUBJECTS: Twenty-five normocholesterolemic volunteers (mean age 32 +/- 11 yrs; 15 women, 10 men) without cardiovascular disease. INTERVENTION: After a 2-week drug-free run-in period, subjects received atorvastatin 80 mg/day orally for 16 weeks. MEASUREMENTS AND MAIN RESULTS: All lipoprotein level measurements were performed with the subject in the fasting state. The CD40L concentrations were measured by immunofluorescence detection in serum and leukocyte culture supernates after 24-hour incubation, and treatment effect was analyzed. Baseline mean +/- SD total cholesterol, LDL, high-density lipoprotein cholesterol, and triglyceride levels were 179 +/- 33, 97 +/- 29, 62 +/- 20, and 102 +/- 69 mg/dl, respectively. Mean changes in each of these levels, respectively, after 16 weeks of atorvastatin were -34%, -59%, +3%, and -23%. The median serum CD40L level was lower at 16 weeks (2.3 ng/ml, interquartile range [IQR] 1.2-5.0 ng/ml) than at baseline (3.0 ng/ml, IQR 2.1-3.7 ng/ml), but the change was not significant (p=0.24). However, atorvastatin significantly lowered CD40L produced from leukocytes by 57% (21 pg/mg of protein [IQR 10-38 pg/mg] vs 49 pg/mg [IQR 21-149 pg/mg], p=0.045). Effects were independent of reduction in cholesterol levels. CONCLUSION: Although atorvastatin did not significantly lower serum CD40L levels, significant reduction in leukocyte production was seen independent of degree of LDL reduction. These pilot data suggest a potential benefit in normocholesterolemic individuals that should be further investigated, and that leukocyte CD40L concentrations should be considered in the drug response.

Adult↗
PubMed2006

Complementary and alternative medicine use among individuals participating in research: implications for research and practice.

STUDY OBJECTIVES: To determine the frequency and type of complementary and alternative medicine (CAM) use among healthy volunteers participating in research, and to investigate the potential for interactions between commonly used CAM modalities and various drugs. DESIGN: Prospective evaluation. SETTING: University general clinical research center. SUBJECTS: Sixty healthy adults participating in an ongoing drug study. MEASUREMENTS AND MAIN RESULTS: The clinical study database was queried to determine the use and type of existing and newly started CAM throughout the study period. Baseline characteristics were compared between users and nonusers of CAM to identify differences between them. Potential CAM-drug interactions were classified based on curated databases and primary literature sources. Of the 60 subjects enrolled, 30 (50%) used CAM during the study. Of these, 26 (87%) were using CAM at study entry. Baseline CAM users were on average 7 years older than nonusers (p=0.03) and had high-density lipoprotein cholesterol concentrations 10 mg/dl higher than those of nonusers (p=0.04). The group using CAM had more women and nonsmokers than the other group. Several potential CAM-drug interactions were identified. CONCLUSION: Because of high rates of CAM use (50% of the subjects were using biologically based CAM) and the many potential CAM-drug interactions, CAM use should be rigorously addressed in clinical practice and research. Failure to capture this information may have clinical repercussions through pharmacokinetic and pharmacodynamic interference of clinical response and clinical trial results. Clinicians and researchers may be able to identify those most likely to use CAM by their baseline characteristics; this would help target those patients and research subjects for more thorough assessment and follow-up.

Adult↗
PubMed2006

Modulatory effects of atorvastatin on endothelial cell-derived chemokines, cytokines, and angiogenic factors.

STUDY OBJECTIVE: To investigate the immunomodulatory effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) by determining whether atorvastatin alters the production of specific endothelium-derived immunoactive proteins and whether its treatment effects depend on its concentration and/or inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase. DESIGN: In vitro study using a multiplexing method for protein measurement. SETTING: University laboratory. MEASUREMENTS AND MAIN RESULTS: Human umbilical vein endothelial cells were cultured to approximately 80% confluence and treated with atorvastatin 1-50 microM alone or with mevalonate for 24 hours. Untreated cells served as controls. Culture-conditioned media were removed and multiplex assayed for protein content of epithelial neutrophil-activating peptide-78, interleukin-8, monocyte chemotactic protein-1, interleukin-6, interleukin-10, fibroblast growth factor, and granulocyte colony stimulating factor. Atorvastatin significantly reduced the production of epithelial neutrophil-activating peptide-78, interleukin-6, interleukin-8, and monocyte chemotactic protein-1 (p<0.001 to p<0.05) in a concentration-dependent manner without affecting basal production of interleukin-10, fibroblast growth factor, and granulocyte colony stimulating factor. The treatment effects of atorvastatin were reversed with concurrent mevalonate therapy. CONCLUSION: By inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, atorvastatin lowered concentrations of several inflammatory molecules derived from basal-state endothelial cells in a concentration-dependent manner. The in vivo importance of these immunomodulatory effects needs further investigation.

Atorvastatin↗
PubMed2006

Discordant beta-blocker effects on clinic, ambulatory, resting, and exercise hemodynamics in patients with hypertension.

STUDY OBJECTIVES: To determine the correlation between ambulatory and clinic blood pressure in assessing antihypertensive response to beta-blockade, to test whether blood pressure response to metoprolol is associated with the heart rate response, and to determine whether exercise and resting heart rate responses to metoprolol are correlated. DESIGN: Post hoc analysis of a prospective cohort study. SETTING: University-affiliated general clinical research center. PATIENTS: Fifty-one patients aged 35-65 years with uncomplicated hypertension. Intervention. All patients received metoprolol at a dosage titrated to achieve a diastolic blood pressure below 90 mm Hg. MEASUREMENTS AND MAIN RESULTS: Clinic and 24-hour ambulatory blood pressure measurements were obtained and exercise treadmill testing was performed before and after metoprolol treatment. Based on ambulatory blood pressure data, 24 patients (47%) responded (defined as at least a 10% reduction in diastolic blood pressure) to metoprolol compared with 36 patients (71%) based on clinic blood pressure data (p=0.027). Clinic blood pressure was associated with a 67% false-positive rate (responsive blood pressure by clinic data that was actually nonresponsive by ambulatory data). Blood pressure responders and nonresponders exhibited similar reductions in exercise heart rate (24% and 23%, p=0.74). However, responses to metoprolol measured by exercise heart rate versus resting heart rate were not significantly correlated (r=0.24, p=0.105). CONCLUSION: Reliance on clinic blood pressure or resting heart rate for making beta-blocker treatment decisions may yield less than optimal assessment of the antihypertensive response or degree of beta-blockade.

Adrenergic beta-Antagonists↗
PubMed2005

Global differences in blood pressure control and clinical outcomes in the INternational VErapamil SR-Trandolapril STudy (INVEST).

BACKGROUND: The INternational VErapamil SR-Trandolapril Study (INVEST), a prospective, randomized, antihypertensive trial, found that two different medication regimens produced similar blood pressure (BP) control with equivalent cardiovascular (CV) outcomes (death from any cause, nonfatal myocardial infarction [MI], or nonfatal stroke). HYPOTHESIS: The study was undertaken to investigate whether differences exist by global regions in demographics, treatment, and outcomes in the INVEST trial. METHODS: Data were analyzed for 22,576 patients with stable coronary artery disease (CAD) enrolled in INVEST. We investigated differences in patient characteristics, treatment approaches, BP control, and clinical outcomes by creating three global regions based on geographical location: Northern Americas (NA), Caribbean (CA), and Eurasia (EA). RESULTS: We observed significant regional differences in patient characteristics, treatment patterns, BP control, and CV outcomes. At baseline, patients from NA were older and had greater body mass index, higher rates of diabetes, peripheral vascular disease, and coronary revascularization, but lower rates of MI or left ventricular hypertrophy than patients in CA and EA. At 24 months, there were regional differences in both study and nonstudy antihypertensive drug use. Despite having higher mean baseline BP, patients from CA and EA achieved lower mean systolic BP throughout study follow-up. Furthermore, patients from both CA and EA had lower rates of all-cause mortality, fatal or nonfatal MI, fatal or nonfatal stroke, and newly diagnosed diabetes than patients from NA. CONCLUSIONS: In INVEST, regional differences in medication utilization, BP control, and CV outcomes were identified. These disparities warrant further investigation to define appropriate care for patients with hypertension and stable CAD from an international public health perspective.

Aged↗
PubMed2004

Pharmacokinetics and CYP2D6 genotypes do not predict metoprolol adverse events or efficacy in hypertension.

OBJECTIVE: Beta-Blocker use can be associated with adverse effects that may have an impact on adherence or harm patients. The commonly prescribed beta-blocker metoprolol is metabolized by the polymorphic cytochrome P450 (CYP) 2D6 enzyme, resulting in widely variable drug exposure. We investigated whether metoprolol plasma concentrations, CYP2D6 polymorphisms, or genotype-derived phenotype was associated with adverse effects or efficacy in patients with hypertension. METHODS: Fifty hypertensive patients received metoprolol by use of a dose-titration algorithm until target blood pressure was reached, intolerable side effects occurred, or maximal daily dose was achieved. CYP2D6 genotype was determined by methods based on polymerase chain reaction-restriction fragment length polymorphism and included 19 allelic variants. Patients were assigned to standard phenotype groups on the basis of genotype. Patients were also assigned activity scores based on functional activity of the alleles. General and dose-limiting adverse events and blood pressure responses were analyzed in relation to metoprolol steady-state pharmacokinetic profile and CYP2D6 genotype-derived phenotype. RESULTS: Poor metabolizers had a significantly longer elimination half-life, higher S-metoprolol area under the plasma concentration-time curve (AUC), and lower oral clearance (P < or = .007 for all parameters). There was a 29.6-fold variability in AUC among extensive metabolizers, which was largely explained by CYP2D6 activity scores (P = .032 for ordered differences in AUC by activity score among extensive metabolizers). Overall general and dose-limiting adverse event rates were 46% and 14%, respectively. General adverse event rates did not differ by AUC quartile (66.7% [95% confidence interval (CI), 35.4%-88.7%] and 41.7% [95% CI, 16.5%-71.4%] in the lowest and highest quartiles, respectively; P = .09 among all quartiles). Dose-limiting adverse event rates were also not different by AUC quartile (16.7% [95% CI, 2.9%-49.1%] and 8.3% [95% CI, 0.4%-40.2%] in the lowest and highest quartiles; P = .35 among all quartiles). Furthermore, adverse event rates did not differ by activity scores or between extensive, intermediate, or poor metabolizers. Antihypertensive response rate and blood pressure changes also were not influenced by differences in plasma concentrations or CYP2D6 genotypes. CONCLUSIONS: As expected, CYP2D6 genotype-phenotype correlates with differences in metoprolol pharmacokinetics. However, there was no association between variable pharmacokinetics or CYP2D6 genotype and beta-blocker-induced adverse effects or efficacy.

Adrenergic beta-Antagonists↗
PubMed2003

Beta 1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol.

OBJECTIVES: Marked interpatient variability exists in blood pressure response to beta-blocker monotherapy. We tested the hypothesis that 2 common polymorphisms in the gene for beta(1)-adrenergic receptor are associated with antihypertensive response to metoprolol in patients with uncomplicated hypertension. METHODS: Forty hypertensive men and women aged 35 to 65 years were studied. Baseline studies included 24-hour ambulatory blood pressure monitoring. Patients took 50 mg metoprolol twice daily with weekly titration to response or 200 mg twice daily. After a minimum of 4 weeks at stable dose, treatment phase 24-hour ambulatory blood pressure monitoring was repeated. The codon 49 and 389 genotypes for beta(1)-adrenergic receptor were determined by polymerase chain reaction with restriction fragment length polymorphism. Multilinear regression was performed to determine the impact of genotype and other variables on blood pressure response to metoprolol. RESULTS: Patients homozygous for Arg at codon 389 had a nearly 3-fold greater reduction in daytime diastolic blood pressure (-13.3% +/- 8.4% versus -4.5% +/- 8.2%, P =.0018) compared with those who carried the variant allele. The haplotype pair (diplotype) for beta(1)-adrenergic receptor was also a significant predictor of response, with patients having the Ser49Arg389/Ser49Arg389 diplotype demonstrating a decline in blood pressure of 14.7 mm Hg versus 0.5 mm Hg in patients with the Gly49Arg389/Ser49Gly389 diplotype. In multiregression analysis, baseline daytime diastolic blood pressure, codon 389 genotype, and codon 49 genotype were significant predictors of blood pressure after treatment. CONCLUSIONS: Our data suggest that beta(1)-adrenergic receptor polymorphisms are important determinants of antihypertensive response to metoprolol. In the future, codon 49 and 389 genotypes or beta(1)-adrenergic receptor haplotypes might be used to predict the diastolic blood pressure response to metoprolol in patients with hypertension.

Adrenergic beta-1 Receptor Antagonists↗
PubMed2003

The evolving role of nesiritide in advanced or decompensated heart failure.

Nesiritide is a recombinant form of human brain natriuretic peptide (BNP) that is structurally and biochemically identical to endogenously produced BNP. In humans, BNP is important in hemodynamic and neurohormonal equilibrium, helping to maintain adequate vascular volume and pressure in response to volume overload. The pharmacodynamic effects of nesiritide mimic the biologic effects of BNP. The molecular biology and actions of nesiritide and BNP are reviewed, with the therapeutic rationale for nesiritide in patients with acute or advanced decompensated heart failure highlighted. In addition, recommendations for its administration are provided, and unresolved therapeutic considerations are discussed.

Heart Failure↗