Optimizing aminoglycoside selection for KPC-producing Klebsiella pneumoniae with the aminoglycoside-modifying enzyme (AME) gene aac(6')-Ib.

OBJECTIVES: KPC-producing Klebsiella pneumoniae (KPC-Kp) isolates commonly co-harbour the aminoglycoside-modifying enzyme (AME) gene aac(6')-Ib, which encodes an AME that can confer resistance to some of the commercially available aminoglycosides. We sought to determine the influence of AAC(6')-Ib in KPC-Kp on the pharmacodynamic activity of aminoglycosides. METHODS: Six KPC-Kp clinical isolates, three with and three without aac(6')-Ib, were analysed. Using these isolates, the bacterial killing of amikacin, gentamicin and tobramycin was assessed in static time-kill experiments. The pharmacodynamic activity of the aminoglycosides was then assessed in a dynamic one-compartment infection model over 72 h using simulated human pharmacokinetics of once-daily dosing with amikacin (15 mg/kg), gentamicin (5 mg/kg) and tobramycin (5 mg/kg). RESULTS: At clinically relevant aminoglycoside concentrations in time-kill experiments and the dynamic one-compartment model, gentamicin was more active than amikacin or tobramycin against the isolates harbouring aac(6')-Ib. Amikacin, gentamicin and tobramycin all showed progressively reduced bacterial killing with exposure to repeated doses against most isolates in the dynamic one-compartment model. MIC values were generally not a good predictor of gentamicin pharmacodynamic activity against KPC-Kp, but were more reliable for amikacin and tobramycin. CONCLUSIONS: Gentamicin may be preferred over amikacin or tobramycin for treatment of KPC-Kp infections. However, gentamicin MICs are not a consistent predictor of its pharmacodynamic activity and unexpected treatment failures are possible.

A randomized, open-label pharmacokinetic trial of tacrolimus extended-release dosing in obese de novo kidney transplant recipients.

PURPOSE: Tacrolimus extended-release (TAC-ER; Astagraf XL® ) is utilized in many immunosuppressive regimens post-renal transplantation. Current dosing recommendation for the TAC-ER in renal transplant is 0.15-0.2 mg/kg/day administered once daily. The purpose of this study was to determine the best method of dosing TAC-ER in obese renal transplant recipients. METHODS: De novo obese kidney transplant recipients were randomized to receive TAC-ER 0.15 mg/kg/day based on either adjusted body weight (aBW) or ideal body weight (IBW). Post-transplant patients underwent three pharmacokinetic assessments over 14 days. The primary endpoint was the difference in TAC-ER exposure (AUC0-24) in obese patients dosed using aBW compared with IBW. RESULTS: A total of 20 obese renal transplant recipients were randomized to participate in the study (10 aBW and 10 IBW). Results of the primary outcome (AUC0-24) on Study Day 1, 7, and 14 were not statistically different between the two groups. There was no difference in the number of days to therapeutic trough concentration between the two dosing weights (aBW = 5.1, IBW = 4.9, days; P = 0.90). CONCLUSION: In a population of obese renal transplant recipients, comparable trough concentrations and overall exposure in both groups indicate that IBW may be preferred, as less initial drug was needed to attain adequate exposure.

Isolation and identification of three new chromones from the leaves of Pimenta dioica with cytotoxic, oestrogenic and anti-oestrogenic effects.

CONTEXT: Pimenta dioica (L.) Merr. (Myrtaceae) is used in Costa Rican traditional medicine for women's health. Our previous work showed that P. dioica extracts were oestrogenic. OBJECTIVES: This work identifies phytochemicals from P. dioica that are responsible for the plant's oestrogen-like activities. MATERIALS AND METHODS: P. dioica leaves were collected in Costa Rica in 2005. Fractions resulting from chromatographic separation of a methanol extract were tested at 50 µg/mL in a competitive oestrogen receptor-binding assay. Active compounds were isolated by HPLC and identified by NMR and MS. Pure compounds were tested at 1 µM in the oestrogen-responsive SEAP reporter gene assay. The effects on cell viability, cytotoxicity and apoptosis were investigated in breast cancer (MCF-7 and SK-BR3) and gastric cancer (AGS and NCI-N87) cell lines using the ApoTox-Glo and Caspase-Glo assays and qPCR. RESULTS: Quercitrin and three new chromones, including a 2-phenoxychromone, 6,8-di-C-methylcapillarisin (1) were isolated and identified. Compound 1 caused a 6.2-fold increase in SEAP expression at 1 µM (p < 0.05). This activity was blocked by the ER antagonist ICI 182,780. Compound 2 caused a 6.0-fold increase in SEAP, inhibited the growth of MCF-7, AGS and NCI-N87 cells (IC50 54.27, 38.13 and 51.22 µg/mL, respectively), and induced apoptosis via caspase 8 and increased the Bax/Bcl-2 mRNA ratio in MCF-7 cells. Compound 3 was anti-oestrogenic in MCF-7 cells. DISCUSSION AND CONCLUSIONS: Compounds from P. dioica have oestrogenic, anti-oestrogenic and cytotoxic effects that may explain the ethnomedical use of this plant.

Circulating Procollagen Type III N-Terminal Peptide and Mortality Risk in African Americans With Heart Failure.

BACKGROUND: Procollagen type III N-terminal peptide (PIIINP) is a biomarker of cardiac fibrosis that is associated with heart failure prognosis in whites. Its prognostic significance in African Americans is unknown. We sought to determine whether PIIINP is associated with outcomes in African Americans with heart failure. METHODS AND RESULTS: Blood was collected from 138 African Americans with heart failure for determining PIIINP and genetic ancestry, and patients were followed prospectively for death or hospitalization for heart failure. PIIINP was inversely correlated with West African ancestry (R(2) = 0.061; P = .010). PIIINP > 4.88 ng/mL was associated with all-cause mortality on univariate (hazard ratio [HR] 4.9, 95% confidence interval [CI] 2.2-11.0; P < .001) and multivariate (HR 5.8; 95% CI 1.9-17.3; P = .002) analyses over a median follow-up period of 3 years. We also observed an increased risk for the combined outcome of all-cause mortality or hospitalization for heart failure with PIIINP > 4.88 ng/mL on univariate (HR 2.6, 95% CI 1.6-5.0; P < .001) and multivariate (HR 2.4, 95% CI 1.2-4.7; P = .016) analyses. CONCLUSIONS: High circulating PIIINP is associated with poor outcomes in African Americans with chronic heart failure, suggesting that PIIINP may be useful in identifying African Americans who may benefit from additional therapy to combat fibrosis as a means of improving prognosis.

Genetic variant in folate homeostasis is associated with lower warfarin dose in African Americans.

The anticoagulant warfarin has >30 million prescriptions per year in the United States. Doses can vary 20-fold between patients, and incorrect dosing can result in serious adverse events. Variation in warfarin pharmacokinetic and pharmacodynamic genes, such as CYP2C9 and VKORC1, do not fully explain the dose variability in African Americans. To identify additional genetic contributors to warfarin dose, we exome sequenced 103 African Americans on stable doses of warfarin at extremes (≤ 35 and ≥ 49 mg/week). We found an association between lower warfarin dose and a population-specific regulatory variant, rs7856096 (P = 1.82 × 10(-8), minor allele frequency = 20.4%), in the folate homeostasis gene folylpolyglutamate synthase (FPGS). We replicated this association in an independent cohort of 372 African American subjects whose stable warfarin doses represented the full dosing spectrum (P = .046). In a combined cohort, adding rs7856096 to the International Warfarin Pharmacogenetic Consortium pharmacogenetic dosing algorithm resulted in a 5.8 mg/week (P = 3.93 × 10(-5)) decrease in warfarin dose for each allele carried. The variant overlaps functional elements and was associated (P = .01) with FPGS gene expression in lymphoblastoid cell lines derived from combined HapMap African populations (N = 326). Our results provide the first evidence linking genetic variation in folate homeostasis to warfarin response.

Poor warfarin dose prediction with pharmacogenetic algorithms that exclude genotypes important for African Americans.

OBJECTIVES: Recent clinical trial data cast doubt on the utility of genotype-guided warfarin dosing, specifically showing worse dosing with a pharmacogenetic versus clinical dosing algorithm in African Americans. However, many genotypes important in African Americans were not accounted for. We aimed to determine whether omission of the CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*11 alleles and rs12777823 G > A genotype affects performance of dosing algorithms in African Americans. METHODS: In a cohort of 274 warfarin-treated African Americans, we examined the association between the CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*11 alleles and rs12777823 G > A genotype and warfarin dose prediction error with pharmacogenetic algorithms used in clinical trials. RESULTS: The http://www.warfarindosing.org algorithm overestimated doses by a median (interquartile range) of 1.2 (0.02-2.6) mg/day in rs12777823 heterozygotes (P<0.001 for predicted vs. observed dose), 2.0 (0.6-2.8) mg/day in rs12777823 variant homozygotes (P = 0.004), and 2.2 (0.5-2.9) mg/day in carriers of a CYP2C9 variant (P < 0.001). The International Warfarin Pharmacogenetics Consortium (IWPC) algorithm underdosed warfarin by 0.8 (-2.3 to 0.4) mg/day for patients with the rs12777823 GG genotype (P < 0.001) and overdosed warfarin by 0.7 (-0.4 to 1.9) mg/day in carriers of a variant CYP2C9 allele (P = 0.04). Modifying the http://www.warfarindosing.org algorithm to adjust for variants important in African Americans led to better dose prediction than either the original http://www.warfarindosing.org (P < 0.01) or IWPC (P < 0.01) algorithm. CONCLUSION: These data suggest that, when providing genotype-guided warfarin dosing, failure to account for variants important in African Americans leads to significant dosing error in this population.

The mediating effect of prefrontal asymmetry on the relationship between the COMT Val(158)Met SNP and trait consummatory positive affect.

The Val(158)Met rs4680 polymorphism in the COMT gene regulates dopamine catabolism in the prefrontal cortex (PFC). Dopamine's involvement in reward experience suggests those with the methionine (Met) variant may exhibit trait-level sensitivity to reward due to more post-synaptic dopamine in the PFC. A physiological mediator of this association may be greater relative left asymmetry in the PFC, a putative biomarker for trait positive emotionality. Electroencephalograms of 120 participants were measured during a task that assesses two aspects of reward processing: pre-reward anticipation and post-reward consummatory affect. Participants provided genetics samples and completed the Temporal Experience of Pleasure Scale (TEPS), which assesses trait-level anticipatory and consummatory positive affect. Met carriers had higher TEPS-Consummatory scores. This effect was mediated by greater relative left activation in the post-reward phase of the task. No effects were observed for the pre-reward phase. Results suggest that frontal asymmetry is an endophenotype between COMT genotype and trait reward responsivity.

Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study.

BACKGROUND: VKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans. METHODS: We did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged ≥18 years) who were taking a stable maintenance dose of warfarin were obtained at International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham (Birmingham, AL, USA). Patients enrolled at IWPC sites but who were not used for discovery made up the independent replication cohort. All participants were genotyped. We did a stepwise conditional analysis, conditioning first for VKORC1 -1639G→A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecified a genome-wide significance threshold of p<5×10(-8) in the discovery cohort and p<0·0038 in the replication cohort. FINDINGS: The discovery cohort contained 533 participants and the replication cohort 432 participants. After the prespecified conditioning in the discovery cohort, we identified an association between a novel single nucleotide polymorphism in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide significance (p=1·51×10(-8)). This association was confirmed in the replication cohort (p=5·04×10(-5)); analysis of the two cohorts together produced a p value of 4·5×10(-12). Individuals heterozygous for the rs12777823 A allele need a dose reduction of 6·92 mg/week and those homozygous 9·34 mg/week. Regression analysis showed that the inclusion of rs12777823 significantly improves warfarin dose variability explained by the IWPC dosing algorithm (21% relative improvement). INTERPRETATION: A novel CYP2C single nucleotide polymorphism exerts a clinically relevant effect on warfarin dose in African Americans, independent of CYP2C9*2 and CYP2C9*3. Incorporation of this variant into pharmacogenetic dosing algorithms could improve warfarin dose prediction in this population. FUNDING: National Institutes of Health, American Heart Association, Howard Hughes Medical Institute, Wisconsin Network for Health Research, and the Wellcome Trust.

Association of variants in DRD2 and GRM3 with motor and cognitive function in first-episode psychosis.

Similar smooth pursuit eye tracking dysfunctions are present across psychotic disorders. They include pursuit initiation and maintenance deficits that implicate different functional brain systems. This candidate gene study examined psychosis-related genotypes regulating dopamine and glutamate neurotransmission in relation to these pursuit deficits. One hundred and thirty-eight untreated first-episode patients with a psychotic disorder were genotyped for four markers in DRD2 and four markers in GRM3. The magnitude of eye movement abnormality in patients was defined in relation to performance of matched healthy controls (N = 130). Eighty three patients were followed after 6 weeks of antipsychotic treatment. At baseline, patients with a -141C deletion in DRD2 rs1799732 had slower initiation eye velocity and longer pursuit latency than CC insertion carriers. Further, GRM3 rs274622_CC carriers had poorer pursuit maintenance than T-carriers. Antipsychotic treatment resulted in prolonged pursuit latency in DRD2 rs1799732_CC insertion carriers and a decline in pursuit maintenance in GRM3 rs6465084_GG carriers. The present study demonstrates for the first time that neurophysiological measures of motor and neurocognitive deficits in patients with psychotic disorders have different associations with genes regulating dopamine and glutamate systems, respectively. Alterations in striatal D2 receptor activity through the -141C Ins/Del polymorphism could contribute to pursuit initiation deficits in psychotic disorders. Alterations in GRM3 coding for the mGluR3 protein may impair pursuit maintenance by compromising higher perceptual and cognitive processes that depend on optimal glutamate signaling in corticocortical circuits. DRD2 and GRM3 genotypes also selectively modulated the severity of adverse motor and neurocognitive changes resulting from antipsychotic treatment.

Quantitative target engagement of RIPK1 in human whole blood via the cellular thermal shift assay for potential pre-clinical and clinical applications.

The cellular thermal shift assay (CETSA®) is a target engagement method widely used for preclinical characterization of small molecule compounds. CETSA® has been used for semi-quantitative readouts in whole blood with PBMC isolation, and quantitative, plate-based readouts using cell lines. However, there has been no quantitative evaluation of CETSA® in unprocessed human whole blood, which is preferred for clinical applications. Here we report two separate assay formats - Alpha CETSA® and MSD CETSA® - that require less than 100 µL of whole blood per sample without PBMC isolation. We chose RIPK1 as a proof-of-concept target and, by measuring engagement of seven different inhibitors, demonstrate high assay sensitivity and robustness. These quantitative CETSA® platforms enable possible applications in preclinical pharmacokinetic-pharmacodynamic studies, and direct target engagement with small molecules in clinical trials.

CYP2C9 promoter region single-nucleotide polymorphisms linked to the R150H polymorphism are functional suggesting their role in CYP2C9*8-mediated effects.

Cytochrome P450 2C9 (CYP2C9) c.449G>A (*8) is common in African Americans and is associated with decreased warfarin clearance. We examined the effect of promoter region variants inherited with 449G>A on warfarin clearance, dose requirements, and CYP2C9 expression. In an African American cohort, 449G>A was in linkage disequilibrium with c.-1766T>C (r(2) = 0.89) and c.-1188T>C (D' = 1). The combination of the -1766C and 449A alleles with the -1188CC genotype was associated with lower S-warfarin clearance (0.86 ± 0.22 vs. 1.66 ± 0.75 ml/min/m(2); n = 48; P < 0.01) and dose requirements [33 (25-49) vs. 43 (35-56) mg/week; n = 243; P = 0.03] compared with other genotypes. In liver tissue, alleles with the -1766C/-1188C/449A haplotype showed two-fold decreased mRNA expression compared with reference alleles. In a promoter reporter assay, the -1766C/-1188C haplotype decreased CYP2C9 promoter activity. These data suggest that promoter region polymorphisms inherited with 449G>A decrease CYP2C9 expression and contribute to CYP2C9*8 effects on warfarin clearance and dose requirements.

Sarcina ventriculi associated gastritis: Mimicking lymphoma on endoscopy.

Sarcina Ventriculi is a gram-positive anaerobic coccus rarely reported in patients with delayed gastric emptying, emphysematous gastritis, gastric ulcers, and perforation. So far, less than 30 cases of sarcina isolated from the stomach have been reported. Herein, we describe a case of a 66-year-old male with a history of persistent epigastric pain and regurgitation. The upper gastrointestinal (GI) endoscopy revealed gastric erythema, edema, ulceration, and food bezoar. A gastric biopsy was done to rule out lymphoma. On histopathological examination, sarcina Ventriculi was identified. This organism is likely to get underreported as it may not be that obvious on routinely stained biopsies. Given its association with life-threatening illness such as emphysematous gastritis and perforation, awareness of this organism is important. It's presence in gastric biopsies must be mentioned in the report and should prompt the clinicians to investigate further for functional causes of delayed gastric emptying and gastric outlet obstruction like occult malignancy.

Association of the GGCX (CAA)16/17 repeat polymorphism with higher warfarin dose requirements in African Americans.

OBJECTIVE: Little is known about genetic contributors to higher than usual warfarin dose requirements, particularly for African Americans. This study tested the hypothesis that the γ-glutamyl carboxylase (GGCX) genotype contributes to warfarin dose requirements greater than 7.5 mg/day in an African American population. METHODS: A total of 338 African Americans on a stable dose of warfarin were enrolled. The GGCX rs10654848 (CAA)n, rs12714145 (G>A), and rs699664 (p.R325Q); VKORC1 c.-1639G>A and rs61162043; and CYP2C9*2, *3, *5, *8, *11, and rs7089580 genotypes were tested for their association with dose requirements greater than 7.5 mg/day alone and in the context of other variables known to influence dose variability. RESULTS: The GGCX rs10654848 (CAA)16 or 17 repeat occurred at a frequency of 2.6% in African Americans and was overrepresented among patients requiring greater than 7.5 mg/day versus those who required lower doses (12 vs. 3%, P=0.003; odds ratio 4.0, 95% confidence interval, 1.5-10.5). The GGCX rs10654848 genotype remained associated with high dose requirements on regression analysis including age, body size, and VKORC1 genotype. On linear regression, the GGCX rs10654848 genotype explained 2% of the overall variability in warfarin dose in African Americans. An examination of the GGCX rs10654848 genotype in warfarin-treated Caucasians revealed a (CAA)16 repeat frequency of only 0.27% (P=0.008 compared with African Americans). CONCLUSION: These data support the GGCX rs10654848 genotype as a predictor of higher than usual warfarin doses in African Americans, who have a 10-fold higher frequency of the (CAA)16/17 repeat compared with Caucasians.

Aztreonam in combination with imipenem-relebactam against clinical and isogenic strains of serine and metallo-ß-lactamase-producing enterobacterales.

OBJECTIVE: The objective of this study was to evaluate the in vitro activity of aztreonam plus imipenem-relebactam against clinical and isogenic strains of Escherichia coli and Klebsiella pneumoniae co-harboring NDM and >1 serine ß-lactamase. METHODS: Thirteen isolates were included: 4 clinical E. coli, 4 clinical K. pneumoniae, and 5 isogenic E. coli. Drugs were tested in time-kill analyses alone, in dual ß-lactam combinations, and in triple drug combinations against all strains. RESULTS: All isolates were resistant to imipenem and imipenem-relebactam, and 85% were aztreonam-resistant. Neither imipenem nor imipenem-relebactam was bactericidal alone while aztreonam was bactericidal against 54% of isolates. The combination of aztreonam+imipenem was bactericidal and synergistic against 7/13 and 10/13 isolates. The addition of relebactam to this combination resulted in synergy against all 11 aztreonam-resistant clinical isolates. CONCLUSION: Aztreonam plus imipenem-relebactam may be a viable treatment option for aztreonam-non-susceptible NDM and serine ß-lactamase-producing E. coli and K. pneumoniae.

Warfarin Dosing in Patients With CYP2C9*5 Variant Alleles.

Pharmacogenetic dosing improves the accuracy of warfarin dosing, but current pharmacogenetic dosing algorithms are less accurate in populations of African ancestry. The cytochrome P450 2C9*5 (CYP2C9*5) allele is found almost exclusively in populations of African ancestry, and in vitro studies suggest CYP2C9*5 is associated with reduced clearance of warfarin. The clinical relevance of this single-nucleotide variation (SNV) (formerly SNP) is uncertain. In this multicentered study of 2,298 patients (49% female, 35% Black) taking warfarin, we quantified the association between the CYP2C9*5 allele and warfarin requirements. The CYP2C9*5 SNV was present in 2.3% of Black and 0.07% of White patients. Without taking CYP2C9*5 into account, pharmacogenetic algorithms that include other SNVs overestimated the warfarin dose by 30% (95% confidence interval (19-40%), P < 0.001), an average of 1.87 mg/day (SD 1.64) in heterozygotes (P < 0.001). Noncarriers required a slightly (0.23 mg/day, SD 2.09) higher than predicted dose. Genotyping for CYP2C9*5 corrected the potential overdose and halved overall dosing error in heterozygotes. Patients carrying CYP2C9*5 require a clinically relevant reduction in warfarin dose. Given the potential to improve the accuracy and safety of warfarin dosing in populations of African ancestry, we have incorporated this SNV into a nonprofit website to assist warfarin initiation (www.WarfarinDosing.org).

Pharmacogenomics of warfarin dose requirements in Hispanics.

While Hispanics are the largest and most rapidly growing minority population in the United States, they are underrepresented in pharmacogenomic studies with warfarin. We sought to determine the combination of clinical and genetic influences of warfarin dose requirements in Hispanics. In addition, we tested the performance of published warfarin dosing algorithms derived from largely non-Hispanic cohorts in an inner-city U.S. Hispanic population. Genetic samples and clinical data were obtained from 50 Hispanics on a stable dose of warfarin. The contribution of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex-1 (VKORC1) genotypes and clinical factors to warfarin dose requirements was determined. The correlation between the predicted dose using published algorithms and therapeutic dose was also assessed. Compared to the VKORC1-1639 GG genotype, warfarin dose requirements were 30% and 62% lower with the GA and AA genotypes, respectively (p=0.001). The combination of the VKORC1-1639G>A and CYP2C9 genotypes and clinical factors explained 56% of the inter-patient variability in warfarin dose. Warfarin dose predicted using algorithms derived from mostly non-Hispanic cohorts was significantly correlated with the therapeutic dose in our Hispanic cohort (r(2)=0.43 to 0.49; p<0.001); the predicted dose was within 1.0 mg/day of the therapeutic dose for 40% to 50% of patients. Our data suggest that factors influencing warfarin dose requirements in Hispanic Caucasians are similar to those previously described in European Caucasians and that dosing algorithms derived from non-Hispanic Caucasian cohorts are applicable to Hispanics living in the U.S.

The pharmacokinetics of codeine and its metabolites in Blacks with sickle cell disease.

PURPOSE: We conducted a prospective, open-label study in 54 adult subjects with sickle cell disease to determine the relationship between morphine concentrations, cytochrome P450 (CYP) 2D6 genotype, and clinical outcomes. METHODS: A blood sample was obtained for genotyping and serial blood samples were drawn to measure codeine and its metabolites in the plasma before and after oral codeine sulfate 30 mg. Codeine and its metabolites were measured by liquid chromatography-tandem mass spectrometry (LC-MS). CYP2D6 genetic testing included four single nucleotide polymorphisms (SNP) indicative of three variant alleles: *17 (1023T); *29 (1659A, 3183A); and *41 (2988A) alleles. RESULTS: Thirty subjects (group I) had a mean (standard deviation) maximal morphine concentration of 2.0 (1.0) ng/ml. Morphine was not measurable in the remaining 24 subjects (group II). Nine (30%) subjects in group I and 11 (46%) subjects in group II carried a variant *17, *29, or *41 allele (p = 0.23); one (3%) subject in group I and 5 (21%) subjects in group II were homozygous for *17 or *29 allele (p = 0.07). Emergency room visits (group I 1.5 +/- 1.8 vs. group II 2.1 +/- 4.3, p = NS) did not differ based on metabolic status, but more hospital admissions (0.9 +/- 1.4 vs. 2.2 +/- 4.1, p = 0.05) were documented in patients with no measurable morphine concentrations. CONCLUSIONS: We conclude that Blacks with sickle cell disease without measurable plasma morphine levels after a single dose of codeine were not more likely to be a carrier of a single variant allele commonly associated with reduced CYP2D6 metabolic capacity; however, homozygosity for a variant CYP2D6 allele may result in reduced metabolic capacity. Furthermore, it appears that subjects without measurable morphine concentrations were more likely to be admitted to the hospital for an acute pain crisis.

Predictors of unstable anticoagulation in African Americans.

OBJECTIVE: We sought to identify contributors to unstable anticoagulation in African Americans. PATIENTS AND METHODS: Sixty African Americans on warfarin were enrolled. Cytochrome P450 2C9 and vitamin K epoxide reductase genotypes and vitamin K intake were assessed, and clinical and dietary data during the 12 months prior to enrollment were collected. Data were compared between stable and unstable patients, classified based on the proportion of international normalized ratio (INR) values outside the therapeutic range. RESULTS: The median proportion of out-of-range INRs among study participants was 44%; 28 patients had a higher proportion of INRs out-of-range and were included in the unstable group, with the remaining constituting the stable group. The median (IQR) number of clinic visits/year was higher among unstable versus stable patients [18 (15-22) vs. 16 (13-19); P = 0.03]. Higher warfarin doses, lower adherence, vomiting or diarrhea, and use of antiinfective agents were more common among unstable patients. Genotype was not associated with anticoagulation stability. After regression analysis, only poor adherence and gastrointestinal illness remained predictive of unstable anticoagulation. In a control group of Caucasians of similar age and sex distribution, poor adherence, but not gastrointestinal illness, was associated with unstable anticoagulation. CONCLUSION: We conclude that poor warfarin adherence and gastrointestinal illness are major contributors to unstable anticoagulation in African Americans. Our data suggest that, similar to Caucasians, improving warfarin adherence rates may be an important mean to improve anticoagulation control in African Americans. In addition, close monitoring during acute illness may be particularly important in this population.

Factors influencing pharmacokinetics of warfarin in African-Americans: implications for pharmacogenetic dosing algorithms.

AIM: This study attempted to identify predictors of S-warfarin clearance (CL[S]) and to make a pharmacokinetic evaluation of genotype-based dosing algorithms in African-Americans. METHODS: Using plasma S-warfarin concentration (Cp[S]) at a steady state and eight SNPs previously shown to influence warfarin dose in African-Americans, CL(S) and its predictors were estimated by population pharmacokinetic analysis in 60 African-Americans. The time courses of Cp(S) following either the loading dose or maintenance dose were simulated using the population pharmacokinetic estimates. RESULTS: CYP2C9*8 and body surface area or body weight were predictors of CL(S) (-30 and -5% per -0.1 m(2)/-10 kg reduction in CL[S], respectively) in African-Americans. Simulations of Cp(S) showed that Cp(S) at steady state was 1.4-times higher in patients with CYP2C9*8 than in those with CYP2C9*1/*1, irrespective of the algorithm for loading dose or maintenance dose. CONCLUSION: African-Americans possess independent predictors of CL(S), possibly leading to a prediction error of any dosing algorithm that excludes African-specific variant(s). Original submitted 3 September 2014; Revision submitted 3 November 2014.

Pharmacogenetic associations of the type-3 metabotropic glutamate receptor (GRM3) gene with working memory and clinical symptom response to antipsychotics in first-episode schizophrenia.

RATIONALE: Type-3 metabotropic glutamate receptor gene (GRM3) single nucleotide polymorphisms (SNPs) have been associated with cognitive performance and prefrontal cortex brain activity in chronically treated schizophrenia patients. Whether these SNPs are associated with cognitive and symptom response to antipsychotic therapy has not been extensively evaluated. OBJECTIVES: The aim of the study was to examine pharmacogenetic relationships between GRM3 and selected variants in relevant dopamine genes with changes in spatial working memory and clinical symptoms after treatment. METHODS: Sixty-one untreated first-episode schizophrenia patients were assessed before and after 6 weeks of antipsychotic pharmacotherapy, primarily consisting of risperidone. Patients' level of cognitive performance on a spatial working memory task was assessed with a translational oculomotor paradigm. Changes after treatment in cognitive and clinical measures were examined in relationship to genetic polymorphisms in the GRM3, COMT, and DRD2/ANKK1 gene regions. RESULTS: Spatial working memory performance worsened after antipsychotic treatment. This worsening was associated with GRM3 rs1468412, with the genetic subgroup of patients known to have altered glutamate activity having greater adverse changes in working memory performance after antipsychotic treatment. Negative symptom improvement was associated with GRM3 rs6465084. There were no pharmacogenetic associations between DRD2/ANKK1 and COMT with working memory changes or symptom response to treatment. CONCLUSIONS: These findings suggest important pharmacogenetic relationships between GRM3 variants and changes in cognition and symptom response with exposure to antipsychotics. This information may be useful in identifying patients susceptible to adverse cognitive outcomes associated with antipsychotic treatment and suggest that glutamatergic mechanisms contribute to such effects.