Mordechai Muszkat - Academia.edu (original) (raw)

Papers by Mordechai Muszkat

Research paper thumbnail of Natural course of insulin edema

Journal of Endocrinological Investigation, 2000

Research paper thumbnail of Massive subcutaneous emphysema in a long-term ventilated patient

Research paper thumbnail of Major Bleeding Caused by Warfarin in a Genetically Susceptible Patient

Pharmacotherapy, 2002

A 90-year-old woman was hospitalized for gastrointestinal bleeding. Although she had been receivi... more A 90-year-old woman was hospitalized for gastrointestinal bleeding. Although she had been receiving only warfarin 5 mg/day, her international normalized ratio (INR) was 66. Warfarin was discontinued, and her INR fell to 3.7 after transfusion of fresh-frozen plasma. However, it rose again spontaneously to 7.5. Eleven days after the last dose of warfarin had been administered, it was still detectable in the patient's plasma, indicating that impaired warfarin clearance may have caused an enhanced anticoagulation effect. Genetic analysis of the cytochrome P450 (CYP) isoenzyme 2C9, which mediates the major deactivating pathway of S-warfarin, revealed that the patient was a compound heterozygote carrying two variant alleles: CYP2C9*2 and CYP2C9*3. The patient's enhanced sensitivity to warfarin 5 mg/day can be ascribed to decreased clearance of S-warfarin secondary to genetic alteration of the gene encoding CYP2C9, resulting in a life-threatening complication.

Research paper thumbnail of Teaching empathy through poetry: a clinically based model

Research paper thumbnail of The effect of folic acid (FA) supplumentation on warfarin (WAR) dose requirement and the formation clearance of (S)-7' OH-warfarin

Clinical Pharmacology & Therapeutics, 2005

ABSTRACT BackgroundFA supplementation in patients with FA deficiency is associated with increased... more ABSTRACT BackgroundFA supplementation in patients with FA deficiency is associated with increased clearance of phenytoin towards its CYP2C9-mediated metabolite, p-HPPH. The aim of this study was to determine the effect of FA concentration and supplementation on the dose requirement of the CYP2C9 substrate WAR, and the formation clearance of (S)-7' OH-warfarin[CLf7OHW].MethodsWAR dose was recorded, and CLf7OHW and FA concentrations were measured in 98 patients at stable WAR anticoagulation. In 22 patients with FA deficiency CLf7OHW was re-evaluated following FA treatment (5mg/day).ResultsAmong patient with FA deficiency FA concentration was 3.99±1.86 ng/ml prior to and 21.65±5.84 ng/ml following FA treatment (p<0.0001). CLf7OHW increased following FA treatment from 1.06±0.86 to 2.11±2.48, ml/min, (p= 0.017), however there was no difference in WAR dose (5.93± 2.38 vs. 6.06±2.51, mg/day, p=0.30). There was no significant correlation between FA concentration and WAR dose or CLf7OHW in the entire cohort (n=98).Conclusions In patients with FA deficiency, FA supplementation was associated with increased CLf7OHW. Further study is warranted to determine the clinical significance of the interaction between WAR and FA.Clinical Pharmacology & Therapeutics (2005) 77, P41-P41; doi: 10.1016/j.clpt.2004.12.051

Research paper thumbnail of Genetic Variation in Alpha2-Adrenoreceptors and Heart Rate Recovery after Exercise

Physiological genomics, Jan 9, 2015

Heart rate recovery (HRR) after exercise is an independent predictor of adverse cardiovascular ou... more Heart rate recovery (HRR) after exercise is an independent predictor of adverse cardiovascular outcomes. HRR is mediated by both parasympathetic reactivation and sympathetic withdrawal and is highly heritable. We examined whether common genetic variants in adrenergic and cholinergic receptors and transporters affect HRR. One hundred and twenty six healthy subjects (66 Caucasians, 56 African Americans) performed an 8-minute step-wise bicycle exercise test with continuous computerized ECG recordings. We fitted an exponential curve to the post-exercise RR intervals for each subject to calculate the recovery constant (kr) as primary outcome. Secondary outcome was the root mean square residuals averaged over 1 minute (RMS1min), a marker of parasympathetic tone. We used multiple linear regressions to determine the effect of functional candidate genetic variants in autonomic pathways (6 ADRA2A, 1 ADRA2B, 4 ADRA2C, 2 ADRB1, 3 ADRB2, 2 NET, 2 CHT, and 1 GRK5) on the outcomes before and after...

Research paper thumbnail of Variations in the α2A-adrenergic receptor gene and their functional effects

Clinical Pharmacology & Therapeutics, 2006

The ␣ 2A -adrenergic receptor (ADRA2A) plays a central role in the regulation of systemic sympath... more The ␣ 2A -adrenergic receptor (ADRA2A) plays a central role in the regulation of systemic sympathetic activity and hence cardiovascular responses such as heart rate and blood pressure. The objectives of this study were to systematically search for variants in the ADRA2A gene, to define the gene's haplotype structure, and to examine potential functional effects of these variants. Methods: We examined 5957 base pairs of contiguous sequence of ADRA2A (promoter, exonic, and 3-flanking region) using polymerase chain reaction to amplify the genomic target, followed by bidirectional sequencing, in 135 healthy subjects (85 white and 50 black subjects). Haplotypes were inferred by use of an expectationmaximization algorithm. Primary (plasma norepinephrine concentration) and secondary (resting heart rate and blood pressure) phenotypes were compared among subjects grouped by individual polymorphisms and haplotypes. Results: We identified 41 variants, including 24 novel variants. On the basis of 9 optimally selected markers, 11 haplotypes in 5 haplotype groups were inferred, representing approximately 99% of the cohort. Two uncommon variants in complete linkage disequilibrium (G>C at ؊1903 and C>G at ؊1607, identified in 3 black subjects) were associated with significantly increased plasma norepinephrine concentrations (376.7 ؎ 6.1 pg/mL versus 218.4 ؎ 95.0 pg/mL, P ‫؍‬ .011). There was no other significant association between genetic variants or any of the haplotypes with phenotypes. Conclusion: We describe novel variants and the haplotype structure of the ADRA2A gene. Common genetic ADRA2A variants are not important determinants of baseline cardiovascular measures (plasma norepinephrine, heart rate, and blood pressure) in healthy volunteers. (Clin Pharmacol Ther 2006;79:173-85.)

Research paper thumbnail of Endothelial nitric oxide synthase GLU298ASP polymorphism and blood pressure responses to salt

Clinical Pharmacology & Therapeutics, 2003

Clinical Pharmacology & Therapeutics (2003) 73, P98–P98; doi:

Research paper thumbnail of A search for the genomic basis for inter-individual variability in alpha1a-adrenergic receptor response

Clinical Pharmacology & Therapeutics, 2003

Clinical Pharmacology & Therapeutics (2003) 73, P1–P1; doi:

Research paper thumbnail of CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study

Clinical pharmacology and therapeutics, 2008

Warfarin anticoagulation effect is characterized by marked variability, some of which has been at... more Warfarin anticoagulation effect is characterized by marked variability, some of which has been attributed to CYP2C9 polymorphisms. This study prospectively examines whether a priori knowledge of CYP2C9 genotype may improve warfarin therapy. Patients were randomly assigned to receive warfarin by a validated algorithm ("control", 96 patients) or CYP2C9 genotype-adjusted algorithms ("study", 95 patients). The first therapeutic international normalized ratio and stable anticoagulation were reached 2.73 and 18.1 days earlier in the study group, respectively (P<0.001). The faster rate of initial anticoagulation was driven by a 28% higher daily dose in the study group (P<0.001). Study group patients spent more time within the therapeutic range (80.4 vs 63.4%, respectively, P<0.001) and experienced less minor bleeding (3.2 vs 12.5%, P<0.02, respectively). In conclusion, CYP2C9 genotype-guided warfarin therapy is more efficient and safer than the "average...

Research paper thumbnail of Population differences in S-warfarin metabolism between CYP2C9 genotype-matched Caucasian and Japanese patients

Clinical pharmacology and therapeutics, 2003

Our objective was to investigate population differences in the metabolic activity of cytochrome P... more Our objective was to investigate population differences in the metabolic activity of cytochrome P450 (CYP) 2C9 between genotypically matched Caucasian and Japanese patients by using the unbound oral clearance of S-warfarin as an in vivo phenotypic trait measure. Ninety Japanese and 47 Caucasian patients receiving maintenance warfarin therapy were studied. Steady-state plasma unbound concentrations of S-warfarin were measured by a chiral HPLC method coupled with an ultrafiltration technique, and unbound oral clearance for S-warfarin was estimated. By combining plasma unbound concentrations of S-warfarin with the urinary excretion rates of S-7-hydroxywarfarin, the formation clearance of S-7-hydroxywarfarin was also determined. Genotyping of CYP2C9 was performed for 6 distinct alleles (CYP2C9*1, CYP2C9*2, CYP2C9*3, CYP2C9*4, CYP2C9*5, and a T/C transition in intron 2). The frequency distribution of unbound oral clearance for S-warfarin obtained from Japanese patients was shifted toward...

Research paper thumbnail of Fulminant Cushing's syndrome due to an ACTH-producing thymic carcinoid

The Israel Medical Association journal : IMAJ, 2000

Research paper thumbnail of Ticlopidine-induced thrombotic thrombocytopenic purpura

Pharmacotherapy

Thrombotic thrombocytopenic purpura (TTP) occurs in association with a wide variety of disorders ... more Thrombotic thrombocytopenic purpura (TTP) occurs in association with a wide variety of disorders including infections, connective tissue diseases, and solid organ tumors. It also may coincide with administration of drugs such as mitomycin, metronidazole, oral contraceptives, cyclosporine, and many others. We report the occurrence of TTP in a patient shortly after the initiation of ticlopidine.

Research paper thumbnail of Genetic prescribing of warfarin

Clinical Pharmacology & Therapeutics, 2003

Research paper thumbnail of Phenotypic evaluation of CYP2C9 by way of phenytoin metabolic ratio (PMR)

ABSTRACT AimsValidation of PMR as a phenotypic marker of CYP2C9 in the Jewish Israeli population.... more ABSTRACT AimsValidation of PMR as a phenotypic marker of CYP2C9 in the Jewish Israeli population.Methods Seventy-nine Jewish Israeli subjects collected urine over 24 hours following a single dose of 300 mg phenytoin (PHT). A single blood sample was drawn after 12 hours. PMR, a putative index of CYP2C9 activity, was derived from the ratio of urinary 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) to mid-interval plasma PHT concentration. CYP2C9 genotype was identified by PCR followed by incubation with restriction enzymes.ResultsThe ethnic composition of the study population was reflective of the Jewish groups residing in Israel. PMR values exhibited 18-fold inter-individual variability with a typical Gaussian frequency distribution, which was skewed to the right. Forty-one subjects were homozygous for the wild-type allele (CYP2C9*1), 32 were carriers of one mutated allele (16 CYP2C9*2 and 16 CYP2C9*3), and 6 were carriers of 2 mutated alleles. PMR exhibits gene-dose effect so that among CYP2C9*1 homozygous, PMR was 16.17±9.76 ml/min (95% CI, 13.10 to 19.26) and significantly greater than in CYP2C9*2 heterozygous (8.54±4.33 ml/min, 95% CI, 6.24 to 10.85, p&lt;0.05) and CYP2C9*3 heterozygous (7.33±3.55 ml/min, 95% CI, 5.44 to 9.22, p&lt;0.001) or carriers of 2 variant alleles (6.73±4.22 ml/min, 95% CI, 2.30 to 11.15, p&lt;0.01).ConclusionsPMR exhibits marked inter-individual variability and it correlates with CYP2C9 genotype. Its use as a reliable marker of CYP2C9 activity in-vivo should be further evaluated.Clinical Pharmacology &amp; Therapeutics (2005) 77, P60-P60; doi: 10.1016/j.clpt.2004.12.121

Research paper thumbnail of Increased α1 Adrenergic Vascular Sensitivity in The Dorsal Hand Vein in African-Americans

Clinical Pharmacology & Therapeutics, 2003

Research paper thumbnail of A common β1-adrenergic receptor polymorphism (Arg389Gly) affects blood pressure response to β-blockade

Clinical Pharmacology & Therapeutics, 2003

... Full text access provided to Googlebot Access by Web Services. ... E-mail: alastair.wood@vand... more ... Full text access provided to Googlebot Access by Web Services. ... E-mail: alastair.wood@vanderbilt. edu. ... a larger decrease in resting systolic blood pressure (8.7 1.3 mm Hg versus 0.2 1.7 mm Hg, P &amp;amp;lt; .001) and mean arterial blood pressure (7.2 1.0 mm Hg versus 2.0 1.7 mm Hg, P ...

Research paper thumbnail of Alpha‐2B adrenergic receptor (ADRA2B) 301‐303 deletion polymorphism and vascular desensitization in vivo

ABSTRACT Alpha-2 adrenergic receptors (ADRA2) play important roles in both central and peripheral... more ABSTRACT Alpha-2 adrenergic receptors (ADRA2) play important roles in both central and peripheral regulation of vascular tone. The ADRA2B subtype mediates vasoconstriction and a common genetic variation, 301-303 deletion, was associated with loss of agonist-induced desensitization in vitro. Desensitization of vascular ADRA2 responses in vivo has not been previously described; nor is the effect of genetic variation known. We examined the hypothesis that 301-303del polymorphism affects vascular desensitization to the selective ADRA2 agonist, dexmedetomidine (Dex) in vivo. Incremental doses of Dex (0.01|[ndash]|1000 ng/min) were infused into a dorsal hand vein (DHV) in 28 healthy subjects (age 18-45 years) and responses measured using a linear variable differential transformer. A dose-response curve was constructed and the ED50 calculated. On a separate day, the Dex dose that had caused at least 50% venoconstriction in the dose-response study was infused for three hours and response measured every 30 minutes. The area under the curve for DHV response normalized to the initial response (nAUC) was calculated. Genotyping for 301-303del was performed, and relation to nAUC was determined. There was more than 3-fold inter-individual variability in nAUC. This was not related to ADRA2B genotype (p=0.846). Inter-individual variability in vascular responses to ADRA2 agonist over time occurs, but is not explained by the ADRA2B 301-303del.

Research paper thumbnail of Effect of alpha‐2C adrenergic receptor (ADRA2C) 322–325 deletion polymorphism on blood pressure response to dietary sodium in African‐Americans (AA)

ABSTRACT Salt-sensitivity is more common in AA and is associated with increased risk of hypertens... more ABSTRACT Salt-sensitivity is more common in AA and is associated with increased risk of hypertension, but its genetic basis is not known. Genetic variability in ADRA2&#39;s has been implicated in salt sensitivity. An ADRA2C deletion polymorphism (322-325) is common in AA and is associated with reduced responses to agonist in vitro. We examined the hypothesis that the ADRA2C deletion polymorphism (322-325) contributes to salt sensitivity. Nineteen healthy AA subjects received 5 days of low (10 meq/day, LS), and high sodium, (400 meq/day, HS) diet. 24 hour automated blood pressure was monitored on the last day of each diet. The mean arterial blood pressure difference (dMAP) between LS and HS was calculated. An increase of 3 mmHg or greater was regarded as salt sensitivity. Genotyping for ADRA2C 322-325 deletion was performed, and dMAP compared among the three genotypes [wt/wt (5), wt/del (9), del/del (5)]. There was no difference between genotypes in dMAP (p= 0.263) or frequency of salt sensitivity (p= 0.794). [dMAP mmHg (CI): |[minus]|0.07 (|[minus]|9.5 +9.4), |[minus]|2.27 (|[minus]|8.2 +3.7), 4.94 (|[minus]|4.1 +14.0); salt sensitivity: 2/5, 4/9, 3/5, for wt/wt, wt/del and del/del, respectively]. These findings indicate that the ADRA2C 322-325 deletion is not a major determinant of blood pressure response to dietary Sodium in healthy AA subjects.

Research paper thumbnail of The selective alpha-adrenergic receptor agonist dexmedetomidine (DEX) does not affect aortic pressure augmentation

Clinical Pharmacology & Therapeutics, 2005

Research paper thumbnail of Natural course of insulin edema

Journal of Endocrinological Investigation, 2000

Research paper thumbnail of Massive subcutaneous emphysema in a long-term ventilated patient

Research paper thumbnail of Major Bleeding Caused by Warfarin in a Genetically Susceptible Patient

Pharmacotherapy, 2002

A 90-year-old woman was hospitalized for gastrointestinal bleeding. Although she had been receivi... more A 90-year-old woman was hospitalized for gastrointestinal bleeding. Although she had been receiving only warfarin 5 mg/day, her international normalized ratio (INR) was 66. Warfarin was discontinued, and her INR fell to 3.7 after transfusion of fresh-frozen plasma. However, it rose again spontaneously to 7.5. Eleven days after the last dose of warfarin had been administered, it was still detectable in the patient&amp;amp;amp;amp;#39;s plasma, indicating that impaired warfarin clearance may have caused an enhanced anticoagulation effect. Genetic analysis of the cytochrome P450 (CYP) isoenzyme 2C9, which mediates the major deactivating pathway of S-warfarin, revealed that the patient was a compound heterozygote carrying two variant alleles: CYP2C9*2 and CYP2C9*3. The patient&amp;amp;amp;amp;#39;s enhanced sensitivity to warfarin 5 mg/day can be ascribed to decreased clearance of S-warfarin secondary to genetic alteration of the gene encoding CYP2C9, resulting in a life-threatening complication.

Research paper thumbnail of Teaching empathy through poetry: a clinically based model

Research paper thumbnail of The effect of folic acid (FA) supplumentation on warfarin (WAR) dose requirement and the formation clearance of (S)-7' OH-warfarin

Clinical Pharmacology & Therapeutics, 2005

ABSTRACT BackgroundFA supplementation in patients with FA deficiency is associated with increased... more ABSTRACT BackgroundFA supplementation in patients with FA deficiency is associated with increased clearance of phenytoin towards its CYP2C9-mediated metabolite, p-HPPH. The aim of this study was to determine the effect of FA concentration and supplementation on the dose requirement of the CYP2C9 substrate WAR, and the formation clearance of (S)-7&#39; OH-warfarin[CLf7OHW].MethodsWAR dose was recorded, and CLf7OHW and FA concentrations were measured in 98 patients at stable WAR anticoagulation. In 22 patients with FA deficiency CLf7OHW was re-evaluated following FA treatment (5mg/day).ResultsAmong patient with FA deficiency FA concentration was 3.99±1.86 ng/ml prior to and 21.65±5.84 ng/ml following FA treatment (p&lt;0.0001). CLf7OHW increased following FA treatment from 1.06±0.86 to 2.11±2.48, ml/min, (p= 0.017), however there was no difference in WAR dose (5.93± 2.38 vs. 6.06±2.51, mg/day, p=0.30). There was no significant correlation between FA concentration and WAR dose or CLf7OHW in the entire cohort (n=98).Conclusions In patients with FA deficiency, FA supplementation was associated with increased CLf7OHW. Further study is warranted to determine the clinical significance of the interaction between WAR and FA.Clinical Pharmacology &amp; Therapeutics (2005) 77, P41-P41; doi: 10.1016/j.clpt.2004.12.051

Research paper thumbnail of Genetic Variation in Alpha2-Adrenoreceptors and Heart Rate Recovery after Exercise

Physiological genomics, Jan 9, 2015

Heart rate recovery (HRR) after exercise is an independent predictor of adverse cardiovascular ou... more Heart rate recovery (HRR) after exercise is an independent predictor of adverse cardiovascular outcomes. HRR is mediated by both parasympathetic reactivation and sympathetic withdrawal and is highly heritable. We examined whether common genetic variants in adrenergic and cholinergic receptors and transporters affect HRR. One hundred and twenty six healthy subjects (66 Caucasians, 56 African Americans) performed an 8-minute step-wise bicycle exercise test with continuous computerized ECG recordings. We fitted an exponential curve to the post-exercise RR intervals for each subject to calculate the recovery constant (kr) as primary outcome. Secondary outcome was the root mean square residuals averaged over 1 minute (RMS1min), a marker of parasympathetic tone. We used multiple linear regressions to determine the effect of functional candidate genetic variants in autonomic pathways (6 ADRA2A, 1 ADRA2B, 4 ADRA2C, 2 ADRB1, 3 ADRB2, 2 NET, 2 CHT, and 1 GRK5) on the outcomes before and after...

Research paper thumbnail of Variations in the α2A-adrenergic receptor gene and their functional effects

Clinical Pharmacology & Therapeutics, 2006

The ␣ 2A -adrenergic receptor (ADRA2A) plays a central role in the regulation of systemic sympath... more The ␣ 2A -adrenergic receptor (ADRA2A) plays a central role in the regulation of systemic sympathetic activity and hence cardiovascular responses such as heart rate and blood pressure. The objectives of this study were to systematically search for variants in the ADRA2A gene, to define the gene's haplotype structure, and to examine potential functional effects of these variants. Methods: We examined 5957 base pairs of contiguous sequence of ADRA2A (promoter, exonic, and 3-flanking region) using polymerase chain reaction to amplify the genomic target, followed by bidirectional sequencing, in 135 healthy subjects (85 white and 50 black subjects). Haplotypes were inferred by use of an expectationmaximization algorithm. Primary (plasma norepinephrine concentration) and secondary (resting heart rate and blood pressure) phenotypes were compared among subjects grouped by individual polymorphisms and haplotypes. Results: We identified 41 variants, including 24 novel variants. On the basis of 9 optimally selected markers, 11 haplotypes in 5 haplotype groups were inferred, representing approximately 99% of the cohort. Two uncommon variants in complete linkage disequilibrium (G>C at ؊1903 and C>G at ؊1607, identified in 3 black subjects) were associated with significantly increased plasma norepinephrine concentrations (376.7 ؎ 6.1 pg/mL versus 218.4 ؎ 95.0 pg/mL, P ‫؍‬ .011). There was no other significant association between genetic variants or any of the haplotypes with phenotypes. Conclusion: We describe novel variants and the haplotype structure of the ADRA2A gene. Common genetic ADRA2A variants are not important determinants of baseline cardiovascular measures (plasma norepinephrine, heart rate, and blood pressure) in healthy volunteers. (Clin Pharmacol Ther 2006;79:173-85.)

Research paper thumbnail of Endothelial nitric oxide synthase GLU298ASP polymorphism and blood pressure responses to salt

Clinical Pharmacology & Therapeutics, 2003

Clinical Pharmacology & Therapeutics (2003) 73, P98–P98; doi:

Research paper thumbnail of A search for the genomic basis for inter-individual variability in alpha1a-adrenergic receptor response

Clinical Pharmacology & Therapeutics, 2003

Clinical Pharmacology & Therapeutics (2003) 73, P1–P1; doi:

Research paper thumbnail of CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study

Clinical pharmacology and therapeutics, 2008

Warfarin anticoagulation effect is characterized by marked variability, some of which has been at... more Warfarin anticoagulation effect is characterized by marked variability, some of which has been attributed to CYP2C9 polymorphisms. This study prospectively examines whether a priori knowledge of CYP2C9 genotype may improve warfarin therapy. Patients were randomly assigned to receive warfarin by a validated algorithm ("control", 96 patients) or CYP2C9 genotype-adjusted algorithms ("study", 95 patients). The first therapeutic international normalized ratio and stable anticoagulation were reached 2.73 and 18.1 days earlier in the study group, respectively (P<0.001). The faster rate of initial anticoagulation was driven by a 28% higher daily dose in the study group (P<0.001). Study group patients spent more time within the therapeutic range (80.4 vs 63.4%, respectively, P<0.001) and experienced less minor bleeding (3.2 vs 12.5%, P<0.02, respectively). In conclusion, CYP2C9 genotype-guided warfarin therapy is more efficient and safer than the "average...

Research paper thumbnail of Population differences in S-warfarin metabolism between CYP2C9 genotype-matched Caucasian and Japanese patients

Clinical pharmacology and therapeutics, 2003

Our objective was to investigate population differences in the metabolic activity of cytochrome P... more Our objective was to investigate population differences in the metabolic activity of cytochrome P450 (CYP) 2C9 between genotypically matched Caucasian and Japanese patients by using the unbound oral clearance of S-warfarin as an in vivo phenotypic trait measure. Ninety Japanese and 47 Caucasian patients receiving maintenance warfarin therapy were studied. Steady-state plasma unbound concentrations of S-warfarin were measured by a chiral HPLC method coupled with an ultrafiltration technique, and unbound oral clearance for S-warfarin was estimated. By combining plasma unbound concentrations of S-warfarin with the urinary excretion rates of S-7-hydroxywarfarin, the formation clearance of S-7-hydroxywarfarin was also determined. Genotyping of CYP2C9 was performed for 6 distinct alleles (CYP2C9*1, CYP2C9*2, CYP2C9*3, CYP2C9*4, CYP2C9*5, and a T/C transition in intron 2). The frequency distribution of unbound oral clearance for S-warfarin obtained from Japanese patients was shifted toward...

Research paper thumbnail of Fulminant Cushing's syndrome due to an ACTH-producing thymic carcinoid

The Israel Medical Association journal : IMAJ, 2000

Research paper thumbnail of Ticlopidine-induced thrombotic thrombocytopenic purpura

Pharmacotherapy

Thrombotic thrombocytopenic purpura (TTP) occurs in association with a wide variety of disorders ... more Thrombotic thrombocytopenic purpura (TTP) occurs in association with a wide variety of disorders including infections, connective tissue diseases, and solid organ tumors. It also may coincide with administration of drugs such as mitomycin, metronidazole, oral contraceptives, cyclosporine, and many others. We report the occurrence of TTP in a patient shortly after the initiation of ticlopidine.

Research paper thumbnail of Genetic prescribing of warfarin

Clinical Pharmacology & Therapeutics, 2003

Research paper thumbnail of Phenotypic evaluation of CYP2C9 by way of phenytoin metabolic ratio (PMR)

ABSTRACT AimsValidation of PMR as a phenotypic marker of CYP2C9 in the Jewish Israeli population.... more ABSTRACT AimsValidation of PMR as a phenotypic marker of CYP2C9 in the Jewish Israeli population.Methods Seventy-nine Jewish Israeli subjects collected urine over 24 hours following a single dose of 300 mg phenytoin (PHT). A single blood sample was drawn after 12 hours. PMR, a putative index of CYP2C9 activity, was derived from the ratio of urinary 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) to mid-interval plasma PHT concentration. CYP2C9 genotype was identified by PCR followed by incubation with restriction enzymes.ResultsThe ethnic composition of the study population was reflective of the Jewish groups residing in Israel. PMR values exhibited 18-fold inter-individual variability with a typical Gaussian frequency distribution, which was skewed to the right. Forty-one subjects were homozygous for the wild-type allele (CYP2C9*1), 32 were carriers of one mutated allele (16 CYP2C9*2 and 16 CYP2C9*3), and 6 were carriers of 2 mutated alleles. PMR exhibits gene-dose effect so that among CYP2C9*1 homozygous, PMR was 16.17±9.76 ml/min (95% CI, 13.10 to 19.26) and significantly greater than in CYP2C9*2 heterozygous (8.54±4.33 ml/min, 95% CI, 6.24 to 10.85, p&lt;0.05) and CYP2C9*3 heterozygous (7.33±3.55 ml/min, 95% CI, 5.44 to 9.22, p&lt;0.001) or carriers of 2 variant alleles (6.73±4.22 ml/min, 95% CI, 2.30 to 11.15, p&lt;0.01).ConclusionsPMR exhibits marked inter-individual variability and it correlates with CYP2C9 genotype. Its use as a reliable marker of CYP2C9 activity in-vivo should be further evaluated.Clinical Pharmacology &amp; Therapeutics (2005) 77, P60-P60; doi: 10.1016/j.clpt.2004.12.121

Research paper thumbnail of Increased α1 Adrenergic Vascular Sensitivity in The Dorsal Hand Vein in African-Americans

Clinical Pharmacology & Therapeutics, 2003

Research paper thumbnail of A common β1-adrenergic receptor polymorphism (Arg389Gly) affects blood pressure response to β-blockade

Clinical Pharmacology & Therapeutics, 2003

... Full text access provided to Googlebot Access by Web Services. ... E-mail: alastair.wood@vand... more ... Full text access provided to Googlebot Access by Web Services. ... E-mail: alastair.wood@vanderbilt. edu. ... a larger decrease in resting systolic blood pressure (8.7 1.3 mm Hg versus 0.2 1.7 mm Hg, P &amp;amp;lt; .001) and mean arterial blood pressure (7.2 1.0 mm Hg versus 2.0 1.7 mm Hg, P ...

Research paper thumbnail of Alpha‐2B adrenergic receptor (ADRA2B) 301‐303 deletion polymorphism and vascular desensitization in vivo

ABSTRACT Alpha-2 adrenergic receptors (ADRA2) play important roles in both central and peripheral... more ABSTRACT Alpha-2 adrenergic receptors (ADRA2) play important roles in both central and peripheral regulation of vascular tone. The ADRA2B subtype mediates vasoconstriction and a common genetic variation, 301-303 deletion, was associated with loss of agonist-induced desensitization in vitro. Desensitization of vascular ADRA2 responses in vivo has not been previously described; nor is the effect of genetic variation known. We examined the hypothesis that 301-303del polymorphism affects vascular desensitization to the selective ADRA2 agonist, dexmedetomidine (Dex) in vivo. Incremental doses of Dex (0.01|[ndash]|1000 ng/min) were infused into a dorsal hand vein (DHV) in 28 healthy subjects (age 18-45 years) and responses measured using a linear variable differential transformer. A dose-response curve was constructed and the ED50 calculated. On a separate day, the Dex dose that had caused at least 50% venoconstriction in the dose-response study was infused for three hours and response measured every 30 minutes. The area under the curve for DHV response normalized to the initial response (nAUC) was calculated. Genotyping for 301-303del was performed, and relation to nAUC was determined. There was more than 3-fold inter-individual variability in nAUC. This was not related to ADRA2B genotype (p=0.846). Inter-individual variability in vascular responses to ADRA2 agonist over time occurs, but is not explained by the ADRA2B 301-303del.

Research paper thumbnail of Effect of alpha‐2C adrenergic receptor (ADRA2C) 322–325 deletion polymorphism on blood pressure response to dietary sodium in African‐Americans (AA)

ABSTRACT Salt-sensitivity is more common in AA and is associated with increased risk of hypertens... more ABSTRACT Salt-sensitivity is more common in AA and is associated with increased risk of hypertension, but its genetic basis is not known. Genetic variability in ADRA2&#39;s has been implicated in salt sensitivity. An ADRA2C deletion polymorphism (322-325) is common in AA and is associated with reduced responses to agonist in vitro. We examined the hypothesis that the ADRA2C deletion polymorphism (322-325) contributes to salt sensitivity. Nineteen healthy AA subjects received 5 days of low (10 meq/day, LS), and high sodium, (400 meq/day, HS) diet. 24 hour automated blood pressure was monitored on the last day of each diet. The mean arterial blood pressure difference (dMAP) between LS and HS was calculated. An increase of 3 mmHg or greater was regarded as salt sensitivity. Genotyping for ADRA2C 322-325 deletion was performed, and dMAP compared among the three genotypes [wt/wt (5), wt/del (9), del/del (5)]. There was no difference between genotypes in dMAP (p= 0.263) or frequency of salt sensitivity (p= 0.794). [dMAP mmHg (CI): |[minus]|0.07 (|[minus]|9.5 +9.4), |[minus]|2.27 (|[minus]|8.2 +3.7), 4.94 (|[minus]|4.1 +14.0); salt sensitivity: 2/5, 4/9, 3/5, for wt/wt, wt/del and del/del, respectively]. These findings indicate that the ADRA2C 322-325 deletion is not a major determinant of blood pressure response to dietary Sodium in healthy AA subjects.

Research paper thumbnail of The selective alpha-adrenergic receptor agonist dexmedetomidine (DEX) does not affect aortic pressure augmentation

Clinical Pharmacology & Therapeutics, 2005