Walter Kraft | Thomas Jefferson University (original) (raw)

Papers by Walter Kraft

Research paper thumbnail of Pharmacokinetics and Pharmacodynamics of MK-5046, a Bombesin Receptor Subtype-3 (BRS-3) Agonist, in Healthy Patients

The Journal of Clinical Pharmacology, 2012

O besity is a significant worldwide health problem.

Research paper thumbnail of Effects of Extended-release Niacin/Laropiprant on Apolipoprotein B, LDL-Cholesterol, and Non-HDL-cholesterol Targets in Patients with Type 2 Diabetes

Journal of Clinical Lipidology, 2012

small low-density lipoprotein particle (LDL-P) and CHD risk. Purpose: To compare the effects of n... more small low-density lipoprotein particle (LDL-P) and CHD risk. Purpose: To compare the effects of niacin extendedrelease/simvastatin (NER/S) therapy on lipoprotein particles to atorvastatin (Atv) from the SUPREME study. Methods: This is a post-hoc analysis of 137 patients with dyslipidemia from a 12-week, randomized, study of patients treated with daily NER/S (n 5 74, 1000/40 mg x 4 weeks; 2000/40 mg x 8 weeks) or Atv (n 5 63, 40 mg x 12 weeks). A total of 137 patients had particle concentration and size measurements at baseline (BL) and 12 wk by NMR spectroscopy. Results: Patients in both treatment groups had comparable particle values at BL. Treatment with NER/S resulted in a greater increase in large HDL-P concentration (P 5 .078), significantly greater decrease in small HDL-P concentration (P , .05), and significantly greater increase in HDL-P size (P , .001), HDL-C and apoA-I vs Atv. Treatment with NER/S also significantly decreased the concentration of total LDL-P (P , .05) and small LDL-P (P , .05) and significantly increased LDL-P size (P , .01) vs Atv . Conclusions: Compared with Atv 40 mg monotherapy, combination therapy NER/S at 2000/40 mg results in multiple favorable changes in both HDL and LDL metrics. These data show that NER/S treatment promotes a greater shift toward less atherogenic lipoprotein subclasses than Atv.

Research paper thumbnail of Effects of extended release niacin/laropiprant, laropiprant, extended release niacin and placebo on platelet aggregation and bleeding time in healthy subjects

Platelets, Feb 1, 2010

Laropiprant (LRPT) has been shown to reduce flushing symptoms induced by niacin and has been comb... more Laropiprant (LRPT) has been shown to reduce flushing symptoms induced by niacin and has been combined with niacin for treatment of dyslipidemia. LRPT, a potent PGD(2) receptor (DP1) antagonist that also has modest activity at the thromboxane receptor (TP), may have the potential to alter platelet function either by enhancing platelet reactivity through DP1 antagonism or by inhibiting platelet aggregation through TP antagonism. Studies of platelet aggregation ex vivo and bleeding time have shown that LRPT, at therapeutic doses, does not produce clinically meaningful alterations in platelet function. The present study was conducted to assess platelet reactivity to LRPT using methods that increase the sensitivity to detect changes in platelet responsiveness to collagen and ADP. The responsiveness of platelets was quantified by determining the EC(50) of collagen to induce platelet aggregation ex vivo. At 24 hours post-dose on Day 7, the responsiveness of platelets to collagen-induced aggregation was similar following daily treatment with extended-release niacin (ERN) 2 g/LRPT 40 mg or ERN 2 g. At 2 hours post-dose on Day 7, the EC(50) for collagen-induced platelet aggregation was approximately two-fold higher in the presence of LRPT, consistent with a small, transient inhibition of platelet responsiveness to collagen. There was no clinical difference between treatments for bleeding time, suggesting that this small effect on collagen EC(50) does not result in a clinically meaningful alteration of platelet function in vivo. The results of this highly sensitive method demonstrate that LRPT does not enhance platelet reactivity when given alone or with ERN.

Research paper thumbnail of Beta-blocker therapy and impact on outcome after aneurysmal subarachnoid hemorrhage: a cohort study

Journal of neurosurgery, Jan 22, 2016

OBJECTIVE Cerebral vasospasm (cVSP) is a frequent complication of aneurysmal subarachnoid hemorrh... more OBJECTIVE Cerebral vasospasm (cVSP) is a frequent complication of aneurysmal subarachnoid hemorrhage (aSAH), with a significant impact on outcome. Beta blockers (BBs) may blunt the sympathetic effect and catecholamine surge associated with ruptured cerebral aneurysms and prevent cardiac dysfunction. The purpose of this study was to investigate the association between preadmission BB therapy and cVSP, cardiac dysfunction, and in-hospital mortality following aSAH. METHODS This was a retrospective cohort study of patients with aSAH who were treated at a tertiary high-volume neurovascular referral center. The exposure was defined as any preadmission BB therapy. The primary outcome was cVSP assessed by serial transcranial Doppler with any mean flow velocity ≥ 120 cm/sec and/or need for endovascular intervention for medically refractory cVSP. Secondary outcomes were cardiac dysfunction (defined as cardiac troponin-I elevation > 0.05 μg/L, low left ventricular ejection fraction [LVEF] &...

Research paper thumbnail of Impact of Preadmission Beta-blocker Use on Cardiac Abnormalities and In-hospital Mortality in Patients with Aneurysmal Subarachnoid Hemorrhage Recommended Citation Impact of Preadmission Beta-blocker Use on Cardiac Abnormalities and In-hospital Mortality in Patients with Aneurysmal Subarachnoid H...

This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jef... more This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship.

Research paper thumbnail of Indinavir and Rifabutin Drug Interactions in Healthy Volunteers

The Journal of Clinical Pharmacology, 2004

Two studies examined the pharmacokinetics of indinavir and rifabutin when coadministered in healt... more Two studies examined the pharmacokinetics of indinavir and rifabutin when coadministered in healthy subjects. Rifabutin, which induces the expression of cytochrome P450 (CYP) 3A, and indinavir, which inhibits that enzyme system, are frequently coadministered in patients infected with HIV. The second study was undertaken to determine if altering the dose of rifabutin coadministered with indinavir would minimize the drug interaction observed in the first study. Two studies, each with a three-period crossover design, were performed. In study 1, standard doses of rifabutin and indinavir (300 mg of rifabutin qd and 800 mg indinavir q8h) were administered as monotherapy (with placebo to the other drug) or in combination to 10 volunteers for 10 days. In study 2, 150 mg qd of rifabutin together with 800 mg q8h of indinavir, 300 mg qd of rifabutin alone, or 800 mg q8h of indinavir alone was administered to 14 volunteers for 10 days. In study 1, the geometric mean ratio (GMR) (90% confidence interval [CI]) of the AUC((0-8h)) of indinavir, coadministered with rifabutin 300 mg qd compared to indinavir alone (with rifabutin placebo), was 0.66 (0.56, 0.77), while that of the AUC((0-24h)) of rifabutin, coadministered with indinavir compared to rifabutin alone (with indinavir placebo), was 2.73 (1.99, 3.77). In study 2, the GMR (90% CI) of the AUC((0-8h)) of indinavir, coadministered with rifabutin 150 mg qd compared to indinavir alone, was 0.68 (0.60, 0.76), while that of the AUC((0-24h)) of rifabutin, when rifabutin 150 mg qd was coadministered with indinavir compared to rifabutin 300 mg qd alone, was 1.54 (1.33, 1.79). For both studies 1 and 2, indinavir and rifabutin administered alone or in combination were generally well tolerated. No clinical or laboratory adverse experience was serious. These data demonstrate the important pharmacokinetic interactions between indinavir and rifabutin when they are coadministered. Indeed, these observations formed the basis for the subsequent ACTG 365 study that explored dose adjustments for these agents in combination regimens to preserve the sustained antiviral activity of indinavir in the absence of adverse events as a result of elevated circulating levels of rifabutin.

Research paper thumbnail of Population Pharmacokinetic Model of Sublingual Buprenorphine in Neonatal Abstinence Syndrome

Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 2015

Neonatal abstinence syndrome (NAS)-a clinical entity of infants from in utero exposure to psychoa... more Neonatal abstinence syndrome (NAS)-a clinical entity of infants from in utero exposure to psychoactive xenobiotic and buprenorphine-has been successfully used to treat NAS. However, nothing is known about the pharmacokinetics (PK) of buprenorphine in neonates with NAS. To our knowledge, this is the first study to investigate the population pharmacokinetic of sublingual buprenorphine in neonates with NAS. A retrospective population PK analysis of: (1) neonates with NAS treated with sublingual buprenorphine in randomized, double blinded clinical study and (2) data from healthy adults from a previously published pharmacokinetic study. Neonatal intensive care unit and general clinical research unit. Twenty-four neonates with NAS and five healthy adults. All participants received sublingual buprenorphine per study protocol. A total of 303 PK data from 29 neonates and adults were used for model development. A population pharmacokinetic analysis was conducted using a first order conditional estimation with interaction in the NONMEM software program. A two-compartment linear PK model with first-order absorption process best described the pharmacokinetics of sublingual buprenorphine in neonates. The apparent clearance (CL) of buprenorphine was linearly related to body weight and matured with increasing age via two distinct saturated pathways. A typical neonate with NAS (body weight, 2.9 kg; postnatal age; 5.4 days) had a CL of 3.5 L/kg/hour and elimination half-life of 11 hours. Phenobarbital did not affect the clearance of buprenorphine compared to neonates of similar age and weight. This is the first study to investigate the population PK of sublingual buprenorphine in neonatal NAS. To our knowledge, this is also the first report to describe the age-dependent changes of buprenorphine PK in this patient population. No buprenorphine dose adjustment is needed for neonates with NAS treated with buprenorphine and concurrent phenobarbital.

Research paper thumbnail of Randomized Trial Sublingual Buprenorphine for Treatment of Neonatal Abstinence Syndrome: A

Research paper thumbnail of No Evidence of a Drug-Drug Interaction Between Letermovir (MK-8228) and Mycophenolate Mofetil

Biology of Blood and Marrow Transplantation, 2015

Research paper thumbnail of Clinical pharmacology: A paradigm for individualized medicine

Biomarkers in Medicine, 2009

Individualized medicine provides a powerful engine revolutionizing the practice of clinical pharm... more Individualized medicine provides a powerful engine revolutionizing the practice of clinical pharmacology, tailoring genetic and molecular profiles of patients to improve therapeutic specificity, reduce treatment variability and minimize adverse drug events. In that context, advances in individualized medicine have transformed the science of clinical pharmacology and therapeutics from drug discovery through identification of drugable targets, development through stratification of disease risk, regulation through identifying pathways mediating off-target effects and utilization through personalizing drug regimens. This revolution in fundamental and applied therapeutics has entrained an evolution in biology and medicine. Insights in the mechanistic basis of cell, tissue and organ function, and their interface with the environment are being translated to define disease risk, identify processes mediating disease susceptibility, target mechanism-based therapies, and tailor prevention and control paradigms, providing previously unanticipated opportunities for patient-specific disease management. The emerging field of individualized medicine is transforming the practice of clinical pharmacology, driving the leading edge of discovery from the laboratory bench to the evidence basis of practice in the clinic, extending to populations, to transform healthcare and create predictive, personalized and pre-emptive solutions for tailored patient-specific therapeutic strategies.

Research paper thumbnail of Current Therapeutic Research is Now Indexed on PubMed

Current Therapeutic Research, 2014

Research paper thumbnail of Prevalence of obstructive lung disease in HIV population: A cross sectional study

Respiratory Medicine, 2011

A. Hirani). a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e... more A. Hirani). a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / r m e d Respiratory Medicine (2011) 105, 1655e1661 0954-6111/$ -see front matter ª

Research paper thumbnail of Effects of extended release niacin/laropiprant, laropiprant, extended release niacin and placebo on platelet aggregation and bleeding time in healthy subjects

Research paper thumbnail of Sublingual Buprenorphine for Treatment of Neonatal Abstinence Syndrome: A Randomized Trial

PEDIATRICS, 2008

Neonatal abstinence syndrome of severity requiring pharmacologic treatment is associated with lon... more Neonatal abstinence syndrome of severity requiring pharmacologic treatment is associated with long hospitalization. Opioid replacement with morphine is the present preferred treatment. Improved treatment options would be a therapeutic advance.

Research paper thumbnail of A five-year, retrospective, comparison review of survival in neurosurgical patients diagnosed with venous thromboembolism and treated with either inferior vena cava filters or anticoagulants

Journal of Thrombosis and Thrombolysis, 2007

[corrected] The optimal role of inferior vena cava filters (IVCF) in the management of venous thr... more [corrected] The optimal role of inferior vena cava filters (IVCF) in the management of venous thromboembolism (VTE) is not well defined. The purpose of this study was to compare mortality risk for VTE patients treated with IVCF or anticoagulants. Analyses were based on data from 175 VTE patients, who had concurrent conditions of central nervous system (CNS) cancer or brain hemorrhage, and who were seen at Thomas Jefferson University Hospital between 1998 and 2002. Patients who received filters (n = 136) and those who were treated with anticoagulants only (n = 39) were compared on in-hospital mortality via logistic regression and on overall mortality via survival analyses methods. A total of 17 study patients (9.7%) died in-hospital. After controlling for patient sociodemographic, medical, and treatment characteristics, the filter group had a 65% reduction of risk compared to the anticoagulant group (adjusted odds ratio, OR = 0.36, P = 0.138). Age, renal disease, and ventriculoperitoneal shunt/ventriculostomy were independent predictors of higher in-hospital mortality. A total of 128 deaths (73.1%) were recorded during the study's entire follow-up period. Unadjusted median survival was 21 weeks for the filter group and 11 weeks for the anticoagulant group (P = 0.177). In adjusted analyses, the filter group had a 28% reduction of risk compared to the anticoagulant group (adjusted hazard ratio, HR = 0.72, P = 0.181). Caucasian race and CNS cancer were independent predictors of higher overall mortality. Neither in-hospital nor overall mortality differences between the two treatment groups was significant, although we found some indication of a beneficial effect of filter placement with respect to short-term, in-hospital survival.

Research paper thumbnail of The incidence of deep vein thrombosis detected by routine surveillance ultrasound in neurosurgery patients receiving dual modality prophylaxis

Journal of Thrombosis and Thrombolysis, 2011

Research paper thumbnail of Indinavir and Rifabutin Drug Interactions in Healthy Volunteers

The Journal of Clinical Pharmacology, 2004

Two studies examined the pharmacokinetics of indinavir and rifabutin when coadministered in healt... more Two studies examined the pharmacokinetics of indinavir and rifabutin when coadministered in healthy subjects. Rifabutin, which induces the expression of cytochrome P450 (CYP) 3A, and indinavir, which inhibits that enzyme system, are frequently coadministered in patients infected with HIV. The second study was undertaken to determine if altering the dose of rifabutin coadministered with indinavir would minimize the drug interaction observed in the first study. Two studies, each with a three-period crossover design, were performed. In study 1, standard doses of rifabutin and indinavir (300 mg of rifabutin qd and 800 mg indinavir q8h) were administered as monotherapy (with placebo to the other drug) or in combination to 10 volunteers for 10 days. In study 2, 150 mg qd of rifabutin together with 800 mg q8h of indinavir, 300 mg qd of rifabutin alone, or 800 mg q8h of indinavir alone was administered to 14 volunteers for 10 days. In study 1, the geometric mean ratio (GMR) (90% confidence interval [CI]) of the AUC((0-8h)) of indinavir, coadministered with rifabutin 300 mg qd compared to indinavir alone (with rifabutin placebo), was 0.66 (0.56, 0.77), while that of the AUC((0-24h)) of rifabutin, coadministered with indinavir compared to rifabutin alone (with indinavir placebo), was 2.73 (1.99, 3.77). In study 2, the GMR (90% CI) of the AUC((0-8h)) of indinavir, coadministered with rifabutin 150 mg qd compared to indinavir alone, was 0.68 (0.60, 0.76), while that of the AUC((0-24h)) of rifabutin, when rifabutin 150 mg qd was coadministered with indinavir compared to rifabutin 300 mg qd alone, was 1.54 (1.33, 1.79). For both studies 1 and 2, indinavir and rifabutin administered alone or in combination were generally well tolerated. No clinical or laboratory adverse experience was serious. These data demonstrate the important pharmacokinetic interactions between indinavir and rifabutin when they are coadministered. Indeed, these observations formed the basis for the subsequent ACTG 365 study that explored dose adjustments for these agents in combination regimens to preserve the sustained antiviral activity of indinavir in the absence of adverse events as a result of elevated circulating levels of rifabutin.

Research paper thumbnail of Effect of Aprepitant on the Pharmacokinetics of Intravenous Midazolam

The Journal of Clinical Pharmacology, 2007

Oral aprepitant 125 mg, an antiemetic and a moderate inhibitor of the metabolism of oral midazola... more Oral aprepitant 125 mg, an antiemetic and a moderate inhibitor of the metabolism of oral midazolam, was assessed for interaction with intravenous midazolam in 12 subjects randomized to intravenous midazolam 2 mg +/- oral aprepitant 125 mg. The hypothesis was that midazolam AUC would not change by more than 2-fold (consistent with no more than weak inhibition) when midazolam + aprepitant was compared with midazolam alone. An AUC geometric mean ratio (midazolam + aprepitant/midazolam) with 90% confidence interval upper bound < or =2.0 (an increase in midazolam felt to be of modest clinical significance in the highly monitored perioperative period) was prespecified. Aprepitant increased intravenous midazolam AUC(0-infinity) 1.47-fold (90% confidence interval, 1.36-1.59), which fell within the prespecified criterion.

Research paper thumbnail of The Pharmacokinetics of Taurolidine Metabolites in Healthy Volunteers

The Journal of Clinical Pharmacology, 2007

NJ 07311 (Present affiliation, J.L.P.)

Research paper thumbnail of Relationship of Arachidonic Acid Concentration to Cyclooxygenase-Dependent Human Platelet Aggregation

The Journal of Clinical Pharmacology, 2003

Inhibition of ex vivo arachidonic acid (AA)-induced aggregation is a biomarker for the isotype se... more Inhibition of ex vivo arachidonic acid (AA)-induced aggregation is a biomarker for the isotype selectivity of cyclooxygenase (COX) inhibitors since platelets express COX-1 but not COX-2. At low concentrations, there is broad inter- and intrasubject variability in AA-induced aggregation of platelets ex vivo. This study defined a concentration that reliably induces aggregation without overcoming inhibition by therapeutic aspirin therapy (ASA, 81-mg) treatment. Logistic regression analysis of ex vivo aggregation, induced with increasing concentrations of AA in platelet-rich plasma (PRP), estimated that platelets from > or = 90% of subjects would aggregate at > or = 1.5 mM AA (95% confidence interval [CI], 1.1, 2.1). A concentration of 1.6 mM AA failed to aggregate platelets from 26 healthy volunteers, who had previously aggregated at this concentration, following six daily oral doses of 81 mg of ASA. These data demonstrate that 1.6 mM AA reproducibly induces platelet aggregation in PRP from healthy volunteers without overcoming the antiplatelet effect of daily low-dose aspirin therapy.

Research paper thumbnail of Pharmacokinetics and Pharmacodynamics of MK-5046, a Bombesin Receptor Subtype-3 (BRS-3) Agonist, in Healthy Patients

The Journal of Clinical Pharmacology, 2012

O besity is a significant worldwide health problem.

Research paper thumbnail of Effects of Extended-release Niacin/Laropiprant on Apolipoprotein B, LDL-Cholesterol, and Non-HDL-cholesterol Targets in Patients with Type 2 Diabetes

Journal of Clinical Lipidology, 2012

small low-density lipoprotein particle (LDL-P) and CHD risk. Purpose: To compare the effects of n... more small low-density lipoprotein particle (LDL-P) and CHD risk. Purpose: To compare the effects of niacin extendedrelease/simvastatin (NER/S) therapy on lipoprotein particles to atorvastatin (Atv) from the SUPREME study. Methods: This is a post-hoc analysis of 137 patients with dyslipidemia from a 12-week, randomized, study of patients treated with daily NER/S (n 5 74, 1000/40 mg x 4 weeks; 2000/40 mg x 8 weeks) or Atv (n 5 63, 40 mg x 12 weeks). A total of 137 patients had particle concentration and size measurements at baseline (BL) and 12 wk by NMR spectroscopy. Results: Patients in both treatment groups had comparable particle values at BL. Treatment with NER/S resulted in a greater increase in large HDL-P concentration (P 5 .078), significantly greater decrease in small HDL-P concentration (P , .05), and significantly greater increase in HDL-P size (P , .001), HDL-C and apoA-I vs Atv. Treatment with NER/S also significantly decreased the concentration of total LDL-P (P , .05) and small LDL-P (P , .05) and significantly increased LDL-P size (P , .01) vs Atv . Conclusions: Compared with Atv 40 mg monotherapy, combination therapy NER/S at 2000/40 mg results in multiple favorable changes in both HDL and LDL metrics. These data show that NER/S treatment promotes a greater shift toward less atherogenic lipoprotein subclasses than Atv.

Research paper thumbnail of Effects of extended release niacin/laropiprant, laropiprant, extended release niacin and placebo on platelet aggregation and bleeding time in healthy subjects

Platelets, Feb 1, 2010

Laropiprant (LRPT) has been shown to reduce flushing symptoms induced by niacin and has been comb... more Laropiprant (LRPT) has been shown to reduce flushing symptoms induced by niacin and has been combined with niacin for treatment of dyslipidemia. LRPT, a potent PGD(2) receptor (DP1) antagonist that also has modest activity at the thromboxane receptor (TP), may have the potential to alter platelet function either by enhancing platelet reactivity through DP1 antagonism or by inhibiting platelet aggregation through TP antagonism. Studies of platelet aggregation ex vivo and bleeding time have shown that LRPT, at therapeutic doses, does not produce clinically meaningful alterations in platelet function. The present study was conducted to assess platelet reactivity to LRPT using methods that increase the sensitivity to detect changes in platelet responsiveness to collagen and ADP. The responsiveness of platelets was quantified by determining the EC(50) of collagen to induce platelet aggregation ex vivo. At 24 hours post-dose on Day 7, the responsiveness of platelets to collagen-induced aggregation was similar following daily treatment with extended-release niacin (ERN) 2 g/LRPT 40 mg or ERN 2 g. At 2 hours post-dose on Day 7, the EC(50) for collagen-induced platelet aggregation was approximately two-fold higher in the presence of LRPT, consistent with a small, transient inhibition of platelet responsiveness to collagen. There was no clinical difference between treatments for bleeding time, suggesting that this small effect on collagen EC(50) does not result in a clinically meaningful alteration of platelet function in vivo. The results of this highly sensitive method demonstrate that LRPT does not enhance platelet reactivity when given alone or with ERN.

Research paper thumbnail of Beta-blocker therapy and impact on outcome after aneurysmal subarachnoid hemorrhage: a cohort study

Journal of neurosurgery, Jan 22, 2016

OBJECTIVE Cerebral vasospasm (cVSP) is a frequent complication of aneurysmal subarachnoid hemorrh... more OBJECTIVE Cerebral vasospasm (cVSP) is a frequent complication of aneurysmal subarachnoid hemorrhage (aSAH), with a significant impact on outcome. Beta blockers (BBs) may blunt the sympathetic effect and catecholamine surge associated with ruptured cerebral aneurysms and prevent cardiac dysfunction. The purpose of this study was to investigate the association between preadmission BB therapy and cVSP, cardiac dysfunction, and in-hospital mortality following aSAH. METHODS This was a retrospective cohort study of patients with aSAH who were treated at a tertiary high-volume neurovascular referral center. The exposure was defined as any preadmission BB therapy. The primary outcome was cVSP assessed by serial transcranial Doppler with any mean flow velocity ≥ 120 cm/sec and/or need for endovascular intervention for medically refractory cVSP. Secondary outcomes were cardiac dysfunction (defined as cardiac troponin-I elevation > 0.05 μg/L, low left ventricular ejection fraction [LVEF] &...

Research paper thumbnail of Impact of Preadmission Beta-blocker Use on Cardiac Abnormalities and In-hospital Mortality in Patients with Aneurysmal Subarachnoid Hemorrhage Recommended Citation Impact of Preadmission Beta-blocker Use on Cardiac Abnormalities and In-hospital Mortality in Patients with Aneurysmal Subarachnoid H...

This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jef... more This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship.

Research paper thumbnail of Indinavir and Rifabutin Drug Interactions in Healthy Volunteers

The Journal of Clinical Pharmacology, 2004

Two studies examined the pharmacokinetics of indinavir and rifabutin when coadministered in healt... more Two studies examined the pharmacokinetics of indinavir and rifabutin when coadministered in healthy subjects. Rifabutin, which induces the expression of cytochrome P450 (CYP) 3A, and indinavir, which inhibits that enzyme system, are frequently coadministered in patients infected with HIV. The second study was undertaken to determine if altering the dose of rifabutin coadministered with indinavir would minimize the drug interaction observed in the first study. Two studies, each with a three-period crossover design, were performed. In study 1, standard doses of rifabutin and indinavir (300 mg of rifabutin qd and 800 mg indinavir q8h) were administered as monotherapy (with placebo to the other drug) or in combination to 10 volunteers for 10 days. In study 2, 150 mg qd of rifabutin together with 800 mg q8h of indinavir, 300 mg qd of rifabutin alone, or 800 mg q8h of indinavir alone was administered to 14 volunteers for 10 days. In study 1, the geometric mean ratio (GMR) (90% confidence interval [CI]) of the AUC((0-8h)) of indinavir, coadministered with rifabutin 300 mg qd compared to indinavir alone (with rifabutin placebo), was 0.66 (0.56, 0.77), while that of the AUC((0-24h)) of rifabutin, coadministered with indinavir compared to rifabutin alone (with indinavir placebo), was 2.73 (1.99, 3.77). In study 2, the GMR (90% CI) of the AUC((0-8h)) of indinavir, coadministered with rifabutin 150 mg qd compared to indinavir alone, was 0.68 (0.60, 0.76), while that of the AUC((0-24h)) of rifabutin, when rifabutin 150 mg qd was coadministered with indinavir compared to rifabutin 300 mg qd alone, was 1.54 (1.33, 1.79). For both studies 1 and 2, indinavir and rifabutin administered alone or in combination were generally well tolerated. No clinical or laboratory adverse experience was serious. These data demonstrate the important pharmacokinetic interactions between indinavir and rifabutin when they are coadministered. Indeed, these observations formed the basis for the subsequent ACTG 365 study that explored dose adjustments for these agents in combination regimens to preserve the sustained antiviral activity of indinavir in the absence of adverse events as a result of elevated circulating levels of rifabutin.

Research paper thumbnail of Population Pharmacokinetic Model of Sublingual Buprenorphine in Neonatal Abstinence Syndrome

Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 2015

Neonatal abstinence syndrome (NAS)-a clinical entity of infants from in utero exposure to psychoa... more Neonatal abstinence syndrome (NAS)-a clinical entity of infants from in utero exposure to psychoactive xenobiotic and buprenorphine-has been successfully used to treat NAS. However, nothing is known about the pharmacokinetics (PK) of buprenorphine in neonates with NAS. To our knowledge, this is the first study to investigate the population pharmacokinetic of sublingual buprenorphine in neonates with NAS. A retrospective population PK analysis of: (1) neonates with NAS treated with sublingual buprenorphine in randomized, double blinded clinical study and (2) data from healthy adults from a previously published pharmacokinetic study. Neonatal intensive care unit and general clinical research unit. Twenty-four neonates with NAS and five healthy adults. All participants received sublingual buprenorphine per study protocol. A total of 303 PK data from 29 neonates and adults were used for model development. A population pharmacokinetic analysis was conducted using a first order conditional estimation with interaction in the NONMEM software program. A two-compartment linear PK model with first-order absorption process best described the pharmacokinetics of sublingual buprenorphine in neonates. The apparent clearance (CL) of buprenorphine was linearly related to body weight and matured with increasing age via two distinct saturated pathways. A typical neonate with NAS (body weight, 2.9 kg; postnatal age; 5.4 days) had a CL of 3.5 L/kg/hour and elimination half-life of 11 hours. Phenobarbital did not affect the clearance of buprenorphine compared to neonates of similar age and weight. This is the first study to investigate the population PK of sublingual buprenorphine in neonatal NAS. To our knowledge, this is also the first report to describe the age-dependent changes of buprenorphine PK in this patient population. No buprenorphine dose adjustment is needed for neonates with NAS treated with buprenorphine and concurrent phenobarbital.

Research paper thumbnail of Randomized Trial Sublingual Buprenorphine for Treatment of Neonatal Abstinence Syndrome: A

Research paper thumbnail of No Evidence of a Drug-Drug Interaction Between Letermovir (MK-8228) and Mycophenolate Mofetil

Biology of Blood and Marrow Transplantation, 2015

Research paper thumbnail of Clinical pharmacology: A paradigm for individualized medicine

Biomarkers in Medicine, 2009

Individualized medicine provides a powerful engine revolutionizing the practice of clinical pharm... more Individualized medicine provides a powerful engine revolutionizing the practice of clinical pharmacology, tailoring genetic and molecular profiles of patients to improve therapeutic specificity, reduce treatment variability and minimize adverse drug events. In that context, advances in individualized medicine have transformed the science of clinical pharmacology and therapeutics from drug discovery through identification of drugable targets, development through stratification of disease risk, regulation through identifying pathways mediating off-target effects and utilization through personalizing drug regimens. This revolution in fundamental and applied therapeutics has entrained an evolution in biology and medicine. Insights in the mechanistic basis of cell, tissue and organ function, and their interface with the environment are being translated to define disease risk, identify processes mediating disease susceptibility, target mechanism-based therapies, and tailor prevention and control paradigms, providing previously unanticipated opportunities for patient-specific disease management. The emerging field of individualized medicine is transforming the practice of clinical pharmacology, driving the leading edge of discovery from the laboratory bench to the evidence basis of practice in the clinic, extending to populations, to transform healthcare and create predictive, personalized and pre-emptive solutions for tailored patient-specific therapeutic strategies.

Research paper thumbnail of Current Therapeutic Research is Now Indexed on PubMed

Current Therapeutic Research, 2014

Research paper thumbnail of Prevalence of obstructive lung disease in HIV population: A cross sectional study

Respiratory Medicine, 2011

A. Hirani). a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e... more A. Hirani). a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / r m e d Respiratory Medicine (2011) 105, 1655e1661 0954-6111/$ -see front matter ª

Research paper thumbnail of Effects of extended release niacin/laropiprant, laropiprant, extended release niacin and placebo on platelet aggregation and bleeding time in healthy subjects

Research paper thumbnail of Sublingual Buprenorphine for Treatment of Neonatal Abstinence Syndrome: A Randomized Trial

PEDIATRICS, 2008

Neonatal abstinence syndrome of severity requiring pharmacologic treatment is associated with lon... more Neonatal abstinence syndrome of severity requiring pharmacologic treatment is associated with long hospitalization. Opioid replacement with morphine is the present preferred treatment. Improved treatment options would be a therapeutic advance.

Research paper thumbnail of A five-year, retrospective, comparison review of survival in neurosurgical patients diagnosed with venous thromboembolism and treated with either inferior vena cava filters or anticoagulants

Journal of Thrombosis and Thrombolysis, 2007

[corrected] The optimal role of inferior vena cava filters (IVCF) in the management of venous thr... more [corrected] The optimal role of inferior vena cava filters (IVCF) in the management of venous thromboembolism (VTE) is not well defined. The purpose of this study was to compare mortality risk for VTE patients treated with IVCF or anticoagulants. Analyses were based on data from 175 VTE patients, who had concurrent conditions of central nervous system (CNS) cancer or brain hemorrhage, and who were seen at Thomas Jefferson University Hospital between 1998 and 2002. Patients who received filters (n = 136) and those who were treated with anticoagulants only (n = 39) were compared on in-hospital mortality via logistic regression and on overall mortality via survival analyses methods. A total of 17 study patients (9.7%) died in-hospital. After controlling for patient sociodemographic, medical, and treatment characteristics, the filter group had a 65% reduction of risk compared to the anticoagulant group (adjusted odds ratio, OR = 0.36, P = 0.138). Age, renal disease, and ventriculoperitoneal shunt/ventriculostomy were independent predictors of higher in-hospital mortality. A total of 128 deaths (73.1%) were recorded during the study's entire follow-up period. Unadjusted median survival was 21 weeks for the filter group and 11 weeks for the anticoagulant group (P = 0.177). In adjusted analyses, the filter group had a 28% reduction of risk compared to the anticoagulant group (adjusted hazard ratio, HR = 0.72, P = 0.181). Caucasian race and CNS cancer were independent predictors of higher overall mortality. Neither in-hospital nor overall mortality differences between the two treatment groups was significant, although we found some indication of a beneficial effect of filter placement with respect to short-term, in-hospital survival.

Research paper thumbnail of The incidence of deep vein thrombosis detected by routine surveillance ultrasound in neurosurgery patients receiving dual modality prophylaxis

Journal of Thrombosis and Thrombolysis, 2011

Research paper thumbnail of Indinavir and Rifabutin Drug Interactions in Healthy Volunteers

The Journal of Clinical Pharmacology, 2004

Two studies examined the pharmacokinetics of indinavir and rifabutin when coadministered in healt... more Two studies examined the pharmacokinetics of indinavir and rifabutin when coadministered in healthy subjects. Rifabutin, which induces the expression of cytochrome P450 (CYP) 3A, and indinavir, which inhibits that enzyme system, are frequently coadministered in patients infected with HIV. The second study was undertaken to determine if altering the dose of rifabutin coadministered with indinavir would minimize the drug interaction observed in the first study. Two studies, each with a three-period crossover design, were performed. In study 1, standard doses of rifabutin and indinavir (300 mg of rifabutin qd and 800 mg indinavir q8h) were administered as monotherapy (with placebo to the other drug) or in combination to 10 volunteers for 10 days. In study 2, 150 mg qd of rifabutin together with 800 mg q8h of indinavir, 300 mg qd of rifabutin alone, or 800 mg q8h of indinavir alone was administered to 14 volunteers for 10 days. In study 1, the geometric mean ratio (GMR) (90% confidence interval [CI]) of the AUC((0-8h)) of indinavir, coadministered with rifabutin 300 mg qd compared to indinavir alone (with rifabutin placebo), was 0.66 (0.56, 0.77), while that of the AUC((0-24h)) of rifabutin, coadministered with indinavir compared to rifabutin alone (with indinavir placebo), was 2.73 (1.99, 3.77). In study 2, the GMR (90% CI) of the AUC((0-8h)) of indinavir, coadministered with rifabutin 150 mg qd compared to indinavir alone, was 0.68 (0.60, 0.76), while that of the AUC((0-24h)) of rifabutin, when rifabutin 150 mg qd was coadministered with indinavir compared to rifabutin 300 mg qd alone, was 1.54 (1.33, 1.79). For both studies 1 and 2, indinavir and rifabutin administered alone or in combination were generally well tolerated. No clinical or laboratory adverse experience was serious. These data demonstrate the important pharmacokinetic interactions between indinavir and rifabutin when they are coadministered. Indeed, these observations formed the basis for the subsequent ACTG 365 study that explored dose adjustments for these agents in combination regimens to preserve the sustained antiviral activity of indinavir in the absence of adverse events as a result of elevated circulating levels of rifabutin.

Research paper thumbnail of Effect of Aprepitant on the Pharmacokinetics of Intravenous Midazolam

The Journal of Clinical Pharmacology, 2007

Oral aprepitant 125 mg, an antiemetic and a moderate inhibitor of the metabolism of oral midazola... more Oral aprepitant 125 mg, an antiemetic and a moderate inhibitor of the metabolism of oral midazolam, was assessed for interaction with intravenous midazolam in 12 subjects randomized to intravenous midazolam 2 mg +/- oral aprepitant 125 mg. The hypothesis was that midazolam AUC would not change by more than 2-fold (consistent with no more than weak inhibition) when midazolam + aprepitant was compared with midazolam alone. An AUC geometric mean ratio (midazolam + aprepitant/midazolam) with 90% confidence interval upper bound < or =2.0 (an increase in midazolam felt to be of modest clinical significance in the highly monitored perioperative period) was prespecified. Aprepitant increased intravenous midazolam AUC(0-infinity) 1.47-fold (90% confidence interval, 1.36-1.59), which fell within the prespecified criterion.

Research paper thumbnail of The Pharmacokinetics of Taurolidine Metabolites in Healthy Volunteers

The Journal of Clinical Pharmacology, 2007

NJ 07311 (Present affiliation, J.L.P.)

Research paper thumbnail of Relationship of Arachidonic Acid Concentration to Cyclooxygenase-Dependent Human Platelet Aggregation

The Journal of Clinical Pharmacology, 2003

Inhibition of ex vivo arachidonic acid (AA)-induced aggregation is a biomarker for the isotype se... more Inhibition of ex vivo arachidonic acid (AA)-induced aggregation is a biomarker for the isotype selectivity of cyclooxygenase (COX) inhibitors since platelets express COX-1 but not COX-2. At low concentrations, there is broad inter- and intrasubject variability in AA-induced aggregation of platelets ex vivo. This study defined a concentration that reliably induces aggregation without overcoming inhibition by therapeutic aspirin therapy (ASA, 81-mg) treatment. Logistic regression analysis of ex vivo aggregation, induced with increasing concentrations of AA in platelet-rich plasma (PRP), estimated that platelets from > or = 90% of subjects would aggregate at > or = 1.5 mM AA (95% confidence interval [CI], 1.1, 2.1). A concentration of 1.6 mM AA failed to aggregate platelets from 26 healthy volunteers, who had previously aggregated at this concentration, following six daily oral doses of 81 mg of ASA. These data demonstrate that 1.6 mM AA reproducibly induces platelet aggregation in PRP from healthy volunteers without overcoming the antiplatelet effect of daily low-dose aspirin therapy.