Mark Sostek - Academia.edu (original) (raw)
Papers by Mark Sostek
A case of a pedunculated adenomatous polyp of the sigmoid colon was found to have a primary focus... more A case of a pedunculated adenomatous polyp of the sigmoid colon was found to have a primary focus of signet ring cell carcinoma. Histologic examination of the medium-sized polyp was consistent with an adenoma to carcinoma sequence for signet ring cell carcinoma of the colon, similar to that for the common adenocarcinomas.
The Journal of Clinical Pharmacology, 2015
Naloxegol, a peripherally acting μ-opioid receptor antagonist, was recently approved in the Unite... more Naloxegol, a peripherally acting μ-opioid receptor antagonist, was recently approved in the United States for the treatment of opioid-induced constipation. This study evaluated the effects of CYP3A inhibition and induction on the PK, safety, and tolerability of naloxegol. Separate open-label, nonrandomized, fixed-sequence, 3-period, 3-treatment, crossover studies of naloxegol (25 mg by mouth [PO]) in the absence or presence of the inhibitors ketoconazole (400 mg PO) and diltiazem extended release (240 mg PO), or the inducer rifampin (600 mg PO) were conducted in healthy volunteers. Area under the curve (AUCinf ) for naloxegol was increased with coadministration of either ketoconazole (12.9-fold) or diltiazem (3.4-fold) and decreased by 89% with coadministration of rifampin compared with AUCinf for naloxegol alone. Naloxegol was generally safe and well tolerated when given alone or coadministered with the respective CYP3A modulators; one subject discontinued because of elevations in liver enzymes attributed to rifampin. The exposure of naloxegol was affected substantially by ketoconazole, diltiazem, and rifampin, suggesting that it is a sensitive in vivo substrate of CYP3A4. This article is protected by copyright. All rights reserved.
Aliment Pharmacol Therapeut, 2006
To assess the relationship between the percentage of time intragastric pH >4.0 and healing of ero... more To assess the relationship between the percentage of time intragastric pH >4.0 and healing of erosive oesophagitis.
Aliment Pharmacol Therapeut, 2007
Intravenous (IV) formulations of proton pump inhibitors are effective for patients in whom oral t... more Intravenous (IV) formulations of proton pump inhibitors are effective for patients in whom oral therapy is not appropriate.
The Journal of Clinical Pharmacology, 2015
Naloxegol is a PEGylated, oral, peripherally acting μ-opioid receptor antagonist approved in the ... more Naloxegol is a PEGylated, oral, peripherally acting μ-opioid receptor antagonist approved in the United States for treatment of opioid-induced constipation in patients with noncancer pain. Naloxegol is metabolized by CYP3A, and its properties as a substrate for the P-glycoprotein (PGP) transporter limit its central nervous system (CNS) permeability. This double-blind, randomized, 2-part, crossover study in healthy volunteers evaluated the effect of quinidine (600 mg PO), a CYP3A/PGP transporter inhibitor, on the pharmacokinetics and CNS distribution of naloxegol (25 mg PO). In addition, the effects of quinidine on morphine (5 mg/70 kg IV)-induced miosis and exposure to naloxegol were assessed. Coadministration of quinidine and naloxegol increased naloxegol AUC 1.4-fold and Cmax 2.5-fold but did not antagonize morphine-induced miosis, suggesting that PGP inhibition does not increase the CNS penetration of naloxegol. Naloxegol pharmacokinetics were unaltered by coadministration of morphine and either quinidine or placebo; conversely, pharmacokinetics of morphine and its metabolites (in the presence of quinidine) were unaltered by coadministration of naloxegol. Naloxegol was safe and well tolerated, alone or in combination with quinidine, morphine, or both. The observed increase in exposure to naloxegol in the presence of quinidine is primarily attributed to quinidine's properties as a weak CYP3A inhibitor. This article is protected by copyright. All rights reserved.
Int. Journal of Clinical Pharmacology and Therapeutics, 2015
United European Gastroenterology Journal, 2015
Treatment options for patients with opioid-induced constipation (OIC) and inadequate response to ... more Treatment options for patients with opioid-induced constipation (OIC) and inadequate response to laxatives (LIR) are few. Assess the efficacy and safety of orally administered naloxegol in patients with prospectively confirmed OIC and LIR. We analyzed pooled data from two identical randomized, double-blind, placebo-controlled, Phase 3 trials of naloxegol in patients with non-cancer pain, OIC and LIR in which naloxegol (12.5 mg, n = 240; 25 mg, n = 241) or placebo (n = 239) were administered daily. We assessed the response rates, time to first post-dose laxation, spontaneous bowel movements (SBMs), OIC symptoms and patient-reported outcomes over 12 weeks. OIC response rates for the naloxegol 25-mg (p < 0.001) and the 12.5-mg (p = 0.005) LIR dose groups were higher than placebo. Median times to first post-dose SBM were 7.6, 19.2 and 41.1 hours for the naloxegol 25 mg, naloxegol 12.5 mg and placebo groups, respectively. Other SBM measures, daily symptoms of OIC, and both the Patient Assessment of Constipation - Symptoms and Patient Assessment of Constipation-Quality of Life scores improved from baseline with naloxegol treatment. Changes from baseline in opioid dose, pain scores and opioid withdrawal scores were similar among treatment groups. Naloxegol was efficacious, generally safe and well tolerated in the patients with OIC and LIR, while preserving opioid analgesia. ClinicalTrials.gov identifiers: NCT01309841; NCT01323790.
British journal of clinical pharmacology, Jan 28, 2015
Naloxegol, a polyethylene glycol conjugated derivative of the opioid antagonist naloxone, is in c... more Naloxegol, a polyethylene glycol conjugated derivative of the opioid antagonist naloxone, is in clinical development for treatment of opioid-induced constipation (OIC). The aim of the study was to develop a population pharmacokinetic model describing the concentration vs. time profile of orally administered naloxegol, and determine the impact of pre-specified demographic and clinical factors and concomitant medication on population estimates of apparent clearance (CL/F) and apparent central compartment volume of distribution (Vc /F). Analysis included 12 844 naloxegol plasma concentrations obtained from 1247 healthy subjects, patients with non-OIC and patients with OIC in 14 phase 1, 2b and 3 clinical studies. Pharmacokinetic analysis used the non-linear mixed effects modelling program. Goodness of fit plots and posterior predictive checks were conducted to confirm concordance with observed data. The final model was a two compartment disposition model with dual absorptions, comprisi...
Clinical Pharmacology in Drug Development, 2015
Clinical Pharmacology in Drug Development, 2015
ABSTRACT
Alimentary Pharmacology & Therapeutics, 2014
Opioid-induced constipation is common and debilitating. We investigated the efficacy and safety o... more Opioid-induced constipation is common and debilitating. We investigated the efficacy and safety of naloxegol, an oral, peripherally acting, μ-opioid receptor antagonist, for the treatment of opioid-induced constipation.
The American Journal of Gastroenterology, 2006
The American Journal of Gastroenterology is published by Nature Publishing Group (NPG) on behalf ... more The American Journal of Gastroenterology is published by Nature Publishing Group (NPG) on behalf of the American College of Gastroenterology (ACG). Ranked the #1 clinical journal covering gastroenterology and hepatology*, The American Journal of Gastroenterology (AJG) ...
The American Journal of Gastroenterology, 2007
To evaluate the efficacy and safety of oral esomeprazole in the control of gastric acid hypersecr... more To evaluate the efficacy and safety of oral esomeprazole in the control of gastric acid hypersecretion in patients with hypersecretory states. In this 12-month, open-label, multicenter study, acid output (AO) was evaluated at baseline, day 10, and months 3, 6, and 12. The starting dose of esomeprazole was 40 mg or 80 mg twice daily. On day 10, patients with controlled AO were maintained on the same dose, while those with uncontrolled AO had their doses increased (maximum dose 240 mg/day) until control was attained. Esophagogastroduodenoscopy (EGD) was performed at baseline and at 6 and 12 months. Safety and tolerability were assessed throughout the study by EGD, gastric analysis, and adverse events. Twenty-one patients (19 with Zollinger-Ellison syndrome [ZES], 2 with idiopathic gastric acid hypersecretion [IGH]) completed the study. Of the 20 patients with controlled AO at day 10, 18 (90%) had sustained AO control for the rest of the study. At 12 months, AO was controlled in 14 of 16 patients receiving esomeprazole 40 mg twice daily, in all 4 patients receiving esomeprazole 80 mg twice daily, and in the 1 patient receiving esomeprazole 80 mg 3 times daily. At 6 and 12 months, no patient had endoscopic evidence of mucosal disease. Esomeprazole was well tolerated; 1 patient had a serious adverse event (hypomagnesemia) attributed to treatment that resolved with magnesium supplementation during continued treatment. Esomeprazole in appropriately titrated doses controls AO over 12 months in patients with hypersecretory states and is well tolerated.
The American Journal of Gastroenterology, 2003
The American Journal of Gastroenterology, 2002
Поиск в библиотеке, Расширенный поиск. ...
American Journal of Gastroenterology, 2003
The charts of 112 patients (88 F, 24 M, 50 Ϯ 16 year old) referred to the motility center for eva... more The charts of 112 patients (88 F, 24 M, 50 Ϯ 16 year old) referred to the motility center for evaluation of dysphagia were reviewed. All patients had previously undergone upper endoscopy to rule out mechanical obstruction. Patients underwent esophageal motility studies using a solid state manometry catheter. Esophageal body and lower esophageal sphincter (LES) function were evaluated in response to 5 food swallows (1 teaspoon of fruit cocktail) and 10 liquid swallows (5 cc water at 45 sec interval). All patients answered a series of questions to document the frequency, severity, and duration of their dysphagia prior to the motility study. Results: Half of the study population (50.9%) complained of severe dysphagia, 27.7% of mild dysphagia, and 18.8% had minimal symptoms. 27.7% of the study population had complaints of dysphagia for at least the last 48 months, and 12.5% for less than 6 months. 47.3% of the patients described their symptoms as located above the suprasternal notch, while 33% described their symptoms as below, and 18.8% had both upper and lower locations. No correlation was noted between the amplitude, the duration and propagation characteristics of esophageal body contractions and the severity and duration of the symptoms of dysphagia. Similarly, there was no relationship between the basal pressure and relaxation characteristics of the LES and the UES and the location of the dysphagia either. There was a trend for the percent of LES relaxation to be negatively correlated with the severity of symptoms during water swallows (pϭ0.06) but not during food swallows. Conclusions: In patients with dysphagia, symptoms of duration, frequency, intensity and location do not have any predictive value of esophageal body function during either liquid or solid swallows. Only the amplitude of the LES relaxation during water swallows may have a predictive value for symptom severity. A detailed history of the patients' complaints may be taken, although this may not be beneficial in predicting manometry findings.
A case of a pedunculated adenomatous polyp of the sigmoid colon was found to have a primary focus... more A case of a pedunculated adenomatous polyp of the sigmoid colon was found to have a primary focus of signet ring cell carcinoma. Histologic examination of the medium-sized polyp was consistent with an adenoma to carcinoma sequence for signet ring cell carcinoma of the colon, similar to that for the common adenocarcinomas.
The Journal of Clinical Pharmacology, 2015
Naloxegol, a peripherally acting μ-opioid receptor antagonist, was recently approved in the Unite... more Naloxegol, a peripherally acting μ-opioid receptor antagonist, was recently approved in the United States for the treatment of opioid-induced constipation. This study evaluated the effects of CYP3A inhibition and induction on the PK, safety, and tolerability of naloxegol. Separate open-label, nonrandomized, fixed-sequence, 3-period, 3-treatment, crossover studies of naloxegol (25 mg by mouth [PO]) in the absence or presence of the inhibitors ketoconazole (400 mg PO) and diltiazem extended release (240 mg PO), or the inducer rifampin (600 mg PO) were conducted in healthy volunteers. Area under the curve (AUCinf ) for naloxegol was increased with coadministration of either ketoconazole (12.9-fold) or diltiazem (3.4-fold) and decreased by 89% with coadministration of rifampin compared with AUCinf for naloxegol alone. Naloxegol was generally safe and well tolerated when given alone or coadministered with the respective CYP3A modulators; one subject discontinued because of elevations in liver enzymes attributed to rifampin. The exposure of naloxegol was affected substantially by ketoconazole, diltiazem, and rifampin, suggesting that it is a sensitive in vivo substrate of CYP3A4. This article is protected by copyright. All rights reserved.
Aliment Pharmacol Therapeut, 2006
To assess the relationship between the percentage of time intragastric pH >4.0 and healing of ero... more To assess the relationship between the percentage of time intragastric pH >4.0 and healing of erosive oesophagitis.
Aliment Pharmacol Therapeut, 2007
Intravenous (IV) formulations of proton pump inhibitors are effective for patients in whom oral t... more Intravenous (IV) formulations of proton pump inhibitors are effective for patients in whom oral therapy is not appropriate.
The Journal of Clinical Pharmacology, 2015
Naloxegol is a PEGylated, oral, peripherally acting μ-opioid receptor antagonist approved in the ... more Naloxegol is a PEGylated, oral, peripherally acting μ-opioid receptor antagonist approved in the United States for treatment of opioid-induced constipation in patients with noncancer pain. Naloxegol is metabolized by CYP3A, and its properties as a substrate for the P-glycoprotein (PGP) transporter limit its central nervous system (CNS) permeability. This double-blind, randomized, 2-part, crossover study in healthy volunteers evaluated the effect of quinidine (600 mg PO), a CYP3A/PGP transporter inhibitor, on the pharmacokinetics and CNS distribution of naloxegol (25 mg PO). In addition, the effects of quinidine on morphine (5 mg/70 kg IV)-induced miosis and exposure to naloxegol were assessed. Coadministration of quinidine and naloxegol increased naloxegol AUC 1.4-fold and Cmax 2.5-fold but did not antagonize morphine-induced miosis, suggesting that PGP inhibition does not increase the CNS penetration of naloxegol. Naloxegol pharmacokinetics were unaltered by coadministration of morphine and either quinidine or placebo; conversely, pharmacokinetics of morphine and its metabolites (in the presence of quinidine) were unaltered by coadministration of naloxegol. Naloxegol was safe and well tolerated, alone or in combination with quinidine, morphine, or both. The observed increase in exposure to naloxegol in the presence of quinidine is primarily attributed to quinidine's properties as a weak CYP3A inhibitor. This article is protected by copyright. All rights reserved.
Int. Journal of Clinical Pharmacology and Therapeutics, 2015
United European Gastroenterology Journal, 2015
Treatment options for patients with opioid-induced constipation (OIC) and inadequate response to ... more Treatment options for patients with opioid-induced constipation (OIC) and inadequate response to laxatives (LIR) are few. Assess the efficacy and safety of orally administered naloxegol in patients with prospectively confirmed OIC and LIR. We analyzed pooled data from two identical randomized, double-blind, placebo-controlled, Phase 3 trials of naloxegol in patients with non-cancer pain, OIC and LIR in which naloxegol (12.5 mg, n = 240; 25 mg, n = 241) or placebo (n = 239) were administered daily. We assessed the response rates, time to first post-dose laxation, spontaneous bowel movements (SBMs), OIC symptoms and patient-reported outcomes over 12 weeks. OIC response rates for the naloxegol 25-mg (p < 0.001) and the 12.5-mg (p = 0.005) LIR dose groups were higher than placebo. Median times to first post-dose SBM were 7.6, 19.2 and 41.1 hours for the naloxegol 25 mg, naloxegol 12.5 mg and placebo groups, respectively. Other SBM measures, daily symptoms of OIC, and both the Patient Assessment of Constipation - Symptoms and Patient Assessment of Constipation-Quality of Life scores improved from baseline with naloxegol treatment. Changes from baseline in opioid dose, pain scores and opioid withdrawal scores were similar among treatment groups. Naloxegol was efficacious, generally safe and well tolerated in the patients with OIC and LIR, while preserving opioid analgesia. ClinicalTrials.gov identifiers: NCT01309841; NCT01323790.
British journal of clinical pharmacology, Jan 28, 2015
Naloxegol, a polyethylene glycol conjugated derivative of the opioid antagonist naloxone, is in c... more Naloxegol, a polyethylene glycol conjugated derivative of the opioid antagonist naloxone, is in clinical development for treatment of opioid-induced constipation (OIC). The aim of the study was to develop a population pharmacokinetic model describing the concentration vs. time profile of orally administered naloxegol, and determine the impact of pre-specified demographic and clinical factors and concomitant medication on population estimates of apparent clearance (CL/F) and apparent central compartment volume of distribution (Vc /F). Analysis included 12 844 naloxegol plasma concentrations obtained from 1247 healthy subjects, patients with non-OIC and patients with OIC in 14 phase 1, 2b and 3 clinical studies. Pharmacokinetic analysis used the non-linear mixed effects modelling program. Goodness of fit plots and posterior predictive checks were conducted to confirm concordance with observed data. The final model was a two compartment disposition model with dual absorptions, comprisi...
Clinical Pharmacology in Drug Development, 2015
Clinical Pharmacology in Drug Development, 2015
ABSTRACT
Alimentary Pharmacology & Therapeutics, 2014
Opioid-induced constipation is common and debilitating. We investigated the efficacy and safety o... more Opioid-induced constipation is common and debilitating. We investigated the efficacy and safety of naloxegol, an oral, peripherally acting, μ-opioid receptor antagonist, for the treatment of opioid-induced constipation.
The American Journal of Gastroenterology, 2006
The American Journal of Gastroenterology is published by Nature Publishing Group (NPG) on behalf ... more The American Journal of Gastroenterology is published by Nature Publishing Group (NPG) on behalf of the American College of Gastroenterology (ACG). Ranked the #1 clinical journal covering gastroenterology and hepatology*, The American Journal of Gastroenterology (AJG) ...
The American Journal of Gastroenterology, 2007
To evaluate the efficacy and safety of oral esomeprazole in the control of gastric acid hypersecr... more To evaluate the efficacy and safety of oral esomeprazole in the control of gastric acid hypersecretion in patients with hypersecretory states. In this 12-month, open-label, multicenter study, acid output (AO) was evaluated at baseline, day 10, and months 3, 6, and 12. The starting dose of esomeprazole was 40 mg or 80 mg twice daily. On day 10, patients with controlled AO were maintained on the same dose, while those with uncontrolled AO had their doses increased (maximum dose 240 mg/day) until control was attained. Esophagogastroduodenoscopy (EGD) was performed at baseline and at 6 and 12 months. Safety and tolerability were assessed throughout the study by EGD, gastric analysis, and adverse events. Twenty-one patients (19 with Zollinger-Ellison syndrome [ZES], 2 with idiopathic gastric acid hypersecretion [IGH]) completed the study. Of the 20 patients with controlled AO at day 10, 18 (90%) had sustained AO control for the rest of the study. At 12 months, AO was controlled in 14 of 16 patients receiving esomeprazole 40 mg twice daily, in all 4 patients receiving esomeprazole 80 mg twice daily, and in the 1 patient receiving esomeprazole 80 mg 3 times daily. At 6 and 12 months, no patient had endoscopic evidence of mucosal disease. Esomeprazole was well tolerated; 1 patient had a serious adverse event (hypomagnesemia) attributed to treatment that resolved with magnesium supplementation during continued treatment. Esomeprazole in appropriately titrated doses controls AO over 12 months in patients with hypersecretory states and is well tolerated.
The American Journal of Gastroenterology, 2003
The American Journal of Gastroenterology, 2002
Поиск в библиотеке, Расширенный поиск. ...
American Journal of Gastroenterology, 2003
The charts of 112 patients (88 F, 24 M, 50 Ϯ 16 year old) referred to the motility center for eva... more The charts of 112 patients (88 F, 24 M, 50 Ϯ 16 year old) referred to the motility center for evaluation of dysphagia were reviewed. All patients had previously undergone upper endoscopy to rule out mechanical obstruction. Patients underwent esophageal motility studies using a solid state manometry catheter. Esophageal body and lower esophageal sphincter (LES) function were evaluated in response to 5 food swallows (1 teaspoon of fruit cocktail) and 10 liquid swallows (5 cc water at 45 sec interval). All patients answered a series of questions to document the frequency, severity, and duration of their dysphagia prior to the motility study. Results: Half of the study population (50.9%) complained of severe dysphagia, 27.7% of mild dysphagia, and 18.8% had minimal symptoms. 27.7% of the study population had complaints of dysphagia for at least the last 48 months, and 12.5% for less than 6 months. 47.3% of the patients described their symptoms as located above the suprasternal notch, while 33% described their symptoms as below, and 18.8% had both upper and lower locations. No correlation was noted between the amplitude, the duration and propagation characteristics of esophageal body contractions and the severity and duration of the symptoms of dysphagia. Similarly, there was no relationship between the basal pressure and relaxation characteristics of the LES and the UES and the location of the dysphagia either. There was a trend for the percent of LES relaxation to be negatively correlated with the severity of symptoms during water swallows (pϭ0.06) but not during food swallows. Conclusions: In patients with dysphagia, symptoms of duration, frequency, intensity and location do not have any predictive value of esophageal body function during either liquid or solid swallows. Only the amplitude of the LES relaxation during water swallows may have a predictive value for symptom severity. A detailed history of the patients' complaints may be taken, although this may not be beneficial in predicting manometry findings.