PubMed Health⌕ Search

Biomedical subjects

Chandra Prakash

Publications and source records attributed to Chandra Prakash.

At least 19 recordsLinked to original sources
PubMed2006

Tricyclic antidepressants for chronic vomiting in diabetic patients.

Chronic vomiting in diabetic patients often is unresponsive to prokinetic agents and poorly explained by delayed gastric emptying or neuropathy. This retrospective study examines clinical response to tricyclic antidepressants, a treatment of reported benefit in nondiabetic patients with unexplained vomiting syndromes. Outcomes were studied in 24 diabetic outpatients who had been treated with tricyclic antidepressants specifically for nausea and vomiting after an unsatisfactory response to prokinetic therapy. Symptom patterns and treatment response were determined from chart review and telephone interview. Ten patients (42%) had recurrent, stereotypical vomiting episodes with symptom-free intervals suggesting cyclic vomiting syndrome; 14 (58%) had persistent symptoms. By chart review, at least moderate symptom response to tricyclic antidepressant treatment (median dosage, 50 mg/day) occurred in 88% of subjects, with complete or nearly complete resolution of symptoms in one-third. At follow-up interview, 77% self-reported at least moderate symptom improvement during therapy and 68% rated tricyclic antidepressants the most effective treatment received. Duration of diabetes, presence of neuropathy, and psychiatric status were not predictive of treatment outcome in multivariate analysis, but a cyclical symptom pattern attenuated antidepressant response (P< 0.05). In this retrospective review, the majority of diabetic patients with chronic vomiting and incomplete response to prokinetic therapy benefited from tricyclic antidepressants in low-dose, open-label regimens and rated them the most effective treatment received. This therapeutic option should be further studied in diabetic patients considering the morbidity of chronic vomiting in this population.

Adult↗
PubMed2006

Zonisamide or levetiracetam for adults with cyclic vomiting syndrome: a case series.

BACKGROUND & AIMS: Management of cyclic vomiting syndrome in adults is limited by the small number of effective medications for maintenance therapy. The clinical response to treatment with 2 newer antiepileptic drugs was evaluated retrospectively to see whether they might have a prophylactic role in this syndrome. METHODS: Outpatient records from 20 adult patients with cyclic vomiting syndrome attending a university-based practice were reviewed. Each had received zonisamide (median dose, 400 mg/d) or levetiracetam (median dose, 1000 mg/d) because tricyclic antidepressants alone were unsatisfactory as maintenance medications. Outcome was graded from chart review and directed interview; characteristics of the vomiting episodes were compared before and after initiation of antiepileptic drug therapy. RESULTS: At least moderate clinical response was described by 15 (75.0%) subjects, and 4 of these (20.0% of the total) reported symptomatic remission during 9.5 +/- 1.8 months of follow-up. Rate of vomiting episodes decreased from 1.3 +/- 0.3 to 0.5 +/- 0.2 per month (P = .01). Tricyclic antidepressants were discontinued in 11 (61.1%) of the 18 subjects who were still taking the medications when antiepileptic drug therapy was initiated. Moderate or severe side effects were reported by 45.0%, but by switching drugs, intolerance to antiepileptic drug therapy occurred in only 1 subject. CONCLUSIONS: Newer antiepileptic drugs, specifically zonisamide and levetiracetam, appeared beneficial as maintenance medications for nearly three fourths of adults with cyclic vomiting syndrome in this uncontrolled clinical experience. Although side effects occur in a large proportion of subjects, newer antiepileptic drugs might offer an alternative for patients who fail conventional treatment.

Adult↗
PubMed2006

Endoscopic removal of the wireless pH monitoring capsule in patients with severe discomfort.

BACKGROUND: Few patients have significant symptoms during wireless esophageal pH monitoring, and the capsule typically sloughs spontaneously. Severe discomfort during monitoring can occur that requires endoscopic dislodgement of the capsule. OBJECTIVE: To determine the frequency with which endoscopic capsule dislodgement is required and the outcomes of the intervention. DESIGN: Chart review. SETTING: University-based outpatient endoscopy facility. PATIENTS: A total of 452 consecutive patients undergoing wireless pH monitoring over a 3.5-year period. INTERVENTIONS: Endoscopic dislodgement of the capsule by using nudging with the endoscope tip and cold snare techniques. RESULTS: Eight subjects (1.8%) required endoscopic capsule dislodgement because of severe chest pain or odynophagia (n = 7) or severe foreign-body sensation (n = 1). Chest pain was the initial indication for pH monitoring in 5 (62.5%) of the subjects. Initial nudging with the endoscope tip successfully dislodged 2 capsules; continued nudging produced mucosal stripping in 3 subjects, which required hemostasis in 1. A cold snare was used successfully, without complication, to separate the capsule from stripped mucosa and as a primary removal method in the remainder of subjects. Capsule removal uniformly resulted in marked improvement of discomfort. CONCLUSIONS: Endoscopic removal of the capsule was required in <2% of subjects who underwent wireless pH monitoring. Separation of the capsule from the mucosa with a cold snare may be the preferred method of accomplishing uncomplicated removal.

Adult↗
PubMed2006

Wireless pH monitoring in patients with non-cardiac chest pain.

OBJECTIVES: Gastroesophageal reflux disease (GERD) is an important cause of non-cardiac chest pain (NCCP), and its detection can require ambulatory pH monitoring. The purpose of this study was to determine the advantages of a wireless ambulatory pH monitoring system and 2 days of recording in diagnosing GERD in NCCP patients. METHODS: Results from ambulatory pH studies using the BRAVO capsule were reviewed from 62 subjects referred for evaluation of NCCP after non-diagnostic response to proton pump inhibitor therapy. Acid exposure time (AET) and symptom-reflux association tests were calculated after 1 day of recording and compared to the final outcome from the 2-day study. RESULTS: Extending the recording time increased the number of subjects having elevated AET from 16 after 1 day to 22 after 2 days of recording, a 9.7% gain in subjects (95% CI 4.6-19.6%). The number of chest pain episodes doubled from 1 to 2 days, and 4 subjects (7.3%) developed symptoms only on the second day of monitoring. Statistically significant reflux-symptom association probabilities surfaced in an additional 13 subjects (21.0%; 95% CI 12.7-32.7%) by the conclusion of the 2-day study. The effect primarily was to identify significant associations in patients with lower proportions of reflux-associated symptoms. Taken together, 19.4% (95% CI 11.5-30.9%) of the subject group gained meaningful information suggesting a reflux diagnosis by extending the pH monitoring time to 2 days. CONCLUSIONS: Extending monitoring to 2 days with a wireless pH monitoring system increases the detection of GERD in a clinically significant proportion of patients with NCCP.

Adult↗
PubMed2006

Xenobiotic-metabolizing enzymes in human lung.

Human lung is a major target organ for all inhaled drugs, environmental toxicants and carcinogens. Recent hypotheses suggesting a role for environmental toxicants in the pathogenesis of lung diseases, such as lung cancer and chronic obstructive pulmonary disease have stimulated interest in research on the xenobiotic metabolizing capability of the lung. Many of the compounds associated with these diseases require enzymatic activation to exert their deleterious effects on pulmonary cells. Interindividual differences in in situ activation and inactivation of xenobiotics may contribute to the risk of developing of lung diseases associated with these compounds. The major xenobiotic metabolizing enzymes, including both phase I and phase II enzymes, have been detected in animal and human lung tissues. Although the lung cytochrome P450 (CYP) and other xenobiotic metabolizing enzymes share many common features with those present in other tissues such as liver, kidney and gut, there are some distinctive differences. It is evident from the studies carried out to date CYP1A1, 1B1, 2A13, 2F1, 2S1 and 4B1 are preferentially expressed in the lung together with CYP2E1 and 3A5. This review provides a detailed picture of major xenobiotic-metabolizing phase I (CYPs, epoxide hydrolases, flavin monooxygenases, etc.) and phase II enzymes (conjugation enzymes, including several transferases) expressed in human lung. The roles of individual metabolizing enzymes and their genetic polymorphisms are also discussed.

Cytochrome P-450 Enzyme System↗
PubMed2006

High performance liquid chromatography/atmospheric pressure ionization/tandem mass spectrometry (HPLC/API/MS/MS) in drug metabolism and toxicology.

Studies of the metabolic fate of drugs and other xenobiotics in living systems may be divided into three broad areas: (1) elucidation of biotransformation pathways through identification of circulatory and excretory metabolites (qualitative studies); (2) determination of pharmacokinetics of the parent drug and/or its primary metabolites (quantitative studies); and (3) identification of chemically-reactive metabolites, which play a key role as mediators of drug-induced toxicities (mechanistic studies). Mass spectrometry has been regarded as one of the most important analytical tools in studies of drug metabolism, pharmacokinetics and biochemical toxicology. With the commercial introduction of new ionization methods such as those based on atmospheric pressure ionization (API) techniques and the combination of liquid chromatography-mass spectrometry (LC-MS), it has now become a truly indispensable technique in pharmaceutical research. Triple stage quadrupole and ion trap mass spectrometers are presently used for this purpose, because of their sensitivity and selectivity. API-TOF mass spectrometry has also been very attractive due to its enhanced full-scan sensitivity, scan speed, improved resolution and ability to measure the accurate masses for protonated molecules and fragment ions. This review aims to survey the utility of mass spectrometry in drug metabolism and toxicology and to highlight novel applications and future trends in this field.

Animals↗
PubMed2005

Metabolism and excretion of erlotinib, a small molecule inhibitor of epidermal growth factor receptor tyrosine kinase, in healthy male volunteers.

Metabolism and excretion of erlotinib, an orally active inhibitor of epidermal growth factor receptor tyrosine kinase, were studied in healthy male volunteers after a single oral dose of [14C]erlotinib hydrochloride (100-mg free base equivalent, approximately 91 microCi/subject). The mass balance was achieved with approximately 91% of the administered dose recovered in urine and feces. The majority of the total administered radioactivity was excreted in feces (83+/-6.8%), and only a low percentage of the dose was recovered in urine (8.1+/-2.8%). Only less than 2% of what was recovered in humans was unchanged erlotinib, which demonstrates that erlotinib is eliminated predominantly by metabolism. In plasma, unchanged erlotinib represented the major circulating component, with the pharmacologically active metabolite M14 accounting for approximately 5% of the total circulating radioactivity. Three major biotransformation pathways of erlotinib are O-demethylation of the side chains followed by oxidation to a carboxylic acid, M11 (29.4% of dose); oxidation of the acetylene moiety to a carboxylic acid, M6 (21.0%); and hydroxylation of the aromatic ring to M16 (9.6%). In addition, O-demethylation of M6 to M2, O-demethylation of the side chains to M13 and M14, and conjugation of the oxidative metabolites with glucuronic acid (M3, M8, and M18) and sulfuric acid (M9) play a minor role in the metabolism of erlotinib. The identified metabolites accounted for >90% of the total radioactivity recovered in urine and feces. The metabolites observed in humans were similar to those found in the toxicity species, rats and dogs.

Biotransformation↗
PubMed2005

Metabolism, excretion, and pharmacokinetics of (3-{[4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic acid, an EP2 receptor-selective prostaglandin E2 agonist, in male and female Sprague-Dawley rats.

Metabolism, excretion, and pharmacokinetics of a highly selective EP2 agonist, CP-533,536 (3-{[4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic acid), were investigated in male and female Sprague-Dawley rats following an intravenous administration of a single 15 mg/kg dose of [(14)C]CP-533,536. At 144 h after the dose, the cumulative excretion of radioactivity averaged 98.2 +/- 3.44% and 97.0 +/- 4.82% in male and female rats, respectively. The radioactivity was predominantly excreted in feces, reaching 87% of the dose. Mean exposure [area under the concentration-time curve (AUC(0-infinity))] for both CP-533,536 and total radioactivity was higher in female rats than in male rats, whereas the plasma clearance of CP-533,536 and metabolites was lower in female rats compared to male rats. CP-533,536 was extensively metabolized in both male and female rats. The major oxidative pathway was due to the oxidation of the tert-butyl side chain to form the omega-hydroxy metabolite M4 (males, 19.7%; females, 6.5%). M4 was further oxidized to form the omega-carboxy metabolite M3 (males, 32.8%; females 1.66%) or conjugated via sulfation to form metabolite M6 (males 12.7%; females 36.2%). Other metabolites were due to N-oxidation of the pyridine ring (M5) and aromatic hydroxylation (M12), and conjugation with glucuronic acid. The secondary metabolites were due to N-dealkylation of the methyl-phenoxyacetic acid moiety and phase II conjugation. CP-536,536 accounted for about 63 and 72% of the AUC of the total radioactivity for male and female rats, respectively. Gender-related differences in the metabolism and pharmacokinetics were observed. omega-Carboxy metabolite M3 was the major metabolite in male rats, whereas M3-sulfate was identified as the major metabolite in female rats.

Animals↗
PubMed2005

Characterization of a novel metabolite intermediate of ziprasidone in hepatic cytosolic fractions of rat, dog, and human by ESI-MS/MS, hydrogen/deuterium exchange, and chemical derivatization.

Ziprasidone (Geodone), a novel atypical antipsychotic agent, is recently approved for the treatment of schizophrenia. It undergoes extensive metabolism in preclinical species and humans after oral administration, and only a very small amount of administered dose is excreted as unchanged drug. In vitro studies using human liver microsomes have shown that the oxidative metabolism of ziprasidone is mediated primarily by CYP3A4. However, coadministration of ziprasidone with ketoconazole, a CYP3A4 inhibitor, showed only a modest increase in its exposure. Therefore, in vitro metabolism of ziprasidone was investigated in hepatic cytosolic fractions to further understand its clearance mechanisms in preclinical species and humans. The major metabolite from incubation of ziprasidone in cytosolic fractions of rat, dog, and human was characterized by liquid chromatography-tandem mass spectrometry and found to be the product of reductive cleavage. Derivatization and hydrogen/deuterium exchange were used to deduce that the addition of two hydrogen atoms had occurred at the benzisothiazole moiety. Further studies to determine the enzyme involved in the formation of this metabolite are currently in progress. The identification of this novel metabolite in cytosol has clarified the clearance mechanism of ziprasidone in humans and preclinical species.

Animals↗
PubMed2005

Value of extended recording time with wireless pH monitoring in evaluating gastroesophageal reflux disease.

BACKGROUND & AIMS: Extending an ambulatory pH study by using a wireless capsule system could improve diagnosis of gastroesophageal reflux disease in patients with symptoms potentially related to acid reflux events. We determined the relative value of a 2-day versus a 1-day study in detection of abnormal esophageal acid exposure and reflux symptom associations. METHODS: Subjects who had undergone pH monitoring with the wireless system for symptom evaluation and who had at least 1 typical or atypical symptom during monitoring were studied (n = 157). Acid exposure time, symptom index, and a measure of reflux-associated symptom probability were calculated after 1 day of recording and compared to final results from analysis of 2 days of data. RESULTS: Extending recording time increased the number of subjects recording symptoms by 6.8% and doubled the number of symptoms available for association with acid reflux events. Other advantages were greater in subjects off antireflux therapy, wherein lengthening recording time increased the proportion of subjects with abnormal acid exposure time by 12.4% and significantly increased the likelihood of a positive reflux symptom relationship in subjects with atypical symptoms. Accuracy of a 1-day study ranged from 0.87-0.88 for acid exposure time to as low as 0.72-0.87 for the probability test, the most sensitive of the symptom association tests. CONCLUSIONS: Extending recording time to 2 days with the wireless pH monitoring system increases the likelihood of detecting reflux disease in patients undergoing symptom evaluation. Benefits are most evident for subjects with atypical symptoms and for establishing reflux symptom associations by probability testing.

Adult↗
PubMed2005

Quantitative analysis of the immunosuppressant CP-690,550 in whole blood by column-switching high-performance liquid chromatography and mass spectrometry detection.

A fast and accurate method to quantify the new immunosuppressive JAK3 inhibitor CP-690,550 in whole blood using a dual-pump liquid chromatography-liquid chromatography-mass spectrometry (LC/LC-MS) system was developed and validated in nonhuman primate blood. Before injection, blood samples were prepared by precipitation with a reagent that included methanol and acetonitrile (30:70, vol/vol) along with the internal standard (CP-istd). Column-switching LC/LC-MS analysis used online extraction followed by separation on a C8 analytic column and MS detection of the [M + H] CP-690,550 (m/z = 313.1) and CP internal standard (m/z = 288.1). Linearity was always better than r = 0.99 (n = 7) for CP-690,550 (range 2.5-750 ng/mL), with a lower limit of quantification (LLOQ) of 2.5 ng/mL. The intrarun accuracy and precision ranged from 103.0% to 105.4% and 2.7% to 4.3%, respectively (n = 5), and the interday precision ranged from 8.7% to 11.1%, and the interday accuracy ranged from 98.1% to 103.8% of nominal values (n = 14). The injection repeatability for the method was 1.3% (n = 7). Except for the LLOQ, the intraday accuracy and precision in human blood were also within 15% (n = 5). The combination of simple sample preparation and short analytic run time of this sensitive procedure makes it effective for monitoring the concentration of CP-690,550 in whole blood in organ-transplant recipients.

Animals↗
PubMed2004

An interface for direct analysis of (14)c in nonvolatile samples by accelerator mass spectrometry.

We describe here apparatus and methods for direct analysis of (14)C in biological specimens by accelerator mass spectrometry (AMS). Liquid samples, including plasma and urine, are deposited by pipet into a bed of CuO powder that fills a space within a rigid, refractory support. Volatile components are removed under reduced pressure prior to analysis. The CuO matrix is locally heated with an infrared laser while it is contained within a sealed chamber that is swept with He carrier gas. Heating induces combustion of the applied sample, and the carrier gas transports the CO(2) that is formed to the AMS instrument's ion source, which is appropriately modified for use with CO(2). A rodent study of drug clearance with [(14)C]-acetaminophen was performed to provide plasma and urine specimens, which were analyzed with this overall approach and by liquid scintillation counting for comparison. Results presented here confirm the potential utility of laser-induced sample combustion as an alternative to graphite production for AMS analysis of (14)C. Anticipated benefits of the present approach include reduced risk of sample cross-contamination, decreased analysis time, and greater compatibility with robotics.

Acetaminophen↗
PubMed2004

Unusual presentations of aorto-enteric fistula.

BACKGROUND: Aorto-enteric fistula is rare but can result in exsanguination without timely surgery or endovascular stent placement. METHODS: Four cases of aorto-enteric fistula were reviewed in which the presentation was unusual and diagnosis difficult. OBSERVATIONS: The first patient had an aorto-sigmoid fistula in the setting of an aorto-bi-femoral graft. Two patients had a primary aorto-enteric fistula, one to the stomach from a suprarenal aortic aneurysm, and the other, to the duodenum in the setting of retroperitoneal spread of renal cancer. The aortoduodenal fistula recurred in the 4th patient within 3 months of surgical repair; this patient is the only one who survived long term. CONCLUSIONS: When presentation is atypical, the diagnosis of aorto-enteric fistula can be extremely difficult. Because investigative studies are not consistently useful in making a definitive pre-operative diagnosis, a strong index of clinical suspicion and a willingness to consider surgical exploration are essential for timely and successful management.

Aged↗
PubMed2003

Acute small bowel bleeding: a distinct entity with significantly different economic implications compared with GI bleeding from other locations.

BACKGROUND: Historically, acute lower intestinal bleeding has incorporated small bowel with colonic sources. This potentially obscures the unique characteristics of small bowel bleeding, which are eclipsed by the attributes of the much more common colonic bleeding. Separating acute lower intestinal bleeding into small bowel and colonic sources may delineate characteristics of each, thereby making it possible to determine whether clinical outcomes vary by anatomic level of bleeding. METHODS: A total of 29 consecutive patients (15 women, 14 men; age 68.6 +/-2.4 years) with acute small bowel bleeding were compared with two other groups, each with 29 consecutive patients, with either acute colonic bleeding or acute upper GI bleeding. Clinical presentation, outcomes, and resource utilization for small bowel bleeding were compared with similar parameters for acute colonic bleeding and upper GI bleeding. RESULTS: Although the clinical presentation did not always distinguish the 3 groups, resource utilization was significantly higher in the small bowel bleeding group. The latter group required a higher number of diagnostic procedures (p < 0.001) and blood transfusions (p < 0.001), remained in hospital longer (p < 0.05), and had a higher cost of hospitalization (p < 0.001) compared with the colonic bleeding and upper GI bleeding groups. The mortality rate for patients with small bowel bleeding was 10%. Although none of the patients with upper GI bleeding and only 14% of those with colonic bleeding required greater than 3 diagnostic procedures, 79% of patients with small bowel bleeding required 4 procedures for diagnostic localization (p < 0.0001). CONCLUSIONS: Small bowel bleeding ("mid-intestinal bleeding") is a distinct clinical entity with significantly worse outcomes compared with colonic bleeding and upper GI bleeding. The focus of the investigation should be directed to the small bowel, with enteroscopy or capsule endoscopy, when 3 investigative procedures fail to localize recurrent overt GI bleeding.

Acute Disease↗
PubMed2003

Esophageal motor disorders.

Motor dysfunction is an important cause of oropharyngeal dysphagia and distal esophageal symptoms. Minimally invasive surgical methods of managing Zenker diverticula and achalasia, important disorders associated with these presentations, continue to take center stage in the literature. Detection and characterization of hypomotility before antireflux surgery may be less important than systematically excluding achalasia, as the vague and variable presentations of this motor disorder become appreciated. The many processes that can mimic idiopathic achalasia continue to be exposed.

Journal Article↗