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C Prakash

Publications and source records attributed to C Prakash.

At least 19 recordsLinked to original sources
PubMed2003

Identification of the human cytochrome P450s responsible for the in vitro metabolism of a leukotriene B4 receptor antagonist, CP-195,543.

1. The major human cytochrome P450 (CYP) form(s) responsible for the metabolism of CP-195,543, a potent leukotriene B4 antagonist, were investigated. 2. Incubation of CP-195,543 with human liver microsomes resulted in the formation of three major metabolites, M1-3. M1 and M2 were diastereoisomers and formed by oxidation on the benzylic position. M3 was formed by aromatic oxidation of the benzyl group attached to the 3-position of the benzopyran ring. 3. The results from experiments with recombinant CYPs, correlation studies and inhibition studies with form-selective inhibitors and a CYP3A antibody strongly suggest that the CYP3A4 plays a major role in the metabolism of CP-195,543. Recombinant CYP3A5 did not metabolize CP-195,543. 4. The apparent K(m) and V(max) for the formation of M1-3 in human liver microsomes were determined as 36 microM and 4.1 pmol min(-1) pmol(-1) P450, 44 microM and 10 pmol min(-1) pmol(-1) P450, and 34 microM and 2.0 pmol min(-1) pmol(-1) P450, respectively. The average in vitro intrinsic clearance for M2 was the highest both in human liver microsomes and recombinant CYP3A4 compared with M1 and M3. Intrinsic clearance for M2 in human liver microsomes and recombinant CYP3A4 was 0.231 and 0.736 ml min(-1) pmol(-1) P450, respectively. The intrinsic clearances for M1 and M3 in human liver microsomes and CYP3A4 were 0.114 and 0.060 and 0.197 and 0.088 ml min(-1) pmol(-1) P450, respectively. This suggests that benzylic oxidation is the predominant phase I metabolic pathway of CP-195,543 in man.

Adolescent↗
PubMed2001

Esophageal motor disorders.

Esophageal motor function remains of investigative and clinical interest because of its relevance to symptoms and its relation to the occurrence and management of gastroesophageal reflux disease. Refinement in diagnostic methods continues to occur, and improved tests for identifying the nature or severity of motor disturbances in both the proximal and distal esophageal regions are now well described. Controversy concerning the management of achalasia, the best-understood distal motor disorder, is resolving as the benefits and disadvantages of available treatment options are becoming recognized. The relation of esophageal motor dysfunction to outcomes from antireflux surgery remains incompletely understood.

Journal Article↗
PubMed2001

Similarities in cyclic vomiting syndrome across age groups.

OBJECTIVE: Cyclic vomiting syndrome is well recognized in children yet has poorly defined pathogenesis and treatment. Cyclic vomiting syndrome is occasionally diagnosed in older subjects, but little attempt has been made to determine if such cases represent a unique disorder. METHODS: We reviewed clinical data from 39 patients aged 1.8-75 yr with cyclic vomiting syndrome meeting published criteria for diagnosis. Clinical characteristics were compared between subjects with symptom onset in childhood (<12 yr, n = 18) and subjects with onset at an older age (> or =12 yr, n = 21; mean age at onset 34.8+/-3.8 yr). RESULTS: All patients had stereotypical episodes of vomiting separated by varying symptom-free intervals. The prevalence rates of prodromal symptoms, triggering events, alleviants, associated symptoms including abdominal pain and diarrhea, and past or family history of migraine were similar in the children and older subjects with the syndrome (p > 0.3 for each). Delay in diagnosis was greater in the older subset (3.1+/-0.8 yr vs 7.9+/-3.1 yr, p < 0.05). Interepisode intervals and total number of hospitalizations did not differ significantly between younger and older patients, but duration of episodes was significantly longer in the older group (2.0+/-0.5 days vs 3.8+/-0.4 days, p < 0.01). When subjects were further substratified by age of illness onset, duration of episodes progressively increased from infant/toddlers (1.8+/-0.4 days) through childhood (2.3+/-0.5 days) and adolescence (2.9+/-1.0 days) and into adulthood (3.9+/-0.5; p < 0.05 across groups). Episode duration did not lengthen further in subgroups >20 yr of age. CONCLUSIONS: Many characteristics of cyclic vomiting syndrome are similar irrespective of age at disorder onset, suggesting a uniform pathogenesis. Duration of episodes increases with age to age 20 yr. Increased awareness of the condition and a high index of suspicion may help decrease delay in diagnosis after symptom onset.

Adolescent↗
PubMed2000

Narrow-bore high-performance liquid chromatography in combination with ionspray tandem mass spectrometry for the determination of the substance P receptor antagonist ezlopitant and its two active metabolites in plasma.

A simple, but highly sensitive and specific, assay was developed for the quantitative determination of ezlopitant and its two active metabolites in human plasma using narrow-bore reversed-phase high-performance liquid chromatography (HPLC) coupled with electrospray tandem mass spectrometry (ES-MS-MS). Ezlopitant, its two pharmacologically active metabolites, an alkene analogue (CJ-12 458) and a benzyl alcohol analogue (CJ-12 764), and their corresponding trideuterated internal standards (I.S.), were extracted from plasma with methyl tert.-butyl ether (MTBE). The dried MTBE extracts were reconstituted and analyzed using a narrow-bore (2.1 mm I.D.) YMC basic HPLC column and a mobile phase of acetonitrile-20 mM ammonium acetate, pH 5 (60:40, v/v). Column effluent was monitored by pneumatically assisted electrospray tandem mass spectrometry. Multiple reaction monitoring (MRM) using the parent to product ions was used to quantify ezlopitant and its two active metabolites. The assay exhibited a linear dynamic range of 0.1-100 ng/ml. Average absolute recoveries from plasma were approximately 71, 80 and 99% for ezlopitant and its two active metabolites CJ-12 485 and CJ-12 764, respectively. The precision (RSD %) and accuracy (Deviation %) values for the method were within +/- 12% and +/- 15%, respectively, for all analytes. Sample analysis times were less than 5 min from one injection to the next. The assay proved to be suitable for pharmacokinetics studies.

Benzylamines↗
PubMed2000

Acute gastrointestinal bleeding.

Acute gastrointestinal bleeding is a significant worldwide medical problem. Despite modern measures for diagnosis and treatment, morbidity and mortality rates associated with gastrointestinal bleeding remain largely unchanged. Aggressive medical resuscitation while initiating an evaluation to localize the site of blood loss remains the key to successful management of acute gastrointestinal bleeding. A multidisciplinary approach with early involvement of a gastroenterologist, surgeon, and radiologist can be extremely helpful in the management of these patients. With the logical and direct approach to the evaluation of patients with gastrointestinal bleeding described in this article, most episodes can be managed successfully.

Acute Disease↗
PubMed2000

Identification of the major human liver cytochrome P450 isoform(s) responsible for the formation of the primary metabolites of ziprasidone and prediction of possible drug interactions.

AIMS: To identify the cytochrome P450 (CYP) isoform(s) responsible for the formation of the primary metabolite of ziprasidone (ziprasidone sulphoxide), to determine the kinetics of its formation and to predict possible drug interactions by investigating CYP isoform inhibition in an in vitro study. METHODS: In vitro metabolism of [14C]-ziprasidone was studied using human liver microsomes. The metabolites were identified using mass spectrometry. The kinetics of metabolite formation were determined using [14C]-ziprasidone (10-200 microM) over 5 min, and Km and Vmax were estimated from Lineweaver-Burk plots. IC50 values for the inhibition of specific probe substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, by ziprasidone, risperidone and 9-hydroxyrisperidone were also determined using human liver microsomes from three subjects. Mean Ki values were calculated. RESULTS: Three CYP-mediated metabolites - ziprasidone sulphoxide, ziprasidone sulphone and oxindole acetic acid - were identified. The apparent Km and Vmax values for the formation of the major metabolite, ziprasidone sulphoxide (measured as the sum of sulphoxide and sulphone) were 235 microM and 1.14 nmol mg(-1) protein min(-1), respectively. Isoform-selective inhibitors and recombinant enzymes indicated that CYP3A4 is responsible for the formation of ziprasidone metabolites. Ziprasidone was not a substrate for the other isoforms studied. Similar in vitro inhibition of CYP2D6 (Ki 6.9-16 microM) and CYP3A4 (Ki 64-80 microM) was obtained with ziprasidone, risperidone and 9-hydroxyrisperidone. The in vivo free drug concentrations associated with clinically effective doses of ziprasidone are at least 1500-fold lower than the mean Ki for either CYP2D6 inhibition or CYP3A4 inhibition. CONCLUSIONS: Ziprasidone is predominantly metabolized by CYP3A4 in human liver microsomes and is not expected to mediate drug interactions with coadministered CYP substrates, at clinically effective doses.

Antipsychotic Agents↗
PubMed2000

Sphincter of oddi manometry: is it necessary to measure both biliary and pancreatic sphincter pressures?

BACKGROUND: Data are scant on the miss rate of sphincter of Oddi dysfunction if basal pressure in both biliary and pancreatic sphincter segments is not measured during manometry. METHODS: Motility tracings with basal pressure measurements of both sphincter segments were retrospectively analyzed. Basal sphincter pressure greater than 40 mm Hg was considered abnormal in either sphincter segment. RESULTS: The study population consisted of 73 subjects (64 women, 9 men; age 45.3 +/- 1.6 yr). The basal pressures in the 2 sphincter segments were highly discordant (correlation coefficient = 0.2, p = 0.04). Basal pressures were normal in both segments in 19%, abnormal in both segments in 40%, and abnormal in 1 segment but normal in the other in 41%. The negative predictive value of normal biliary sphincter pressure in excluding sphincter dysfunction was 0. 42; when the pancreatic sphincter pressure was normal, the negative predictive value was 0.58. The incidence of pancreatitis with dual duct manometry was comparable to the institutional experience with all sphincter studies. CONCLUSIONS: Although the clinical relevance of individually elevated sphincter pressures remains uncertain, there is significant discordance of basal pressures between the biliary and pancreatic sphincter segments. If only the biliary sphincter pressure were to be measured, one fourth of abnormal sphincter pressures would be missed. Therefore, if the first sphincter segment has a normal basal pressure, the other segment should also be evaluated.

Adult↗
PubMed2000

Esophageal motor disorders.

Motor dysfunction is responsible for symptomatic illnesses both in the proximal skeletal muscle region and in the distal smooth muscle esophagus. Practical methods for diagnosing and treating oropharyngeal dysphagia continue to reach consensus. Achalasia, the most significant of the distal motor disorders, is of investigative interest because of the expanded armamentarium of treatment options. Minimally invasive surgical methods have taken an important foothold as a primary treatment of this disorder. Appreciation is growing for sensory dysfunction that accompanies distal motor disorders. Such dysfunction may help explain the observed discrepancies between symptoms and measurable motility abnormality.

Journal Article↗
PubMed2000

Topographic esophageal manometry: an emerging clinical and investigative approach.

Topographic esophageal manometry utilizes an increased number of pressure sensors and three-dimensional displays to fully reveal the pressure continuum representing peristalsis. The techniques demonstrate that peristalsis is comprised of a chain of pressure segments, beginning at the upper esophageal sphincter and continuing through lower sphincter aftercontraction. Topographic methods have already proven useful in both research and clinical settings. Description of the techniques, the topographic representation of normal and abnormal esophageal motility, and advantages of topography over conventional manometric methods are discussed in this review.

Esophageal Motility Disorders↗
PubMed2000

Response to hepatitis B vaccination in high risk population.

Hepatitis B vaccine is well established as very efficacious, but immune response to the vaccine is highly individual specific. A study involving fifty vaccinees was undertaken at the Hepatitis Laboratory, National Institute of Communicable Disease, Delhi. One ml (20 microgram) of Engerix B vaccine (recombinant yeast derived vaccine) was administered in the standard three dose schedule (0, 1 and 6 months). The sero-conversion of the vaccinees was 24%, 66%, 76% and 78% at 1 month, 6 months, 7 months, and 12 months respectively. There was no seroconversion in 22% of the vaccinees. Sero-conversion was assessed using Macro ELISA test (Ausab, Abbott Labs) for Anti HBs reactivity.

Adult↗
PubMed1999

Long-term outcome from tricyclic antidepressant treatment of functional chest pain.

Antidepressants are of demonstrated value in short-term treatment of functional chest pain, but long-term outcome data are unavailable. Follow-up information over a median of 2.7 years (0.8-8.6 years) was systematically obtained from 21 outpatients treated with tricyclic antidepressants after incomplete response to antireflux therapy. Initial treatment produced at least moderate symptom reduction or remission in 17 subjects (81.0%). Of these, 7 (41.2%) were successfully treated continuously or for symptom relapses over an average of 2.6 years; 5 (29.4%) discontinued successful treatment after >0.5 years with sustained benefits; and 5 (29.4%) eventually discontinued treatment because of side effects or for uncertain reasons (1 having a sustained remission). Low-dose tricyclic antidepressants were considered the most effective long-term chest pain treatment significantly more often than were antireflux medications or calcium-channel blockers in this selected patient group (P<0.05 for each). We conclude from this retrospective review that fully three fourths of subjects with functional chest pain who initially respond to open-label treatment with low-dose tricyclic antidepressants will use them continuously or for symptom relapses over at least the next two to three years and consider them the most effective treatment for their symptoms.

Antidepressive Agents, Tricyclic↗
PubMed1999

Endoscopic hemostasis in acute diverticular bleeding.

BACKGROUND AND STUDY AIMS: Early reports of urgent colonoscopy in acute lower intestinal bleeding suggest a role for endoscopic therapy for bleeding colonic lesions, but scant data exist on bleeding diverticula. We report our experience with endoscopic hemostasis in acute diverticular bleeding. PATIENTS AND METHODS: Bleeding diverticula were identified on urgent diagnostic endoscopy in five patients with acute gastrointestinal bleeding, two in the duodenum, and three in the colon. All patients had co-morbid conditions preventing more conventional therapeutic approaches. The five cases are described, including the technique of endoscopic hemostasis and outcome. RESULTS: Endoscopic therapy using epinephrine injection, thermal cautery and/or laser therapy successfully induced hemostasis in all patients. One patient died of co-morbid illness during the hospital stay, while the remaining four patients had no recurrent bleeding over a mean follow-up period of 20.6 months. CONCLUSION: Endoscopic therapy of bleeding diverticula is technically possible when the culprit diverticulum can be identified. This therapeutic modality may have a place in debilitated patients in whom other more invasive procedures are contraindicated, but further experience is needed to establish its safety.

Acute Disease↗
PubMed1999

Diagnosis and management of small intestinal diseases.

Advances in the diagnosis and management of small bowel diseases are the subject of this review. Topics covered include improving the specificity of breath tests for bacterial overgrowth; small bowel enteroscopy; early diagnosis of mesenteric ischemia; the use of polymerase chain reaction for diagnosing central nervous system involvement in Whipple's disease; progress in defining the cause and pathogenesis of chronic idiopathic intestinal pseudoobstruction and the Peutz-Jeghers syndrome; defining the role of gut barrier function in health and disease; the therapeutic role for bile acid-binding resins in diarrhea after refeeding in critically ill patients; use of genetic techniques and topical steroid therapy in treating graft-versus-host disease; and the beneficial effects of combination hormonal therapy in occult gastrointestinal blood loss resulting from angiodysplasia.

Journal Article↗
PubMed1999

Esophageal motor disorders.

A consolidation of ideas regarding the pathogenesis and management of esophageal motor disorders occurred over the past year. The development and application of diagnostic techniques has stimulated new thinking about the events responsible for peristalsis and has provided novel avenues for studying mechanisms of symptom production. Achalasia remains the most investigated and understood motor disorder, and the year's research focused heavily on management approaches for this important condition. Other topics addressed in this review include proximal esophageal symptoms and disorders, spastic disorders, and esophageal hypomotility.

Journal Article↗
PubMed1999

Cyclic vomiting syndrome in adults: clinical features and response to tricyclic antidepressants.

OBJECTIVE: Cyclic vomiting syndrome (CVS) has been described infrequently in adults, and treatment in both children and adults remains unsatisfactory. We report clinical features of a group of adults with CVS and anecdotal outcome from open-label treatment with tricyclic antidepressants, medications that have some efficacy in other unexplained gastrointestinal disorders. METHODS: Clinical data were examined from 17 adult patients with CVS seen over a 10-yr period, each having been treated with a tricyclic antidepressant. Outpatient records were reviewed, clinical outcome was extracted using a priori criteria, and findings were compared with 37 patients having usual functional nausea and vomiting who also received tricyclic antidepressant therapy. RESULTS: Symptoms in CVS began at age 35 yr (range 14-73 yr); the average episode length was 6 days (range 1-21 days) and the symptom-free interval averaged 3.1 months (range 0.5-6 months). Vomiting cycles typically began without warning, and fewer than one-third of the subjects reported a prodrome or potential trigger event, such as menstrual periods, pregnancy, or large meals. Sleep was seemingly beneficial in 23.5%. Tricyclic antidepressant therapy was associated with complete remission in 17.6% and partial response in 58.8%, but was less effective than for functional nausea and vomiting (p = 0.02). CONCLUSIONS: CVS is a rare diagnosis with distinctive features in adults. Duration of episodes and cycles varies considerably across subjects. In open-label, uncontrolled use, tricyclic antidepressants appear beneficial for some subjects but are less effective in CVS than in chronic, persistent functional nausea and vomiting.

Adolescent↗