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Biomedical subjects

Philip Abraham

Publications and source records attributed to Philip Abraham.

At least 19 recordsLinked to original sources
PubMed2006

Synthesis, nicotinic acetylcholine receptor binding, antinociceptive and seizure properties of methyllycaconitine analogs.

A series of methyllycaconitine (1a, MLA) analogs was synthesized where the (S)-2-methylsuccinimidobenzoyl group in MLA was replaced with a (R)-2-methyl, 2,2-dimethyl-, 2,3-dimethyl, 2-phenyl-, and 2-cyclohexylsuccinimidobenzoyl (1b-f) group. The analogs 1b-f were evaluated for their inhibition of [(125)I]iodo-MLA binding at rat brain alpha7 nicotinic acetylcholine receptors (nAChR). In order to determine selectivity, MLA and the analogs 1b-f were evaluated for inhibition of binding to rat brain alpha,beta nAChR using [(3)H]epibatidine. At the alpha7 nAChR, MLA showed a K(i) value of 0.87 nM, analogs 1b-e possessed K(i) values of 1.67-2.16 nM, and 1f showed a K(i) value of 26.8 nM. Surprisingly, the analog 1e containing the large phenyl substituent (K(i)=1.67 nM) possessed the highest affinity. None of the compounds possessed appreciable affinity for alpha,beta nAChRs. MLA antagonized nicotine-induced seizures with an AD(50)=2 mg/kg. None of the MLA analogs were as potent as MLA in this assay. MLA and all of the MLA analogs, with the exception of 1b, antagonized nicotine's antinociceptive effects in the tail-flick assay. Compound 1c (K(i)=1.78 nM at alpha7 nAChR) with an AD(50) value of 1.8 mg/kg was 6.7 times more potent than MLA (AD(50)=12 mg/kg) in antagonizing nicotine's antinociceptive effects but was 5-fold less potent than MLA in blocking nicotine-induced seizures. Since MLA has been reported to show neuroprotection against beta-amyloid(1-42), these new analogs which have high alpha7 nAChR affinity and good selectivity relative to alpha,beta nAChRs will be useful biological tools for studying the effects of alpha7 nAChR antagonist and neuroprotection.

Aconitine↗
PubMed2005

Synthesis and monoamine transporter binding properties of 2,3-diaryltropanes.

Synthetic procedures were developed for the synthesis of 2beta,3beta- and 2alpha,3alpha-diaryltropanes. These compounds are analogues of the 3-aryltropane-2beta-carboxylic acid methyl ester class of monoamine uptake inhibitors, where the 2beta-carbomethoxy group has been replaced by an aryl group. The compounds were evaluated for inhibition of radioligand binding at the dopamine, norepinephrine, and serotonin transporters (DAT, NET, and 5-HTT, respectively). The results showed that the replacement of the 2beta-carbomethoxy group in the 3-aryltropane class with a 2beta-aryl group led to compounds possessing very similar monoamine transporter binding properties. However, the 2beta,3beta-diaryltropanes tended to be more potent at the DAT and more selective for the DAT relative to the NET and 5-HTT. One of the most interesting compounds was 3beta-(4-methylphenyl)-2beta-(4-methylphenyl)tropane (3d), which showed an IC50 of 1.23 nM at the DAT with 289- and 185-fold selectivity for the DAT relative to the NET and 5-HTT. The 2alpha,3alpha-diaryltropanes were much less potent at all three transporters than 2beta,3beta-diaryltropanes.

Animals↗
PubMed2005

Synthesis, structural identification, and ligand binding of tropane ring analogs of paroxetine and an unexpected aza-bicyclo[3.2.2]nonane rearrangement product.

The structural requirements for high affinity at the serotonin transporter (5-HTT) have been investigated through the preparation of rigid paroxetine analogs. Tropane-derived analogs (4a-i) of paroxetine (2) were designed and synthesized as potential inhibitors of serotonin reuptake based on the structural and biological similarity between the two compound classes. Overall, the affinity of tropane-derived analogs at the 5-HTT was found to be at least an order of magnitude lower than that of paroxetine and ranged from 2-400nM. The reduced affinity at the 5-HTT may be attributed to the inability of the rigid tropane-derived analogs to adopt conformations favored by the 5-HTT. Within the series of tropane analogs, the 2beta,3beta- and 2beta,3alpha-isomers, 4a and 4d, were the most potent at the DAT and NET and are also significantly more potent than paroxetine (2) suggesting that their reduced conformational flexibility maximizes residence time in conformations favored by these transporters. Examination of the previously published preparation and structural assignment of 4a by additional NMR and X-ray crystallographic data has established that nucleophilic addition to the intermediate 2beta-methanesulfonyloxymethyl-3beta-(4-fluorophenyl)tropane unexpectedly provided the aza-bicyclo[3.2.2]nonane derivative 10a.

Alkanes↗
PubMed2004

Monoamine transporter binding, locomotor activity, and drug discrimination properties of 3-(4-substituted-phenyl)tropane-2-carboxylic acid methyl ester isomers.

The monoamine transporter binding properties, gross behavior, and locomotor activity effects in mice and drug discrimination results in cocaine-trained rats of the 2 beta,3beta-, 2 beta,3 alpha-, 2 alpha,3beta-, and 2 alpha,3 alpha-isomers of several 3-(4-substituted-phenyl)tropane carboxylic acid methyl esters were compared (2a-f, 3a-f, 4a-f, and 5b,c). The 2 beta,3beta-isomer showed the highest affinity for the dopamine transporter (DAT), and the 2 beta,3 alpha-isomer showed the next highest affinity. The order of potency for the 2 beta,3beta-isomer is 4'-chloro (2c) = 4'-iodo (2e) > 4'-bromo (2d) = 4'-methyl (2f) > 4'-fluoro (2b) > 4'-hydrogen (2a). In the case of the 2 beta,3 alpha-isomer, the order of affinity was 4'-bromo (3d) > 4'-iodo (3e) = 4'- chloro (3c) > 4'-methyl (3f) > 4'-fluoro (3b) > 4'-hydrogen (3a). The 4'-hydrogen, 4'-fluoro, and 4'-methyl 2 alpha,3beta-isomers, 4a, 4b, and 4f, had the lowest affinity for the DAT. While most of the compounds showed their highest affinity at the DAT, none were selective relative to the other two monoamine transporters. In general, the 2 alpha,3 alpha- and 2 alpha,3beta-isomers were more toxic (death and convulsions) than the 2 beta,3beta- and 2 beta,3 alpha-isomers. With the exception of the 2 alpha,3 alpha-isomers, all compounds produced the locomotor activity stimulation typical of dopaminergic drugs. The ED(50) ranges for the 2 beta,3beta- (2a-f), 2 beta,3 alpha- (3a-f), and 2 alpha,3beta-isomers (4a-f) in the locomotor assay were 0.1-1.2, 6.6-21.8, and 2.4-11.7 mg/kg, respectively. With the exception of the 2 alpha,3 alpha-isomer, all compounds generalized to cocaine. The 2 beta,3beta-isomers were at least 10-fold more potent than cocaine and the other three sets of isomers in this test.

Animals↗
PubMed2004

Acute renal tubular injury with acute hepatitis A infection: is it just a coincidence?

Acute renal failure has rarely been reported in association with acute hepatitis A infection. The commonest form of renal injury in such patients has been found to be acute tubular necrosis. We report two cases of hepatitis A infection in which acute renal failure occurred very early in the course of the illness and had a clinical presentation and recovery pattern suggestive of acute tubular necrosis. In both patients, the clinical course of renal dysfunction was almost parallel to the course of hepatic dysfunction. Patient 1 needed dialysis, whereas patient 2 did not need dialysis and had a very rapid recovery from renal function in spite of having more severe azotaemia. Patient 2 was administered acetylcysteine in high doses for suspected fulminant hepatic failure. A potential benefit of a high dose of acetylcysteine in recovery of renal function from acute tubular necrosis is postulated.

Acute Disease↗
PubMed2004

Co-existence of peri-ampullary carcinoma with peripancreatic tuberculous lymphadenopathy.

CONTEXT: Pancreatic tuberculosis and peripancreatic tuberculous lymphadenitis are rare, mimicking various pathologies of the pancreas. The coexistence of peri-ampullary malignancy with peripancreatic tuberculous lymphadenitis has not been reported. CASE REPORT: We present the case of a young woman who had been operated on with a preoperative diagnosis of peri-ampullary adenocarcinoma in whom a frozen section of regional lymph nodes revealed tuberculosis. The final pathology confirmed the co-existence of tuberculosis with malignancy. The patient made an uneventful recovery. CONCLUSION: In countries with high endemicity for tuberculosis, the co-existence of malignancy and tuberculosis should be considered and resection, which is the only chance for cure, should not be abandoned due to observations based solely on frozen sections.

Adult↗
PubMed2003

Pharmacodynamic mechanisms of monoclonal antibody-based antagonism of (+)-methamphetamine in rats.

Our studies examined pharmacokinetic mechanisms involved in high-affinity (K(d) approximately 11 nM) monoclonal antibody-based antagonism of (+)-methamphetamine-induced locomotor effects. Male rats received (+)-methamphetamine (0.3, 1, or 3 mg/kg i.v.) followed 30 min later by saline or anti-(+)-methamphetamine monoclonal antibody. All groups received a constant dose of monoclonal antibody that was equimolar in binding sites to the body burden of a 1 mg/kg i.v. (+)-methamphetamine dose 30 min after administration. The monoclonal antibody antagonized locomotor effects due to 0.3 and 1 mg/kg (+)-methamphetamine. In contrast, monoclonal antibody treatment increased locomotor activity due to 3 mg/kg (+)-methamphetamine. We also investigated the serum and brain pharmacokinetics of (+)-methamphetamine without and with the monoclonal antibody. Rats received (+)-methamphetamine (1 mg/kg i.v.) followed by saline or monoclonal antibody treatment at 30 min. The monoclonal antibody significantly increased serum methamphetamine concentrations and significantly decreased brain methamphetamine concentrations. These data indicate that anti-(+)-methamphetamine monoclonal antibody-induced pharmacodynamics are complex, but are related to time-dependent changes in (+)-methamphetamine brain distribution.

Amphetamine↗
PubMed2002

Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2-exo-2-(2',3'-disubstituted 5'-pyridinyl)-7-azabicyclo[2.2.1]heptanes: epibatidine analogues.

A number of 2',3'-disubstituted epibatidine analogues were synthesized and evaluated in vitro for potency at nicotinic acetylcholine receptors (nAChRs) and in vivo for antinociception activity in the tail-flick and hot-plate models of acute pain and for their ability to affect core body temperature. Compounds that possessed electron-withdrawing groups (F, Cl, Br, and I) in both the 2'- and the 3'-positions showed affinities at the nAChR similar to epibatidine. However, in vivo efficacy did not correlate with affinity. 2-exo-(3'-Amino-2'-chloro-5'-pyridinyl)-7-azabicyclo[2.2.1]heptane (2i), an epibatidine analogue possessing an electron-releasing amino group in the 3'-position, produced the highest affinity. Compound 2i was also the most selective epibatidine analogue with a K(i) of 0.001 nM at alphabeta nAChRs, which is 26 times greater than that of epibatidine, and a alphabeta/alpha(7) K(i) ratio of 14,000, twice that of epibatidine. In vivo testing revealed that this compound potently inhibited nicotine-induced antinociception with AD(50) values below 1 microg/kg. Surprisingly, this same compound was also an agonist at higher doses (ED(50) approximately 20 microg/kg). Thus, the addition of the 3'-amino group to epibatidine confers potent antagonist activity to the compound with little effect on agonist activity. 2,3-Disubstituted epibatidine analogues possessing a 2'-amino group combined with a 3'-bromo or 3'-iodo group showed in vitro and in vivo nAChR properties similar to nicotine.

Analgesics, Non-Narcotic↗
PubMedDate not supplied

Nonfunctioning islet cell tumor presenting with ascites and portal hypertension.

Nonfunctioning islet cell tumors commonly cause no symptoms. A 22-year-old woman presented with lump in the left hypochondrium, refractory high-protein ascites and evidence of left-sided portal hypertension. At exploratory laparotomy, a 30 cm x 15 cm mass was seen at the splenic hilum, with large collateral vessels around. Distal pancreatectomy with splenectomy was done. Histology of the mass showed malignant islet cell tumor infiltrating the spleen. The patient died in the postoperative period.

Adult↗
PubMedDate not supplied

Familial clustering of hepatitis B infection: study of a family.

Familial clustering of hepatitis B virus infection has been reported infrequently. We report a family of 27 members, where 13 members were HBsAg-positive. This included 7 of 10 members in one linear family across four generations. Nine subjects who were tested were HBeAg-negative. Of these nine, three subjects had elevated ALT; histology in one of them showed activity index <3. One subject received lamivudine therapy elsewhere; ALT levels returned to normal in two months.

Adolescent↗
PubMedDate not supplied

Obstructing enterolith as presenting feature in Crohn's disease.

We report a 54-year-old woman with Crohn's disease presenting with intestinal obstruction due to an enterolith impacted at the site of a small bowel stricture. The diseased bowel was successfully resected by laparoscopy-assisted surgery.

Crohn Disease↗
PubMedDate not supplied

Heparin therapy for mistaken cardiac diagnosis in Boerhaave's syndrome.

We describe two patients with Boerhaave's syndrome who presented with chest pain mimicking cardiac pain and received heparin therapy. One patient developed large intramural esophageal hematoma as a complication of heparin therapy. The other patient had no hematoma and his course was dominated by esophageal rupture. Both were managed conservatively.

Aged↗
PubMedDate not supplied

Dieulafoy lesion in mid-esophagus with esophageal varices.

Dieulafoy lesion is an uncommon cause of gastrointestinal (GI) bleeding. Most such lesions are reported in the stomach, though a few have been reported in the distal esophagus. We report a 54-year-old man who presented with upper GI bleeding and had esophageal varices but bled from a Dieulafoy lesion 5 cm above the proximal end of the varices.

Endoscopy, Gastrointestinal↗
PubMedDate not supplied

Thrombophilic conditions in non-cirrhotic portal vein thrombosis.

OBJECTIVE: To study the prevalence of thrombophilic conditions in patients with acute and chronic portal vein thrombosis (PVT) and to compare it with those in patients suffering from deep vein thrombosis (DVT) after lower limb arthroplasty and in healthy subjects. METHODS: Twenty-six patients with spontaneous PVT (20 chronic, 6 acute) with normal liver function and not receiving anticoagulants were evaluated for thrombophilic conditions. Levels of protein C, protein S and antithrombin were compared with those in 50 healthy controls. Factor V gene 'Leiden' mutation (FVL) and high homocysteine levels were looked for in patients with PVT and in 18 patients developing post-arthroplasty lower limb DVT despite anticoagulation. RESULTS: Of 26 patients with PVT, 19 had at least one thrombotic condition (acute PVT 5/6, chronic PVT 14/20) and 12 had more than one such condition; in comparison, of 18 patients with DVT, eight had one thrombophilic condition and one had two such conditions (p=0.03). Patients with PVT had significantly lower levels of protein C, protein S and antithrombin than healthy subjects and those with DVT. Six patients had Factor VIII levels above 150%; four had elevated homocysteine levels and three had detectable anti-cardiolipin antibodies. Three patients with PVT (acute 2, chronic 1) were heterozygous for FVL mutation. CONCLUSIONS: Underlying thrombophilic conditions are common in Indian patients with spontaneous PVT. In many patients, multiple thrombophilic conditions are present and these may play a role in the pathogenesis of PVT.

Adolescent↗
PubMedDate not supplied

Cytomegalovirus involving gastric antrum in immunocompromised hosts: a report of 5 cases.

Cytomegalovirus infection, which is common in immunosuppressed patients, only rarely affects the stomach, especially the gastric antrum. We report five patients with cytomegalovirus infection of the stomach with antral involvement. Of these, four had undergone renal transplant and one had HIV infection. All patients presented with upper gastrointestinal symptoms that did not respond to proton pump inhibitors and prokinetic drugs. In addition, all had systemic symptoms. Diagnosis was made at upper GI endoscopy and biopsy, and ganciclovir treatment led to improvement.

Adult↗
PubMedDate not supplied

Hepatic tuberculosis in absence of disseminated abdominal tuberculosis.

Liver involvement in tuberculosis in absence of miliary tuberculosis is rare. This study was performed to analyse the spectrum and response to treatment of hepatic tuberculosis in the absence of miliary abdominal tuberculosis. Retrospective analysis of seven cases of hepatic tuberculosis without miliary abdominal tuberculosis who presented at the single tertiary referral center were analyzed. All patients presented with fever and hepatomegaly. Five of them had pain in upper abdomen and vomiting. HIV serology was positive in one patient. All patients had normocytic normochromic anaemia, raised erythrocyte sedimentation rate (Mean 65). Mild elevation of liver enzymes and low albumin (Mean 2.4 gm%) with reversal of albumin globulin ratio (Mean 0.6) were seen in all. Two had jaundice. Prothrombin time was normal in all and lactate dehydrogenase values were elevated in all (Mean 794 IU/L). On ultrasonography, 2 had multiple hypodense lesion, 1 had coarse echotexture of liver, 1 had hyperechoic pattern and 3 had just hepatomegaly. Complete resolution of liver lesions on treatment with 4-drug anti-tuberculosis drug chemotherapy was seen. In conclusion, liver tuberculosis has protean manifestations with nonspecific alteration of liver function tests and is best diagnosed on liver biopsy. Overall response to therapy is satisfactory.

Adolescent↗