The Indian Journal of Gastroenterology in perspective.
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Gastroenterology↗
Biomedical subjects
P Abraham
Publications and source records attributed to P Abraham.
Pulmonary function tests in cirrhotic and non-cirrhotic portal hypertension.
OBJECTIVE: To determine pulmonary functions in portal hypertension of different etiologies and with various grades of ascites. SETTING: Gastrointestinal clinic in a large community based and secondary referral hospital. PATIENTS AND METHODS: Forty five patients with portal hypertension, including 19 cirrhotics with tense ascites, 8 with moderate ascites, 6 with no ascites and 12 patients with non-cirrhotic portal hypertension. All patients underwent basal pulmonary function testing by spirometry and helium dilution technique, and arterial blood gas estimation and measurement of ascitic fluid pressure. Patients with tense ascites underwent paracentesis of up to 2 liters following which ascitic fluid pressure and pulmonary functions were estimated again. MAIN RESULTS: In cirrhotic patients without ascites, FVC (forced vital capacity), RV (residual volume), TLC (total lung capacity) and FRC (functional residual capacity) were lower than predicted values. In patients with ascites, FVC, FEV1 (forced expired volume in one second) and FEF25-75 (forced expired volume in one second) and FEF25-75 (forced expiratory flow rate between 25% and 75% of forced vital capacity) were significantly lower as compared to predicted values. FVC, FEV1, FEF25-75, pO2, pCO2 and SaO2% decreased significantly with increasing ascites. Paracentesis in patients with tense ascites led to clinical improvement and significantly improved lung volumes. CONCLUSIONS: Pulmonary functions are impaired in patients with cirrhosis, and ascites causes further deterioration. Patients with non-cirrhotic portal hypertension have normal pulmonary functions.
Adult↗
Splenic abscess--a possible complication of endoscopic variceal sclerotherapy.
Endoscopic variceal sclerotherapy, though a safe and effective therapy for esophageal varices, is not devoid of local and distant complications. We report a patient with postnecrotic cirrhosis and diabetes mellitus who developed a splenic abscess while on a sclerotherapy program. The abscess may have been a consequence of retrograde thrombosis of the portal venous system or of bacteremia following sclerotherapy.
Abscess↗
Laser Doppler flowmetry, transcutaneous oxygen pressure and thermal clearance in patients with vascular intermittent claudication.
In the present study, heat thermal clearance (HTC) was compared to laser Doppler flowmetry (LDF) and transcutaneous oxygen pressure (tcPO2), measured on the forefoot of 17 patients with vascular intermittent claudication and 10 controls in various positions at rest and after a treadmill exercise test. The mean ankle brachial systolic pressure ratio (ABSP) of the patients, measured using ultrasonic Doppler velocimetry, was 0.53 +/- 0.05. Their walking distance was 480 +/- 100 meters, the treadmill exercise being stopped as soon as pain sensation. No statistically significant difference was found between patients and controls for HTC, LDF, tc P02, forefoot and ankle skin temperatures. Statistically significant differences between patients and controls occurred in the sitting position for tcPO2, in standing position for HTC and after treadmill exercise for tcPO2 and LDF. When assuming the sitting position HTC did not vary significantly in patients and decreased in controls, LDF decreased and tcPO2 increased in both groups. After treadmill exercise, HTC in patients did not vary compared to supine values and HTC decreased in controls, tcPO2 remained unchanged in controls and decreased in patients, LDF increased in controls and decreased in patients. No significant correlations were found between the different techniques measured at rest in patients and controls. However in patients, after the treadmill test, LDF correlated with the walking distance (r = 0.667) and with ABSP (r = 0.641), HTC inversely correlated with the walking distance (r = -0.680) and ABSP (r = -0.577). Laser Doppler, tcPO2 and HTC are useful as tools to understand the alterations of cutaneous microcirculation of the lower limbs in patients with V.I.C.. However their results need to be interpreted with caution because these methods do not measure directly blood flow.
Adult↗
Enantiomeric N-substituted N-normetazocines: a comparative study of affinities at sigma, PCP, and mu opioid receptors.
The optical antipodes of N-allyl-N-normetazocine (2; SKF 10047, NANM) were the original compounds used for the classification of the sigma receptor as distinct from other receptors such as the PCP (NMDA), opioid, and dopamine receptors. Later studies showed that (+)-N-(dimethylallyl)-N-normetazocine [(+)-4, (+)-pentazocine] was more potent and selective for the sigma receptor. In order to gain additional structure-activity relationship information, several N-substituted N-normetazocine analogs were prepared and evaluated for their sigma-1 ([3H]-(+)-3-PPP or [3H]-(+)-pentazocine), PCP ([3H]TCP), and mu opioid ([3H]DAMGO) receptor binding affinities. (+)-N-Benzyl-N-normetazocine [(+)-10)] possessed subnanomolar affinities for the sigma site, Ki = 0.67. The analog (+)-10 showed greater than 14,000- and 2400-fold selectivity, respectively, for the sigma receptor relative to the PCP and mu opioid receptors. The N-substituted N-normetazocines were enantioselective for the sigma site. The (+)-N-benzyl analog, (+)-10, showed a 55-fold selectivity relative to (-)-10. Analysis of the data also revealed that (+)-normetazocine [(+)-1] [Ki = 30 nM] possessed the highest affinity for the PCP receptor. However, (+)-metazocine [(+)-5] (Ki = 41 nM) was the most selective compound for the PCP receptor relative to the sigma (51-fold) and mu opioid (greater than 200-fold) sites.
Animals↗
Isopropyl and phenyl esters of 3 beta-(4-substituted phenyl)tropan-2 beta-carboxylic acids. Potent and selective compounds for the dopamine transporter.
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Binding Sites↗
Synthesis and muscarinic receptor activity of ester derivatives of 2-substituted 2-azabicyclo[2.2.1]heptan-5-ol and -6-ol.
Radioligand binding affinities of four new muscarinic antagonists and six potential muscarinic agonists which possess the 2-alkyl-2-azabicyclo[2.2.1]heptane ring system have been determined in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations to examine the selectivity for subtypes of muscarinic receptor. The efficacies of the potential muscarinic agonists were determined by the ratio of binding affinities against [3H]QNB and [3H]Oxo-M. Four muscarinic antagonists which have the 2,2-diphenylpropionate side chain at either the C5 (5-endo or 5-exo) or the C6 (6-endo or 6-exo) positions did not discriminate between the subtypes of muscarinic receptors. The 2,2-diphenylpropionate 5-endo substituted compound was the most potent, showing affinities between 4.23 x 10(-10) and 1.18 x 10(-9) M in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations. The rank order of ester potency was 5-endo greater than 5-exo greater than 6-endo greater than 6-exo. A molecular modeling study based on the pharmacophore developed for azaprophen was used to account for the relative potency of these antagonists. Six potential muscarinic agonists which have acetoxy groups in the C5 or C6 position with an N-methyl or N-benzyl substituent did not discriminate subtypes of muscarinic receptors and had affinities between 6.63 x 10(-6) and 4.76 x 10(-5) M in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations. exo-2-Methyl-5-acetoxy-2-azabicyclo[2.2.1]heptane was the most efficacious partial agonist.
Animals↗
Probes for the cocaine receptor. Potentially irreversible ligands for the dopamine transporter.
Several potentially irreversible ligands (i.e., wash-resistant binding inhibitors) for the cocaine receptor site on the dopamine transporter, derived from (-)-cocaine or 3 beta-phenyltropan-2 beta-carboxylic acid methyl ester (WIN 35,065-2), were prepared and shown to produce wash-resistant inhibition of [3H]-3 beta-(p-fluorophenyl)tropan-2 beta-carboxylic acid methyl ester ([3H]WIN 35,428) binding. All the compounds prepared had the same absolute configuration as cocaine; they include analogues possessing chemically reactive groups such as the isothiocyanato and bromoacetamido as well as photoactive azido groups. The potentially irreversible ligands, as well as all the intermediates prepared in this study, were evaluated for their ability to inhibit the binding of [3H]WIN 35,428 in coincubation experiments. Of the potentially irreversible ligands, 3 beta-(p-chlorophenyl)tropan-2 beta-carboxylic acid 2-[p-(bromoacetamido)phenyl]ethyl ester (6c) had the highest apparent potency. The potentially irreversible ligands were also preincubated, and inhibition of [3H]WIN 35,428 binding was determined both before and after washing the ligand-exposed tissues. The most effective ligands in this regard were 3 beta-(3-iodo-4-azidophenyl)tropan-2 beta-carboxylic acid methyl ester (5) and 3 beta-(p-chlorophenyl)tropan-2 beta-carboxylic acid 2-(3-iodo-4-azidophenyl)ethyl ester (6d). The structure-activity relationships of these data are discussed.
Animals↗
[123/125I]RTI-55, an in vivo label for the serotonin transporter.
[123I]RTI-55, an iodinated derivative of the cocaine analog 3 beta-phenyltropane-2 beta-carboxylic acid methyl ester, was evaluated as an agent for in vivo labeling of the serotonin transporter. Labeling of the precursor of RTI-55 with I-123 was efficient and yielded a high specific activity product. After intravenous injection of [123I]RTI-55 into rats, the tracer accumulated in regions with high densities of serotonin and dopamine uptake sites. The distribution of [123I]RTI-55 binding in areas rich in serotonin uptake sites correlated with [3H]serotonin uptake measured in vitro in the same regions. Specific [123I]RTI-55 binding to serotonin uptake sites was inhibited by paroxetine but not by GBR 12,909. Treatment of rats with neurotoxic doses of fenfluramine caused decreases of 66% (in the hypothalamus) to 83% (in the superior colliculi) of specific [125I]RTI-55 binding in all areas except in the striatum and the olfactory tubercles (regions rich in dopamine transporters). These results indicate that [123/125I]RTI-55 binds, although not selectively, to the serotonin transporter in vivo. Furthermore, they suggest that [123I]RTI-55 holds promise as a SPECT imaging agent for the study of the serotonin transporter in humans in health and disease.
Animals↗
High-affinity binding of [125I]RTI-55 to dopamine and serotonin transporters in rat brain.
RTI-55 (3 beta-(4-iodophenyl)tropan-2 beta-carboxylic acid methyl ester), one of the most potent inhibitors of dopamine uptake reported to date, was radioiodinated and tested as a probe for the cocaine receptor in Sprague-Dawley rat brain. Saturation and kinetic studies in the striatum revealed that [125I]RTI-55 bound to both a high- and low-affinity site. The Kd for the high-affinity site was 0.2 nM, while the Kd for the low-affinity site was 5.8 nM. The corresponding number of binding sites in the striatum was 37 and 415 pmol/g protein. The pharmacological profile of specific [125I]RTI-55 binding in the striatum was consistent with that of the dopamine transporter. Additionally, [125I]RTI-55 was found to bind with high affinity to the cerebral cortex. Scatchard analysis revealed a single high-affinity component of 0.2 nM with a density of 2.5 pmol/g protein. The pharmacological profile demonstrated by [125I]RTI-55 in the cerebral cortex matched that of the serotonin transporter. Autoradiographic analysis of sagittal brain sections with [125I]RTI-55 binding was consistent with these findings. Specific binding of [125I]RTI-55 was blocked by dopamine uptake inhibitors in areas rich in dopaminergic nerve terminals. Conversely, serotonin uptake inhibitors blocked the binding of [125I]RTI-55 in brain areas rich in serotonergic neurons. These results demonstrate that [125I]RTI-55 may be a very useful ligand for the dopamine and serotonin transporters.
Animals↗
In vivo binding of [125I]RTI-55 to dopamine transporters: pharmacology and regional distribution with autoradiography.
Previous studies have demonstrated that para-substituted WIN 35,065-2 analogs of cocaine show high binding affinity for dopamine uptake sites both in vitro and in vivo, and inhibit DA uptake in vitro. These analogs also produce potent cocaine-like behavioral effects in various procedures. The purpose of the present studies was to evaluate the iodinated WIN 35,065-2 analog [125I]RTI-55 as an in vivo ligand for the DA transporter. Following intravenous injection in mice, [125I]RTI-55 showed highest accumulation in areas with high densities of dopamine uptake sites. Light microscopic autoradiography was used to examine binding with higher resolution. Displacement studies demonstrated that [125I]RTI-55 binding in dopamine containing regions, striatum and olfactory tubercles, was saturable and inhibited by other cocaine analogs. GBR 12909 and WIN 35,428 significantly inhibited [125I]RTI-55 binding in striatum, while paroxetine significantly inhibited hypothalamic binding but had little effect in striatum. The latter finding suggests that [125I]RTI-55 also binds to the serotonin transporter. Haloperidol had no effect on [125I]RTI-55 binding in any brain region measured. In addition, treatment of animals with the dopamine neurotoxin MPTP caused significant reductions in striatal [125I]RTI-55 binding. The results of these studies indicate that [125I]RTI-55 binds primarily to the dopamine transporter in the mouse striatum in vivo.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
2 beta-substituted analogues of cocaine. Synthesis and inhibition of binding to the cocaine receptor.
The potencies of a series of 2 beta-substituted cocaine analogues to displace [3H]-3 beta-(p-fluorophenyl)tropane-2 beta-carboxylic acid methyl ester binding in rat striatal membranes demonstrate the requirement for a 2 beta-substituent with two hydrogen-bond acceptors. The insensitivity of the ester moiety to steric and electronic factors suggests its modification to provide site-specific irreversible ligands.
Analgesics↗
N-modified analogues of cocaine: synthesis and inhibition of binding to the cocaine receptor.
Cocaine methiodide (2), N-norcocaine (1b), N-benzyl-N-norcocaine (1c), and N-nor-N-acetylcocaine (1d) were synthesized and evaluated for their ability to inhibit binding of [3H]-3 beta-(4-fluorophenyl)tropane-2 beta-carboxylic acid methyl ester (WIN 35,428) to the cocaine receptor. The study showed that removal of the N-methyl group to give 1b, or replacement with the larger N-benzyl group to give 1c, has a relatively small effect on binding potency. In contrast, replacement of the N-methyl group by the acetyl moiety to give 1d, or the addition of a methyl group to give 2, reduces affinity for the receptor by a large factor. In order to gain preliminary information concerning the importance of the nitrogen location on the tropane ring system, the receptor binding affinity of 8-methyl-8-azabicyclo[3.2.1]octan-3 beta-ol benzoate (5, beta-tropacocaine) was compared to that of the isomeric 6-methyl-6-azabicyclo[3.2.1]octan-3 beta-ol benzoate (4d). The fact that both compounds have similar binding affinities for the cocaine receptor suggests that 3 beta-(benzoyloxy)-6-methyl-6-azabicyclo[3.2.1] octane-2-carboxylic acid methyl ester, which is isomeric with cocaine, may possess binding potency similar to cocaine.
Analgesics↗
Synthesis of 2-(3-substituted-1,2,4-oxadiazol-5-yl)-8-methyl-8-azabicyclo [3.2.1]octanes and 2 alpha-(3-substituted-1,2,4-oxadiazol-5-yl)-8-methyl-8- azabicyclo[3.2.1]oct-2-enes as potential muscarinic agonists.
Radioligand binding affinities of seven muscarinic receptor ligands which possess an oxadiazole ring side chain have been determined in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations to determine the selectivity for subtypes of muscarinic receptor. The ratios of binding constants in brain membranes were measured as an indicator of potential agonist activity against [3H]QNB and [3H]Oxo-M. These muscarinic ligands did not discriminate the subtypes of muscarinic receptors. Six muscarinic ligands which have a 3-amino- or 3-methyl-1,2,4-oxadiazol-5-yl groups attached to the 8-methyl-8-azabicyclo[3.2.1]oct-2-ene or 8-methyl-8-azabicyclo[3.2.1]octane head group show binding constants between 2.04 x 10(-6) and 1.79 x 10(-5) M in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations. 1-Methyl-2-[3-amino-1,2,4-oxadiazol-5-yl]piperidine shows low binding constants of approximately 10(-4) M in rat heart and rat brain. (1R,5S)-2-[3-Amino-1,2,4-oxadiazol-5-yl]-8-methyl-8-azabicyclo- [3.2.1]oct-2-ene [(1R,5S)-17] was the most active compound.
Animals↗
Selective dopamine transporter inhibition by cocaine analogs.
Several isopropyl and phenyl esters of 3 beta-(4-substituted phenyl) tropan-2 beta-carboxylic acid analogs of cocaine are relatively more potent and selective than cocaine and some other compounds in inhibiting dopamine uptake. These analogs can be used as binding ligands and as tools for elucidating the mechanisms of action of cocaine.
Animals↗
Operation Orderly--prevalence and degree of distress among military personnel following their ambulance experiences in London District.
The objective of this study was to determine the prevalence and degree of distress among military personnel following their experiences during Operation Orderly in London District. A questionnaire was distributed at the end of the deployment which inquired about distressing experiences. The General Health Questionnaire (GHQ-28) and the Impact of Event Scale (IES) were included to provide an objective measure of the distress. Thirty two per cent of respondents admitted to distressing experiences, of these a subgroup (20.5%) who were more severely distressed welcomed the opportunity to discuss their experiences.
Adult↗
Oxygen desaturation and tachycardia during upper gastrointestinal endoscopy are transient and benign.
We continuously monitored the arterial oxygen saturation (SaO2) and pulse rate by pulse oximetry in 46 patients undergoing upper gastrointestinal endoscopy for diagnosis (21 cases) or variceal sclerotherapy (25). No premedication or prior topical anaesthesia was used. Significant hypoxaemia (percent drop in SaO2 > 2) occurred in 24 (52%) patients during the procedure; in 16 of these it occurred during introduction of the endoscope. Twenty seven (59%) patients had hypoxaemia during recovery, 25 of these immediately after withdrawal of the endoscope. All these episodes were short-lived and were probably due to gagging; basal levels were reached within 1 to 5 min. Tachycardia (> 100 beats/min) occurred in 41 (89%) patients. Sclerotherapy and history of smoking did not affect the incidence and magnitude of hypoxaemia and tachycardia. Transient cardio-respiratory changes occur during and immediately after endoscopy, but these appear to be clinically benign.
Adolescent↗