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P Abraham

Publications and source records attributed to P Abraham.

At least 19 recordsLinked to original sources
PubMed1998

Synthesis and ligand binding of tropane ring analogues of paroxetine.

(3S,4R)-4-(4-Fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl] piperidine [(3S,9R)-3, paroxetine] is a selective serotonin reuptake inhibitor (SSRI) used as an antidepressant in humans. In previous studies, we reported that certain (1R)-3 beta-(substituted phenyl)nortropane-2 beta-carboxylic acid methyl esters (2a) exhibited high affinity and reasonable selectivity for the serotonin transporter (5-HTT). The major structural differences between 2a and (3S,4R)-3 are that 2a possesses a different absolute stereochemistry and has an ethylene bridge not present in 3. In addition, 2a possesses a carbomethoxy substituent adjacent to the aryl ring, whereas (3S,4R)-3 contains a [3,4-(methylenedioxy)phenoxy]methyl group. In this study, we present the synthesis and biological evaluations of six of the possible eight isomers of 3-(4-fluorophenyl)-2-[[3,4-(methylenedioxy)phenoxy]methyl]nortropane+ ++ (4). The data for inhibition of [3H]paroxetine binding show that (1R)-2 beta, 3 alpha-4c, which has the same stereochemistry as paroxetine, has the highest affinity at the 5-HTT. Strikingly, the most potent compounds for inhibition of [3H]WIN-35,428 binding were not the (1R)-2 beta, 3 beta-isomers but rather (1R)-2 beta, 3 alpha-4c and (1S)-2 beta, 3 alpha-4f. Conformational analyses show that these isomers exist in a flattened boat conformation with pseudoequatorial substituents. Thus, the binding data show that this conformation is recognized by the DAT-associated binding site and also suggest that this conformation of paroxetine is recognized by the 5-HTT-associated binding site.

Binding, Competitive↗
PubMed1998

Vagal dysfunction following endoscopic variceal sclerotherapy.

BACKGROUND: Sclerotherapy is associated with complications which involve adjacent structures like the pleura. The effect of sclerotherapy on function of the vagus nerve, which lies in close proximity to the thoracic esophagus, is not clear. AIM: To study gastric acid secretion as a marker of vagal function in portal hypertensive patients who have undergone sclerotherapy. METHODS: Portal hypertensive patients who had undergone at least three sessions of sclerotherapy were evaluated by mapping gastric acid-secreting mucosa by the Congo red test and by estimating gastric acid secretion using the modified sham feeding test. Patients with portal hypertension who had never been subjected to endoscopic sclerotherapy were recruited as controls. RESULTS: On Congo red test, complete or substantial reduction in acid-secreting mucosa was observed in eight patients in comparison to none of the controls. Significantly lower acid secretion on modified sham feeding test was observed in these eight patients. CONCLUSION: A lower gastric acid secretion, probably secondary to vagal dysfunction, is seen in patients who have undergone multiple sessions of sclerotherapy; vagus nerve involvement may be secondary to periesophageal inflammation.

Adult↗
PubMed1997

Synthesis and transporter binding properties of 2,3-diphenyltropane stereoisomers. Comparison to 3beta-phenyltropane-2beta-carboxylic acid esters.

2beta,3beta-Diphenyl-(5), 2alpha,3alpha-diphenyl-(6), and 2alpha,3beta-diphenyltropane (3) as well as 2,3-diphenyltrop-2-ene (4) were prepared in racemic form and assayed for inhibition of radioligand binding at the dopamine (DA), serotonin (5-HT), and norepinephrine (NE) transporters. Among all three transporters, compounds 4-6 bound the DA transporter with the highest affinity. The 2beta,3beta-diphenyltropane (5) bound the DA transporter with an IC50 value (28 nM) almost identical to that of 3beta-phenyltropane-2beta-carboxylic acid methyl ester (WIN 35,065-2) and has much greater selectivity relative to binding to the serotonin transporter. A comparison of the radioligand data from this study to radioligand data obtained on other WIN 35,065-2 analogs suggests that hydrophobicity of the C-2 substituent of some analogs of the WIN 35,065-2 class may be an important contributing factor to binding at the DA transporter.

Binding, Competitive↗
PubMed1997

N-substituted phenyltropanes as in vivo binding ligands for rapid imaging studies of the dopamine transporter.

Variously substituted phenyltropanes are proven as superb binding ligands for the dopamine transporter (DAT). In this study, we examine four N-substituted phenyltropanes which are derivatives of RTI-55 as in vivo binding ligands in mice. In this series, the methyl group on the nitrogen was replaced by a propyl (RTI-310), an allyl (RTI-311), a butyl (RTI-312), or a fluoropropyl (RTI-313) group. The in vitro binding potencies of these compounds at rat striatal DAT varied somewhat but were about 1 nM. While these compounds did not display marked selectivity for the dopamine transporter, they were more selective than RTI-55. Injection of the radiolabeled compound into mice resulted in striatal-to-cerebellar ratios that varied from about 4.5-6.5. The ratios peaked most rapidly for RTI-311 and RTI-313, at about 20 min. Pharmacological inhibition studies indicated that these compounds were binding to DATs in the striatum, as expected. These findings suggest that some compounds of this type may be excellent in vivo binding ligands for rapid imaging studies of the DAT.

Analysis of Variance↗
PubMed1997

Effects of positive pressure on both femoral venous and arterial blood velocities and the cutaneous microcirculation of the forefoot.

OBJECTIVE: The balance between the apparent beneficial effect and the risk of arterial ischaemia resulting from an external uniform compression is unclear. The purpose of this study was to determine the effects of a positive uniform compression on the lower limb circulation until a critical threshold was reached. METHODS: We used Doppler ultrasound to measure femoral venous and arterial blood velocities. The effects of positive pressure on cutaneous microcirculation were evaluated by laser Doppler flux (LDF), transcutaneous oxygen pressure (tcpO2) and transcutaneous carbon dioxide pressure (tcpCO2) on the forefoot of 17 healthy subjects. RESULTS: The results are expressed as median [lowest observed value-highest observed value]. Whereas the arterial femoral velocity (A.F.V.) decreased from 0.21 [0.08-0.36] to 0.17 [0.08-0.28] m s-1 for an external pressure as low as 10 mmHg (p < 0.001), the venous femoral velocity (V.F.V.) decreased from 0.13 [0.06-0.40] to 0.09 [0.05-0.34] m s-1 at 20 mmHg (p < 0.001). An increase of tcpCO2 from 39.8 [29.9-53.7] to 40.2 [30.0-55.5] mmHg (p < 0.05) and a decrease of LDF from 8.7 [3.1-25.9] to 5.5 [2.3-21.1] A.U. (p < 0.001) occurred at 10 mmHg. However, tcpO2 decreased only from 76.7 [40.2-91.2] to 64.6 [18.9-85.2] mmHg when the splint pressure reached 60 mmHg (p < 0.05). The observed parameters (LDF, tcpO2, V.F.V. and A.F.V.) decreased further (except for tcpCO2 which increased) up to the end of the study as the applied pressure was increased. CONCLUSION: Positive pressure on the full leg provided no significant beneficial effect on femoral venous blood velocity. Whereas we showed that for an external uniform pressure as low as 10 mmHg, significant impairments in both arterial inflow of the lower limb and microcirculation of the forefoot appeared in recumbent healthy young subjects.

Adult↗
PubMed1997

Prolonged asymptomatic micro-embolism after hip or knee arthroplasty.

We studied the time course of micro-embolism by recording high intensity transient signals (HITS) on Doppler venous blood flow studies during a 7-day period in 57 of 63 consecutive patients after hip or knee replacement. No HITS were found before surgery, or in the non-operated leg after surgery. In the operated leg, the median number of HITS per minute showed an exponential decrease with time; a 50% reduction in the number of HITS took 72 minutes. Regardless of the duration and severity of HITS, we found no clinically apparent embolic event. Colour Doppler imaging at days 8 to 10 after operation showed a deep venous thrombosis in 17% of our patients with one thrombosis of the long saphenous vein. The presence or severity of HITS did not predict the venous thrombi. Although we found no pulmonary complications, we detected micro-emboli over a longer period after surgery than is usually reported. Spectral analysis of the Doppler venous signal is a repeatable and non-invasive monitoring technique in the post-surgical period. We failed to prove a correlation between deep venous thrombi and micro-emboli detected by this method.

Aged↗
PubMed1997

External iliac artery endofibrosis in athletes.

Atherosclerosis and inflammatory arterial diseases are rare in young people. Since the early 1980s, an increasing incidence of iliac arterial stenosis in competition cyclists has been reported. Histological findings in these individuals are specific, with fibrosis of the intimal wall on histology and no atherosclerotic or inflammatory lesions. Clinical consequences of this arterial endofibrosis are usually described as an exercise-related subjective sensation of swollen thigh in one or both (15%) legs, with normal clinical and Doppler investigations at rest. Following maximal exercise, ankle-to-brachial systolic pressure index is lower than 0.5 in 85% of individuals with disease and is used as a key argument for diagnosis before deciding upon arteriography. Surgery (recalibrated saphenous grafts or angioplasty-endofibrosectomy) seems to be efficient to allow an early return to competition, but its long term results are still to be evaluated. The physiopathology of this disease and its possible relationship with atherosclerosis are unknown.

Adult↗
PubMed1997

[In situ thrombolysis in the treatment of venous thrombosis of effort in the arm].

From March 1989 to March 1993, six athletic patients were treated in our institution by thrombolytic therapy for acute effort axillary-subclavian vein thrombosis in thoracic outlet syndrome. Mean age of these patients was 20 (range 14 to 27). An in situ infusion with urokinase (2,500 U/kg/h) and Heparin (100 U/kg/12 hours) was given during 64 hours (Range 14 to 72). Phlebography showed a complete reperfusion in three cases (the treatment began within an average period of 5.6 days), partial reperfusion in two cases (the treatment began within an average period of 8.5 days). In one case there was no reperfusion on phlebography: treatment began within an average period of 15 days. For this patient, a venous axillo-jugular bypass graft was performed. In all cases, there was no bleeding complication. A trans-axillary first rib resection was done three months later. Mean follow up was 31 months (range: two to 51 months). All patients recovered their previous physical status. Echo-Doppler exam showed normal subclavian vein flow in four cases, partial occlusion in one case and a total occlusion of the subclavian vein flow in one case. In this last case, the thrombolytic therapy failed to restore the permeability of the subclavian vein. Bypassgraft was patent. Axillary-subclavian vein thrombosis seen within a period of seven days should be treated by local thrombolytic therapy using urokinase and heparin.

Acute Disease↗
PubMed1997

Metronidazole relieves symptoms in irritable bowel syndrome: the confusion with so-called 'chronic amebiasis'.

BACKGROUND: Metronidazole is often administered to patients with irritable bowel syndrome with an erroneous diagnosis of 'chronic amebiasis'. AIMS: To assess how patients with irritable bowel syndrome respond to metronidazole in the absence of amebae in their stools. METHODS: We randomly allocated 45 patients (35 men; aged 15-59 years) with irritable bowel syndrome to receive isapghul (10 g bid x 60 days), metronidazole (400 mg tid X 10 days, followed by placebo x 50 days), or placebo (1 capsule bid x 60 days). Symptoms were evaluated and scored on days 0, 15, 30, 45 and 60. Rectosigmoid manometry was performed in 5 of 15 patients in each group on days 0 and 60. RESULTS: There was a significant time effect and treatment effect on the symptom scores in all groups (isapghul > metronidazole > placebo); total score decreased from mean 25.8, 24.0 and 24.6 on day 0 to 7.2, 10.9 and 18.1 on day 60, respectively. Severity, duration and frequency of pain; and mucus in stool were all significantly reduced in all treatment groups (p < 0.001 for each). Treatment with isapghul increased the mean amplitude of propagated activity from 26.2 mmHg to 30.1 mmHg at 20 cm (p < 0.025) and from 23.1 mmHg to 27.4 mmHg at 10 cm (p < 0.05) from the anal verge, as well as the total duration of propagated activity at both sites (p < 0.05), with decrease in number of propagated contractions per 10 min (p < 0.025). Metronidazole and placebo had no effect on manometric findings. CONCLUSIONS: Metronidazole provides symptom relief in irritable bowel syndrome, without affecting rectosigmoid motility. This symptom response may be misinterpreted as supporting a diagnosis of 'chronic amebiasis'.

Abdominal Pain↗
PubMed1997

External iliac artery endofibrosis: a 40-year course.

External iliac artery endofibrosis is a rare disease affecting mainly highly trained cyclists. As the disease has only recently been described, the long term spontaneous evolution of external iliac artery endofibrosis is not known. We report a suspected case of forty-year spontaneous evolution of endofibrosis in a former competition cyclist. The results of this isolated original report suggest, as we intuitively presumed, that the lesions may stabilise when intensive training is stopped. Therefore, when no symptoms are noted on usual daily activity or submaximal exercise, surgery should not be performed. Surgery should only be considered, at the request of the subjects to allow them to continue competing.

Activities of Daily Living↗
PubMed1996

Synthesis and transporter binding properties of 3 beta-(4'-alkyl-, 4'-alkenyl-, and 4'-alkynylphenyl)nortropane-2 beta-carboxylic acid methyl esters: serotonin transporter selective analogs.

New methods for the synthesis of 3 beta-(4'-alkyl-, 4'-alkenyl-, and 4'-alkynylphenyl)nortropane-2 beta-carboxylic acid methyl esters 2-4, respectively, were developed. These methods involved coupling of the appropriate organometallic reagents to 3 beta-(4'-iodophenyl)tropane-2 beta-carboxylic acid methyl ester (6a, RTI-55) or to an N-protected derivative of 6a followed by N-demethylation or removal of the protecting group. Some analogs were prepared by catalytic reduction of the alkene and alkene analogs 3 and 4 or by isomerization of the alkenes 3. The analogs 2-4 were evaluated for inhibition of radioligand binding to the serotonin (5-HT), dopamine (DA), and norepinephrine (NE) transporters. 3 beta-(4'-Isopropenyl- and 4'-cis-propenylphenyl)nortropane-2 beta-carboxylic acid methyl esters (3b,d), which possessed IC50 values of 0.6 and 1.15 nM, respectively, were the most potent analogs at the 5-HT transporter, and with NE/5-HT IC50 ratios of 240 and 128 nM, respectively, they were selective for the 5-HT relative to the NE transporter. Since interaction with the serotonin transporter may modulate the pharmacological effects resulting from binding to the dopamine transporter, 3 beta-(4'-isopropenylphenyl)tropane-2 beta-carboxylic acid methyl ester (11b) which has good affinity for both the 5-HT and DA transporters but low affinity at the NE transporter may be useful for studying this interaction.

Animals↗
PubMed1996

Synthesis, ligand binding, and quantitative structure-activity relationship study of 3 beta-(4'-substituted phenyl)-2 beta-heterocyclic tropanes: evidence for an electrostatic interaction at the 2 beta-position.

A set of 3 beta-(4'-substituted phenyl)-2 beta-heterocyclic tropanes was designed, synthesized, and characterized. We discovered that these compounds can function as bioisosteric replacements for the corresponding WIN 35,065-2 analogs which possess a 2 beta-carbomethoxy group. Several of the compounds showed high affinity and selectivity for the dopamine transporter (DAT) relative to the serotonin and norepinephrine transporters. From the structure-activity relationship study, the 3 beta-(4'-chlorophenyl)-2 beta-(3'-phenylisoxazol-5-yl)tropane (5d) emerged as the most potent and selective compound. The binding data for 2 beta-heterocyclic tropanes were found to show a high correlation with molecular electrostatic potential (MEP) minima near one of the heteroatoms in the 2 beta-substituents. In contrast, low correlations were found for other MEP minima near the 2 beta-substituent as well as for calculated log P or substituent volume. These quantitative structure-activity relationship studies are consistent with an electrostatic contribution to the binding potency of these WIN 35,065-2 analogs at the DAT.

Animals↗