Biomedical subjects
Publications and source records attributed to P Abraham.
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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.
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.
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.
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.
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.
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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.
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.
PURPOSE: A hypertonic, electrically hyperactive segment has been described in the rectosigmoid region mainly in constipated persons. Anatomic or manometric evidence to satisfy the criteria for a sphincter here is, however, inconclusive. We evaluated the pressure profile of the rectosigmoid region in normal Indian men. METHODS: Fifteen male volunteers with regular bowel habits were studied. Rectosigmoid manometry (1 cm station pull-through) was done in the fasting state using a water-perfused system and three-lumen catheter with radially oriented recording ports 5 cm apart. RESULTS: Eight volunteers had a zone of high pressure. Proximal extent of this zone was identified as the station with a rise in basal pressure of at least 10 mmHg over the previous station. A further rise of at least 10 mmHg in subsequent distal stations was considered essential for defining the existence of the zone. This zone had a median length of 3 cm, with midpoint at median 18 cm from the anal verge and median highest pressure of 36 mmHg. There was no antegrade pressure gradient across the zone; rectal pressures were higher than those in the sigmoid in 12 of 15 volunteers. CONCLUSIONS: Approximately one-half of normal Indian men with regular bowel habits have a high pressure zone in the rectosigmoid region. The role of diet or defecation posture in its etiology and its effect on bowel habit need to be studied.
A selective ligand for the dopamine transporter 3 beta-(4-iodophenyl)tropan-2 beta-carboxylic acid isopropyl ester (RTI-121) has been labeled with iodine-125 by electrophilic radioiododestannylation. The [125I]RTI-121 was obtained in good yield (86 +/- 7%, n = 3) with high radiochemical purity (> 99%) and specific radioactivity (1210-1950 mCi/mumol). After i.v. administration of [125I]RTI-121 to mice, the rank order of regional brain tissue radioactivity (striatum > olfactory tubercles > > cortex, hippocampus, thalamus, hypothalamus, cerebellum) was consistent with dopamine transporter labeling. Specific in vivo binding in striatum and olfactory tubercles was saturable, and was blocked by the dopamine transporter ligands GBR 12,909 and (+/-)-nomifensine. By contrast, binding was not reduced by paroxetine, a serotonin transporter inhibitor, or desipramine, a norepinephrine transporter inhibitor. A variety of additional drugs having high affinities for recognition sites other than the neuronal dopamine transporter also had no effect. The [125I]RTI-121 binding in striatum and olfactory tubercles was inhibited by d-amphetamine in dose-dependent fashion. Nonmetabolized radioligand represents 85% of the signal observed in extracts of whole mouse brain. Thus, [125I]RTI-121 is readily prepared, and is a useful tracer for dopamine transporter studies in vivo.
Recent reports have suggested that minor arterial lesions can be responsible for claudication in athletes occurring only during maximal exercise. Ankle to arm index measurements (AAI) prove the arterial origin of this claudication, but little is known about the normal response of AAI to maximal exercise. Therefore, we studied the response of AAI to maximal exercise in trained and untrained normal subjects. AAI and heart rate (HR) were recorded at rest and following maximal exercise on a cycle ergometer in 15 untrained (VO2 = 41.5 +/- 4.0 ml.kg-1.min-1) and 15 trained (VO2 = 58.4 +/- 2.8 ml.kg-1.min-1) volunteers. All subjects were without known peripheral arterial disease. At rest, AAI was 1.08 +/- 0.08 in untrained subjects and 1.15 +/- 0.05 in trained subjects (P < 0.05). HR was 73.9 +/- 11.0 in untrained subjects and 57.1 +/- 8.3 in trained subjects (P < 0.05). Following exercise, AAI decreased during the first minutes of recovery in all subjects, with a significant difference between untrained and trained subjects. Although untrained subjects sustained a lower workload than trained subjects, at 1 min following exercise AAI was 0.70 +/- 0.06 in untrained versus 0.8 +/- 0.08 in trained subjects (P < 0.05). No difference in AAI to HR relationships was noted between untrained and trained subjects. In conclusion, we suggest that AAI should be interpreted with regard to HR at the end of maximal exercise and we project normal results for the AAI to HR relationships following maximal exercise.
The hepatic perfusion index (HPI), the ratio of hepatic arterial to total liver blood flow, was determined by radionuclide angiography in 28 subjects with normal livers and 62 patients with portal hypertension of various aetiologies. The latter group comprised 50 patients with cirrhosis (14 Child class A, 20 Child class B, 16 Child class C) and 12 patients with non-cirrhotic portal hypertension (7 non-cirrhotic portal fibrosis, 5 extrahepatic portal venous obstruction). The mean (+/- S.D.) HPI was significantly higher among the patients with cirrhosis (Child class A, 53.9 +/- 18.1; Child class B, 65.6 +/- 29.4; Child class C, 78.6 +/- 33.5) and non-cirrhotic portal hypertension (54.9 +/- 17.7) compared with the subjects with normal livers (35.6 +/- 10.5). The patients with non-cirrhotic portal hypertension had a mean value similar to that of the cirrhotic patients in Child class A. A higher HPI was associated with worsening liver status. We conclude, therefore, that the HPI will be high in portal hypertension irrespective of aetiology and a rise in the HPI may indicate a deterioration in the condition of the liver.
Ankle to arm index (AAI) defined as the ratio of ankle systolic blood pressure (ASBP), to brachial systolic blood pressure is largely used in the study of lower extremity arterial disease (LEAD). To study the hypothesis of the shunt of blood away from the skin as the explanation of AAI decrease in exercise, we studied the AAI and ASBP responses to an increase in cardiac output originating from an increase either in muscle blood flow (exercise) or in cutaneous blood flow (thermal stress). Brachial systolic pressure, ankle systolic pressure and heart rate (HR) were measured in 9 healthy subjects at rest, during heart thermal stress and following maximal exercise on a cycle ergometer. Compared to resting values, AAI decreased in all subjects from 1.05 +/- 0.07 to 0.75 +/- 0.07 (P < 0.05) 1 min following exercise and from 1.08 +/- 0.07 to 0.94 +/- 0.05 (P < 0.05) during heat stress. On the other hand, HR increased from 72.8 +/- 12.2 to 112.4 +/- 19.6 (P < 0.05) min following exercise and from 75.5 +/- 13.6 to 96.8 +/- 15.3 (P < 0.05) during heat stress. Since a comparable relation exists between AAI and HR in thermal stress and exercise, we suggest that the decrease in AAI in normal subjects following exercise is due to turbulences at high flow levels, rather than the shunting of blood to active muscles in exercise.
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Little is known about the variability of blood glutathione (GSH) in human subjects. Thus, we wanted to develop and validate a rapid method for measuring GSH concentrations in whole blood and apply this method to ascertain the variation of GSH in a large-scale study of free-living adults. The assay was highly sensitive (detection limit < 5 pmol) and precise, with an interassay variation of 2.3% and a sampling variation of 3.6%. Applying this method to screen 715 adults, we observed a threefold range of GSH concentrations, with a mean of 1.02 mmol/L and CV of 17%. GSH concentrations were 8-10% greater in smokers than in nonsmokers (P < 0.001). Although we observed no sex differences for GSH, GSH/hemoglobin ratios were 8-18% greater in women < 55 years old than in older subjects (P < 0.05). The results presented here validate the use of this method for large-scale human studies and provide information on the variation and normal values of blood GSH in adults.
Glutathione (GSH) availability is an important factor in the maintenance of health. Accordingly, blood GSH has been proposed as an indicator of health status. To validate the use of blood GSH in population studies, we investigated the long-term intraindividual variation of blood GSH and cyst(e)ine (Cys and cystine) concentrations in healthy adults. In a longitudinal study of 10 subjects, GSH and cyst(e)ine were measured in blood samples collected weekly over 8 months. The average within-person CV for GSH was only 9.1% compared with an observed interindividual CV of 20%. Blood cyst(e)ine was more variable within individuals (mean CV 14.7%) than GSH, whereas the interindividual CV for cyst(e)ine was lower (8.6%). The results demonstrate the stability of blood GSH in free-living subjects and the utility of GSH measurements as an indicator of long-term GSH status.
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