Incorporation of vinylogous scaffolds in the C-terminal tripeptide of substance P.

Glycine-9 and leucine-10 of substance P (SP) are critical for (NK)-1 receptor recognition and agonist activity. Propsi(Z)-CH=CH(CH3)-CONH)Leu (or Met) and Propsi((E)-CH=CH(CH3)-CONH)Leu (or Met) have been introduced in the sequence of SP, in order to restrict the conformational flexibility of the C-terminal tripeptide, Gly-Leu-Met-NH2, of SP. Propsi((Z)-CH=C(CH2CH(CH3)2)-CONH)Met-NH2, with an isobutyl substituent to mimic the Leu side-chain, was also incorporated in place of the C-terminal tripeptide. The substituted-SP analogs were tested for their affinity to human NK-1 receptor specific binding sites (NK-1M and NK-1m) and their potency to stimulate adenylate cyclase and phospholipase C in Chinese Hamster ovary (CHO) cells transfected with the human NK-1 receptor. The most potent SP analogs [Pro9psi((Z)CH=C(CH3)CONH)Leu10]SP and [Pro9psi ((E)CH=C(CH3)CONH)Leu10]SP, are about 100-fold less potent than SP on both binding sites and second messenger pathways. These vinylogous (Z)- or (E)-CH=C(CH3)- or (Z)-CH=C(CH2CH(CH3)2) moieties hamper the correct positioning of the C-terminal tripeptide of SP within both the NK-1M- and NK-1m-specific binding sites. The origin of these lower potencies is related either to an incorrect peptidic backbone conformation and/or an unfavorable receptor interaction of the methyl or isobutyl group.

Functional characterization of three mutations of the endothelin B receptor gene in patients with Hirschsprung's disease: evidence for selective loss of Gi coupling.

BACKGROUND: Hirschsprung's disease (HSCR) is one the most common congenital intestinal disease. It leads to aganglionic megacolon in the early childhood. Several susceptibility genes have been identified : RET protooncogene and its ligand, glial cell derived neutrophic factor (GDNF), Sox 10, Endothelin-3 (EDN3) and its receptor B (EDNRB). EDNRB mutations are found in 5% of familial or sporadic HSCR. Only few EDNRB mutations found in HSCR have been explored and some of them seem to be non fonctional variants. MATERIALS AND METHODS: The properties of three mutant human endothelin B receptor (hETB) (G57S, R319W and P383L) in isolated HSCR were analyzed. Stable recombinant cells expressing the three mutants and the wild-type (WT) were established. The hETB receptors were characterized for 125I ET-1 binding, ET-1 induced signaling: calcium transient, AP-1 transcriptional factor activation and cAMP accumulation. RESULTS: Immunofluorescence experiments showed normal cellular distributions of the mutant G57S, R319W and WT hETB receptors. In contrast, the P383L hETB mutant receptor was concentrated near the nucleus and essentially no ET-1 binding was detected. The two other mutants (G57S and R319W) bound ET-1 normally, induced calcium transients and activated the AP-1 pathway in the same way as wild type, but did not inhibit adenylate cyclase. The G57S hETB mutant even stimulated cAMP accumulation which was blocked by pertussis toxin. CONCLUSION: The absence of the P383L mutant receptor from the membrane clearly indicates that this mutation could be involved in HSCR. The G57S and R319W mutant receptors, despite their normal coupling to Gaq, have a defect in the Galphai signaling pathway and the G57S mutation couples to Galphas. These observations allow us to hypothesize that cAMP signaling might be involved in the differenciation of neural cells in the bowel.

Systematic lung scans reveal a high frequency of silent pulmonary embolism in patients with proximal deep venous thrombosis.

BACKGROUND: A high frequency of asymptomatic pulmonary embolism (PE) has been reported in patients with deep venous thrombosis (DVT) in studies of a limited number of patients using varying criteria for lung scan assessment. OBJECTIVES: To estimate the frequency of PE using systematic lung scans in a large group of outpatients with DVT and to compare the results using varying lung scan assessment criteria. METHODS: An international multicenter study comparing 2 different regimens of low-molecular-weight heparin nadroparin in DVT: perfusion lung scans were performed in 622 outpatients with no clinical indication of PE and with proximal DVT confirmed by venography. Three hundred seventy-nine of these patients underwent ventilation lung scans. High-probability (HP) scans for PE were assessed separately using either ventilation scans or chest radiographs to define mismatched perfusion defects. RESULTS: Perfusion scans showed abnormalities in 82% of the patients; 59% had segmental defects and 30% had normal scans or scans with a very low probability of PE. Depending on the criteria used, 32% to 45% had HP scans for PE; these percentages were higher in young patients. No relationship was found between extent of thrombosis and HP scans. The estimated frequency of silent PE was 39.5% to 49.5%. During a 3-month follow-up period during which the patients received therapy, the rate of PE recurrence was low (1.3%) and did not differ between patients with baseline HP scans and those with normal scans. CONCLUSIONS: Regardless of what interpretative criteria are used for assessing lung scans in PE, the frequency of silent PE is 40% to 50% in patients with DVT. A baseline lung scan may easily detect PE in these patients but is not useful for predicting early thromboembolic recurrences that may occur during therapy.

Efficacy of a synthetic pentasaccharide, a pure factor Xa inhibitor, as an antithrombotic agent--a pilot study in the setting of coronary angioplasty.

AIM OF THE STUDY: To assess the antithrombotic properties of SR90107/ORG31540. a sulfated pentasaccharide, which enhances specifically antithrombin III mediated inactivation of factor-Xa, in a clinical setting known to promote arterial thrombosis, i.e. coronary angioplasty. METHODS AND RESULTS: Percutaneous transluminal coronary angioplasty (PTCA) was carried out with conventional balloons with a single 5 min intravenous infusion of 12 mg pentasaccharide, and 500 mg intravenous aspirin. Heparin was not allowed before, during PTCA, and within 24 h after PTCA. The primary end point was the rate of abrupt vessel closure during and within 24 h after the procedure. The sample size was set at 60 evaluable patients, in order to be able to conclude with a good level of confidence (>95%) that the abrupt vessel closure rate was less than 10%, if less than 3 abrupt vessel closures were observed. Seventy-one patients were included in the study, of whom 10 needed elective stenting, and were not considered as evaluable for efficacy. Two out of the 61 remaining evaluable patients experienced acute vessel closure during the study period [3.28%, 95% confidence interval (0.4%; 11.4%)]. No major bleeding occurred. The drug plasma concentrations reached 1.91+/-0.39 mg/], 10 min after pentasaccharide injection, and decreased on average to 1. 18+/-0.27 mg/l at 2 h, and to 0.36+/-0.11 mg/l at 23 h after administration of pentasaccharide. Activated clotting time (ACT) and activated partial thromboplastin (aPTT) time remained within normal range. Thrombin-antithrombin complex levels fell from 22+/-17.1 to 4.5+/-3.4 microg/ml, prothrombin fragment 1+2 levels decreased from 2.15+/-1.01 to 1.73+/-0.87, and activated factor VII levels decreased from 43.4+/-16.8 mU/ml to 18.9+/-7.3 mU/ml respectively from baseline to 2 h following injection of the tested drug. CONCLUSIONS: Administration of pentasaccharide led to the inhibition of thrombin generation without modification of aPTT and ACT. The rate of abrupt vessel closure was within range of rates reported in historical series. Thus we conclude that the anti-thrombotic activity of pentasaccharide, as shown in this pilot trial in the setting of coronary angioplasty, deserves further investigation.

A non-resective therapy for abdominal aortic aneurysm: intravascular thrombosis by dropping inflatable balloons.

A case of subrenal abdominal aortic aneurysm treated by unipolar exclusion and axillobifemoral bypass is reported. The exclusion was performed by inserting inflatable balloons through a femoral access and obstructing the iliac arteries. This technique may be useful in poor-risk patients with a symptom-free aneurysm.

Demographic factors and the antihypertensive effect of diltiazem.

The maximum blood pressure (BP) decrease obtained after dose titration with calcium antagonists is said to be greater in older patients. Because the dose necessary to achieve this maximum effect may also vary, it is not clear whether the sensitivity to treatment is actually increased in older patients. We evaluated the possible influence of pretreatment BP, age, and weight on the BP and heart rate (HR) response to 14-day treatment with a fixed dose of 120 mg diltiazem twice daily (b.i.d.) in 231 hypertensive patients aged 24-82 years (44 +/- 27). Diltiazem decreased BP from 171 +/- 1/103 +/- 7 to 156 +/- 1/91 +/- 1 mm Hg. Decreases in both systolic and diastolic BP (SBP, DBP) were related to their pretreatment values (p less than 0.0001 for both). Although pretreatment SBP was related to age (p less than 0.0001), its decrease with diltiazem was not. Neither pretreatment DBP nor its decrease with diltiazem was related to age; BP decrease was not superior in elderly patients (aged greater than 60 years) as compared with that in younger patients (SBP -16 +/- 2 vs. -15 +/- 1 mm Hg, NS; DBP -13 +/- 1 vs. -12 +/- 1 mm Hg, NS). In conclusion, the response to this average dose of diltiazem is related to pretreatment BP and is not affected by patient's age. Because this result is at variance with the concept that calcium antagonists are more effective in the elderly, this concept should not be used as a general therapeutic guideline.

[Demographic characteristics and response to antihypertensive treatment. Study using fixed doses of diltiazem]. / Caractères démographiques et réponse au traitement antihypertenseur. Etude à dose fixe avec le diltiazem.

Since the stepped care approach has been widened to four classes of antihypertensive drugs, demographic considerations enter into the choice of the first line drug. Calcium antagonists have been claimed to be more active in older patients because the average BP decrease after dose titration could be greater in this age group than in younger people. In this study, the response to a fixed dose of diltiazem has been related to different demographic factors. The selected patients have been treated with diltiazem 120 mg b.i.d. in monotherapy for at least 14 days irrespective of their response to a lower dose. There were 231 patients (115 M, 116 F). Their average age was 59 +/- 11 years (24 to 82) and their treatment duration was 44 +/- 27 days. Diltiazem lowered BP from 171 +/- 1/103 +/- 7 mmHg to 156 +/- 1/91 +/- 1 mmHg. The decline in both SBP and DBP with diltiazem was significantly related to their control values (r = 0.31 and 0.28 respectively, p less than 0.0001 for both). Although control SBP was related to age (r = 0.40, p less than 0.0001), its decrease with diltiazem was not. Neither control DBP nor its decrease with diltiazem were related to age. Although the average SBP was higher in patients over 60 years than in younger patients (176 +/- 2 mmHg, n = 124 vs 166 +/- 2 mmHg, n = 107, p less than 0.01), its decrease with diltiazem was not significantly greater (- 16 +/- 2 vs - 15 +/- 1 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)

Interactions between alcohol and drugs.

There are many interactions between alcohol and drugs. Their practical incidences have already had some medico-legal illustrations, for example in their influence on car driving. This concept of interaction raises a more general problem still, ie that of the possible effects of alcohol on the chemical, toxicologic and nutritional conditions of the body. There is plenty of need for further experiments.

[Traumatic recto-vesical wounds (author's transl)]. / Plaie recto-vésicale traumatique.

The authors report a case of a traumatic recto-vesical wound: such cases are rare and serious. The importance of an early diagnosis, which is not usually difficult, allows quick reparative treatment by the trans vesical route associated with a colostomy higher up which is later closed.