Synthesis and biological evaluation of C-terminal hydroxamide analogues of bombesin.

Bombesin pseudo-peptide analogues containing a hydroxamide function on the C-terminal part of the molecule, e.g. H-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOBzl 1 and H-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH 2 were synthesized. These compounds were tested for their ability to recognize the bombesin receptor on rat pancreatic acini and on 3T3 cells, to stimulate (i) amylase secretion from rat pancreatic acini and (ii) accumulation of tritiated thymidine in 3T3 cells. Compounds 1 and 2 were able to recognize bombesin receptors on both models with high affinity (Ki = 7 +/- 2 and 5.8 +/- 0.9 nM on rat pancreatic acini, and Ki = 4.1 +/- 1.2 and 7.7 +/- 1.9 nM on 3T3 cells, respectively). Interestingly, compound 1 behaved as a potent agonist in stimulating amylase secretion from rat pancreatic acini and is able to stimulate thymidine accumulation in 3T3 cells, while compound 2 was able to potently antagonize bombesin-stimulated amylase secretion (Ki = 22 +/- 5 nM) in rat pancreatic acini and had no proper effect on 3T3 cells; however, it was able to inhibit bombesin-stimulated thymidine accumulation in 3T3 cells with high potency (Ki = 1.6 +/- 0.6 nM).

[Multifactor prevention of endocarditis and cardiac pacemakers. A prospective study apropos of 207 patients]. / Prévention polyfactorielle des endocardites et stimulateurs cardiaques. Une étude prospective à propos de 207 patients.

Infections after cardiac pacemaker implantation are rare (0.13 to 12.6%) but potentially severe complications. Staphylococcus is the genus most frequently isolated (72 to 100% of cases). The use of systematic prophylactic antibiotics remains controversial. From November 1991 to October 1993, 207 consecutive patients were submitted to a series of measures designed to reduce the risk of infection: a) intravenous bolus injection of Cefamindole, 15 minutes before implantation, b) cutaneous disinfection with iodinated polyvindone, c) injection of an ampoule of rifampin before closure of the pacemaker in the pouch, d) absence of drainage system. Patients were predominantly female (60.9%), with a mean age of 77 +/- 10 years, frequently suffering from heart disease (53.8%). The indication for implantation was atrioventricular block (39.7%), carotid sinus syndrome (27.5%), atrial arrhythmia (27.5%), resection of the node-His tract (5.3%). This procedure corresponded to the first implantation in 88.4% or replacement of a previous pacemaker in 11.6% of cases and the pacing mode was single-chamber (38.4% or replacement of a previous pacemaker in 11.6% of cases and the pacing mode was single-chamber (38.7%), or double chamber (61.3%). The mean duration of the procedure was 51.5 min +/- 30 min. The mean follow-up was 12.7 +/- 5 months. The overall mortality was 14% (11 cases of cardiac failure, 6 sudden deaths, 4 cerebrovascular accidents, 4 cases of pneumonia, 4 neoplasms). Only one infectious problem (endocarditis, i.e. 0.48%) was observed.

[Urinary infection in the pregnant woman]. / L'infection urinaire de la femme enceinte.

Urinary tract infections are common during pregnancy. When unrecognized, they can be responsible for complications such as threatened premature labour and impaired intra-uterine development. Detection and appropriate treatment are thus essential. This article reviews the pathophysiology of urinary tract infections during pregnancy and the three major entities involved--different but related to each other--are detailed (significant asymptomatic bacteriuria or SAB, acute cystitis and acute pyelonephritis), together with their specific treatment. SAB tends to persist during pregnancy, then leading in the absence of treatment to a potentially serious complication (acute pyelonephritis) in approximately one woman in five. SAB should be sought at the first prenatal visit by microscopic and bacteriological examination of a properly obtained urine specimen. Lower genital infections should also be sought and treated, without forgetting to remind the patient of preventive measures (adequate hygiene, sufficient urine output, post-coital micturition, regular bowel habit).

Synthesis and biological evaluation of cholecystokinin analogs in which the Asp-Phe-NH2 moiety has been replaced by a 3-amino-7-phenylheptanoic acid or a 3-amino-6-(phenyloxy)hexanoic acid.

Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-2-phenylethyl ester (JMV180), an analog of the C-terminal octapeptide of cholecystokinin (CCK-8), shows interesting biological activities behaving as an agonist at the high-affinity CCK binding sites and as an antagonist at the low-affinity CCK binding sites in rat pancreatic acini. Although we did not observe any major hydrolysis of the ester bond of Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-2-phenylethyl ester in our in vitro studies, we were aware of a possible and rapid cleavage of this ester bond during in vivo studies. To improve the stability of Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-2-phenylethyl ester, we decided to synthesize analogs in which the ester bond would be replaced by a carba (CH2-CH2) linkage. We synthesized the 3-amino-7-phenylheptanoic acid (beta-homo-Aph) with the R configuration in order to mimic the Asp-2-phenylethyl ester moiety and the 3-amino-6-(phenyloxy)hexanoic acid (H-beta-homo-App-OH), an analog of H-beta-homo-Aph-OH in which a methylene group has been replaced by an oxygen. (R)-beta-Homo-Aph and (R)-H-beta-homo-App-OH were introduced in the CCK-8 sequence to produce Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-(R)-beta-homo-Aph-OH and Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-(R)-beta-homo-App-OH. Both compounds were able to recognize the CCK receptor on rat pancreatic acini (IC50 = 12 +/- 8 nM and 13 +/- 5 nM, respectively), on brain membranes (IC50 = 32 +/- 2 nM and 57 +/- 5 nM, respectively), and on Jurkat T cells (IC50 = 75 +/- 15 nM and 65 +/- 21 nM, respectively). Like Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-2-phenylethyl ester, both compounds produced maximal stimulation of amylase secretion (EC50 = 6 +/- 2 nM and 4 +/- 2 nM, respectively) with no decrease of the secretion at high concentration indicating that these compounds probably act as agonists at the high-affinity peripheral CCK-receptor and as antagonists at the low-affinity CCK-receptor. Replacing the tryptophan by a D-tryptophan in such analogs produced full CCK-receptor antagonists. All these analogs might be more suitable for in vivo studies than Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-2-phenylethyl ester.

[Amniotic infection and neonatal bacterial infection. Search for clinical and bacterial predictive arguments]. / De l'infection amniotique à l'infection bactérienne néonatale. Recherche d'arguments cliniques et bactériologiques prédictifs.

Amniotic fluid infection and its principal sequel bacterial infection of the newborn are major problems in obstetric pathology. The authors hav analysed prospectively 346 obstetrical casenotes over a period of 18 months in order to try to describe and specify the clinical features and to try and work out using bacteriological tests the risk of infecting the neonate by materno-fetal transmission. They compared a control group (27 case histories) and the group at risk (235 cases). 4% of the control group and 18.7% of the "at risk" group were biologically infected (p less than 10(-2)). The following are among the classical clinical criteria to correlate this risk: maternal pyrexia, premature delivery, urinary tract infections and fetal distress; an apparent lessening in active fetal movements is also well correlated to the risk of infection. The bacteriological criteria are: the presence of quantities of altered polymorphonuclear cells in the amniotic fluid--this seems to be more important than others (sensitivity = 70%, specificity = 89%, but positive predictive value = 60% and negative predictive value = 93%). From this study it should be possible to work out antenatally whether the newborn baby will be at high risk of developing an infection in order to consider giving antibiotics to prevent materno-fetal transmission.

Bacterial colonization of the large intestine in newborns delivered by cesarean section.

Colonization of the gastrointestinal tract in newborns delivered by Cesarean section occurs during the first days of life by bacteria provided by the environment. It is more rapid in breast-fed infants than in bottle-fed babies. The intestinal flora is more diversified if the infants receive formula feeding. The first bacteria encountered are facultative anaerobes; they remain predominant during the first two weeks of life. In comparison to vaginal delivery, there were low levels of strict anaerobes after Cesarean section; members of the Bacteroides fragilis group were still completely lacking after 14 days of life and Bifidobacteria were only isolated sporadically.