New hydroxamate inhibitors of neurotensin-degrading enzymes Synthesis and enzyme active-site recognition

Selective and mixed inhibitors of the three zinc metallopeptidases that degrade neurotensin (NT), e.g. endopeptidase 24-16 (EC 3.4.24.16), endopeptidase 24-11 (EC 3.4.24.11 or neutral endopeptidase, NEP) and endopeptidase 24-15 (EC 3.4.24.15), and leucine-aminopeptidase (type IV-S), that degrades the NT-related peptides, Neuromedin N (NN), are of great interest. On the structural basis of compound JMV 390-1 (N-[3-[(hydroxyamino)carbonyl]-I-oxo-2(R)-benzylpropyl]-L-isoleucyl-L-leucine), which was a full inhibitor of the major NT degrading enzymes, several hydroxamate inhibitors corresponding to the general formula HONHCO-CH₂-CH(CH₂-C₆H₅)CO-X-Y-OH (with X-Y = dipeptide) have been synthesized. Compound 7a (X-Y = Ile-Ala) was nearly 40-times more potent in inhibiting EC 24-16 than NEP and more than 800-times more potent than EC 24-15, with an IC₅₀ (12 nM) almost equivalent to that of compound JMV 390-1. Therefore, this compound is an interesting selective inhibitor of EC 24-16, and should be an interesting probe to explore the physiological involvement of EC 24-16 in the metabolism of neurotensin. © Munksgaard 1996.     

Synthesis and biological activity of 2-phenylethyl ester analogues of C-terminal heptapeptide of cholecystokinin modified in Trp 30 region

We have tried to evaluate the significance of the tryptophan side chain residue and of the surrounding peptide bonds in the antagonist activity of cholecystokinin analogues lacking the C-terminal amide function and having a d -tryptophan. In order to perform this study, analogues of the C-terminal heptapeptide of cholecystokinin were synthesized by replacing the C-terminal phenylalanine residue with 2-phenylethyl alcohol and by either replacing the tryptophan residue with an alanine, a norleucine and a phenylalanine residue, or introducing a “reduced peptide bond” in the tryptophan 30 region. Most of these compounds were able to reproduce only part of the response of cholecystokinin in stimulating amylase release from rat pancreatic acini, as was already observed for 2-phenylethyl ester analogues of CCK. These results point out the key role of tryptophan 30 in the biological response of cholecystokinin.     

Massive ingestion of isosorbide-5-mononitrate and nitroglycerin: suicide attempt by an adolescent girl without previous heart disease

High plasma levels of isosorbide-5-mononitrate were found ina young girl who had ingested 1.6 g of the drug plus 20mg ofnitroglycerin. These concentrations produced no disturbanceof the patient's state of consciousness and no serious haemodynamiceffects appeared except for a tachycardia in relation to peripheralvasodilatation.     

Acute right ventricular infarction secondary to massive pulmonary embolism

Isolated right ventricular infarction has been found in casesof right ventricular hypertrophy, but there are no reports onright ventricular infarction secondary to massive pulmonaryembolism. Six autopsied patients with massive pulmonary embolismand pure right ventricular infarction, suspected to be secondaryto the embolism, were selected from a population of 216 autopsies.Pulmonary embolism was the suspected diagnosis in five casesdue to typical clinical, electrocardiographic and haemodynamicdata. Right ventricular infarction was a post-mortem finding,not previously diagnosed. In every case the thickness of theright ventricular myocardium was normal. The necrosis of theright ventricle was transmural in four cases and subendcardialin two and the entire right ventricular wall (anterolateralas well as posterior) was involved. No mural thrombi were presentand in no case did the necrosis involve the left ventricle.In one case the coronary arteries were normal, in the otherfive significant lesions of the right or the left coronary arterieswere observed. These lesions may have been, in part, responsiblefor the necrosis of the right ventricle when the massive pulmonaryembolism was added. We conclude that right ventricular infarctionmay be secondary to pulmonary hypertension in the setting ofmassive pulmonary embolism, even in the absence of right ventricularhypertrophy and with normal or stenotic coronary arteries.     

Small-Diameter Implants: Indications and Contraindications

The choice of implant diameter depends on the type of edentulousness, the volume of the residual bone, the amount of space available for the prosthetic reconstruction, the emergence profile, and the type of occlusion. Small-diameter implants are indicated in specific clinical situations, for example, where there is reduced interradicular bone or a thin alveolar crest, and for the replacement of teeth with small cervical diameter. Before using a small-diameter implant, the biomechanical risk factors must be carefully analyzed. Preliminary reports of this type of implant show good short- and medium-term results.
CLINICAL SIGNIFICANCE
Specific clinical situations indicate the use of small-diameter implants: a reduced amount of bone (thin alveolar crest) and where the replacement tooth requires a small cervical diameter. In some cases, the use of small-diameter implants avoids bone reconstruction.     

A Multicenter, Randomized Trial Comparing Calcium Hydroxylapatite to Two Hyaluronic Acids for Treatment of Nasolabial Folds

INTRODUCTION In this study, we examined Radiesse (calcium hydroxylapatite; CaHA), Juvederm 24 (hyaluronic acid; HA-1A), Juvederm 24HV (HA-1B), and Perlane (HA-2) for patient satisfaction, likelihood to return, immediate efficacy, and duration of correction.
OBJECTIVE This multicenter, blinded, randomized study compares patient satisfaction variables, efficacy, and durability of CaHA gel and HA for correction of nasolabial folds (NLFs) through 12 months after 4-month touch-up.
METHODOLOGY A total of 205 randomized patients received either CaHA gel or HA for NLF treatment at initial visit and 4-month touch-up. Patients returned at 4, 8, and 12 months after the second injection for evaluation. Surveys measured patient satisfaction; effectiveness measures included the Global Aesthetic Improvement Scale (GAIS).
RESULTS More CaHA gel patients were satisfied or extremely satisfied than each HA tested. At 8 months, significantly more CaHA gel–treated NLFs were improved on the GAIS than any HA. The volumes of CaHA gel and three HA materials injected through 4 months were 2.2, 2.9, 4.8, and 2.9 mL, respectively ( p <.005). No serious adverse events were observed.
CONCLUSIONS In this controlled study, CaHA gel ranked highest in patient satisfaction and likelihood to return. The material was more effective and longer lasting than each HA in maintaining NLF augmentation.     

On early sensitization to allergens and development of respiratory symptoms

BACKGROUND: Various studies have suggested that a sequence of events occurring in childhood may affect the development of asthma in susceptible individuals. We have investigated whether early childhood sensitization to aeroallergens is an important risk factor in the later development of asthma symptoms. OBJECTIVE AND METHODS: In this study we examine this issue in children enrolled in the Tucson epidemiology study of obstructive airways disease, who had at least two allergen skin tests, one before and one after 8 years of age. Respiratory symptom data were available from 12 survey questionnaires, spanning a period of 20 years. During the first, sixth, seventh and eleventh surveys, skin tests were performed with commercially available allergens. CONCLUSION: As compared with children who were sensitized after 8 years of age, children over 8 years who were sensitized to any allergen before age 8 years were significantly more likely to report shortness of breath with wheeze (SOBWZ), wheeze apart from colds or wheeze most days (OR = 4.1 SOBWZ; OR = 3.88 WZ apart from colds; and OR = 2.83 WZ most days). Children who were sensitized after 8 years were no more likely to have the symptoms described above than children who were never found to be sensitized. Based on these results we conclude that early allergic sensitization is a significant risk factor for later development of wheezy symptoms, where as late sensitization is not.