The cyclic octapeptide cyclo[-Pro1-Pro-Phe-Phe-Ac6c-Ile-ala-Val8-] [C8-Ac6c], containing the Pro1-Pro-Phe-Phe sequence, followed by a bulky helicogenic C alpha,alpha-dialkylated glycine residue Ac6c [1-aminocyclohexane-1-carboxylic acid), and a D-Ala residue at position 7 has been synthesized. This cyclic peptide is a deletion analogue of the naturally occurring cyclic nonapeptide cyclolinopeptide A (CLA). It has been designed with the aim of studying the role that the Ac6c and D-Ala residues play on the conformational behaviour of the whole molecule and their influence on the conformation of the Pro1-Pro-Phe-Phe sequence when compared with cyclolinopeptide A. C8-Ac6c has been investigated in chloroform and acetonitrile solutions by 2D NMR techniques. Only one set of sharp signals is observed in both solvents. This evidence strongly supports the hypothesis that only one conformational state exists in the chosen solvents. The interpretation of the experimental data points to the existence for C8-Ac6c of a very rigid structure stabilized by intramolecular hydrogen bonds. The measured NOE effects allow the calculation of internuclear distances, which have been used as restraints in molecular dynamic calculations. The proposed conformation of the molecule shows that the Pro-Pro-Phe segment retains the conformation observed in natural CLA both in solution and in the solid state and that the Ac6c residue indeed reinforces the ring rigidity not permitting the formation of any appropriate cavity in which inorganic cations could be complexed.

Amino Acid Sequence↗

PubMedDate not supplied

Aging and in vitro vascular responses to endothelin-1 in several rat strains.

The endothelins are a recently discovered family of potent contractile peptides produced by endothelial cells. These peptides have been suggested to play an important role in the pathogenesis of hypertension, myocardial infarction, cardiogenic shock, and so on. The aim of our study was to compare the responses to endothelin-1 (ET-1) with those to L-noradrenaline (NA) in aortic rings from rats of different strains and ages. Thoracic aorta rings from spontaneously hypertensive (SHR), Wistar Kyoto (WKY), Brown Norway (BN) and spontaneously hyperlipemic (Yoshida, YOS) rats 2-4 (young), 6-8 (adult) and 20-25 (old) months old were used. There were no changes in the pD2 values for ET-1 and NA between WKY and SHR rats at the ages studied. The ET-1 and NA Emax in adult SHR rats was significantly lower than in the age-matched WKY animals. Old age reduced the ET-1 and NA Emax in both SHR and WKY rats abolishing the difference observed at 6-8 months in the same groups. The reactivity to ET-1 and NA of BN and YOS rats was modified only in young rats. In YOS strain aging did not modify the ET-1 and NA responses as the pD2 and Emax values remained unchanged. Our findings demonstrate that ET-1 is a more potent vasoconstrictor than NA and that this potency remains unchanged throughout the ages and the pathologies studied. In contrast, the pD2 of NA decreases with old age in SHR and WKY rats. We conclude that rat strain but not hypertension or hyperlipemia can modify the response to ET-1 or NA in old age. We suppose that this functional change may involve alterations in the responsiveness of vascular smooth muscle.

Aging↗

PubMedDate not supplied

Role of nitric oxide on cholinergic component of bronchial tone in pig.

In vitro studies demonstrated that stimulation of intrinsic nerves of airway smooth muscle results in a predominantly contractile response, followed by a relaxant response which involves cholinergic, adrenergic and non-adrenergic non-cholinergic (NANC) nerve activation. Thus, in this paper it is determined whether endogenous nitric oxide (NO) modulates cholinergic neurotransmission in isolated pig airway smooth muscle. Bronchial rings were suspended in organ baths for isometric measurement of tension and the contractions were induced using electrical field stimulation (EFS) techniques. Then, the effects of L-NG-nitroarginine (L-NOARG, 10 microM), an inhibitor of NO synthase, and L-arginine (L-ARG, 1 mM), a precursor of NO synthesis, were evaluated. The cholinergic contractions induced by electrical field stimulation (EFS: 60 V, 2 ms, 60 Hz) of pig lobar bronchial preparations increased (29%) in the presence of L-NOARG (10 microM). This effect may be released by nerves in pig large airways during EFS.

Animals↗

PubMedDate not supplied

Thrombotic thrombocytopenic purpura associated with primary tuberculosis.

Thrombotic thrombocytopenic purpura (TTP) during infectious diseases is a known, but rare event. In this paper a case of TTP associated with primary infection by Mycobacterium tuberculosis is described. Various therapeutic approaches were used with the patient: fresh frozen plasma infusions and plasma exchange, specific anti-tuberculous therapy, anti-platelet drugs and steroids. A complete remission occurred 3 months after the onset of the acute disease. A hypothesis on the pathogenesis of TTP might be an increased pro-coagulant activity of interleukin 1 (IL-1) on endothelial cells.

Adrenal Cortex Hormones↗

PubMedDate not supplied

Management of hypertension by general practitioners: an Italian observational study.

Data on patients receiving antihypertensive therapy were collected from 20 general practitioners (GPs) in Campania, Italy, to determine the prescription of different antihypertensive classes and their use with other drugs for concomitant diseases, to investigate the main factors influencing antihypertensive choice, to document treatment outcome, and to assess adverse drug reactions (ADRs). Each GP completed a data card for each consultation that produced an antihypertensive prescription; 1900 cards were collected. The most frequently used antihypertensives were angiotensin-converting enzyme inhibitors (49.6%), calcium antagonists (24.8%), beta blockers (11.7%), angiotensin II-receptor blockers (5.5%), and alpha blockers (0.9%). In 82% of patients, blood pressure was reduced but did not reach normotensive levels. The choice of antihypertensive treatment was influenced by international guidelines (56%), clinical diagnosis (25%), concomitant diseases (8%), cost (4%), compliance (3%), and other factors (5%). ADRs--most often cough (35.7%), edema (22.7%), headache (13.3%), and tachycardia (7.8%)--occurred in 11.8% of patients.

Antihypertensive Agents↗

PubMedDate not supplied

Self-prescribed laxative use: a drug-utilization review.

This study was conducted to determine the reasons for the choice of self-prescribed laxatives and to acquire information on how they were used and tolerated. From November 1999 to February 2000, 70 pharmacies, uniformly located throughout the Campania region of southern Italy, distributed a questionnaire to purchasers of over-the-counter laxatives. The average age of the (mostly female) respondents was 45.9 years; 23.8% were elderly. Among the 7324 individuals who completed the survey, 77.6% selected an oral product; 22.4% preferred rectal administration. A physician influenced the choice of a laxative in 37.7% of the cases, a pharmacist in 20.5%; other suggestions came from relatives (14%), acquaintances (12.1%), advertisements (11.7%), and miscellaneous sources (4%). Only 59.8% of respondents used these drugs correctly, and 58.2% consulted a physician or pharmacist because of constipation. Adverse effects, mainly gastrointestinal symptoms, occurred in 6.1% of those surveyed. The long-term use or abuse of laxatives can cause serious medical consequences, as well as mask diseases, delaying diagnosis and appropriate treatment. Physicians, pharmacists, and other health-care personnel should counsel patients on the proper use of these easily available, ubiquitous drugs.

Adolescent↗

PubMedDate not supplied

Over-the-counter oral nonsteroidal anti-inflammatory drugs: a pharmacoepidemiologic study in southern Italy.

The Pharmacoepidemiologic Service of the Second University of Naples analyzed the use and tolerability of over-the-counter (OTC) oral nonsteroidal anti-inflammatory drugs (NSAIDs) purchased in Campania, a region of southern Italy. Forty private pharmacies uniformly distributed throughout the region were recruited. The study was conducted by means of a questionnaire completed by purchasers and lasted from December 1, 1999 to March 31, 2000; 2,053 questionnaires were collected. The age of respondents averaged 45.3 +/- 3.49 years (range, 17-85 years). The NSAIDs analyzed were acetylsalicylic acid, paracetamol, ibuprofen, ketoprofen, diclofenac, and piroxicam. Adverse effects, mainly gastrointestinal symptoms, were reported by 5.5% of the users and occurred primarily with diclofenac, piroxicam, ibuprofen, and ketoprofen. Because the use and availability of OTC NSAIDs are increasing, further studies of the tolerability of this important drug class are warranted.

Adolescent↗

PubMedDate not supplied

ACTH 1-17 effects in intrinsic bronchial asthma.

We have studied the effect of Synchrodyn 1-17 (100 micrograms/day/15 days, intramuscularly) on 12 patients with intrinsic asthma, presenting a circadian pattern in several functional parameters related to the bronchial patency (and/or with bouts of nocturnal asthma). Treatment with ACTH 1-17 had two main effects: the pathological rhythms of the bronchial tone disappeared and there was a clear general improvement in the indices of bronchial patency. The drug was well tolerated. Euphoria and water retention were the side effects: they were noticed in a variable number of subjects and disappeared after discontinuation of treatment.

Adrenocorticotropic Hormone↗

PubMedDate not supplied

DNA topoisomerase I: customs officer at the border between DNA and RNA worlds?

DNA topoisomerase I is required for the normal development of multicellular organisms, probably because it plays a role in controlling gene activity, in addition to its function in relieving tortional stress during DNA replication and transcription. The discovery of DNA topoisomerase I as a specific kinase that phosphorylates serine-arginine rich (SR) splicing factors may provide new insights into their precise function in regulating gene expression. It is clear that the splicing factors phosphorylated by DNA topoisomerase I can modulate gene expression by changing the splicing pattern of structural genes. Studies of the splicing mechanism suggest that the phosphorylation of serine residues of SR proteins contribute to their activity. As this phosphorylation can be accomplished by several kinases, it remains to be determined whether phosphorylation by DNA topoisomerase I protein kinase is the limiting step in regulating this process. The availability of specific inhibitors of DNA topoisomerase I, structurally related to the alkaloid camptothecin, have made it possible to address this question experimentally. These inhibitors, which hold great promise as antineoplastic drugs, lead to specific inhibition of SR protein phosphorylation in cultured cells. This observation will hopefully lead to improved understanding of the mechanism by which these drugs act at cellular level.

Animals↗

PubMedDate not supplied

Effect of the selective 5-HT2 antagonist ketanserin on adenosine-induced bronchoconstriction in asthmatic subjects.

In eight asthmatic subjects a randomized, double-blind, placebo controlled study was performed to investigate the effect of inhaled ketanserin, a 5-HT2 receptor blocking agent, in a dose of 10 mg given 30 min before test, on adenosine-induced bronchospasm. The protective effect of ketanserin was significant in all patients, even though it altered basal bronchomotor tone in only two subjects. On the contrary, ketanserin did not inhibit histamine-induced bronchoconstriction in four of these eight asthmatics, even though it modified sensitivity and reactivity in one of them. The results suggest that ketanserin influence on adenosine bronchial reactivity and sensitivity was not due to the bronchodilator effect of ketanserin itself or to its antihistaminic activity. We have no certain explanation for the inhibition of adenosine-induced bronchoconstriction elicited by ketanserin. It is possible that 5-HT may play, at least in part, a role as mediator of adenosine-induced bronchoconstriction.

Adenosine↗

PubMedDate not supplied

On the mechanism of high-dose intravenous immunoglobulin treatment of patients with chronic inflammatory demyelinating polyneuropathy.

A proportion of patients with a chronic inflammatory demyelinating polyneuropathy (CIDP) improves after polyvalent intravenous immunoglobulin (IVIg) treatment. When anti-neuroblastoma cell line (NBL) antibodies are present, they decrease or disappear after IVIg treatment. Purified IgM anti-NBL antibodies from a CIDP patient were inhibited by F(ab')2 of IVIg and by F(ab')2 of a patient recovered from Guillain-Barré syndrome (GBS). Inhibition of anti-NBL antibodies was also found among sera from normal individuals. This suggests that the self-limiting character of GBS and the therapeutic effect of IVIg in CIDP are dependent on suppression of auto-antibodies. This suppression may be mediated by anti-idiotypes present in recovered GBS patients and in the normal donor population contributing to IVIg.

Adolescent↗

PubMedDate not supplied

Endothelin-1 in periaqueductal gray area of mice induces analgesia via glutamatergic receptors.

The aim of the study was to examine whether endothelin-1 (ET-1) injected into dorsolateral periaqueductal gray (PAG) area of mice produces antinociception. ET-1, from 1 to 4 pmol/mouse, induced antinociceptive effect in a dose-dependent manner. This antinociceptive effect was prevented by NMDA receptor antagonists (2-APV and MK-801) injected in the same area (2-APV) or by intraperitoneal route (MK-801). CNQX, a non-NMDA receptor antagonist, did not inhibit the ET-1 effects. Prazosin, an alpha 1-adrenergic blocking agent, also prevented the ET-1 antinociceptive effect. We suggest that the activation of NMDA glutamatergic receptors in the PAG area may be a necessary step for ET-1 induced antinociception.

2-Amino-5-phosphonovalerate↗

PubMedDate not supplied

Myxoid intraneural cysts of external popliteal ischiadic nerve. Report of 2 cases studied with ultrasound, computed tomography and magnetic resonance imaging.

Peripheral neuropathy of the external popliteal ischiadic nerve caused by intraneural cysts is a very rare and peculiar pathological phenomenon compared with diseases associated with extraneural cysts or colliquative phenomena of solid nervous lesions. Two cases of peripheral neuropathy of the external popliteal ischiadic nerve caused by intraneural cysts and evaluated with ultrasound, computed tomography and magnetic resonance are described. The diagnostic efficacy of these imaging modalities is also evaluated with particular reference to MR capability to define the morphology of such lesions and their relationships to the surrounding structures. It is not yet possible to obtain a correct diagnosis about histopathologic features by means of the imaging techniques currently available. Nevertheless, they do provide information about the involvement of the neighboring areas, which are useful indications for possible surgical treatment of the disease.

Adult↗