1,721,007 research outputs found
Novel non-steroidal anti-inflammatory drugs: what we have learned from animal studies
No full textThe use of non-steroidal anti-inflammatory drugs (NSAIDs) is frequently associated with serious adverse effects related to the inhibition of cyclooxygenase (COX) in tissues where prostanoids exert physiological effects, such as gastric mucosal defence, renal homeostasis and platelet aggregation. The discovery of a second COX isoform (COX-2) specifically induced in pathological tissues led to the development of selective COX-2 inhibitors, believed to have an improved safety profile compared to traditional NSAIDs. Animal studies, however, have revealed a protective role for the COX-2 enzyme in the stomach, kidney, heart, vasculature and reproductive system, and therefore, the safety of COX-2 selective inhibitors needs to be reassessed. On the other hand, new therapeutic indications have emerged as a result of the role played by COX-2 overexpression in cancer or Alzheimer's disease. A second approach aimed at obtaining safer NSAIDs is based on the gastroprotective effects of nitric oxide (NO). Traditional NSAIDs chemically linked to NO-releasing moieties retain the therapeutic efficacy, but not the adverse effects, of the parent NSAIDs. Moreover, additional therapeutic applications in cardiovascular diseases, Alzheimer's disease and cancer have been suggested. Animal data, however, need to be confirmed in large clinical trials. Finally, the increase in endogenous NO via a selective increase in inducible NO synthase in the gastric mucosa is the mechanism underlying the good gastric tolerability and the gastroprotective effects of the non-selective NSAID amtolmetin guacyl, documented to date in the ra
Assessment of enteral bacteria
No full textThe disruption of intestinal barrier leads to the penetration of noxious luminal compounds
into the gut wall, causing further damage. This unit describes the assessment of
enteric bacteria translocation into the intestinal wall of rats, an established method for
the evaluation of bowel damage to the mucosal epithelial barrier. The Basic Protocol
provided in the present unit describes collection and preparation of small intestine sample,
performing of sample serial dilutions for bacterial culture, performing of the culture
of aerobic and anaerobic bacteria on petri dishes, incubation of the cultured plates, and
counting of bacterial colonies. The Support Protocols describes the procedures for the
preparation of petri dishes for the culture, using different employable media for aerobes
or anaerobes. The Alternate Protocol describes the use of the “inclusion method,”
suitable for the culture of anaerobic bacteria
Muscarinic M2 receptors interact with neurokininergic NK1 and NK2 receptors in the contractions of isolated bronchi in the horse.
No full textAcetylcholine and neurokinins, known as neurotransmitters that induce bronchoconstriction in horses and
other species, are involved in the pathogenesis of obstructive respiratory diseases. However, the
knowledge about the role of muscarinic receptors in the control of airway contraction in equines is not fully
elucidated and that of neurokininergic receptors is limited.
Bronchial smooth muscle rings of slaughtered horses were obtained from healthy lungs, or from lungs with
macroscopic signs of inflammation, put into organ baths and connected to isotonic transducers. Electrical
field stimulation was applied (50 Hz, 1 ms, 300 mA, 50 V every 120 s), and phasic contractions of bronchial
smooth muscle were evoked. Previous experiments showed the neurogenic cholinergic nature of these
contractions and a central role of muscarinic M3 receptors [1]. The effects of drugs were expressed as
variation of the pre-drug contraction amplitude, assumed as 100%.
Bronchial contractions were partially inhibited by selective M3 receptor antagonist (pFHHSiD) up to 10-6 M,
and totally abolished at 10-5 M in normal and inflamed tissues. Methoctramine, selective M2 receptor
antagonist, was able to reduce the contractions only in healthy bronchial rings, whereas selective M1
receptor antagonist, VU0255035, reduced the contractions only in pathologic ones.
L-732,138 and GR159897, selective NK1- and NK2-receptor antagonist respectively, slightly reduced the
contractions in normal and pathologic tissues, whereas SB218795, selective NK3-receptor antagonist, was
ineffective. In presence of either NK1, NK2, but not NK3 receptor block, M2 antagonist, methoctramine,
was able to reduce the contractions of the pathologic bronchi, while the response in normal tissue was
unchanged.
Muscarinic M1, M2, and M3 receptors are involved in the contractions of horse bronchi, M3 receptors
playing a major role. Present results suggest an interference between cholinergic and neurokininergic
systems involving M2, NK1 and NK2 receptor subtypes. The influence of the excitatory peptidergic system
seems to be more evident in pathologic tissue, and indeed up-regulation of NK2 receptors in horses with
RAO was detected [2]. A localization of inhibitory M2 receptors on neurokininergic neurons releasing
substance P and/or neurokinin A could be hypothesized, as already observed in other species [3]. A better
knowledge of the interactions between cholinergic and neurokininergic systems could help the
development of more effective drugs for the treatment of bronchial hyperactivity in horses and, possibly, in
humans.
[1] Menozzi A, Pozzoli C, Poli E, Delvescovo B, Serventi P, Bertini S. J vet Pharm Ther 2014; in press
[2] Venugopal CS, Holmes EP, Polikepahad S, Laborde S, Kearney M, Moore RM. Can J Vet Res 2009; 73:25-
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[3] Bernardini N, Roza C, Sauer SK,1 Gomeza J, Wess J, Reeh PW. J Neurosci 2002; 22:RC22
Synthesis of 1,2-benzisothiazolyloxypropanolamine derivatives and investigation of their activity at β-adrenoceptors
No full textThe synthesis of 3-methoxy-1,2-benzisothiazole derivatives, substituted in position 5- (compounds 1–7) or 7- (compounds 8–14), with oxypropanolaminic side chains and the pharmacological investigation on their activity at β-adrenoceptors are described. Compounds were prepared in an attempt to explore the ability of the benzisothiazole ring to interact with the β-adrenoceptor site and to establish whether oxypropanolaminic derivatives recognise the β3-adrenoceptor subtype. All the products were tested on rat atria, bladder and small intestine, which preferentially (but not exclusively) express β1-, β2- and β3-adrenoceptors, respectively. When compared with the reference, non-specific, β-adrenoceptor agonist isoprenaline, the products tested did not show any consistent β-adrenoceptor agonistic activity in the different models. Most compounds relaxed smooth muscle preparations, but such effect was resistant to the blockade by propranolol (1 μmol/l), ICI 118,551 (1 μmol/l) or bupranolol (1–10 μmol/l), thus excluding that the spasmolytic effect involves any β-adrenoceptors. When tested as antagonists, some of these products showed a concentration-dependent attenuation of the isoprenaline-induced effects in rat atria, without affecting β-adrenoceptor-mediated relaxation in smooth muscle. These data confirm the ability of the benzisothiazole ring to interact with β-adrenoceptors, but the substitution in 5- or 7-positions with oxypropanolaminic groups does not generate compounds endowed with specific activity at β3-adrenoceptors. Conversely, most of these compounds behave as (specific) antagonists at β1- (cardiac) adrenoceptors. At the maximum concentrations tested (1–100 μmol/l), these compounds also exert direct spasmolytic and negative chronotropic effects, which could be related to a blockade of Ca2+-dependent mechanisms at an intracellular level and/or an anaesthetic-like activity at plasma membranes
Effects of alpha(2)-adrenergic drugs on small intestinal motility in the horse: An in vitro study
No full textThe effects of selective a2-agonists (xylazine, detomidine and medetomidine) and antagonists (yohim- bine and atipamezole) on in vitro small intestine motility in the horse were evaluated. Samples of equine jejunum were placed in isolated organ baths and drug-induced modifications of motility were measured by means of an isotonic transducer. All tested a2-agonists dose-dependently reduced both spontaneous and electrically-evoked phasic contractions. Conversely, a2-antagonists were ineffective when tested alone, and showed a heterogeneous and dose-independent ability to inhibit agonist activity. In particular, the antagonism exerted by higher concentrations of both yohimbine and atipamezole against a2-agonists was weaker than when lower concentrations were used. The data are indicative of the presence of both pre- and post-synaptic a2-adrenoceptors with inhibitory activity on equine jejunum motility, and sup- port a possible therapeutic utility of these drugs in horse intestinal disorders associated with hypermotility
Benzisothiazoles and β-adrenoceptors: Synthesis and pharmacological investigation of novel propanolamine and oxypropanolamine derivatives in isolated rat tissues
No full textIn an attempt to examine the ability of benzisothiazole-based drugs to interact with beta-adrenoceptors, a series of 1,2-benzisothiazole derivatives, which were substituted with various propanolamine or oxypropanolamine side chains in the 2 or 3 position, were synthesised and tested. The pharmacological activity of these compounds at the beta-adrenoceptors was examined using isolated rat atria and small intestinal segments, which preferentially express the beta1- and beta3-adrenoceptor-mediated responses, respectively. None of these products showed any beta-adrenoceptor agonistic activity. In contrast, the 2- and 3-substituted isopropyl, tert-butyl, benzyl, and piperonyl derivatives 2a-d and 3a-d elicited surmountable inhibition of the isoprenaline-induced chronotropic effects in the atria, suggesting competitive antagonism at the beta1-recognition site. The pA2 values revealed tert-butyl 3b and the isopropyl substituted piperonyl derivatives 3a to be the most effective. Remarkably, many of the 2-substituted propanolamines were less active than the corresponding 3-substituted oxypropanolamines. With the exception of compound 3b, none of these drugs antagonised the muscle relaxant activity of isoprenaline in the intestine, suggesting no effect on the beta3-adrenoceptors. These results confirm the ability of the benzisothiazole ring to interact with the beta-adrenoceptors, and demonstrate that 2-substitution with propanolamine or 3-substitution with oxypropanolamine groups yields compounds with preferential antagonistic activity at the cardiac beta1-adrenoceptors. The degree of antagonism depends strongly on both the nature of the substituent and its position on the benzisothiazole ring
Effect of intraurethral administration of atracurium besylate in male cats with urinary obstruction due to naturally acquired urethral plugs.
No full textABSTRACT
Objective. The aim of this study was to evaluate the effect of intraurethral administration of atracurium besylate (AB) on urinary obstruction due to urethral plugs in male cats.
Methods. Forty-five male cats were divided into: (i) the treatment group (n=25) in which the urethral area was irrigated with AB (0.5 mg/ml) and (ii) the control group (n=20) not irrigated with AB.
Results. In the treatment group, the urethral plugs were removed at the first and second attempts in 64% and 36%, respectively, of the animals. The corresponding values in the control group were 15% and 85%. The proportion of cats in which the plug was removed at the first attempt was higher in the treatment group than in the control group (16/25 versus 3/20, respectively; P<0.05). The overall mean (±SD) time required for removal of the urethral plugs was 21.1±16.2 sec in the treatment group and 235.2±232.4 sec in the control group (P<0.001).
Clinical significance. The results of this study indicate that in adult male cats with urethral plugs, urethral administration of AB increases the proportion of animals in which the obstruction is removed at the first attempt and reduces the time required to remove the urethral plugs
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