Stefano Evangelista

Cardioprotective effects of zofenopril, a new angiotensin-converting enzyme inhibitor, on doxorubicin-induced cardiotoxicity in the rat.

We have studied the effect of zofenopril, a new angiotensin-converting enzyme inhibitor in preventing cardiac injury induced by chronic doxorubicin treatment in rats. Cardiac function was assessed by measuring changes in electrocardiogram (ECG) tracings, haemodynamics and cardiac responses in vivo to isoprenaline, 4 weeks after suspension of doxorubicin treatment, in vehicle-treated rats and in animals receiving zofenopril (15 mg/kg/os/day) alone, doxorubicin (1.5 mg/kg i.v. once a week for 5 weeks) or zofenopril+doxorubicin treatment. Doxorubicin induced a significant lengthening of the QalphaT interval, which was completely prevented by zofenopril treatment. The cardiac positive inotropic effect induced by i.v. isoprenaline was selectively depressed by doxorubicin (no changes in chronotropic responses) and this adverse effect of doxorubicin was also prevented in zofenopril+doxorubicin pretreated rats. Doxorubicin induced a significant increase in relative heart weight, which was likewise prevented in zofenopril+doxorubicin treated rats. In separate experiments, zofenopril did not interfere with the antitumor activity of doxorubicin (inhibition of tumor growth in nude mice xenografted with A2780 human tumor line). In conclusion, the oral administration of zofenopril is able to significantly ameliorate, up to 4 weeks after the end of doxorubicin administration, doxorubicin-induced cardiotoxicity without affecting the antitumor activity of this anthracycline.

Cutaneous lesions in capsaicin-pretreated rats. A trophic role of capsaicin-sensitive afferents?

Summary1. The time course and regional distribution of ‘spontaneous’ cutaneous lesions in rats desensitized to capsaicin as newborns was correlated to behavioural observations and regional distribution of substance P-like immunoreactivity (SP-LI) and tachykinin-like immunoreactivity (TK-LI) in various skin areas. 2. ‘Spontaneous’ skin lesions in the form of wounds, scabs and areas of alopecia were observed in 80–90% of rats desensitized to capsaicin. No major sex-related differences were observed with regard to incidence and distribution of the lesions with the possible exception of a lesser tendency to bilateral lesions in female rats. 3. ‘Spontaneous’ skin lesions were almost restricted to the head: the areas most frequently affected were snouts, periocular and retroauricular regions and ventral area of the neck. 4. No major differences were observed between capsaicin- or vehicle-treated animals in spontaneous or novelty-induced grooming as well as in open-field gross behaviour. Likewise, no differences were observed in the mouse-killing behaviour. 5. Both SP-LI and TK-LI in various skin areas were significantly reduced by systemic capsaicin pretreatment. The rank order of various skin areas for SP-LI or TK-LI levels was: snouts > thigh > neck > abdomen ≃ retroauricular region. 6. Intradermal injection of Arg-neurokinin B, a potent and water soluble derivative of neurokinin B, produced a similar plasma extravasation (Evans blue leakage technique) in the skin of vehicle- or capsaicin-pretreated rats. 7. In capsaicin-desensitized rats fur regrowth (measured at abdominal level, 28 days after shaving) was significantly less than in vehicle-treated animals. 8. The s. c. injection of 1 N HCl in the dorsal thoracic region (an area devoid of ‘spontaneous’ lesions in capsaicin-desensitized animals) produced cutaneous ulcers whose area and depth were greater in capsaicin- than vehicle-treated rats. 9. These findings are consistent with the hypothesis that capsaicin-sensitive nerves play a trophic role in the rat skin and contribute to its ability to react and repair injuries. The most consistent explanation for the restricted localization of ‘spontaneous’ skin lesions to the head seems to be that ‘normal’ injurious factors (such as grooming) operate on a distrophic skin to induce lesions by repeated microtrauma.

Influence of capsaicin-sensitive fibres on experimentally-induced colitis in rats

Abstract— Systemic capsaicin pretreatment worsens trinitrobenzene sulphonic acid‐induced colitis but has no effect on colitis induced by ethanol or acetic acid. The influence of capsaicin‐sensitive fibres on experimentally‐induced colitis seems to depend upon the type of ulcerogenic stimuli in relation to its chronic nature.

Effect of ricinoleic acid in acute and subchronic experimental models of inflammation

Observational studies indicate that topical application of ricinoleic acid (RA), the main component of castor oil, exerts remarkable analgesic and anti-inflammatory effects. Pharmacological characterization has shown similarities between the effects of RA and those of capsaicin, suggesting a potential interaction of this drug on sensory neuropeptide-mediated neurogenic inflammation. The aim of this study was to assess RA anti-inflammatory activities in comparison with capsaicin in several models of acute and subchronic inflammation. The acute inflammation was induced by intradermal injection of carrageenan in the mouse or by histamine in the guinea-pig eyelid. In either experiment, the extent of the oedema thickness was measured. Subchronic oedema was induced by complete Freunds adjuvant injection in the ventral right paw of mice. Tissue substance P (SP) was measured in the carrageenan experiments by radioimmunoassay (RIA). It was found that the acute topical application of RA (0.9 mg/mouse) or capsaicin (0.09 mg/mouse) significantly increased the mouse paw oedema induced by carrageenan, while an 8-day repeated topical treatment with the same doses of both compounds resulted in a marked inhibition of carrageenan-induced paw oedema matched by a reduction in SP tissue levels. Similar effects were found against histamine-induced eyelid oedema in guinea-pigs after acute or repeated application of RA or capsaicin. RA and capsaicin given for 1-3 weeks reduced the established oedema induced by Freunds adjuvant, a subchronic model of inflammation, particularly if given by the intradermal route. Either in mouse paw or in guinea-pig eyelid, capsaicin but not RA by itself produced a slight hyperemia and activation of a behavioural response (e.g. scratching of the eyelids). On the basis of the present results, RA may be seen as a new capsaicin-like, non-pungent anti-inflammatory agent suitable for peripheral application.

Topical capsaicin administration protects against trinitrobenzene sulfonic acid-induced colitis in the rat

We used the [3H]resiniferatoxin binding assay to demonstrate for the first time the existence of vanilloid receptors in the rat colon and to explore their expression during trinitrobenzene sulfonic acid-induced colitis. Membranes obtained from control colon bound [3H]resiniferatoxin with an affinity of 3 nM; the receptor density was 450 fmol/mg protein or 9 fmol/mg wet weight. Capsaicin and capsazepine, a competitive antagonist of capsaicin, inhibited specific resiniferatoxin binding with Ki values of 3 microM and 0.1 microM, respectively. Trinitrobenzene sulfonic acid induced a very rapid ulceration in the colon: 1 h after treatment 90% of the colon showed ulcerative damage. Coadministration of 640 microM capsaicin diminished the ulcerative effect of trinitrobenzene sulfonic acid to 64% when examined 1 h after trinitrobenzene sulfonic acid challenge; however, this protective action was lost 23 h later. Colon samples obtained 4 h, 24 h, and 1 week after trinitrobenzene sulfonic acid challenge bound resiniferatoxin, capsaicin, and capsazepine with affinities similar to those of control samples. The receptor density remained at an essentially constant level when expressed in fmol/mg protein but, in keeping with the increased wet weights, showed a reduction when expressed in fmol/mg wet weight. We conclude that acute capsaicin administration protects against the ulcerative action of trinitrobenzene sulfonic acid, most likely via the release of protective neuropeptides from capsaicin-sensitive nerve endings. The loss of this protective action is presumably due to a depletion of the protective neuropeptides rather than to a loss of vanilloid (capsaicin) receptors.

Anti-ulcer activity of calcitonin gene-related peptide in rats

Calcitonin gene-related peptide (CGRP, 5-10 micrograms/kg s.c.). reduced both incidence and degree of indomethacin- or acetylsalicylic acid (ASA) plus HCl-induced gastric as well as cysteamine-induced duodenal ulcers in rats. CGRP had no effect on ethanol-induced gastric lesions. The anti-ulcer activity of CGRP is most likely ascribable to its potent antisecretory properties.

Tachykinin receptor antagonists in clinical trials

Tachykinins (TKs) are small peptides widely distributed in the central and peripheral nervous systems where they act as neurotransmitters. Potent and selective TKs antagonists have been developed in the last 20 years and many efforts have been made to prove their efficacy in the treatment of various diseases. Herein the most prominent results in the clinical development are reported and discussed. For aprepitant, the only compound of this class to have been launched to date, results of clinical studies and postmarketing cost-effectiveness data for the treatment of chemotherapy-induced emesis are discussed. The field is still well active, as currently proof-of-concept studies for indications initially missed (i.e., depression) are ongoing and new targets are under investigation.

Capsaicin‐sensitive mechanisms and experimentally induced duodenal ulcers in rats

The incidence and degree of cysteamine‐ or dulcerozine‐induced duodenal ulcers are increased by systemic capsaicin desensitization (50 mg kg−1 s.c. 4 days before) in adult rats. Acute administration of capsaicin, but not neurokinins or CGRP, produced a small but distinct plasma extravasation (Evans blue leakage) in the rat proximal duodenum which was absent in capsaicin‐pretreated rats. These findings indicate the existence of a capsaicin‐sensitive ‘duodenal defence mechanism’ in rats.

Biological activity of N-terminal fragments of calcitonin gene-related peptide

The i.v. injection of human alpha-calcitonin gene-related peptide (CGRP) in urethane-anesthetized rats produced hypotension and tachycardia. The N-terminal fragments, CGRP-(1-12), CGRP-(1-15) and CGRP-(1-22) displayed biological activity, although with less potency than the natural peptide. These findings provide the first evidence for biological agonist activity of N-terminal CGRP fragments.

On the role of endogenous GABA in the forced swimming test in rats

GABA content was reduced in the nucleus accumbens, cortex and brainstem of rats after 5 but not after 45, 120 min or 24 hr, from the termination of the pretest session. This reduction was not observed in rats performing on rotarod. Intraperitoneal AOAA (25 mg/kg; 24, 5 and 1 hr before the test), reduced at the same extent immobility time regardless whether the animals had been exposed to a pretest session. In pretested animals, reduction in immobility time produced by AOAA (25 mg/kg X 3 times) was similar to that observed following 50 mg/kg, 5 hr before testing. This reduction was not antagonized by GABA antagonists bicuculline (2 mg/kg) or picrotoxin (2 mg/kg), given intraperitoneally 30 and 20 min before the test respectively. Intraperitoneal sodium valproate (200 or 400 mg/kg; 24, 5 and 1 hr before the test) and isoniazide (200 mg/kg) or 4-deoxypyridoxine (400 mg/kg), administered 1 or 1.5 hr before the test, were ineffective. AOAA (25 mg/kg X 3 times) gave a similar increase in GABA levels to 50 mg/kg only once in the brainstem, nucleus accumbens and hypothalamus and a greater increase in the other brain areas. After 5 hr from single dosing, 25 mg/kg AOAA increased GABA levels less than 50 mg/kg AOAA in the brainstem, nucleus accumbens, frontal cortex and striatum, and increased it to same extent in the other areas. Sodium valproate (400 mg/kg X 3 times) increased GABA levels in all brain areas, except hippocampus, although to a lesser extent than AOAA.