Developments and new vistas in the field of melanocortins.

AbstractMelanocortins play a fundamental role in several basic functions of the organism (sexual activity, feeding, inflammation and immune responses, pain sensitivity, response to stressful situations, motivation, attention, learning, and memory). Moreover, a large body of animal data, some of which were also confirmed in humans, unequivocally show that melanocortins also have impressive therapeutic effects in several pathological conditions that are the leading cause of mortality and disability worldwide (hemorrhagic, or anyway hypovolemic, shock; septic shock; respiratory arrest; cardiac arrest; ischemia- and ischemia/reperfusion-induced damage of the brain, heart, intestine, and other organs; traumatic injury of brain, spinal cord, and peripheral nerves; neuropathic pain; toxic neuropathies; gouty arthritis; etc.). Recent data obtained in animal models seem to moreover confirm previous hypotheses and preliminary data concerning the neurotrophic activity of melanocortins in neurodegenerative diseases, in particular Alzheimer's disease. Our aim was (i) to critically reconsider the established extrahormonal effects of melanocortins (on sexual activity, feeding, inflammation, tissue hypoperfusion, and traumatic damage of central and peripheral nervous system) at the light of recent findings, (ii) to review the most recent advancements, particularly on the effects of melanocortins in models of neurodegenerative diseases, (iii) to discuss the reasons that support the introduction into clinical practice of melanocortins as life-saving agents in shock conditions and that suggest to verify in clinical setting the impressive results steadily obtained with melanocortins in different animal models of tissue ischemia and ischemia/reperfusion, and finally, (iv) to mention the advisable developments, particularly in terms of selectivity of action and of effects

Pharmacokinetics of sumatriptan in non-respondent and in adverse drug reaction reporting migraine patients

Sumatriptan is a selectiveagonist of 5HT1 (1B/1D) receptors,which has proved to be effectiveand safe for the acute treatment ofmigraine attacks. Nevertheless, itsuse by migraine sufferers is stilllimited and some patients consideradverse reactions related to sumatriptan,especially chest symptoms,unacceptable even if not serious.Moreover, in clinical trials, almostone third and one sixth of patients,respectively, fail to experienceheadache relief either after oral orafter subcutaneous sumatriptanadministration. Our aim was to verifywhether differencies in sumatriptanpharmacokinetics couldexplain non-response and/oradverse drug reactions. Sumatriptanlevels were determined by HPLCwith electrochemical detection.Pharmacokinetic parameters werecalculated using a computer program(PK Solutions 2.0; non compartmentalPharmacokinetics DataAnalysis). After oral administration,sumatriptan is rapidly absorbed andsometimes displays multiple peaksof plasma concentration. This “multiplepeaking” gives rise to considerableinter-subject variability inthe time of reaching maximumplasma concentration.Pharmacokinetic parameters ofsumatriptan, both after oral andsubcutaneous administration, weresimilar in the three patient groups.Blood pressure and heart rate didnot show any significant differencesbetween groups. Pharmacokineticparameters and bioavailability ofsumatriptan did not seem to be correlatedeither to the lack of efficacyor the appearance of side effects.These results could depend on thelimited number of patients studied

Bombesin reverses experimental hemorrhagic shock

Bombesin reverses experimental hemorrhagic shoc

Dual acting anti-inflammatory drugs: a reappraisal

Rheumatic diseases are the most prevalent causes of disability in western countries, and nonsteroidal anti-inflammatory drugs (NSAIDs) are still the most commonly used remedies. However, NSAIDs cause several serious adverse effects, the most important being from gastric injury to gastric ulceration and renal damage. Attempts to develop non-steroidal anti-inflammatory remedies devoid of these shortcomings-especially gastrointestinal toxicity-have followed several strategies. Non-steroidal antiinflammatory drugs have, therefore, been associated with gastroprotective agents that counteract the damaging effects of prostaglandin synthesis suppression; however, a combination therapy introduces other problems of pharmacokinetics, toxicity, and patient´s compliance. More recently, incorporation of a nitric oxide (NO)-generating moiety into the molecule of several NSAIDs was shown to greatly attenuate their ulcerogenic activity; however, several findings suggest a possible involvement of NO in the pathogenesis of arthritis and subsequent tissue destruction. A most promising approach seemed to be the preparation of novel NSAIDs, targeted at the inducible isoform of prostaglandin synthase (COX-2); they appear to be devoid of gastrointestinal toxicity, in that they spare mucosal prostaglandin synthesis. However, a number of recent studies have raised serious questions about the two central tenets that support this approach, namely that the prostaglandins that mediate inflammation and pain are produced solely via COX-2 and that the prostaglandins that are important in gastrointestinal and renal function are produced solely via COX-1. So, a growing body of evidence shows that COX-2 (riot only COX-1) also plays a physiological role in several body functions and that, conversely, COX-1 (not only COX-2) may also be induced at sites of inflammation. More recent and puzzling data shows that COX-2 is induced during the resolution of an inflammatory response, and at this point it produces anti-inflammatory (PGD(2) and PGF(2 alpha)), but not proinflammatory (PGE(2)) prostaglandins; inhibition of COX-2 at this point thus results in persistence of the inflammation. Moreover, COX-2 selective NSAIDs have lost the cardiovascular protective effects of nonselective NSAIDs, effects which are mediated through COX-1 inhibition (in addition, COX-2 has a role in sustaining vascular prostacyclin production). The generation of other very important products of the arachidonic acid cascade (besides cyclooxygenase-produced metabolites) is inhibited neither by non-selective nor by COX-2 selective NSAIDs. The products generated by the 5-lipoxygenase pathway (leukotrienes) are particularly important in inflammation; indeed, leukotrienes increase microvascular permeability and are potent chemotactic agents. Moreover, inhibition of 5-lipoxygenase indirectly reduces the expression of TNF-alpha (a cytokine that plays a key role in inflammation). These data and considerations explain the efforts to obtain drugs able to inhibit both 5-lipoxygenase and cyclooxygenases, the so-called dual acting anti-inflammatory drugs. Such compounds retain the activity of classical NSAIDs, while avoiding their main drawbacks, in that curtailed production of gastroprotective prostaglandins is associated with a concurrent curtailed production of the gastro-damaging and bronchoconstrictive leukotrienes. Moreover. thanks to their mechanism of action, dual acting anti-inflammatory drugs could not merely alleviate symptoms of rheumatic diseases, but might also satisfy, at least in part, the criteria of a more definitive treatment. Indeed, leukotrienes are pro-inflammatory, increase microvascular permeability, are potent chemotactic agents and attract eosinophils, neutrophils and monocytes into the synovium

Anti-shock effect of ACTH-(1-24): influence of subtotal hepatectomy

Subtotally hepatectomized or sham-operated rats were bled to hypovolemic shock (mean arterial pressure = 18-25 mmHg) and then treated with an intravenous bolus injection of ACTH-(1-24), 160 ug/kg. The treatment caused a prompt and sustained reversal of hypotension, with survival of all sham-operated animals, at least for the first 2 h, while in hepatectomized rats the arterial pressure increase was negligible and there was a 50% mortality within 2 h after treatment. Moreover, the blood volume which could be drained from an arterial catheter prior to death, measured 15-20 min after ACTH injection, was 1.51 +/- 0.12 and 0.64 +/- 0.11 ml/100 g b.w. in sham-operated and hepatectomized rats, respectively. These results further support the idea that the effect of ACTH in haemorrhagic shock is due to the mobilization of blood pooled in peripheral reserve organs

INFLUENCE OF OXYTOCIN ON NOCICEPTION AND MORPHINE ANTINOCICEPTION

In the hot plate test the intracerebroventricular (i.c.v.) injection of oxytocin produced a significant decrease in nociception, starting from the dose of 1 mug/rat. A comparable effect was obtained with 10-200 times higher intraperitoneal (i.p.) doses. The i.c.v. injection of the oxytocin antagonist d(CH2)5-Tyr(Me)-[Orn8]-vasotocin, while having no influence per se, completely prevented the antinociceptive effect of an equal i.c.v. dose of oxytocin. The antinociceptive effect of oxytocin was also prevented by naltrexone, and oxytocin caused a small but significant increase of the antinociceptive effect of morphine and of its duration. These data indicate that pharmacological amounts of oxytocin produce antinociception, that occurs through the activation of oxytocin receptors; endogenous opioid systems seem to be involved altogether

Physostigmine has a life-saving effect in rats subjected to prolonged respiratory arrest

We have previously reported that centrally-acting cholinomimetic drugs have a prompt and sustained resuscitating effect in pre-terminal conditions of hemorrhagic shock in rats. Here we have studied the effect of physostigmine in another experimental condition of hypoxia in anesthetized rats, which were endotracheally intubated and subjected to prolonged (5 min) interruption of ventilation. This led to a dramatic fall in mean arterial pressure (MAP), pulse pressure (PP), heart rate (HR), pH, PO2, SO2 and base excess, while PCO2 increased; the electroencephalogram (EEG) became isoelectric, and the electrocardiogram (EGG) showed marked bradycardia, P-wave inversion, partial atrio-ventricular block and S-T segment elevation; all saline-treated rats died of cardiac arrest within 7.01 +/- 0.85 min of ventilation being resumed. When ventilation resumption was associated with the simultaneous intravenous (i.v.) injection of physostigmine (70 mu g/kg) there was an almost immediate and impressive increase in MAP, PP and HR, with normalization of ECG within 4 min and full recovery of EEG after 30-50 min. This was associated with a normalization of blood gases and pH. Fifteen days later 40% of treated animals were still alive and apparently in normal health, the mean survival time of the remaining 60% animals being 22.67 +/- 10.19 h. Pretreatment with atropine sulfate or hemicholinium-3 did not modify the response to physostigmine, which, however, was strongly antagonized by the intracerebroventricular injection of mecamylamine. These results suggest that centrally-acting cholinomimetic agents may have a resuscitating effect in pre-terminal conditions produced by prolonged asphyxia, probably through the direct activation of nicotinic receptors in the central nervous system

Behavioral activity and active avoidance learning and retention in rats neonatally exposed to painful stimuli.

Twice daily for the first 15 days after birth, rats from the same litters were either placed for 5 sec on a hot plate (55 degrees C) (treated group), or on a plate maintained at body temperature (38 degrees C) (manipulated group). Controls were left undisturbed. When 90 days old, they were studied for pain threshold, open-field behavior, and two-way active avoidance learning and retention. Weight gain, pain threshold, open-field behavior, and active avoidance retention were not significantly different in the three groups. On the other hand, the rate of two-way active avoidance learning was significantly greater in treated rats. These results suggest that repeated neonatal exposure to painful stimuli, in rats raised under otherwise normal conditions, improves later active avoidance performance. The most likely mechanisms are discussed

Effect of polyamines on perfused rat heart contractility

The influence of polyamines (putrescine, spermidine and spermine) on heart contractility was studied using perfused rat ventricle strips (2 X 10 mm), electrically driven at 1 Hz. Putrescine (100 microM) caused a negative inotropic effect gradually increasing in intensity, whereas spermidine and spermine (10 and 100 microM) caused a sharp, positive inotropic effect, followed by a rapid and more marked fall. The possibility that these effects of polyamines on heart contractility may be due to their role in Ca++ fluxes and mobilization, and in membrane functions, is discussed