Effect of TYB-2285 on lung anaphylaxis in actively sensitized rats

• 1.1. We examined the effect of TYB-2285 on the acute phase and the late phase of lung anaphylaxis in rats.
• 2.2. TYB-2285 (3-30 mg/kg PO) inhibited antigen-induced bronchoconstriction and TxB₂ production during the acute phase of lung anaphylaxis in a dose-dependent manner.
• 3.3. Ketotifen fumarate (30 mg/kg PO) inhibted bronchoconstriction and TxB₂ production less potently than TYB-2285.
• 4.4. TYB-2285 (30 mg/kg PO) inhibited the accumulation of neutrophils during the late phase of lung anaphylaxis significantly without a significant change in total cells.
• 5.5. Hydrocortisone acetate (100 mg/kg PO) inhibited the accumulation of total cells as potent as neutrophils.

     

On the relation of calcium channel blockers to rat parotid and submandibular glands function in vivo

• 1.1. The effects of nifedipine, verapamil and diltiazem on rat parotid and submandibular glands function were studied.
• 2.2. Nifedipine (5 mg/kg), verapamil (5 mg/kg) and diltiazem (10 mg/kg) were injected intraperitoneally 15 min before saliva collection.
• 3.3. Animals were anesthetized with 50 mg/kg of sodium pentobarbital and 8 mg/kg of pilocarpine was used as secretagogue.
• 4.4. Submandibular saliva was analyzed for flow rate, protein and calcium concentrations; and parotid saliva for calcium and amylase contents.
• 5.5. In treated groups, flow rate and calcium of submandibular saliva were significantly lower than controls. Parotid calcium in the nifedipine group was decreased and in verapamil and diltiazem groups was increased. Parotid amylase was significantly decreased in both the nifedipine and diltiazem groups.
• 6.6. It is concluded that a blockade of calcium channels in salivary glands acinar cells by CCBs causes some alterations in salivary secretions.

     

The influence of various experimental conditions on the expression of naloxone-induced withdrawal symptoms in mice

• 1.1. Physical dependence was induced in mice by repeated injections of increasing doses of morphine for either 4 or 7 days.
• 2.2. Withdrawal symptoms induced by naloxone (1 mg/kg, i.p.) given 3 hr postmorphine were more severe in mice treated for 7 than for 4 days.
• 3.3. In mice that developed a similar degree of dependence, various doses of naloxone (0.1–10 mg/kg) given 3 hr postmorphine produced withdrawal symptoms of different intensities.
• 4.4. Withdrawal jumping was maximal at naloxone (1 mg/kg) but declined with further increases in the dose of the antagonist.
• 5.5. “Wet dog” shakes progressively increased with increasing doses of naloxone (0.1–10 mg/kg).
• 6.6. Variation in the temporal time interval between the last dose of morphine and that of naloxone (1 mg/kg) influenced the intensity of withdrawal symptoms.
• 7.7. In male and female mice that developed a similar degree of dependence, no major differences were observed in the severity of withdrawal symptoms-induced by naloxone (1 mg/kg) given 3 hr postmorphine.

     

Effect of cyproheptadine treatment on conditioned avoidance response in female rats

• 1.1. The percentage of conditioned avoidance response was higher during proestrus compared to diestrus.
• 2.2. Cyproheptadine (CPH) significantly enhanced avoidance behavior during diestrus.
• 3.3. On the other hand, CPH treatment did not alter avoidance behavior during proestrus.
• 4.4. Serum progesterone and testosterone levels were determined at the end of 60 trials for acquisition of conditioned avoidance response after prolonged (12–15 days) CPH treatment (0.5 mg/kg for 24 h per os (p.o.).
• 5.5. Prolonged CPH treatment lowered adrenal testosterone levels, and rats with impaired avoidance had higher testosterone and progesterone levels.
• 6.6. The results of this study indicate a positive role for CPH in the acquisition of avoidance response during diestrus, and a negative effect of progesterone and adrenal testosterone on the avoidance response.

     

Influence of opiate tolerance and calcium channel antagonists on the antinociceptive effects of L-arginine and NG-nitro L-arginine

• 1.1. The antinociceptive effects induced by L-arginine (L-Arg 300–600 mg sc) or N^G-nitro-L-arginine (NOArg 20–70 mg sc) in mice were assessed by the hot-plate test.
• 2.2. The antinociception induced by both agents was antagonized by naloxone. L-Arg significantly reduced the effects of the largest doses of morphine (3, 5, and 10 mg/kg) or pentazocine (7.5, 15, and 30 mg/kg).
• 3.3. Morphine antagonized L-Arg-induced antinociception but did not change the responses to NOArg.
• 4.4. Diltiazem (10 mg/kg) or verapamil (10 mg/kg) decreased L-Arg antinociceptive responses, whereas the effects of NOArg were enhanced.
• 5.5. The antinociceptive effects of L-Arg and NOArg were also tested in mice rendered tolerant to morphine or pentazocine. Whereas the effect of L-Arg were lower in tolerant animals, the responses to NOArg were unchanged.
• 6.6. The results suggest the involvement of opiate mechanisms and NO synthesis in L-ARG-induced antinociception and a lesser influence of opiate mechanisms in the antinociception induced by NOArg.

     

Alteration by ouabain of rat submandibular glands function

• 1.1. Effects of various doses of intraperitoneal ouabain (1, 2 and 5 mg/kg) on rat submandibular saliva were investigated in this study.
• 2.2. Potassium and calcium and their product (K⁺ × Ca²⁺) were found to be elevated in all groups.
• 3.3. Changes in salivary flow were not the major cause of the alterations in electrolytes.
• 4.4. Protein concentrations were elevated in the doses of 1 and 2 mg/kg of the drug and somewhat reduced in the dose of 5 mg/kg of ouabain but still above the base line.
• 5.5. The results show that there is an ouabain-induced close parallelism between magnesium and total protein secretion from rat submandibular glands.

     

Increased toxicity of methamphetamine in morphine-dependent mice

• 1.1. The effect of methamphetamine on morphine-dependent mice was investigated by calculating the LD₅₀ (IP), measuring motor activity, anorectic actions, and body temperature.
• 2.2. Methamphetamine was more toxic in morphine-dependent mice (LD₅₀=20.6 mg/kg) than in normal mice (LD₅₀=43.2 mg/kg).
• 3.3. Methamphetamine-induced locomotor activity was greater in morphinized than in nonmorphinized mice at doses of 2.5 and 5 mg/kg IP.
• 4.4. Methamphetamine also increased the body temperature of morphinized mice more than that of normal mice (P<0.05).
• 5.5. These findings suggest that methamphetamine is more toxic in morphine-dependent than in nondependent mice.

     

Hemodynamic effects of barnidipine hydrochloride in conscious squirrel monkeys

• 1.1. The effects of barnidipine, a new dihydropyridine Ca²⁺ antagonist, on cardiovascular and renin-angiotensin-aldosterone systems were investigated in conscious squirrel monkeys.
• 2.2. Barnidipine (0.3–3 mg/kg p.o.) produced a dose-related decrease in systolic blood pressure. The hypotensive action after 3 mg/kg p.o. lasted more than 8 hr.
• 3.3. Barnidipine increased heart rate, but did not affect the PQ-interval of the electrocardiograph.
• 4.4. Barnidipine (1 and 3 mg/kg p.o.) increased plasma renin activity dose-dependently. However, it had no significant effect on plasma aldosterone concentration.
• 5.5. These results indicate that barnidipine produces a sustained hypotension without affecting atrioventricular conduction time and plasma aldosterone concentration in conscious squirrel monkeys.

     

3-(3-Hydroxyphenyl)-N-(1-Propyl)piperidine elicits convulsant effects in mice

• 1.1. The behaviour and EEG effects of the dopamine and sigma (σ) ligands (+) 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)3-PPP) were studied in mice.
• 2.2. (+) 3-PPP dose-dependently (60–100 mg/kg i.p.) produced behavioural and electrical tonic-clonic seizures.
• 3.3. The incidence of the tonic seizures elicited by 100 mg/kg of the drug was significantly (P < 0.05) prevented by spiperone (0.5 mg/kg i.p.) and haloperidol (0.5 mg/kg i.p.).
• 4.4. The results show an influence on the behavioural and electrical threshold of convulsions by (+) 3-PPP depending on a prevalent interference on dopamine receptors.

     

Antinociceptive effects of clebopride in the mouse

• 1.1. The effects of the substituted benzamide clebopride, an orthopramide, on nociception of chemical and thermal stimuli were investigated.
• 2.2. Clebopride (0.5, 1.0 and 2.0 mg/kg) promoted significant analgesia in the tail-flick and hot-plate tests and against abdominal constrictions produced by acetic acid or acetylcholine.
• 3.3. The analgesic effects of clebopride were not influenced by pretreatment with naltrexone (1-3 mg/kg).
• 4.4. These results suggest that clebopride induces analgesia against both thermal and chemical nociceptive stimuli, which is not mediated via opioid mechanisms.

     

Effects of vinca alkaloids on rat parotid and submandibular glands function in vivo

• 1.1. Vincristine (1 mg/kg) and vinblastine (2 mg/kg) were injected intraperitoneally into the rats, 24 hr before the experiments.
• 2.2. Animals were anesthetized with 50 mg/kg of sodium pentobarbital and saliva was collected from vincristine-treated, vinblastine-treated and control animals using 8 mg/kg of pilocarpine as secretagogue.
• 3.3. Parotid saliva was analyzed for protein, amylase and Ca²⁺ content, and submandibular saliva for flow rate, protein and Ca²⁺ concentration.
• 4.4. Saliva from two treated groups was significantly lower (P < 0.01) in flow rate, amylase and protein content than that of control groups. Calcium level was significantly increased (P < 0.05) in treated animals.
• 5.5. It is concluded that the antisecretory effects of vinca alkaloids may be consistent with their actions on salivary cell microtubules.

     

The therapeutic effect of a combination of cofpropamine,a caffeine derivative,and cyclophosphamide on the development of adjuvant arthritis of rats and collagen arthritis of mice

• 1.1. Cofpropamine (Cofa), a caffeine derivative that inhibits polyadenoribosylation, enhances the therapeutic effect of cyclophosphamide (CPA) in two animal models of arthritis.
• 2.2. The development of adjuvant arthritis of rats is reduced by treatment with 2 × 50 mg/kg IP CPA and 2 × 50 mg/kg IP Cofa.
• 3.3. The development of collagen arthritis in mice is prevented by treatment with 12.5 mg/kg IP CPA and 150 mg/kg IP Cofa three times per week.

     

Effects of oxotremorine and pilocarpine on striatal acetylcholine release as studied by brain dialysis in anesthetized rats

• 1.1. The effects of oxotremorine and pilocarpine on striatal acetylcholine (ACh) release were investigated using brain microdialysis techniques in urethan-anesthetized rats.
• 2.2. Oxotremorine (0.1 and 0.5 mg/kg, IV), a preferential M₂ agonist, dose-dependently decreased ACh release in the striatum. On the other hand, pilocarpine, at 5 mg/kg (IV), showed a tendency to decrease ACh release in the striatum but, at 7.5 and 10 mg/kg (IV), significantly enhanced release in a dose-dependent manner.
• 3.3. The effect of oxotremorine was blocked by scopolamine (0.1 mg/kg, IV) but not by pirenzepine (10 mg/kg, IV), a selective M₁ antagonist.
• 4.4. Pilocarpine (10 mg/kg, IV) enhancement of striatal ACh release was not affected by 10 mg/kg pirenzepine, but 5 mg/kg pilocarpine significantly increased ACh release in scopolamine (0.1 mg/kg) pretreated rats without affecting the release by itself.
• 5.5. These results suggest that oxotremorine-induced decrease in striatal ACh release is due to stimulation of presynaptic M₂ autoreceptor, and that the increase of striatal ACh release by pilocarpine is mediated by mechanism(s) other than effects on muscarinic ACh receptors.

     

Modification of testicular cytochrome P-450 after fenitrothion administration

• 1.1. The effect of fenitrothion on testicular microsomal system was analyzed and compared to the modifications induced by the drug at the hepatic level.
• 2.2. Acute (165 mg/kg, 1 day) and subacute (55 mg/kg, 3 days) administration of fenitrothion caused a significant decrease on testicular cytochrome P-450 content (51 and 50% respectively) but no modification on cytochrome b₅ and NADPH cytochrome c reductase. No changes were induced by fenitrothion in testicular microsomal system after chronic treatment (5.5 mg/ml, 30 days).
• 3.3. Results obtained in the liver were very similar to those observed in testis even though the percentage of cytochrome P-450 inhibition obtained after acute and subacute drug administration (45 and 43%) was smaller.
• 4.4. In addition, changes in testosterone blood concentrations were also analyzed. A significant reduction of hormone plasma levels were detected at 165 and 55 mg/kg doses of fenitrothion (98% in both cases). Fenitrothion was not able to modify the levels of testosterone in the blood after chronic administration.

     

Dexamethasone modifies the behavioral effects induced by clonidine in mice

• 1.1. The present study examines the influence of dexamethasone on behavioral effects induced by clonidine in mice.
• 2.2. The behavior elements considered were locomoter activity, rota rod, catalepsy and stereotyped behavior (rearing, grooming, social response test, crossing, smelling, washing face, scratching and bar holding).
• 3.3. Clonidine (0.1-0.5-1.0 mg/kg, IP) induced a significant reduction of all behavioral elements studied when compared to the saline treated group: the behavioral reduction was significant 10 min after administration and lasted for the entire recording period (120 min).
• 4.4. Dexamethasone (0.1-0.5-1.0 mg/kg, IP) per se did not induce significant changes in the behavior elements recorded.
• 5.5. Dexamethasone (0.1-0.5 mg/kg, IP) did not affect behavioral effects induced by the 3 doses of clonidine, whereas the high dose (1 mg/kg) of the steroid significantly reduced its behavioral inhibition.
• 6.6. The results of the present study suggest that dexamethasone induces significant effects on clonidine-induced behavioral effects and that this may be related to an interference with the monoaminergic system.

     

Inhibition by ginseng total saponin of the development of morphine reverse tolerance and dopamine receptor supersensitivity in mice

• 1.1. Ginseng total saponin (GTS), 200 mg/kg i.p. 3 hr prior to morphine, inhibited the development of reverse tolerance to the ambulatory-accelerating effect of morphine.
• 2.2. GTS, 200 mg/kg, also prevented the development of dopamine receptor supersensitivity induced by the chronic administration of morphine, 10 mg/kg a day for 7 days.
• 3.3. These results suggest that GTS may be useful for the prevention and therapy of the adverse action of morphine.

     

Protection from acetaminophen-induced liver damage by the synergistic action of low doses of the poly(ADP-ribose) polymerase-inhibitor nicotinamide and the antioxidant N-acetylcysteine or the amino acid l-methionine

• 1.1. An array of therapeutically used analgetic and antirheumatic drugs cause severe liver damage. The present study investigates the hepatoprotective effects of inhibitors of NAD-dependent adenoribosylation reactions and of antioxidants in analgesic-induced hepatic injury.
• 2.2. Male NMRI mice were treated PO with 500 mg/kg of acetaminophen, and the activities of both glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) were determined in serum.
• 3.3. The acetaminophen-induced release of both GOT and GPT from injured liver cells could be inhibited in a dose-dependent manner, when mice were injected additionally either with increasing amounts (from (25 mg/kg to 100 mg/kg IP) of the PARP-inhibitor nicotinamide, with increasing amounts (from 25 mg/kg to 100 mg/kg IP) of the antioxidant N-acetylcysteine, or with increasing amounts (from 50 mg/kg to 300 mg/kg IP) of the amino acid l-methionine.
• 4.4. A combination of both nicotinamide and N-acetylcysteine (at the low dose of 12.5 mg/kg IP each) results in a complete protection from acetaminophen-induced release of GOT and GPT from injured liver cells.
• 5.5. A combination of both L-methionine and N-acetylcysteine or nicotinamide (at the low dose of 12.5 mg/kg IP each) resulted also in complete protection from acetaminophen-induced release of GOT and GPT.

     

Pharmacological evidence that nitric oxide can act as an endogenous antipyretic factor in endotoxin-induced fever in rabbits

• 1.1. This study investigates the effects of the nitric oxide donors on lipopolysaccharide-induced fever in rabbits, and the effect of brain nitric oxide synthase inhibition on the febrile response in pyrogen tolerant animals.
• 2.2. The febrile response was reduced by intravenous injections of the nitric oxide donors molsidomine (1.0 mg/kg) and isosorbide dinitrate (0.5 mg/kg) 60min after intravenous treatment with lipopolysaccharide.
• 3.3. The magnitude of fever was also attenuated by intracerebroventricular administration of molsidomine (75 μg).
• 4.4. Intracerebroventricular pretreatment with the nitric oxide synthase inhibitor, N^G-nitro-l-arginine (100μg) 10 min before the injection of lipopolysaccharide significantly enhanced the febrile response in pyrogen tolerant animals.
• 5.5. The results suggest that nitric oxide is involved in the central mechanisms of thermoregulation during fever as one of the effective endogenous antipyretics.

     

Comparison of the protective effect of (R)-α-methylhistamine and its prodrugs on gastric mucosal damage induced by ethanol in the rat

• 1.1. The gastroprotective activity of two azomethine prodrugs of (R)-α-methylhistamine was examined in lesions induced by absolute ethanol (1 ml/rat intragastrically for 1 h).
• 2.2. Pretreatment with (R)-α-methylhistamine as well as with the prodrugs (30 and 100 mg/kg intragastrically [IG]) significantly reduced macroscopically visible lesions caused by ethanol, with protection being almost complete at 100 mg/kg.
• 3.3. Histologically, in rats pretreated with the three compounds at a dose of 100 mg/kg, the evidence of damage was rare, with the appearance of gastric mucosa being similar in the different treatment groups.
• 4.4. Present results are suggestive of a local component in the protective activity of (R)-α-methylhistamine.

     

Preventive and curative effects of Artemisia absinthium on acetaminophen and CCl4-induced hepatotoxicity

• 1.1. Effect of aqueous-methanolic extract of Artemisia absinthium (Compositae) was investigated against acetaminophen- and CCl₄-induced hepatic damage.
• 2.2. Acetaminophen produced 100% mortality at the dose of 1 g/kg in mice while pretreatment of animals with plant extract (500 mg/kg) reduced the death rate to 20%.
• 3.3. Pretreatment of rats with plant extract (500 mg/kg, orally twice daily for two days) prevented (P < 0.01) the acetaminophen (640 mg/kg) as well as CCl₄ (1.5 ml/kg)-induced rise in serum transaminases (GOT and GPT).
• 4.4. Post-treatment with three successive doses of extract (500 mg/kg, 6 hr) restricted the hepatic damage induced by acetaminophen (P < 0.01) but CCl₄-induced hepatotoxicity was not altered (P > 0.05).
• 5.5. Plant extract (500 mg/kg) caused significant prolongation (P < 0.05) in pentobarbital (75 mg/kg)-induced sleep as well as increased strychnine-induced lethality in mice suggestive of inhibitory effect on microsomal drug metabolizing enzymes (MDME).
• 6.6. These results indicate that the crude extract of Artemisia absinthium exhibits hepatoprotective action partly through MDME inhibitory action and validates the traditional use of plant in hepatic damage.