Effects of administration of phentonium bromide on opioid withdrawal syndrome in rats

This study has tested whether phentonium bromide, a quaternary ammonium anti-muscarinic agent, could reverse the signs of precipitated opioid withdrawal. Rats were treated with either saline or morphine for 4 days, after which half the rats received naloxone and half saline. Each animal also received one of four doses of phentonium bromide (0, 1, 3 and 9 mg kg(-1), i.p.). Administration of phentonium bromide in rats receiving naloxone after chronic morphine treatment reduced the intensity of withdrawal signs such as increased defecation or micturition, salivation and wet-dog shakes, and elevated the nociceptive threshold values. The effects of administration of phentonium bromide might result from its anti-muscarinic activity interfering peripherally with the mechanisms involved in the regulation of the withdrawal symptoms. The use of this drug is thus suggested as a possible means of controlling some of the signs observed during the acute phase of opioid withdrawal in heroin addicts.     

Effect of prenatal haloperidol administration on anxiety patterns in rats

Haloperidol (0.1 mg/kg, i.p.) treatment was given from day 12 to 20 of gestation to pregnant rats, this being the critical period for neural development in this species. The pups born were subjected to open-field exploratory behaviour, tunnel-board exploratory behaviour, elevated zero-maze and elevated plus maze behaviour tests at 7-8 weeks of age. The results indicate that prenatal haloperidol treatment induces a significant increase in open-field ambulations and rearings, decrease in scratching and licking/washing behaviours whereas grooming and faecal droppings remain unchanged. Significantly reduced activity in the centre and increased activity in the periphery of the tunnel board was noted. These suggest presence of anxiety in these animals. Significant anxiogenic behavioural patterns were also observed on elevated zero-maze and plus-maze in the prenatally haloperidol treated offsprings. The results suggest that prenatal exposure of haloperidol leaves a lasting effect on offsprings resulting in hyper-emotional responsiveness and anxiety state.     

Effects exerted by otilonium bromide administration on precipitated opioid withdrawal syndrome in rats

An opioid withdrawal syndrome was induced in rats by repeated morphine administration and final naloxone injection. The withdrawal causes alteration of several physiological signs. The aim of the study was to prevent the altered physiological profiles by utilising otilonium bromide. Morphine was administered in three daily i.p. injections for 4 days at doses of 9, 16 and 25 mg/kg (1st day), 25, 25 and 50 mg/kg (2nd day), 50, 50 and 50 mg/kg (3rd day) and 50, 50 and 100 mg/kg (4th day). Naloxone was injected (30 mg/kg) i.p. 180 min after the last morphine injection. Otilonium bromide was administered orally at 0, 2, 4 and 8 mg/kg, 120 min before the naloxone administration. Signs like faecal and urine excretion, rectal temperature and pain threshold levels, salivation, jumping and wet dog shakes were affected in different ways. Notably the administration of otilonium bromide in rats receiving morphine together with naloxone decreased the intensity of certain withdrawal symptoms, such as excretion of faeces, wet dog shake behaviour, and elevated the nociceptive threshold values. The effects exhibited by otilonium bromide administration may be explained through its calcium antagonist activity interfering with a mechanism involved in the regulation of these previously mentioned withdrawal symptoms. The use of this drug is thus suggested as a possible control of some acute opioid withdrawal signs in heroin addicts.     

Decrease in effects of muscimol on the dorsal root after repeated administration of diazepam in rats

In in situ experiments on spinal rats transected at the C1 level and on non-spinal rats, muscimol (3 mg/kg, i.v.) depolarized the primary afferent fibers and diazepam (3 mg/kg, i.v.) potentiated this effect of muscimol. When diazepam was given for 14 days, the effect of muscimol was significantly reduced in non-spinal rats. These findings suggest that diazepam probably interacts with GABA-ergic mechanisms more closely in supraspinal regions of the rat.     

Is there a beneficial effect of the calcium channel blocker diltiazem on cyclosporine A nephrotoxicity in rats?

To investigate whether or not there is a beneficial effect of diltiazem (D) on cyclosporine A (CsA) nephrotoxicity, renal function, CsA blood levels, and effects of CsA on biotransformation in the liver and on lipid peroxidation were characterized in rats. A single administration of D (60 mg/kg b.wt.) reduced urinary volume (UV), GFR and excretion of Na+ and K+, whereas a single dose of CsA (60 mg/kg b.wt.) alone had no respective effects. P-aminohippurate excretion was almost equal in all groups. Lower doses of D (and CsA) were without effects. After repeated CsA treatment a retardation in body weight gain was seen, with little effect of a co-administration with D hereon. In all tests, thymus mass was reduced by CsA, the weight of spleen, liver, adrenal glands, and kidney were not generally affected by any of the treatments. Furthermore, after repeated administration of CsA and/or D, urinary volume, GFR and Na+ excretion were reduced by CsA, too. Electrolyte concentrations in plasma showed no evident changes by any of the treatments for Na+ and Ca2+. After long time treatment, CsA and CsA + D quite similarly led to higher K+ but lower Mg2+ concentrations in plasma. Only with 7 days highest dosage treatment PAH excretion was reduced significantly by CsA and CsA + D treatment. Surprisingly, CsA levels measured in blood and in kidney tissue, showed lower values after co-administration with D compared to CsA treatment alone. This could be caused by higher activities of monooxygenase functions revealed after pretreatment with D alone. Reduced glutathione (GSH) contents in kidney were elevated in CsA and CsA + D treated groups. In general no significant differences were to be observed concerning lipid peroxidation and stimulated H2O2 formation. Altogether evident protective effects of diltiazem on CsA nephrotoxicity in rats could not be proven.     

Differential effects of diazepam on anxiety in streptozotocin induced diabetic and non-diabetic rats

In the absence of added Fe2+, the ATPase activity of isolated Schizosaccharomyces pombe plasma membranes (5-7 mumol P(i) per mg protein per min) is moderately inhibited by H2O2 in a concentration-dependent manner. Sizable inactivation occurs only at 50-80 mmol/L H2O2. The process, probably a direct oxidative action of H2O2 on the enzyme, is not induced by the indigenous membrane-bound iron (19.3 nmol/mg membrane protein), is not affected by the radical scavengers mannitol and Tris, and involves a decrease of both the K(m) of the enzyme for ATP and the V of ATP splitting. On exposing the membranes to the Fenton reagent (50 mumol/L Fe2+ + 20 mmol/L H2O2), which causes a fast production of HO. radicals, the ATPase is 50-60% inactivated and 90% of added Fe2+ is oxidized to Fe3+ within 1 min. The inactivation occurs only when Fe2+ is added before H2O2 and can thus bind to the membranes. The lack of effect of radical scavengers (mannitol, Tris) indicates that HO. radicals produced in the bulk phase play no role in inactivation. Blockage of the inactivation by the iron chelator deferrioxamine implies that the process requires the presence of Fe2+ ions bound to binding sites on the enzyme molecules. Added catalase, which competes with Fe2+ for H2O2, slows down the inactivation but in some cases increases its total extent, probably due to the formation of the superoxide radical that gives rise to delayed HO. production.     

Effect of KATP channel blocker U37883A on renal function in experimental diabetes mellitus in rats

An increase in glomerular filtration rate (GFR) in early diabetes mellitus is considered a risk factor for the development of diabetic nephropathy. Insulin deficiency may increase the activity of ATP-sensitive potassium channels (KATP), which could promote afferent arteriolar vasodilation und thus contribute to glomerular hyperfiltration in early diabetes mellitus. To further elucidate this hypothesis we performed renal clearance experiments in anesthetized rats at 2 and 6 weeks after onset of streptozotocin-induced insulin-treated diabetes mellitus and studied the acute effect of the putative KATP channel blocker 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexylhydr ochloride (U37883A) on renal function. In control rats, application of U37883A (1.5 mg/kg i.v. bolus plus 1.5 mg/kg/hr) induced a significant reduction in heart rate, but did not affect or even slightly increased mean arterial blood pressure. Furthermore, U37883A did not significantly affect renal vascular resistance, renal blood flow or GFR, but caused an eukaliuretic diuresis and natriuresis and lowered plasma renin activity. Diabetic rats at both 2 or 6 weeks after streptozotocin exhibited essentially an identical response to U37883A; in particular, RVR and glomerular hyperfiltration remained unchanged. These results show that in both control and diabetic rats, the renal excretory function, renin secretion and pace setting in the heart were sensitiv to U37883A, implying a functional contribution of KATP channel activity. However, in both control and diabetic rats, renal vascular resistance, renal blood flow, or GFR were not altered by U37883A. These results argue against a substantial role for KATP channels in the basal control of renal hemodynamics in both nondiabetic and diabetic rats.     

Use of amrinone and glucagon in a case of calcium channel blocker overdose

Hypotension resulting from calcium channel blocker ingestion often is refractory to standard therapeutic modalities. Amrinone and glucagon have been used separately and in combination with other agents in the treatment of calcium channel blocker overdose. We report the successful use of both amrinone and glucagon in the treatment of a 30-year-old woman who ingested 3.6 g of verapamil and presented with refractory hypotension. The use of the two agents together may provide improved inotropic support with minimal increases in myocardial oxygen consumption. In this case, the combination of amrinone and glucagon was safe and effective in the management of the hemodynamic instability associated with calcium channel blocker overdose.     

Effects of nicotine dose and administration method on withdrawal symptoms and side effects during short-term smoking abstinence.

The effects of using several different nicotine replacement treatments on self-reported withdrawal symptoms and side effects during 2-day periods of smoking cessation, with 5 days of ad lib smoking between cessation days, were evaluated. Participants (N ?=?18) experienced the following conditions: nicotine gum, 24-hr patch, 16-hr patch, 24-hr patch plus gum, double 24-hr patch, and no nicotine replacement. The present study found morning urge to smoke was greater during the 16-hr than during the 24-hr patch condition. Double-patch use resulted in significantly greater insomnia than the smoking baseline and 16-hr patch conditions. The no medication and gum alone conditions resulted in similar withdrawal symptoms, and both tended to result in greater reported withdrawal symptoms than the smoking baseline condition. There were no significant withdrawal symptom differences between the 24-hr, patch-gum, and double-patch conditions. The 24-hr and double-patch conditions were preferred by two thirds of the participants (6 each). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Metabolism and pharmacokinetics of barnidipine hydrochloride, a calcium channel blocker, in man following oral administration of its sustained release formulation

1. The metabolism and pharmacokinetics of barnidipine hydrochloride, a 1, 4-dihydropyridine calcium antagonist were evaluated following single oral administration of a sustained release formulation (SR) capsule comprising of quick and slow release pellets to healthy male volunteers. 2. Various metabolites were identified and quantitated by newly established GC-MS analytical methods. Major metabolites were the hydrolyzed product of the benzyl-pyrrolidinyl ester (M-3) in plasma and its oxidized pyridine product (M-4) in plasma and urine. The pyridine form of unchanged barnidipine and the N-debenzylated product were observed as minor metabolites. Therefore, the primary metabolic pathways in man are (a) hydrolysis of the benzylpyrrolidine ester, (b) N-debenzylation, and (c) oxidation of the dihydropyridine ring. 3. When the SR and normal capsules were administered at a dose of 10 mg to six subjects in a crossover design, AUC 0-infinity of unchanged drug, M-3 and 4 in each subject receiving the SR were 97 +/- 15, 85 +/- 31 and 76 +/- 21% respectively of those subjects receiving the normal formulation. The sum of the excretion of urinary metabolites for the SR formulation was 65 +/- 6% of that for the normal formulation. These data suggest that the absorption of the SR formulation is slightly reduced but that its bioavailability is comparable to that of the normal formulation.     

Prevention of salt-dependent cardiac remodeling and enhanced gene expression in stroke-prone hypertensive rats by the long-acting calcium channel blocker lacidipine

OBJECTIVE: To analyze the effect of the long-acting calcium channel blocker lacidipine on cardiovascular remodeling induced by salt loading in a genetic model of hypertension. DESIGN: We examined the influence of threshold doses of lacidipine, with little blood-pressure lowering effect, on cardiac weight and gene expression in stroke-prone spontaneously hypertensive rats (SHRSP). METHODS: SHRSPs (8-week-old) were randomly allocated to four groups: control, salt-loaded SHRSP and salt-loaded SHRSP treated with lacidipine at 0.3 and 1 mg/kg per day. Systolic blood pressure was measured by the tail-cuff method. At the end of 6 weeks of treatment, ventricles were collected and weighed. Ventricular messenger RNA was extracted and subjected to Northern blot analysis. RESULTS: Lacidipine (0.3 mg/kg per day) not only prevented the salt-dependent cardiac hypertrophy and the slight increase in systolic blood pressure induced by salt, but also prevented, largely or completely, salt-dependent increases in ventricular levels of several gene products: skeletal and cardiac alpha-actin, beta-myosin heavy chain (beta-MHC), type I collagen, long-lasting (L)-type calcium channel and preproendothelin-1. At a higher dose of 1 mg/kg per day, lacidipine further decreased systolic blood pressure below the level of control SHRSP, completely prevented salt-dependent overexpression of the beta-MHC gene and markedly attenuated salt-dependent overexpression of the transforming growth factor-beta1 gene. CONCLUSIONS: Lacidipine prevents the cardiac remodeling and enhanced gene expression induced by salt loading in SHRSP at doses that only minimally affect the high systolic blood pressure.     

Inhibitory effect of agmatine on naloxone-precipitated abstinence syndrome in morphine dependent rats

Effects of agmatine, which is an endogenous polyamine metabolite formed by decarboxylation of L-arginine, were investigated on the morphine abstinence syndrome in rats. Two pellets containing 75 mg morphine base (total 150 mg) were implanted subcutaneously on the back of rats. Seventy-two hours after morphine implantation, agmatine sulphate (20, 30 and 40 mg/kg) or saline was injected intraperitoneally. Forty-five min later, naloxone (2 mg/kg) was injected intraperitoneally to induce precipitated withdrawal. Immediately after naloxone injection, rats were observed for 15 min, and abstinence syndrome signs, which included jumping, wet dog shake, writhing, defecation, ptosis, teeth chattering and diarrhea were counted or rated. Agmatine attenuated all of the signs of the morphine abstinence syndrome dose dependently and significantly. Our results suggest that agmatine prevents naloxone-precipitated abstinence syndrome in morphine dependent rats; thus, this drug may be beneficial in the treatment of opioid dependence.     

Effect of calcium channel blockers on developing nervous syndrome of high pressure and nitrogen narcosis in mice

In the experiments conducted on mice which prior to compression in a heliox environment have been injected the blockers of various types of calcium channels (flunarezine, verapramil and nifedipine) as well as bemethyl (actoprotector) and oxymethacye (antioxidant) there escaped detection of noticeable effect of these drugs on developing the high pressure nervous syndrome (HPNS). On exposure to the hyperbaric nitrogen-oxygen environment verapromil (phenylalkulamine blocker of L-type calcium channels) had a protection effect with respect to a convulsive component of the nitrogen narcosis.     

Effect of calcium channel blockers and salbutamol on oxytocin and PGF2 alpha induced uterine contractions in rats

Calcium channel blockers verapamil (2, 10nM), diltiazem (11, 22nM), nifedipine (2.9, 14nM) and salbutamol (21, 42nM) produced concentration dependent inhibition of oxytocin induced contractions in non-pregnant rats. With verapamil and nifedipine the effect was more marked at both low and high doses. Verapamil (1,2nM), diltiazem (2.2, 11nM), nifedipine (1.4, 2.9nM) and salbutamol (2.1, 4.2nM) produced significant inhibitory effect on PGF2 alpha (0.3 microgram) induced phasic tension. However, basal tension was significantly reduced by salbutamol and nifedipine only.     

Systemic effects and withdrawal syndrome in chronic users of corticosteroids]

Three newly found vibrational levels at energies Te(v) = 45127.88(3), 51900.40(4), and 52604.95(3) cm-1 allow the first application of resonance-enhanced multiphoton ionization for detecting the SO radical in its low-energy singlet states, a1Delta and b1Sigma+. The analysis of the spectra is based on the observation of 10 rotationally resolved bands starting from a1Delta v = 0, 6 ellipsis 11 and b1Sigma+ v = 8, covering a typical range of J = 5 ellipsis 40 or 50. Population of these SO singlet states has been achieved by two-photon dissociation of SO2 in a molecular beam environment, applying wavelengths in the 248 to 291 nm range. This paper presents an analysis of the rotational, vibrational, and electronic properties of the new levels. Reviewing earlier works on the singlet states of SO, a revised term energy scheme is provided which connects the singlet and triplet systems of the molecule. Copyright 1998 Academic Press.     

Comparative effects of the N-methyl-D-aspartate antagonist MK-801 and the calcium channel blocker KB-2796 on neurologic and metabolic recovery after spinal cord ischemia

The effects of maternal exposure to picrotoxin (PT) during the prenatal and postnatal periods of sexual brain differentiation were studied. Behavioral (sexual behavior), physical (sexual maturation, body, and organ weights) and neurochemical (striatal and hypothalamic monoamine and respective metabolite levels) data were assessed in the offspring of PT-treated dams. The following results were obtained: 1) sexual maturation as measured by the day of testis descent and testis weight comparison was unchanged; 2) a decrease in male sexual behavior occurred, as well as a decrease in body, ductus deferens, and seminal vesicle weights and in plasma testosterone levels of adult male offspring; 3) striatal dopamine (DA) and homovanillic acid (HVA) levels were decreased and hypothalamic norepinephrine (NE) levels were increased. These results indicate that perinatal exposure to PT during the critical periods of male brain sexual differentiation has long-term effects on the reproductive physiology and behavior of male rats.     

Comparison of the potassium channel blocker tedisamil with the beta-adrenoceptor blocker esmolol and the calcium antagonist gallopamil in patients with coronary artery disease

BACKGROUND: Tedisamil is a new bradycardic agent proven to exert anti-ischemic and antiarrhythmic effects by blockade of the different cardiac and vascular K+ currents. HYPOTHESIS: It was the aim of the present study to compare the favorable anti-ischemic effects of tedisamil, with two long established representatives in the treatment of coronary artery disease (CAD), namely, the beta1 blocker esmolol and the Ca2 antagonist gallopamil. METHODS: The hemodynamic and neurohumoral effects of the new potassium channel blocker tedisamil, an agent with negative chronotropic and class III antiarrhythmic properties, were compared with the ultra-short-acting beta1-selective adrenoceptor blocker esmolol and the calcium antagonist gallopamil. A total of 22 patients with angiographically proven CAD and reproducible ST-segment depression in the exercise electrocardiogram was included in two studies with an almost identical design and inclusion criteria. The investigation was carried out using right heart catheterization and bicycle ergometry. A subgroup of 8 patients receiving 0.3 mg/kg body weight tedisamil intravenously (i.v.) in an open dose-finding study was compared with a group of 14 patients who had received esmolol (i.v. bolus of 500 micrograms/kg, maintenance dose 200 micrograms/kg/min) and gallopamil (initial dose 0.025 mg/kg, maintenance dose 0.0005 mg/kg/h) in a second intraindividual comparison. RESULTS: Tedisamil and esmolol reduced heart rate at rest by 13% (p < 0.001), and 6% (p < 0.05), and at maximum working levels by 8% (p < 0.01) and 9% (p < 0.05), respectively. Gallopamil increased heart rate at rest by 7% (p < 0.05), with only slight changes occurring during exercise. Corresponding findings for each drug were observed for cardiac output both at rest and during exercise [tedisamil: at rest -10% (NS), max. exercise -8%; esmolol: at rest -14% (NS), max. exercise -18% (NS); gallopamil: no significant changes]. Compared with tedisamil, stroke volume was reduced by esmolol [at rest and max. workload: -9% (NS)] and gallopamil [rest: -6% (NS), max. exercise: -2% (NS)]. Of the indirect parameters of ventricular function, that is, mean capillary wedge pressure (PCWPm) and right ventricular ejection fraction, only PCWPm demonstrated significant differences between tedisamil and gallopamil (+18% and -6% at rest, +17% and -21% during exercise, respectively; p < 0.001). Compared with gallopamil, both tedisamil and esmolol were superior in their effects on rate-pressure product, myocardial oxygen consumption, and ST-segment depression, whereas plasma lactate concentration was more reduced by tedisamil and gallopamil. Tedisamil led to a fall in norepinephrine levels in particular. CONCLUSION: Tedisamil and esmolol showed almost equipotent anti-ischemic effects at the doses administered. Tedisamil acts mainly by reductions in heart rate, and esmolol, though to a lesser degree, also by reductions in systolic blood pressure. The mechanism of gallopamil is to reduce afterload and to improve coronary perfusion. At the doses applied, however, it has lower antianginal potency compared with tedisamil and esmolol.     

Selegiline prevents long-term changes in dopamine efflux and stress immobility during the second and third weeks of abstinence following opiate withdrawal

Selegiline is an irreversible inhibitor of monoamine oxidase B with trophic and neuroprotective effects. Because of evidence for decreased dopaminergic function during the withdrawal syndromes associated with opiates and other medications with potential for abuse, we investigated effects of treatment with selegiline on in vitro measures of dopamine efflux following opiate withdrawal. Treatment with 2.0 mg/kg/day of selegiline did not modify the severity of opiate withdrawal, as assessed by weight loss over the first 3 days of abstinence. Opiate withdrawal increased immobility in response to a forced warm water swim test performed during the second and third weeks of abstinence following the onset of withdrawal. Brain slices obtained from the nucleus accumbens of opiate-withdrawn animals immediately following swim stress testing displayed diminished efflux of tritiated dopamine after two in vitro exposures to cocaine or amphetamine. Cocaine increases neurotransmitter efflux through blockade of dopamine reuptake, while amphetamine augments efflux by stimulating release of dopamine from intracellular storage vesicles. Although slices from opiate withdrawal subjects showed decreases in efflux after in vitro treatment with these agents, no differences were observed after exposure to 4-aminopyridine, which increases neurotransmitter release by prolonging action potential duration. These findings indicate mechanisms of action that are specific for catecholamine neurotransmitter systems are important for demonstrating long-term changes in dopaminergic function following opiate withdrawal. Selegiline prevented decreases in the efflux of tritiated dopamine in slices obtained from opiate-withdrawn subjects. In addition, selegiline decreased withdrawal-induced immobility during warm water swim testing. In conclusion, treatment with selegiline can prevent long-term changes in stress-induced immobility and deficits in presynaptic dopaminergic function that occur following the opiate withdrawal syndrome.