ISSN:0272-4391    

DOI:10.1002/ddr.430280202

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractWAY 100289, endo‐N‐[8‐methyl‐8‐azabicyclo [3.2.1.] octan‐3‐yl) aminocarbonyl]‐2‐cyclopropylmethoxybenzamide, was an antagonist of 5‐HT evoked depolarization (5‐HT3receptor‐mediated) of the rat isolated cervical vagus nerve (pA2value 8.9). Schild‐plot analysis was consistent with a competitive antagonist mechanism (slope 0.8), though antagonism was not fully surmountable. WAY 100289 was a relatively weak antagonist of 5‐HT3receptor‐mediated contractions of the guinea‐pig isolated ileum longitudinal muscle‐myenteric plexus preparation (pA2value 6.2). In 5‐HT3receptor binding studies in rat entorhinal cortex membranes WAY 100289 displaced [3H]‐zacopride with a pK1value of 8.4, in good agreement with results in the vagus nerve. In urethane anaesthetised rats the 5‐HT evoked Bezold‐Jarisch reflex was blocked by WAY 100289 with an ED50of 1.3 μg/kg i.v., consistent with 5‐HT3receptor antagonism. In the conscious rat WAY 100289 was approximately 30‐fold more potent by the i.v. than by the p.o. route. Following a dose of 1 mg/kg of WAY 100289 the Bezold‐Jarisch reflex was reduced by more than 50% for in excess of 6 h. In a series of in vitro functional and ligand binding assays WAY 100289 showed good selectivity for the 5‐HT3receptor with the only notable additional activity that of non‐competitive antagonism of nicotinic receptor mediated depolarization of the rat vagus nerve (−log IC50value 6.7). The compound was without significant effect as an inhibitor of the uptake of 5‐hydroxytryptamine, noradrenaline or dopamine by rat brain synaptasomes. In general, WAY 100289 is a novel, achiral 5‐HT3receptor antagonist with good in vitro potency and selectivity and good in vivo activity, oral bio‐

ISSN:0272-4391    

DOI:10.1002/ddr.430280203

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractIn support of prospective human tests, the cardiovascular, pharmacokinetic, and histopathologic drug interactions between the dihydropyridine calcium channel blocker nimodipine and the lipid peroxidase inhibitor tirilazad mesylate were examined in conscious beagle dogs. Chronic arterially cannulated dogs first received repeated oral doses of nimodipine (1 mg/kg q 4 h × 2 days) to establish its steady‐state pharmacokinetics prior to 30 min iv infusions of a citrate buffered vehicle (4 and 20 ml/kg) and tirilazad mesylate (6 and 30 mg/kg). Both vehicle and tirilazad infusions were very well tolerated in the placebo‐ and nimodipine‐pretreated dogs, and resulted in negligible changes in the plasma kinetics of the test agents. Nimodipine's phasic hypotensive response was largely unaffected by tirilazad, although its reflex tachycardia was moderately prolonged. Electrocardiographic and routine clinical parameters were within the range seen with the nimodipine plus citrate buffer combination. Plasma cholesterol, total lipids, and triglyceride levels increased slightly with tirilazad, independent of oral nimodipine therapy. Gross necropsy findings were limited to slight inflammatory liver changes in all dogs, which were attributed to the doses of heparin used to maintain catheter patency. This study demonstrates that in normal conscious dogs, standard and supratherapeutic iv doses of tirilazad mesylate can safely be combined with chronic oral nimodipine without untoward cardiovascular, pharmacokinetic, or histopathologic drug interactions. © 1993 Wiley‐

ISSN:0272-4391    

DOI:10.1002/ddr.430280204

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractMale Sprague‐Dawley rats injected with a single acute dose of carbofuran (1.5 mg/kg, sc) developed chewing movements and fine tremors within 5–7 min. The signs of maximal severity with hypercholinergic preponderance including muscle fasciculations, convulsions, tracheobronchial secretions, and diarrhea were evident within 15–30 min and lasted for about 2 h. Various antidotal drugs, alone or in combination with atropine sulfate (ATS), were administered as pretreatment or as therapeutic measures to alleviate carbofuran‐induced cholinergic toxicity. In fact, pyridine‐2‐aldoxime methylchloride (2‐PAM) or diazepam alone or in combination with ATS did not provide any beneficial antidotal effects. Combined pretreatment with memantine (MEM, 18 mg/kg, sc) and ATS (16 mg/kg, sc) provided complete protection against carbofuran toxicity and reversal of clinical evidence when given therapeutically. Carbofuran intoxication caused significant alterations in the activities of biomarker enzymes such as creatine kinase (CK) and lactic dehydrogenase (LDH) and their isoenzymes patterns in serum as a result of their leakage from the target organs (brain, muscles, and heart). Significant increases in the levels of transaminases (GOT and GPT) and glucose were also noted, MEM in the aforementioned parameters, in addition to similar protective effects reported on target enzyme acetylcholinesterase (AChE). These results, along with those reported previously, indicate that MEM antagonizes carbamates toxicity by maintaining cell membrane permeability and integrity through multiple mechanisms, in addition to muscarinic receptor blocking effect of ATS. © 1993 W

ISSN:0272-4391    

DOI:10.1002/ddr.430280205

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractApraclonidine (p‐aminoclonidine) a recognized α2‐adrenergic agonist, has been approved for use with ocular laser surgery and is under consideration for use as a chronic treatment for glaucoma. The potential cardiovascular actions of apraclonidine in conscious animals has yet to be fully explored. The present studies were performed in conscious, chronically instrumented dogs to evaluate these possible cardiovascular effects. In a first study, apraclonidine was administered iv in dosages ranging from 5 to 200 μg. When administered by this route, apraclonidine elicited profound, but transient, cardiovascular actions. Mean arterial pressure (MAP) and left ventricular systolic pressure (LVSP) showed significant increases at dosages of 50–100 μg or higher, while heart rate (HR) showed a significant reduction. No variables had values significantly different from control values 60 min after administration. In a second study, apraclonidine was applied topically to either one or both eyes in total dosages of 125–1,000 μg. In contrast to iv administration, even with doses of up to 1,000 μg, topical apraclonidine administered in the eye elicited no significant change in cardiovascular variables. In the third set of studies, the neurotransmitters acetylcholine (1–10 μg/kg) and norepinephrine (0.2–2 μg/kg) were administered iv both before and 45 min after 500 μg apraclonidine was applied to the eye. Topical apraclonidine enhanced the mean AP response to norepinephrine by as much as 18% and the LVSP response to norepinephrine by as much as 17% No effect on the response to acetylcholine was seen. We conclude that all cardiovascular changes following iv apraclonidine can be attributed to its vasoconstrictor action with the consequent rise in MAP. The absence of measurable effects after topical application was likely due to a much slower entry into the circulation, although the vasoconstrictor action of apraclonidine after topical applications seemed to be additive to that of iv norepinephrine. ©

ISSN:0272-4391    

DOI:10.1002/ddr.430280206

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractA new experimental model to assess analgesic activity of both analgesic and non‐steroidal antiinflammatory drugs in described. It uses the unilateral intra‐articular knee injection of an uric acid suspension in mineral oil to produce acute inflammation, pain, and functional motor impairment. The model, named “pain‐induced functional impairment in the rat” (PIFIR) assesses analgesic activity by measuring the capacity to walk with the injured extremity. The procedure determines both the potencies of analgesic drugs and the time course of the effect. Analgesia of selected reference agents was followed for 4 h and the effect versus time curves were constructed. The area under the curve (effect versus time), an expression of the overall activity during the observation period, increased in a dose‐dependent manner. The area under the curve, Emax, TEmax, and ED50of reference agents tested are reported. The PIFIR procedure was sensitive to opiate and nonopiate analgetics (nonsteroidal antiinflammatory drugs) and possibly steroidal antiinflammatory drugs. These characteristics make it suitable for screening purposes. © 1993 Wil

ISSN:0272-4391    

DOI:10.1002/ddr.430280207

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractThe present study characterized the antinociceptive effects of tramadol with emphasis on the site of action, the possible development of antinociceptive tolerance, and possible cross‐tolerance to morphine. Both tramadol and morphine produced antinociception as assessed in male, ICR mice using the warm water (55°C) tail‐flick test. Intrathecal (i.t.) tramadol produced an antinociceptive response, but with a shallow dose‐response curve (DRC), but i.c.v. tramadol was ineffective up to toxic doses (>380 nmol). Simultaneous co‐administration of tramadol by the i.c.v. and i.t. routes in a 1:1 fixed dose‐ratio resulted in a synergistic interaction. Construction of a naloxone dose‐response curve against an A90dose of agonist yielded an AD50(and 95% C.L.) of 0.19 (0.14–0.33) and 0.55 (0.38–0.74) μmol/kg against morphine and tramadol, respectively; both agonists were completely antagonized by naloxone. In mice pretreated twice daily (8:00 a.m. and 5:00 p.m.) with s.c. morphine the DRC for morphine was displaced 16‐fold to the right, indicating significant development of antinociceptive tolerance. The same pretreatment resulted in only a 3‐fold right‐ward shift in the tramadol DRC. Chronic twice‐daily (8:00 a.m. and 5:00 p.m.) pretreatment with tramadol resulted in only an approximate 3‐ and 4‐fold rightward displacement in the tramadol and morphine DRCs, respectively. These results suggest that tramadol has an unusual antinociceptive mechanism which may reflect a primary site of action at spinal sites with a synergistic spinal/supraspinal interaction. Further, the lack of complete cross‐tolerance between tramadol and morphine supports the suggestion of a non‐opioid mechanism for this compound, whereas the complete antagonism by naloxone apparently reflects the opioid component of its mechanism in this test. Finally, the minimal development of tolerance to tramadol antinociception reinforces the view of a favorable tolerance‐dependence profile for th

ISSN:0272-4391    

DOI:10.1002/ddr.430280208

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

Abstract3‐Nitropropionic acid (NPA) elicited a dose‐dependent relaxation of precontracted rabbit aortic rings. Since the NPA effect was independent of the contractile agonist used, it did not appear to act by blocking a specific set of receptors. Aortic rings precontracted with KCl were less sensitive to relaxation by NPA suggesting that at least part of the mechanism of vasodilation is not related to an inhibition of calcium influx through the voltage‐dependent Ca+ +channel. The arterial relaxation induced by NPA is independent of endothelium and it is not mediated by muscarinic, β‐adrenergic, nor histaminergic (H1) receptors. On the other hand, methylene blue clearly inhibited the vasodilation induced by NPA suggesting that it is a consequence of guanylate cyclase stimulation. Finally, a mild but consistent decrease of both systolic and diastolic arterial blood pressure was observed after oral NPA administration during 4 weeks to renal hypertensive dogs. The data in the present study clearly demonstrate that NPA possesses vasodilator and antihypertensive properties. © 1993 Wiley

ISSN:0272-4391    

DOI:10.1002/ddr.430280209

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractA sample of adults (n = 148) which reflected age, gender, and race characteristics of the 1980 U.S. Census was surveyed on the incidence of obtaining over the counter (OTC) drugs during the previous year and the nature of the drugs used. Most (78%) reported obtaining OTC drugs, and of 15 categories, headache or pain remedies, cold or flu remedies, and vitamins were most frequently (>50%) reported as used. No gender or race effects were found for obtaining OTC drugs or for the nature of OTC drugs used. Identified patterns of OTC drug use were related to previous research and have implications for drug development, health care, and marketing concerns. © 1993 Wiley‐Liss, I

ISSN:0272-4391    

DOI:10.1002/ddr.430280210

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430280211

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY