摘要:

AbstractDrugs remain a key element in the effective containment of health care costs. In 1993, 29 new drugs were approved for marketing by the US Food and Drug Administration (FDA). These entities, according to a 1993 Office of Technology Assessment study, each took on average 12 years and $359 million each to discover and develop. The FDA reported that the average review time for these entities was 26.5 months, some 3 months less than reported in 1992. Under the prescription Drug User Fee Act of 1992, which will generate an additional $327 million over the period 1993–1997, the FDA will hire an additional 600 review staf

ISSN:0272-4391    

DOI:10.1002/ddr.430320302

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

年代:1994

数据来源: WILEY

摘要:

AbstractExtracellular ATP can produce various effects acting via P2‐purinoceptors. ATP is rapidly broken down by ecto‐ATPase and other ecto‐enzymes that limit its effect. Further, adenosine, a metabolite of ATP breakdown, can produce its own effect acting via P1‐purinoceptors, sometimes masking the effects of ATP. An inhibitor of ATP degradation would be a useful pharmacological tool to discriminate between effects of ATP and its metabolites, as well as to potentiate its actions. Diverse compounds that have been claimed to be inhibitors of ATP‐metabolising ectoenzymes are evaluated, but specific and selective Ca2+/Mg2+‐dependent ecto‐ATPase inhibitors still appear

ISSN:0272-4391    

DOI:10.1002/ddr.430320303

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

年代:1994

数据来源: WILEY

摘要:

AbstractThis review discusses available information on the neurotoxicity of N‐methyl‐D‐aspartate (NMDA) antagonists in the posterior cingulate/retrosplenial (PC/RS) cortex of rats. NMDA antagonists block the NMDA receptor, a central nervous system ionotropic glutamate receptor, and are neuroprotective since they reduce injury in animal models of ischemia. There is interest in the development and use of NMDA antagonists in treating human cerebrovascular diseases. However, with certain NMDA antagonists, dose‐dependent vacuolization of neurons in the neuroanatomically localized PC/RS cortex occurs as a side effect in rats. NMDA antagonists that cause vacuolization also appear to induce heat shock protein expression and heightened glucose metabolism in the same cortical region. Electron microscopy has shown that after treatment with MK‐801 (dizocilpine maleate), a prototypic noncompetitive NMDA antagonist, the onset of vacuolization is very rapid. Additional studies with MK‐801 have indicated that susceptibility to vacuolization increases between 30 and 90 days of age. Histologic time course studies have demonstrated that as the dose of MK‐801 is increased, some vacuolated neurons become necrotic. Necrotic neurons are readily evident by light microscopy in routine preparations. At a given dose of MK‐801, neuronal necrosis is more extensive in female rats than male rats. Furthermore, necrosis increases along an anterior to posterior gradient within the susceptible PC/RS cortex. A number of compounds with varied central nervous system (CNS) pharmacologic activity (anticholinergics, GABAmimetics, antipsychotics, and general anesthetics) partially or completely prevent neuronal vacuolization. These data suggest a complex pathogenesis for NMDA antagonist‐mediated neurotoxicity and indicate variables which require consideration when designing and interpreting studies with these compounds. Since recent reports have described failure of some NMDA antagonists to produce these side effects, the issues discussed in this review may or may not apply to all

ISSN:0272-4391    

DOI:10.1002/ddr.430320304

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

年代:1994

数据来源: WILEY

摘要:

AbstractAmesergide and LY215840 are potent and long‐lasting 5‐HT2receptor antagonists after oral administration to animals. In animals, these ergolines are metabolized to their desisopropyl ergoline congeners which have lower affinity (40–60 nM) at 5‐HT2receptors in the rat relative to higher 5‐HT2receptor affinity (2–3 nM) at the cloned human 5‐HT2receptor. Because amesergide and LY215840 are effective in rabbit models of thrombosis, we asked whether their efficacy in the rabbit was related in part to the activity of both the parent and desisopropyl metabolites at rabbit platelet 5‐HT2receptors. Platelet aggregation responses were first optimized to ADP and the combination of ADP and serotonin with regard to platelet number (300,000 platelets/μl of plasma) and time (70 to 140 min after platelet harvest). In ex vivo studies, both amesergide and LY215840 (3.0 mg/kg p.o.) showed similar and marked antagonism of rabbit platelet 5‐HT2receptors at 1 and 24 h after their oral administration to rabbits. Furthermore, the desisopropyl ergoline metabolites of both amesergide and LY215840 inhibited serotonin‐amplified platelet aggregation responses in vitro as did amesergide and LY215840. Thus, these studies add support to the hypothesis that the desisopropyl metabolites of amesergide and LY215840 may contribute to the oral antithrombotic efficacy of the parent

ISSN:0272-4391    

DOI:10.1002/ddr.430320305

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

年代:1994

数据来源: WILEY

摘要:

AbstractMK‐996 (N‐((4′‐((5,7‐Dimethyl‐2‐ethyl‐3H‐imidazo[4,5‐b]pyridin‐3‐yl)methyl) (1,1′‐biphenyl)‐2‐yl) sulfonylbenzamide) interacted in a competitive manner with rabbit aortic angiotensin II (All) receptors as determined by Scatchard analysis of specific binding of [125l]‐Sar1lle8‐All. MK‐996 also exhibited high affinity at All receptors in several tissues from different animal species (Ki= 0.1–0.4 nM). In vitro functional assays utilizing All‐induced aldosterone release in rat adrenal cortical cells demonstrated further that MK‐996 acts as a competitive, high affinity antagonist of All (pA2= 10.3) and lacks agonist activity. MK‐996 also potently inhibited All‐induced contractile response in isolated rabbit aorta and pulmonary artery with a reduction in maximal response. The specificity of MK‐996 for All receptors was demonstrated by its lack of activity (IC50>1 μM) in several other receptor binding assays and its inability to affect in vitro functional responses produced by other agonists. MK‐996 demonstrated a very high selectivity for the AT1compared to AT2receptor subtype (AT2IC50≥ 2 μM). Direct binding studies using [3H]‐MK‐996 in rat adrenal indicated specific binding of [3H]‐MK‐996 is saturable and of high affinity (Kd= 0.47 nM). The specific [3H]‐MK‐996 binding in rat adrenal represents binding to pharmacologically relevant AT1receptors as demonstrated by the similar Kivalues for various All agonists and antagonists in inhibiting specific3H‐MK‐996 and [125l]‐All binding to AT1receptors. Dissociation rate studies of specific [3H]‐MK‐996 binding indicated a t1/2 of 103 min. This slow dissociation may account for the r

ISSN:0272-4391    

DOI:10.1002/ddr.430320306

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

年代:1994

数据来源: WILEY

摘要:

AbstractIn support of human congestive heart failure (CHF) trials, the cardiovascular effects of the vasodilators nicorandil (NIC) and nitroprusside (NP) were examined in anesthetized and conscious dogs pretreated with the diuretic furosemide (FURO) and the cardiac glycoside digoxin (DIG). In anesthetized control dogs, iv NP (2–19 μg/kg/min) and NIC (24–105 μg/kg/min) maximally reduced mean arterial pressure (MAP) by 43 and 40 mmHg, respectively, with moderate increases in heart rate (HR). These hypotensive responses to NP and NIC were unmodified by iv FURO (2.65 mg/kg) + DIG (0.075 mg/kg) pretreatment (PT). FURO + DIG reduced central venous pressure (CVP) BY 3 mmHg, masking the separate effects of NP and NIC. In a third group, FURO's fluid volume depletion and DIG's plasma concentrations were unaffected by adjunctive NIC infused for 2.5 h at a mean 17 μg/kg/min iv. No untoward interactions were seen with any combination. In conscious dogs, the hypotension and tachycardia seen with iv NP (2–20 μg/kg/min) and NIC (20–160 μg/kg/min) were also unchanged after 5 days of oral FURO (5 mg/kg/day) and DIG (0.0125 mg/kg/day), with no intolerance. Repeated oral NIC (7.5 mg/kg/day × 3 days) in these chronic FURO + DIG dogs ws consistently hypotensive but steadily more tachycardiac. This study offers a prototype of 3‐way CHF drug interaction, demonstrates that NIC and NP can be safely combined with acute and chronic FURO and DIG, and shows that these CHF agents minimally affect the cardiovascular responses to NIC

ISSN:0272-4391    

DOI:10.1002/ddr.430320307

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

年代:1994

数据来源: WILEY

摘要:

AbstractPrevious studies have shown that (±) S 20244 (8‐(4‐[N‐(5‐methoxychroman‐3‐yl)N‐propylamino] butyl) 8‐azaspiro[4,5]decane‐7,9 dione) and its isomers (+) S 20499 and (−) S 20500 are full agonists at 5‐HT1Areceptors. In the present study, the effects of these three compounds were investigated in two animal models of anxiety, the elevated plus‐maze and social interaction tests. Subcutaneous administration of (±) S 20244 (19 μmol/kg−1.9 μmol/kg), (+) S 20499 (470 μmol/kg) or (−) S 20500 (94–940 μmol/kg) or per os administration of (+) S 20499 (190 μmol/kg−19 μmol/kg) produced anxiolytic‐like effects in the elevated plus‐maze while per os administration of (−) S 20500 was without effect. Subcutaneous administration of (±) S 20244 (19 μmol/kg−1.9 μmol/kg) or per os administration of (+) S 20499 (190 μmol/kg−19 μmol/kg) also produced anxiolytic‐like effects in the social interaction test. With both substances, bell‐shaped dose‐response relationships were found. The absence of activity of (−) S 20500 when administered per os suggests that the distribution and/or absorption kinetics of the two isomers may be different. In conclusion, (±) S 20244 and (+) S 20499 both display anxiolytic‐lik

ISSN:0272-4391    

DOI:10.1002/ddr.430320308

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

年代:1994

数据来源: WILEY

摘要:

AbstractThe in vitro effects of two pure glycosides, i.e., asperoside (K029) and strebloside (K030) isolated from a traditionally used medicinal plantStreblus asperon the bovine filarial parasiteSetaria cervifemales were studied. Both K029 and K030 caused death of the worms within 2 to 3 hours at concentrations of 10 μg/ml (1.7 pmoles) and were found to inhibit motility and glucose uptake of the parasites at lower concentrations (0.1 μg/ml; 0.17 pmoles). These glycosides also inhibited the incorporation of [U‐14]C‐glucose into macromolecules ofS. cervifemales. Parasites preincubated with either K029 or K030 had lowered profiles of glucokinase (EC 2.7.1.2), malate dehydrogenase (EC 1.1.1.37) and succinate dehydrogenase (EC 1.3.99.1) activities, suggesting that the lethal effects of the glycosides were due to effects on glucose metab

ISSN:0272-4391    

DOI:10.1002/ddr.430320309

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

年代:1994

数据来源: WILEY

摘要:

AbstractThe renal hemodynamic and excretory effects of intravenous N‐0861, a non‐xanthine adenosine A1‐receptor antagonist, were evaluated in conscious and anesthetized male Sprague‐Dawely rats. In conscious rats, N‐0861 (10, 30 μmol/kg, iv) significantly increased the excretion of urine, Na+, and K+; UClV was increased only in the rats treated with 10 μmol/kg, N‐0861. The relative excretion of K+was similar to that of Na+. Lower doses of N‐0861 (1, 3 μmol/kg, iv) had no effect. During clearance studies in anesthetized rats, N‐0861 (3, 10, 30 μmol/kg, iv) had little effect on systemic or renal hemodynamics, but provoked significant saluresis that was poorly related to dose, and that was characterized by a somewhat greater excretion of Na+and Cl−−relative to K+. These results indicate that the selective adenosine A1receptor antagonist N‐0861 has little influence on resting renal hemodynamics and suggest that the natriuretic responses are due to inhibition o

ISSN:0272-4391    

DOI:10.1002/ddr.430320310

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

年代:1994

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430320301

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

年代:1994

数据来源: WILEY