摘要:

AbstractThe human immunodeficiency virus (HIV) that produces the acquired immune deficiency syndrome (AIDS) continues to evade all strategies for potential therapeutic intervention. Global efforts in the search for potential anti‐HIV‐1 agents have mainly centered around the design of enzyme inhibitors and derivatives that inhibit viral binding or gene expression. Both nucleoside and non‐nucleoside reverse transcriptase inhibitors have demonstrated potent anti‐HIV‐1 activity. However, toxicity considerations and the emergence of resistant strains will require further structural manipulations to diminish these undesirable properties. Protease inhibitors also exhibit activities at nanomolar concentrations, but many of these agents may suffer from problems of absorption and biodegradation. These apparent shortcomings have been circumvented by the preparation of peptidomimetic molecules. Similarly, smaller CD4 mimetics have emerged as alternatives to the larger soluble CD4 derivatives as inhibitors of viral binding. Other viral binding inhibitors, the anionic molecules, suffer from an inherent inability to enter cells and potential anticoagulant activity. These properties may be remedied by rational analog design and synthesis. Oligonucleotides can be constructed to inhibit specific segments of selected regulatory genes of the virus. These agents have been critiqued on the basis of stability, cellular uptake, and assurance of hybridization. Once again, structure activity relationship studies have revealed that many of these apparent problems can be overcome. The more recently discovered agents belong to the unique classes oftatantagonists or viral uncoating inhibitors. © 1993 Wiley‐Liss, Inc. © 1993 Wi

ISSN:0272-4391    

DOI:10.1002/ddr.430290102

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

年代:1993

数据来源: WILEY

摘要:

AbstractThe compound BMY 33462 (4‐amino‐N‐(1‐azabicyclo‐[2,2,2]oct‐3‐yl)‐2‐(butan‐2‐one‐3‐yl)oxy‐5‐chlorobenzamine 1.25 fumerate hydrate) has been shown to be a selective and potent serotonin type‐3 (5‐HT3) receptor antagonist. Its receptor binding profile includes subnanomolar affinity for the 5‐HT3receptor (Ki, 0.22 ± 0.06 nM) and no affinity for other serotonergic, dopaminergic, and adrenergic receptors (Ki>1,000 nM). BMY 33462 was also shown to be a potent inhibitor of the Bezold‐Jarisch reflex in the anesthetized rat (ED50, 0.09 μg/kg, iv), a functional correlate of 5‐HT3receptor antagonism in vivo. It has been reported that ondansetron and other 5‐HT3antagonists have the ability to block hyperactivity in rats induced by DiMe‐C7 ([pGlu5, Me‐Phe8, Sar9]SP5–11), a metabolically stable analogue of substance P [Hagan et al. (1990): Br J Pharmacol 99:227–232]. DiMe‐C7‐induced hyperactivity is thought to occur through activation of mesolimbic dopamine (DA) neurons which project to the nucleus accumbens [West and Michael (1991): Brain Res Bull 26:229–233]. BMY 33462 was examined for its ability to block DiMe‐C7‐induced hyperactivity as was haloperiodol and ondansetron. The dopamine‐2 (D2) antagonist haloperidol produced the greatest inhibition of DiMe‐C7‐induced hyperactivity at a dose of 0.025 mg/kg (53.7%). Ondansetron significantly inhibited the DiMe‐C7‐induced increase in locomotor activity at doses of 0.10 mg/kg and 0.50 mg/kg (42% and 30%, respectively). BMY 33462, at doses of 0.025 mg/kg and 0.05 mg/kg, significantly decreased DiMe‐C7‐induced hyperactivity by 41% and 37%, respectively. Haloperidol proved to be highly efficacious and potent in blocking increases in DiMe‐C7‐induced locomotor activity, a phenomenon which may correlate with its clinical effectiveness as a neuroleptic agent. BMY 33462 and ondansetron were equally efficacious, however, BMY 33462 was more potent. The ability of 5‐HT3antagonists to alter a mesolimbic DA‐mediated behavior indicates a complex interaction between these two neurotransmitter systems and perhaps a role for central 5‐HT3receptors and 5‐HT in the regulation of DA transmission. In addition, BMY 33462 and ondansetron were unable to inhibit stereotypy induced by apomorphine (inactive at 100 mg/kg, orally) suggesting a lack of interaction with the nigrostriatal DA pathway. These results support the notion that 5‐HT3antagonists may be potential therapeutic agents for the treatment of hyperdopaminergic disease states, such as schizophrenia, without the side

ISSN:0272-4391    

DOI:10.1002/ddr.430290103

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

年代:1993

数据来源: WILEY

摘要:

AbstractThe cardiovascular effects of FK664, [6‐(3, 4‐dimethoxyphenyl)‐1‐ethyl‐4‐mesitylimino‐3‐methyl‐3, 4‐dihydro‐2 (1H)‐pyrimidinone], were examined in both in vitro and in vivo preparations. FK664 is an orally effective noncatechol and nonglycoside cardiotonic agent. FK664 has vasodilating activity not only in resistance vessels but also in capacitance vessels in both in vitro and in vivo studies (venodilation). This venodilating effect of FK664 has been observed at much lower concentrations than those required to produce an inotropic response. FK664 is effective in the conscious dog at 1 mg/kg (2.5 μmol/kg) orally and in a dog model of congestive heart failure at 3.2 μg/kg/min (7.8 nmol/kg/min), intravenously. The vasodilating and positive‐inotropic activities of FK664 are mainly due to an increase in cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) levels due to inhibition of cyclic AMP phosphodiesterase. Moreover, FK664 does not affect the balance between myocardial oxygen supply and demand due to a significant increase in coronary blood flow, though the agent does increase myocardial oxygen consumption. In conclusion, the agent produces potent preload reduction and mild cardiac stimulation. This unique pharmacological profile may be beneficial in the management of congestive hear

ISSN:0272-4391    

DOI:10.1002/ddr.430290104

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

年代:1993

数据来源: WILEY

摘要:

AbstractThe deleterious effects of postnatal lead (Pb) exposure on neural development, synaptic plasticity, and cognitive function have been well documented in laboratory animals. While the exact mechanisms by which Pb produces long‐lasting neurotoxicity remain unknown, recent evidence suggests that Pb may interact with and/or disrupt the N‐methyl‐D‐aspartate/phencyclidine receptor complex and the associated ion channel. In addition to perturbations of excitatory amino acid neurotransmission, chronic Pb exposure may also have deleterious effects on inhibitory mechanisms such as that provided by purinergic neuromodulation. In order to further examine the possibility that alterations of both excitatory and inhibitory neurotransmission may contribute to the neurotoxic actions of Pb, the effects of early Pb exposure on ligand binding to postnatal rat brain N‐methyl‐D‐aspartate (NMDA), phencyclidine (PCP), and adenosine A1receptors were examined using quantitative autoradiography techniques. Rat pups nursed mothers exposed to 4% PbCO3in their diet or a Na2CO3control diet from postnatal day 1 (P1) to P25. At P25, rats were sacrificed and the regional distributions of brain NMDA, PCP, and adenosine A1receptors were examined. Chronic lead exposure was found to produce a specific increase in [3H]CGP 39653 binding to NMDA receptors in the hippocampus. [3H]1‐(1‐[2‐thienyl)cyclohexyl]‐piperdine ([3H]TCP) binding to PCP receptors was largely unaffected by the chronic Pb treatment. In contrast, [3H]cyclohexyladenosine ([3H]CHA) binding to adenosine A1receptors was markedly reduced in many brain regions with the largest decreases observed in the cerebellum. These results indicate that neonatal Pb exposure produces a specific alteration of both excitatory and inhibitory neuromodulatory mechanisms in the postnatal rat forebrain that may underlie the behavioral hyperactivity and increased seizure sensitivity associated with Pb neurotoxicity.

ISSN:0272-4391    

DOI:10.1002/ddr.430290105

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

年代:1993

数据来源: WILEY

摘要:

AbstractAnimal models of depression which use stress to induce abnormal behavior generally cannot discriminate antidepressants from drugs which are central stimulants and predominantly stimulate dopamine (DA) neurons. Thus these models lack pharmacological specificity. The present study shows that the Learned Helplessness (LH) model, applied to Wistar rats, becomes a more valid pharmacological model if registration of the animals' behavior during the interval between each trial of the LH shuttlebox test is added. The DA drugs amphetamine, methylphenidate, nomifensine, apomorphine, quinpirole (specific D2 agonist), SKF 81297 (specific D1 agonist), and the antidepressants imipramine, amitriptyline, and isocarboxazide were tested. The results show that the DA drugs had an acute effect and increased the number of shuttle box crossings in the intervals between the test trials. The antidepressants had no acute effect and did not increase the number of intertrial crossings in the therapeutic dose range. The LH model thus seems to be advantageous when discrimination between drugs with DA psychomotor stimulating properties and drugs with antidepressant properties is needed. © 1993 Wiley‐Liss, I

ISSN:0272-4391    

DOI:10.1002/ddr.430290106

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

年代:1993

数据来源: WILEY

摘要:

AbstractThe effect of the iron chelator, desferrioxamine (DFO) upon the hepatotoxic effects associated with the use of adriamycin as a cytotoxic agent were evaluated in normal albino mice. Hepatocellular toxicity was assessed by measuring serum aspartate transaminase (SGOT), serum alanine transaminase (SGPT) and serum alkaline phosphatase (ALP) activity. In addition, glucose‐6‐phosphatase (G‐6‐PTase) activity, nucleic acids, calcium, magnesium, and iron levels in liver tissue were also measured. Adriamycin treatment (2 mg/kg i.p.), administered every other day for a total of 5 doses produced a 2.5‐fold increase in SGOT and SGPT, while ALP activity showed a 30% increase in comparison to normal, untreated controls. However, hepatic G‐6‐PTase activity showed a significant decrease after the adriamycin treatment regimen. The calcium and iron content of liver showed also a marked decrease, while magnesium levels were increased two‐fold after treatment with adriamycin. In the presence of the iron chelator, DFO (100 mg/kg i.p., administered every other day for 5 doses), adriamycin treatment did not result in any significant changes in SGOT, SGPT, ALP, or hepatic G‐6‐PTase activity. Histopathological examination of mouse liver showed diffuse ballooning degeneration of liver cells with perivascular cellular infiltration after adriamycin treatment. In the presence of DFO, only focal cellular degenerative and minimal fatty changes were observed. The observed hepatocellular damage is believed to be a result of the lipid peroxidation induced by adriamycin. The role of DFO in preventing lipid peroxidation has been discussed. This study provides evidence that DFO may be useful for prevention of the lipid peroxidation and hepatocellular damage induced by adriamycin. ©

ISSN:0272-4391    

DOI:10.1002/ddr.430290107

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

年代:1993

数据来源: WILEY

摘要:

AbstractPotassium channels are present on airway smooth muscle cells and their activation results in hyperpolarization and relaxation. Because these effects may have therapeutic relevance to asthma, the aim of our study was to examine the activity of SR 47063, a potassium channel opener (KCO), against a variety of spasmogens or against electrical field stimulation in guinea‐pig isolated trachea and in human isolated bronchi in vitro; the effects of SR 47063 were compared with those of cromakalim, isoprenaline, and theophylline. Like cromakalim, SR 47063 reduced the contractility of guinea‐pig isolated trachea and the human isolated bronchus in basal tone with pD2of 7.79 ± 0.01 and 7.83 ± 0.09, respectively, or during precontractions induced by acetylcholine 10−4M, histamine 10−5M, or low concentrations of KCl (<30 mM), but not by high KCl concentrations (≥30 mM); these effects were antagonized by glibenclamide 10−5M. This spectrum of action is typical of the compounds known as potassium channel openers. Electrical field stimulation (EFS: 16 Hz, 1 ms, 320 mA for 10 sec in the presence of indomethacin 10−6M and propranolol 10−6M) of guinea‐pig isolated main bronchi induced 2 successive contractile responses. Both contractions were reduced significantly by SR 47063 and cromakalim. Although we have not studied the effects of KCOs on exogenous neurokinin A‐ or substance P‐induced contractions, it might be suggested as a hypothesis that this inhibition seems to take place presynaptically and to affect the release of neuromediators produced by electrical field stimulation. In conclusion, SR 47063 exerts in vitro on the bronchial smooth muscle an inhibitory effect which seems to be due to the opening of glibenclamide‐sensitive potassium channels. SR 47063 is 3‐ to 10‐fold more potent than croma

ISSN:0272-4391    

DOI:10.1002/ddr.430290108

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

年代:1993

数据来源: WILEY

摘要:

AbstractThe aim of this work was to study the scavenging action of the flavonoids, silymarin and silybinin (two well known hepatoprotective agents) against different types of oxygen radicals which were generated by specific chemical reactions and detected by luminol‐sensitized chemiluminescence. A well known scavenger for each radical was used as control for the paradigm and for comparing its effect with those of the flavonoids. It was found that 0.8 μg/ml of silymarin and 5.5 mg/ml of silybinin produced the same effect as 3.2 ng/ml superoxide dismutase (SOD). An alkoxy radical scavenging effect similar to the one produced by 0.35 ng/ml of vitamin E was caused by 2 μ/ml silymarin and 1.6 ng/ml silybinin. Silybinin was evaluated as a scavenger of hydroxyl radicals by determining the inhibition of the chemiluminescence produced by the Fenton reaction with luminol; this was compared with the results obtained from a more conventional method which determines the inhibition of the damage to 2‐deoxyribose by the Fenton reaction. In both methods, inhibition was observed at a relatively high concentration of the flavonoid as compared with ethanol. The action of silymarin and silybinin as scavengers of oxygen radicals may explain the protective effect of these flavonoids in certain forms of liver disease where free radicals are involved. However, other properties of these compounds cannot be discarded for their hepatoprotective actions. © 1993 Wiley‐L

ISSN:0272-4391    

DOI:10.1002/ddr.430290109

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.430290110

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.430290101

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

年代:1993

数据来源: WILEY