摘要:

AbstractThe 1988 decision by the U.S. Health Care Financing Administration (HCFA) not to accord special reimbursement treatment to Genentech's tissue plasminogen activator (Activase™) was a signal event in the growing dilemma of biotechnology. In the U.S. (and to a degree in Japan and major Western European nations as well), therapeutic biotechnology investment appears to be on a collision course with health care cost containment efforts. During this time of renewed political interest in pharmaceutical pricing, there is urgent need for dialogue among the affected parties. Otherwise, repercussions of a collision could damage both private and public sector biotechnology innovation. The purpose of this article is to outline the nature of, and clarify the reasons for, the dilemma of biotechnology. ©1993 Wiley‐Liss,

ISSN:0272-4391    

DOI:10.1002/ddr.430290302

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

年代:1993

数据来源: WILEY

摘要:

AbstractWe investigated PAL (protocatechualdehyde), one of the metabolites of ACP (3,4‐diacetoxy benzylidene diacetate) which is a candidate novel antirheumatic agent. Specifically, we studied the effect and mechanism of action of PAL on chondrocyte metabolism using a primary culture of chondrocytes from rabbit articular cartilage. Proteoglycan (PG) depletion in the chondrocyte matrix was induced by the addition of human recombinant interleukin‐1α (hrlL‐1α) or phorbol myristate acetate (PMA). PAL (10–100 μM) significantly reduced the induced PG depletion and [35S]‐PG release in the chondrocyte matrix. The matrix metalloproteinase (MMPs) inhibitor, 1,10‐phenanthroline, and protein kinase C (PKC) inhibitor, H‐7, also blocked PG depletion and [35S]‐PG release. Furthermore, H‐7 reduced the production of MMPs induced by hrlL‐1α in the culture media of chondrocytes. These results indicate that hrlL‐1α causes MMPs production by the activation of PKC, which is followed by [35S]‐PG release in the chondrocyte matrix. While PAL also resulted in significant inhibition of MMPs production, which might be mediated by PKC activation, it had no direct influence on PKC activity. These results suggest that PAL affects chondrocyte metabolism by the inhibition of MMPs produ

ISSN:0272-4391    

DOI:10.1002/ddr.430290303

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

年代:1993

数据来源: WILEY

摘要:

AbstractThe effect of a leukotriene biosynthesis inhibitor (MK‐0591) on LTB4synthesis was examined in a rabbit model of joint inflammation. Intra‐articular (ia) injection of human recombinant interleukin‐1β (rlL‐1β, 50–400 ng/joint) resulted in dose‐dependent infiltration of leukocytes into the synovium but produced only background levels of LTB4over a time course of 14–16 h, suggesting that the leukocytes were not activated with respect to LTB4metabolism. The influx of leukocytes in the synovial space was not inhibited by MK‐0591. Injection of A23187 (100 nmol/joint, ia) in addition to rlL‐1β elicited significant LTB4release in the synovial fluid. MK‐0591 given iv 30 min before A23187 significantly inhibited the release of LTB4(ED50= 0.3 mg/kg), without affecting the number of leukocytes in the synovium. In rabbit whole blood challenged with A23187 in vitro, MK‐0591 also potently inhibited LTB4synthesis (IC50= 126 ± 29 nM). The in vivo inhibitory action of MK‐0591 was in good agreement with the plasma levels of the compound (0.62 μM in the group treated with MK‐0591 at 3 mg/kg) and its biochemical efficacy in vitro (100% inhibition of LTB4synthesis). The effect of MK‐0591 was comparable to that of another leukotriene biosynthesis inhibitor, MK‐886. Indomethacin at dose up to 3 mg/kg iv did not affect the production of LTB4in the joint. The present study demonstrates that MK‐0591 inhibits LTB4biosynthesis with high potency in the rabbit synovium, a microenvironment rich in protein and leukocytes. It would be of interest to determine whether such an action would be beneficial in the management of rheumatoid arthritis or other inflammatory conditi

ISSN:0272-4391    

DOI:10.1002/ddr.430290304

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

年代:1993

数据来源: WILEY

摘要:

AbstractCardiac muscle force development and shortening result from the interaction between actin and myosin within the myofibrillar contractile unit. This interaction is dependent upon intracellular Ca2+and is controlled by the troponin‐tropomyosin regulatory proteins situated along the length of the actin thin filament. Enhancing the Ca2+sensitivity of cardiac contractile protein interactions has been proposed as a novel mechanism for some positive inotropic agents. These myofibrillar Ca2+sensitizers have variable effects on myofibrillar MgATPase activity among nonhuman animal species, and different effects between myofibrils from failed nonhuman hearts are evident. In this study, we have evaluated several myofibrillar calcium sensitizers, at maximal testable concentrations, for their effects on the calcium‐activated MgATPase of myofibrils prepared from normal human hearts and from hearts of patients with congestive heart failure. Bepridil (100 μM) increased MgATPase at pCA 9.0 (basal activity) and pCa 6.5 (an intermediate concentration of Ca2+which stimulated activity 42–56% of maximal), with no effect at pCa 5.0 (maximal Ca2+activity) in both normal and failing hearts. APP 201–533 (300 μM) increased MgATPase at pCa 6.5 in all hearts, but increased MgATPase at pCa 5.0 only in normal hearts. Pimobendan (100 μM) increased MgATPase at pCa 6.5 only in normal hearts and increased activity at pCa 5.0 only in failing hearts. In contrast, trifluoperazine (100 μM) reduced MgATPase at pCa 5.0 and pCa 9.0 in all hearts and at pCa 6.5 in failing hearts. The stimulating effects of bepridil, APP 201–533, and pimobendan (approximately 7–17%) were less than those observed in studies with nonhuman cardiac myofibrils (typically 30–40%). These data suggest that some myofibrillar Ca2+sensitizers can have either modest stimulatory or inhibitory activity on human cardiac myofibrillar MgATPase activity. While these (Ca+‐sensitizing) effects on MgATPase activity are statistically significant, the biological relevance with respect to enhancing cardiac contractility is equivocal. Furthermore, both pimobendan and APP 201–533 inhibited cAMP‐phosphodiesterase III purified from failing human hearts with IC50values of 0.35 and 2.0 μM, respectively. Since other inotropic mechanisms, such as cAMP‐phosphodiesterase inhibition, are also evident at much lower concentrations with some of these agents, the relevance of myofibrillar Ca2+sensitization as the predominant inotropic mechanism of action of these compounds is questionab

ISSN:0272-4391    

DOI:10.1002/ddr.430290305

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

年代:1993

数据来源: WILEY

摘要:

AbstractLinopirdine, HP 749, and glycyl‐prolyl‐glutamate (GPE) are compounds that have been reported to alter the release of neurotransmitters. This study compares the potassium‐stimulated neurotransmitter release enhancing properties maximal release enhancement. HP 749 increased the extracellular concentrations of the catecholamines, [3H]NE and [3H]DA, but not [3H]ACh or [3H]d‐Asp. HP 749 was a potent inhibitor of both [3H]NE and [3H]DA uptake, and this may, in part, be responsible for the apparent release enhancing activity of the drug. GPE was devoid of release enhancing activity under the conditions of these compounds in parallel. While not affecting the apparent release of [3H]norepinephrine ([3H]NE), linopirdine at a concentration of 10 μM enhanced the potassium evoked release of cerebral cortical and hippocampal [3H]acetylcholine ([3H]ACh) release by 143% and 200% over control, respectively, and striatal [3H]dopamine ([3H]DA) and hippocampal [3H]d‐aspartate ([3H]d‐Asp) release by 236% and 65% over control, respectively. The release enhancing effects of linopirdine were not due to inhibition of high‐affinity uptake processes, since the drug did not inhibit neurotransmitter uptake at the concentration (10 μM) which caused used in the present study. © 1993

ISSN:0272-4391    

DOI:10.1002/ddr.430290306

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

年代:1993

数据来源: WILEY

摘要:

AbstractZatosetron is a potent, orally active 5‐HT3receptor antagonist with a long duration of activity in laboratory animals and humans. Several metabolites have been detected in plasma and urine of humans and experimental animals receiving zatosetron. The present study was designed to explore the pharmacological activity of the detected metabolites, 3‐hydroxyzatosetron, 3‐ketozatosetron, andN‐desmethylzatosetron, relative to the parent molecule. These three metabolites had relatively high affinity at 5‐HT3receptors based on in vitro radioligand binding and inhibited serotonin‐induced bradycardia in urethane‐anesthetized rats after intravenous administration. However, these metabolites had lower affinity and were less potent than zatosetron. Of these metabolites, 3‐hydroxyzatosetron (ED50= 4.0 μg/kg iv) was approximately 5‐fold less potent than zatosetron (ED50= 0.8 μg/kg iv) in vivo and had approximately 10‐fold lower affinity at 5‐HT3receptors in vitro relative to zatosetron.N‐desmethylzatosetron and 3‐ketozatosetron were approximately 15‐fold less potent than zatosetron in vivo as 5‐HT3receptor antagonists. With regard to duration of activity in vivo, after intravenous administration, 3‐hydroxyzatosetron and 3‐ketozatosetron blocked 5‐HT3receptors longer than zatosetron, whereasN‐desmethylzatosetron showed a duration of pharmacological activity similar to zatosetron. A fourth metabolite, zatosetron‐N‐oxide can exist in two isomeric forms, with stereoselectiveN‐oxidation of zatosetron resulting in formation of only one isomer in humans, zatosetron‐β‐N‐oxide. Zatosetron‐β‐N‐oxide had approximately 100‐fold lower 5‐HT3receptor affinity relative to zatosetron and was approximately 150‐fold less active as an antagonist at 5‐HT3receptors in vivo (ED50= 115 μg/kg iv). Thus, although pharmacological activity was observed with all four metabolites, they were all less active in vivo than zatosetron. Therefore, these metabolites would contribute significantly to the activity of zatosetron only if plasma (and tissue)

ISSN:0272-4391    

DOI:10.1002/ddr.430290307

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

年代:1993

数据来源: WILEY

摘要:

AbstractMany of the pathophysiological effects of endotoxin (ETX) can be mimicked by the administration of platelet activating factor (PAF), and the latter has been implicated as a possible mediator of the derangements seen in endotoxic shock. In this investigation, two new potent PAF antagonists, bepafant (WEB‐2170) and L‐659,989, were studied for their effects in experimental endotoxic and septic shock in rats. Pretreatment with the PAF antagonists, 15 min prior to the iv administration ofEscherichia coliendotoxin (ETX), was found to be highly effective in decreasing the mortality caused by the lipopolysaccharide. The antagonists were less effective in reducing mortality when given as post‐treatment 15 min after ETX, and were ineffective when post‐treatment was delayed until 30 min after ETX. Administration of ETX caused manifestations of disseminated intravascular coagulation (DIC), including thrombocytopenia, prolongation of prothrombin time (PT) and partial thromboplastin time (PTT), hypofibrinogenemia, elevation of serum fibrin(ogen) degradation products (FDP), and gastrointestinal hemorrhage. With the exception of the thrombocytopenia, the PAF antagonists reduced or abolished all of the hematological manifestations of DIC caused by ETX. Septic shock was produced by ligation and puncture of the cecum in rats. The PAF antagonists, given as two iv doses (an initial 2.0 mg/kg dose administered 1.5 or 2.5 h after cecal puncture and a second dose given 5 h later), significantly reduced the cumulative 24‐h mortality. These results provide added evidence of the importance of PAF and DIC in the pathophysiology of ETX and suggest that PAF antagonists may be useful in the clinical management of septicemia/endotoxemia. © 1993 Wiley

ISSN:0272-4391    

DOI:10.1002/ddr.430290308

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

年代:1993

数据来源: WILEY

摘要:

AbstractAmantadine is used in the symptomatic treatment of Parkinson's disease to improve the akinesia and rigidity associated with this neurodegenerative disorder. Amantadine acts on the synthesis and release of dopamine (DA). In order to further characterize its mechanism of action, the drug was administered to MPTP‐treated mice which were used as a model of the neurochemical deficits associated with Parkinson's disease. The DA turnover in corpus striatum was evaluated. Adult male Swiss albino mice were injected ip with 12.5 mg/kg (82.6 μmol/kg) or 25 mg/kg (165 μmol/kg) of amantadine and 30 min later with MPTP (30 mg/kg, 143 μmol/kg). Both the amantadine and MPTP treatments were repeated for 3 consecutive days. Groups of mice were treated with amantadine or MPTP alone. Seven days after the last injection of drugs, the striatal content of DA and homovanillic acid (HVA) were measured by HPLC‐EC analysis. Additional groups of mice were treated with 3 consecutive daily doses of MPTP (30 mg/kg, 143 μmol/kg) and 7 days after the last administration received a single dose of amantadine at 25 mg/kg (165 μmol/kg). Turnover rate was measured by HVA content determination. The results indicate that amantadine induced a significantly increased striatal DA turnover rate (34%) in MPTP‐treated animals as compared with those animals treated with only MPTP. © 1993 Wile

ISSN:0272-4391    

DOI:10.1002/ddr.430290309

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

年代:1993

数据来源: WILEY

摘要:

AbstractDifferent psychotropic drugs were investigated in order to determine their effect on the release of prolactin and corticosterone and their influence on the tuberoinfundibular dopamine (TIDA) neuron activity. The results were used in a principal component analysis, which grouped the psychotropic drugs into different clusters. In the plot showing these clusters the anxiolytic drugs were found to be grouped together and differ from the antidepressant drugs by their potent ability to increase plasma corticosterone. The antipsychotic drugs formed a separate group being clustered together. Typical neuroleptic and atypical antipsychotic drugs could be separated within the cluster by their different effects on plasma prolactin and corticosterone and on TIDA neuron activity. The results indicate that the neuroendocrine profiles of antidepressant and anxiolytic drugs are different from those of antipsychotic drugs and that the neuroendocrine measurements could be a useful tool in the early classification of psychotropic drugs. © 1993 Wiley‐Liss, I

ISSN:0272-4391    

DOI:10.1002/ddr.430290310

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

年代:1993

数据来源: WILEY

摘要:

AbstractThe pharmacological profile and antidepressant potential of cyanodothiepin (BTS 56 424) have been compared to those of dothiepin, cianopramine, and imipramine. Rat brain synaptosomes and human platelets were used to measure the effects of drugs on radiolabeled monoamine uptake in vitro. The 2‐nitrile substitution converted the actions of dothiepin from nonselective inhibition of 5‐hydroxytryptamine (5‐HT) and noradrenaline uptake to those of cyanodothiepin, a potent and very selective 5‐HT uptake inhibitor (Ki = 4.8 and 597 nM vs. 5‐HT and noradrenaline uptake, respectively; rat brain synaptosomes). Nitrile substitution similarly conferred in vitro 5‐HT selectivity on cianopramine (Ki = 0.71 and 15 nM vs. 5‐HT and noradrenaline) compared to imipramine. The selectivity of cyanodothiepin as a 5‐HT reuptake inhibitor was maintained in vivo in a variety of rodent models. Cianopramine was a more potent but less selective 5‐HT reuptake inhibitor than cyanodothiepin in these paradigms. In monoamine‐depletor based tests for antidepressant activity, cyanodothiepin was weakly active compared to cianopramine and imipramine; cyanodothiepin was active in the Porsolt test for antidepressants. Compared to cianopramine, cyanodothiepin showed weaker affinity for muscarinic cholinergic and 5‐HT2 receptors in vitro and in vivo, and for α1‐adrenergic, dopamine (D1 and D2) receptors in vitro. Cyanodothiepin was less sedative than cianopramine and was also a weaker enhancer of drug‐induced loss of righting reflex in mice. Overall, cyanodothiepin is a potent and selective 5‐HT reuptake inhibitor which exhibits antidepressant potential and probably possesses a lower propensity to induce side effects associated with tricyclic antidepress

ISSN:0272-4391    

DOI:10.1002/ddr.430290311

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

年代:1993

数据来源: WILEY