摘要:

AbstractMonosialoganglioside GM1is a new pharmacological agent used to enhance recovery after central nervous system (CNS) injury. This agent is a natural component of cell membranes, and its clinical use is based on extensive experimental work which demonstrates that many parameters of brain function in CNS‐injured animals are positively influenced by the parenteral administration of monosialoganglioside GM1. The key mechanism through which monosialoganglioside GM1is able to exert its clinical effects is by enhancing the neuroplasticity of the CNS. The recovery‐promoting effect is mediated through neuroprotective and neuronotrophic activities exerted or enhanced by monosialoganglioside GM1. The neuroprotective activity is based on the prevention of the neuronotoxic consequences of indiscriminate excitatory amino acid receptor activation, particularly of glutamate receptors. In vitro and in vivo evidence indicates that the product enhances the trophic response of neurons to neurotrophic factors induced as a response to the lesion. The neuropharmacological effects of monosialoganglioside GM1in humans have been confirmed in controlled clinical trials in head and spinal cord injury and stroke. The therapeutic use of monosialoganglioside GM1is a significant innovation in an area of neuropharmacology that has been neglected until the functional significance of CNS neuroplasticity was recogni

ISSN:0272-4391    

DOI:10.1002/ddr.430190302

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

年代:1990

数据来源: WILEY

摘要:

AbstractFibroblast growth factor (FGF) is a monomeric mitogenic protein that exists as an acidic and a basic form and is distributed widely in tissues of the eye. Because FGF interacts with the cells and with the extracellular matrix, it has potential as a therapeutic agent, either alone or in combination with other agents such as epidermal growth factor, in promoting healing of corneal wounds, in restoring corneal endothelial cell loss due to dystrophic, degenerative, and surgical insults, as well as in regenerating lens cells after cataract surgery. Excess FGF probably plays a significant role in the pathogenesis of blinding disorders of the eye such as neovascular glaucoma, age‐related macular degeneration, and proliferative diabetic vitreoretinopathy, as well as failure of surgical filtering procedures for glaucoma. The use of transforming growth factor‐beta, anti‐FGF antibodies, and other blocking agents in the treatment of such diseases seems lo

ISSN:0272-4391    

DOI:10.1002/ddr.430190303

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

年代:1990

数据来源: WILEY

摘要:

AbstractHP 818 (1‐benzoyl‐6‐fluoro‐3‐(1‐methyl‐4‐piperidinyl)‐1H‐indazole) exhibits the profile of a potent nonnarcotic analgesic with neuroleptic properties. HP 818 blocks the effects of chemical (phenylquinone), pressure (tail clip), and radiant heat (tail flick) painful stimuli in mice (ED50values of 0.3, 1.2, and 4.1 mg/kg s.c., respectively). This compound displays antinociceptive activity by the subcutaneous, oral, and intravenous routes of administration. It is also effective in the shock titration assay in squirrel monkeys and in a model of surgically induced pain. The rank order of potency of HP 818 and several other standard compounds in these tests for analgesia was Innovar>fentanyl>HP 818>codeine>droperidol. In addition to its antinociceptive effects, HP 818 possesses neuroleptic properties. It is active in the climbing mouse, pole climb avoidance, and intracranial self‐stimulation assays (ED50values of 1.8, 1.7, and 2.5 mg/kg i.p., respectively). Moreover, HP 818 inhibits amphetamine‐ and apomorphine‐induced stereotypy, indicative of D2‐dopaminergic blocking properties. HP 818, unlike typical neuroleptic agents, does not induce supersensitivity to the effects of apomorphine when administered chronically in mice. In contrast to the clinical standard neuroleptanalgesic Innovar, HP 818 (1.0–3.0 mg/kg i.v.) produces no significant cardiovascular or respiratory changes in the anesthetized dog. Thus, HP 818 is potentially an effective presurgical medication due to its nonnarcotic analgesic activity and sedative neuroleptic effects, along with its lack of limiting c

ISSN:0272-4391    

DOI:10.1002/ddr.430190304

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

年代:1990

数据来源: WILEY

摘要:

AbstractThe stability and control of ligand‐receptor interaction obeying the mass action law were analyzed with a control model that is applicable to drugs and endogenous compounds. Whereas the local concentration of drugs, and consequent receptor occupancy, depend on pharmacokinetic parameters and, possibly, intrinsic control, natural substances are almost certainly controlled. The model assumes constant ligand production, with first‐order elimination and a feedback function (ϕ) that modulates these. The feedback signal, which may originate at a site proximal or distal to the receptor, is expressed as a function of the occupied receptor concentration (y). Instantaneous values of free (z) and bound (y) ligand represent a state or a point of the system. Basal values of y and z define a critical point that is stable; that is, perturbations producing states away from it will return in time to this critical point. In contrast, other critical points can be unstable, meaning that movements near such points will result in loss of control and possible chaos. It is shown that any critical point at which the derivative ϕ'(y)0 at such points. The model predicts at least one unstable point or repellor. The distance between these points is crucial to maintenance of control. Loss of control may account for certain abnormalities such as vasospasm and other pathologic conditions. The model, containing four parameters that control the three of the ligand‐receptor interaction, predicts conditions that alter stability. These insights may be useful for drug use and dev

ISSN:0272-4391    

DOI:10.1002/ddr.430190305

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

年代:1990

数据来源: WILEY

摘要:

AbstractInitial evaluation of the safety of wound‐healing growth factors, whether manufactured by biotechnology or not, is dictated by the extent of knowledge of the physiologic, pharmacologic, and toxicologic effects, in vitro and in vivo in animals, and in man at the proposed dose and duration of administration. Prior to Phase 1 clinical study, products are studied to establish evidence of pharmacologic activity, understand the mechanism of action, evaluate the potential human risk, and establish a clinical study dose range. It is difficult to establish a generic plan and generic protocols for the preclinical development of wound‐healing growth factors because the toxicologic concerns and suggested studies are tailored to the uniqueness of each product. The quantity of useful information which can be gained from preclinical studies is considered for each product on a case‐by‐case basis, taking into account the availability of a relevant model. Preliminary information regarding (1) production of the active moiety, (2) ingredients in the final formulation as it is to be marketed, (3) characterization of the growth factor, (4) the proposed dose and route of administration, (5) the known actions and effects, (6) the similarity to the endogenous growth factors, and (7) the proposed target clinical study population is needed to determine the most appropriate preclinical pharmacological and toxicologic studies. Use of this information and additional data relating the pharmacokinetic and toxicologic profiles will be discussed with respect to generalizations in study concepts for pharmacology and toxicology studies and individualization of these preclinical studies which may occur, based upon the uniqueness of the c

ISSN:0272-4391    

DOI:10.1002/ddr.430190306

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

年代:1990

数据来源: WILEY

摘要:

AbstractDuP 996, in micromolar concentrations, enhances the K+‐stimulated release of acetylcholine (ACh) in rat cerebral cortex, hippocampus, and caudate nucleus slices in vitro, without effect on basal release. DuP 996 has very weak affinity for rat brain muscarinic or nicotinic receptors and does not inhibit acetylcholinesterase activity of rat brain. Upon subcutaneous administration, DuP 996, in doses of 0.1 to 1 mg/kg, increase the output of ACh from the cerebral cortex of awake, freely moving rats. In the mouse, scopolamine‐induced hyperactivity is reduced by DuP 996 in doses of 0.3–0.5 mg/kg (s.c.). In addition, pancuronium HBr‐induced neuromuscular blockade is reversed by DuP 996 (ED50= 1.7 mg/kg s.c.). The enhancement by DuP 996 of K+‐stimulated transmitter release is not limited to the cholinergic system but is also observed in the dopaminergic system in the rat caudate nucleus and in serotonergic systems. K+‐stimulated release of gamma‐aminobutyric acid and glutamic acid in rat cerebral cortex, however, is only slightly enchanced by DuP 996, whereas no effects are observed on K+‐stimulated release of cortical norepinephrine. DuP 996 may have therapeutic value in the treatment of diseases involving chlinergic and minoaminergic deterioration, like Alzh

ISSN:0272-4391    

DOI:10.1002/ddr.430190307

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

年代:1990

数据来源: WILEY

摘要:

AbstractDuP 996, 3,3,‐Bis(4‐pyridinylmethyl)‐1‐phenylindolin‐2‐one, a potent in vitro and in vivo releaser of acetylcholine (ACh), dopamine (DA), and serotonin (5HT) in rat brain, significantly enhanced the performance of rats and mice in several behavioral test procedures. At doses of 0.01–0.1 mg/kg s.c. DuP 996 protected against a hypoxia‐induced passive avoidance deficit in rats. In active avoidance procedures, DuP 996 enhanced acquisition of responses: in rats, at doses between 0.085 and 0.85 mg/kg s.c. and 0.25 and 0.85 mg/kg p.o.; in mice, at doses between 0.85 and 2.5 mg/kg s.c. These effects occurred without any alteration of sensitivity to foot‐shock. In addition, Dup 996 prevented a CO2‐induced retention deficit of a passive avoidance response when administered prior to acquisition testing. In a test for acquisition of lever pressing for food in the rat, DuP 996 increased the proportion of animals acquiring this response. Thus, DuP 996 was active in both the shock‐ and appetitive‐motivated procedures and was shown to enhance performance levels when administered post‐training as well as before training trials. These results suggest that DuP 996 may be useful in the treatment

ISSN:0272-4391    

DOI:10.1002/ddr.430190308

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

年代:1990

数据来源: WILEY

摘要:

AbstractTwelve non‐depressed DSM‐III obsessive compulsive disorder (OCD) patients were treated with fluoxetine in a 12 week open fixed dose study. After a 2 week washout period, patients were treated with 20 mg/day of fluoxetine for 1 week. The dosage was then raised to 40 mg/day for the remainder of the study. The Yale‐Brown Obsessive Compulsive Scale (Y‐BOCS) score (mean ± SD) decreased from 25.8 ± 4.5 to 15.4 ± 7.0 (P<0.01) and the Symptom Check List‐90‐Obsessive Compulsive Subscale (SCL‐90‐OC) score (mean ± SD) also showed a decrease from 2.4 ± 0.8 to 1.3 ± 0.9 (P<0.005). The results suggest that fluoxetine is effective in non‐depressed OCD patients. Our results also show that a 40 mg/day dosage is effective in contrast to previous studies that used 80 mg/day. Our finding of a significant treatment reduction in the SCL‐90‐OC is also in contrast to a previous OCD study in which the SCL‐58‐O

ISSN:0272-4391    

DOI:10.1002/ddr.430190309

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

年代:1990

数据来源: WILEY

摘要:

AbstractTrapidil and some other 5,7‐disubstituted s‐triazolo(1,5‐a) pyrimidine derivatives (TD's: AR 12455, AR 12456, AR 12463, AR 12465), which have been shown to possess inhibitory effects on proliferative activity in cultured cells, influenced the cyclic nucleotide level in human intima cells cultured from atherosclerotic plaques. The intracellular cAMP content was increased by all tested substances in concentrations of 10−4M and 10−5M, respectively. The effects of these substances were similar to those of the phosphodiesterase inhibitor methylisobutylxanthine. A significant decrease of intracellular cGMP level was provoked by trapidil and the TD's AR 12456 and AR 12463. It is discussed that trapidil and TD's have antiatherosclerotic properties mediated by changes of the intracellular cyclic nucleotid

ISSN:0272-4391    

DOI:10.1002/ddr.430190310

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

年代:1990

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430190301

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

年代:1990

数据来源: WILEY