bluuebunny/crossref_metadata_2025 huggingface dataset:
Current approaches to inhibition of proliferation in atherosclerosis
Authors: Handley Dean A.
Published: January 2005

Athersclerosis is characterized by progressive arterial stenosis of the major vessels of the systemic circulation. In man, atherosclerotic lesions are composed principally of smooth muscle cells, connective matrix derived from these cells, and variable amounts of lipid. Emphasized is the role of the platelet mitogen, platelet‐derived growth factor (PDGF), as a potent stimulus for the proliferation of smooth muscle cells in the development of atherosclerotic lesions. Animal models of proliferative atherosclerosis are reviewed, as are published references of approaches to inhibit smooth muscle cell hyperplasia in these models by drug administration. The results are discussed in terms of the potential therapeutic application of antiproliferative drugs designed to inhibit the mitogenic role of PDGF as a contributory factor in atherogenesis.
Pharmacological effects of HR 375: A new potential antipsychotic agent
Authors: Hock Franz J. , Kruse Hansjörg , Gerhards Hermann J. , Konz Elmar
Published: January 2005

HR 375, a 3‐(4‐(3‐(4‐fluorobenzoyl)‐propyl‐piperazino‐l‐yl‐isoquinolino‐ hydrochloride is a new compound with marked effects in tests of predictive value for neuroleptic activity. Its pharmacological profile is different from classical neuroleptics. HR 375 has inhibitory activity in apomorphine‐induced climbing, amphetamine aggregation toxicity, Sidman avoidance, and amphetamine‐induced hypermotility. On the other hand, only weak activity is seen in antagonizing amphetamine‐induced stereotypy, apomorphine‐turning, and apomorphine emesis. It does not include catalepsy in rats and cynomolgus monkeys even in high doses. Also, its sedative or muscle relaxant properties are weak and short‐lasting. The psychopharmacological profile of HR 375 indicates a split between its effects on the mesolimbic and nigrostriatal system.
The effects of indomethacin upon physiological indices of gastric mucosal integrity
Authors: Pendleton Robert G. , Stavorski John M.
Published: January 2005

Indomethacin was studied for its effects on three indices of gastric mucosal integrity in anesthetized cats. Following intragastric administration of the compound under conditions of constant stomach acidity and electrolyte concentrations, the transgastric potential difference declined in a gradual, linear fashion during the 210 min of the experimental period. These changes, which were dose related over the range of 1.25‐5 mg/kg of indomethacin, were accompanied by increased concentrations of luminal pepsin and blood. The results suggest that the transgastric potential difference is a sensitive indicator of gastric mucosal integrity under the conditions of this study.
Response of isolated renal artery rings to adenosine and inosine
Authors: Sinclair Richard J. , Randall John R. , Wise Gary E. , Jones Carl E.
Published: January 2005

The responses to adenosine and its analog, inosine, were compared in isolated rings of canine small renal arteries (0.5–1.3 mm o.d.). The rings were not contracted prior to nucleoside administration in order to detect any contraction response due to the nucleoside itself. Relaxation responses were elicited by progressively increasing the nucleoside concentration in the bathing medium. The maximal response (Rmax) was expressed as a percentage of the decrease in isometric tension. The ED50 for adenosine and inosine was 0.18 ± .002 μM and 202 ± 44 μM, respectively (P < 0.05) The Rmax for inosine was significantly less (P < 0.05) than that for adenosine, with a mean ratio of adenosine Rmax inosine Rmax of 1.47 ± 0.2. The results of these experiments indicated that adenosine and inosine directly relax isolated small renal arterial rings, although the classic in situ renal response to adenosine is increased resistance. Also, the relaxing action of adenosine, but not inosine, is significantly attenuated by 10 μM aminophylline. Further, renal arterial rings exhibit a greater sensitivity to adenosine than that previously reported for canine coronary artery rings, while the response to inosine is virtually identical.
Animal models to investigate drug effects on coronary physiology
Authors: Jones Carl E. , Gwirtz Patricia A.
Published: January 2005

Coronary blood flow is regulated by local intrinsic mechanisms according to the oxygen need of the myocardium, but the coronary circulation is also modulated by nervous, humoral, and extravascular influences. Therefore, any method used to study drug effects on the coronary circulation must take into account not only the direct effects of the drug but also any secondary drug effects that might indirectly influence the coronary vasculature. The simplest methods involve the use of isolated vessels. With these methods, the environment of the vessel can be precisely controlled, although usually only vessels larger than true resistance vessels can be studied. Isolated heart models have also been successfully employed, and in these models, effects of the drug on the myocardium must be considered. More complex models include in vivo anesthetized animal techniques with intracoronary drug administratiorl. With these models, drug effects on the coronary circulation as well as on other cardiac variables can be examined. The use of conscious, instrumented animals perhaps provides the most physiologic preparation and is very useful, particularly if intracoronary administration of drugs is employed.
The neuropharmacological profile of tefludazine, a potential antipsychotic drug with dopamine and serotonin receptor antagonistic effects
Authors: Svendsen O. , Arnt J. , Boeck V. , Bøgesø K. P. , Christensen A. V. , Hyttel J. , Larsen J.‐J.
Published: January 2005

The neuropharmacology of tefludazine, a new neuroleptic with phenylindan structure, has been investigated in comparison with cis(Z)‐flupentixol, fluphenazine, haloperidol, methiothepin, thioridazine, and clozapine. Tefludazine showed potent dopamine (DA) antagonistic activity in a broad range of test models in vitro and in vivo in mice, rats, and dogs (receptor binding, antagonism of DA agonist‐induced behavior, inhibition of conditioned avoidance, catalepsy, etc.). High oral activity and long duration of action was found. Interestingly, the cataleptogenic potency at the time of peak effect was seven times weaker than the antistereotypic activity, in contrast with that observed with cis(Z)‐flupentixol, fluphenazine, and haloperidol. In addition to DA antagonism, tefludazine was equipotent at 5‐HT receptors (in vitro receptor binding, 5‐HT antagonism in isolated peripheral tissue, cardiovascular 5‐HT antagonism, antagonism of I‐5‐HTP‐ and 5‐MeODMT‐induced behaviors). No antimuscarinic and low α‐adrenoceptor blocking effect was found in pithed rats and in denervated cat nictitating membrane preparation. The DA/5‐HT activity profile of tefludazine resembled that of methiothepin, which, however, had potent α‐adrenoceptor blocking effect. It is concluded that tefludazine has a neuropharmacological profile that should combine antipsychotic potential with lower risk of extrapyramidal symptoms.
Angiotensin I‐converting enzyme (ACE) inhibition and antihypertensive effects of EU‐5476, a new, potent, and long‐acting ACE inhibitor
Authors: Huang Chau Ting , Brooks Robert R. , Pong Schwe Fang , Skuster James R. , White Ralph L. , Moore Alan F.
Published: January 2005

EU‐5476 is a new, orally active angiotensin I‐converting enzyme (ACE) inhibitor. In vitro, EU‐5476 produced a concentration‐dependent inhibition of ACE purified from rabbit lung (IC50 = 0.084 μ). Inhibition showed complex kinetics and was reversible as determined by equilibrium dialysis. EU‐5476 inhibited plasma ACE in mice (93.8% inhibition at 5 μmol/kg) and produced dose‐dependent inhibition of plasma ACE in dogs (ID50 = 2.52 μmol/kg) after oral administration. In acute aortic coarctate hypertensive rats, EU‐5476 administered orally produced dose‐dependent decreases in blood pressure (ED30 = 0.53 μmol/kg). The magnitude and duration of blood pressure reduction in hypertensive rats were similar to those of plasma ACE inhibition in dogs, suggesting that plasma ACE inhibition per se is one of the mechanisms of the antipertensive action of EU‐5476. Comparative studies showed that EU‐5476, like enalapril, was more potent and longer acting than captopril in producing plasma ACE inhibition and an antihypertensive response. EU‐5476 is a potent and long‐acting, orally effective ACE inhibitor potentially useful in the treatment of hypertension.
Hemodynamic effects of a series of new trypanocidal indoleamidino compounds
Authors: Steinmann U. , Estler C.‐J. , Dann O.
Published: January 2005

The influence of 17 recently developed trypanocidal amidino compounds on blood pressure, heart rate, and carotid blood flow has been investigated in rats. Their cardiovascular effects were compared with those produced by pentamidine (Lomidine®) and diminazen (Berenil®). All compounds lowered the arterial blood pressure, especially the diastolic pressure, and almost all agents caused a reflex tachycardia and some reduction of the carotid blood flow. The hypotensive potency of the compounds can be reduced by alterations of the chain length between the cation moieties.
Interactions of central acting compounds with hepatic drug‐metabolizing enzyme systems: I. Effects of dsp‐4 on liver microsomal enzymes
Authors: Hock Franz J. , Beyhl Friedrich E.
Published: January 2005

The action of DSP‐4 [N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromo‐benzylamine] on drug‐metabolizing liver enzymes was studied in the rat. Seventy‐two hours after a single subcutaneous (sc) dose of DSP‐4 (75 mg/kg), mixed‐function oxidases, glucuronyltransferases, and cytochrome P‐450 were decreased, whereas aniline hydroxylase, cytochrome c reductase, and glutathione S‐transferase remained unchanged. Thus, in addition to DSP‐4′s central action, effects on peripheral organs are also exerted.
Comparative evaluation of the relaxant effects of MDL‐257, its metabolits, and some related compounds on guinea pig tracheal cylindrical segments
Authors: Abdallah Abdulmuniem H. , Burnell James W. , Cregge Robert J.
Published: January 2005

The smooth muscle relaxant activities of MDL‐257 [8‐methyl‐6‐piperidino‐s‐triazolo (4,3‐b)pyridazine], a new, nonsympathomimetic bronchodilator, its metabolites (in man and rats), and some related compounds were compared to that of aminophylline in guinea pig tracheal cylindrical segments. The IC50 of MDL‐257 against KCl‐, histamine‐, acetylcholine, and 5‐hydroxytryptamine‐induced contractions were 5.2 × 10−5, 5.3 × 10−5, 9.1 × 10−5, and 1.4 × 10−5M, respectively. The relaxant activity of aminophylline was equal to that of MDL‐257 against all of the spasmogens studied. Dihydroxy substitution on the piperidine ring of MDL‐257 reduced its relaxant activity against KCl, histamine, and 5‐hydroxytryptamine 25‐‐43‐fold and its activity against acetylcholine was almost abolished. The monohydroxy and the amino alcohol metabolites of MDL‐257 were two to 20 times less potent than the parent compound and their activities against acetylcholine‐induced contractions were minimal. The acidic metabolites of MDL‐257 exhibited very weak activity against all of the spasmogens tested.
Cognitive disorders related to immune dysfunction: Novel animal models for drug development
Authors: Lal Harbans , Forster Michael J.
Published: January 2005

With the recent emphasis on drug development for mental disorders of late life, a need has arisen for animal models useful in preclinical evaluation of potential treatment strategies. Although the animal models now available exhibit behavioral and neurological commonalities with their target clinical syndromes, few models incorporate etiologic similarities. A review of the literature is presented relating immune factors to aging‐associated cognitive disorders, and parallels are drawn to immune factors and related behavioral impairments in autoimmune New Zealand black and nonautoimmune C57BL/6 mice. These mouse strains are proposed as potentially useful immunologic models for both theoretical investigation and drug development.
Cumulative dose‐effect curves in rats run twice a week on an interresponse‐time > 72‐sec schedule
Authors: Pollard Gerald T. , Howard James L.
Published: January 2005

Ovariectomized Long‐Evans rats were trained to emit a lever‐press response on an interresponse‐time (IRT) > 72‐sec schedule of food reinforcement and were maintained on a regimen of two sessions per week. This regimen yielded acceptably stable baseline behavior with moderate response rates and low reinforcement rates. Within‐session cumulative dose‐effect curves for four standard psychoactive drugs were generated by injecting five ascending doses per os at 20‐min intervals. d‐Amphetamine (0.125‐‐2.0 mg/kg) increased responses. Chlorpromazine (1.25‐‐20 mg/kg) decreased responses. Chlordiazepoxide and pentobarbital (1.25‐‐20 mg/kg) increased responses at low and moderate doses and decreased responses at higher doses; overall increases resulted from a burst‐and‐pause pattern. Drug effects were similar to those previously reported for the typical daily 1‐hr session. We concluded that cumulative dosing in rats run twice a week on an IRT > 72‐sec schedule could increase the ouput of routine operant data.
Behavioral pharmacology of the pyrazoloquinoline CGS 9896, a novel putative anxiolytic
Authors: File Sandra E. , Pellow Sharon
Published: January 2005

CGS 9896, a pyrazoloquinoline that displaces [3H]benzodiazepines from their CNS receptors, has been claimed to be a nonsedative anxiolytic in animals. However, conflicting results have been obtained with this compound in animal tests of anxiety and seizures. The present study reports the effects of CGS 9896 in three animal tests of anxiety, against seizures induced by picrotoxin and pentylenetetrazole, and on the holeboard test in rats. CGS 9896 (injected intraperitoneally) has an anxiolytic‐like activity in the social interaction test (5‐‐10 mg/kg) and in the elevated plus‐maze (10‐‐20 mg/kg) but not in the Vogel punished drinking procedure (5‐‐10 mg/kg). CGS 9896 had potent anticonvulsant effects against pentylenetetrazole (total protection at 5 mg/kg) but was considerably less potent against picrotoxin‐induced seizures (only 50% reduction at 40 mg/kg). CGS 9896 (10 mg/kg) caused significant reductions in spontaneous exploratory and locomotor behavior in the holeboard test in rats. In all test procedures, CGS 9896 was considerably less potent than the benzodiazepines diazepam or chlordiazepoxide. In conclusion, these data support the evidence suggesting that CGS 9896 possesses anxiolytic and anticonvulsant properties in rodents but suggest that caution should be observed in concluding that a compound is nonsedative on the basis of one or two measures.
Prevention of experimental amnesia by peripherally administered cholecystokinin octapeptide in the rat
Authors: Katsuura Goro , Itoh Shinji
Published: January 2005

The effect of subcutaneously injected cholecystokinin octapeptide (CCK‐8) on amnesia induced by electroconvulsive shock (ECS), CO2 inhalation, or cycloheximide injection was investigated in rats. In normal rats, single administration of CCK‐8 had no significant effect on the passive avoidance response. Treatment with ECS, CO2, or cycloheximide markedly decreased the latency of the passive avoidance response, but CCK‐8 in doses from 0.1 to 10 μg/kg could prevent the induced amnesia when injected 30 min before the training trials, immediately after foot shock or amnesic treatments, and 30 min before the first retention test. The results indicate that peripheral administration of CCK‐8 is effective in preventing amnesia in the rat.
Pentylenetetrazol‐induced antinociceptive responses in the mouse
Authors: Valli M. , Mesdjian E. , Tamalet C. , Jadot G. , Vion‐Dury J. , DeFeudis F. V. , Mandel P.
Published: January 2005

We describe studies that tested the hypothesis that pentylenetrazol (PTZ) produces analgesia in mice. Indeed, the studies demonstrated analgesia in both of the analgesimetric procedures (hot plate test, acetic acid‐induced writhing response) with a clear degree of separation between the antinociceptive and convulsant doses of PTZ. Antagonists for four neurotransmitters failed to antagonize the analgesia produced by PTZ.
Altered vasodilator and endothelium‐dependent responses in hypertension
Authors: Winquist Raymond J.
Published: January 2005

A compromised ability to relax has been described as a characteristic of vascular smooth muscle from animal models of hypertension. Since the discovery that many vasodilators act via the release of an endothelium‐derived relaxant factor (EDRF), studies have been designed to assess whether endothelium‐dependent vs. ‐independent relaxations are impaired in the hypertensive state. A decreased maximal relaxation for such endothelium‐dependent vasodilators as acetylcholine, A23187, and histamine exists in both large conduit and resistance vessels from hypertensive animals compared to their normotensive counterparts. Endothelium‐independent vasodilators (i.e., sodium nitroprusside) typically achieve similar maximal percent relaxations in hypertensive vs. normotensive vascular preparations. This defect for endothelium‐dependent vasodilators has been described in vessels from genetic, renal, mineralocorticoid, and coarctation models of hypertension. An altered endothelium‐dependent relaxation could be a corollary of the documented structural changes which occur in hypertension although it remains to be determined if there exists an abnormal coupling between EDRF and its putative receptor in vascular smooth muscle. Several complexities hamper interpretation of altered endothelium‐dependent responses in hypertersion such as regional vascular differences, suitability of reference endothelium‐independent vasodilators, and endothelium‐dependent contractile responses elicited by acetylcholine.
Endothelial bound lipases and lipoprotein metabolism in disease and drug development
Authors: Oka Kazuhiro , Paterniti James R.
Published: January 2005

Current awareness of the role of lipoproteins in the pathogenesis of atherosclerosis has focused attention on their metabolic aspects. Lipoproteins originate in both the gut and the liver. They undergo important metabolic conversions when they interact with the endothelial surfaces of the vascular compartment. Endothelial bound triglyceride lipase activities (i.e., lipoprotein lipase and hepatic triglyceride lipase) are central to the metabolism and interconversion of the lipoprotein classes. Fatty acids released during lipase mediated hydrolysis equilibrate with the endothelial surfaces prior to their transport to the underlying parenchymal tissue for storage or utilization. These underlying tissues are the sites of synthesis of the lipolytic enzymes, which must in turn travel to the lumenal endothelial surfaces. Thus an intricate interplay exists between the outer lining and substrata of the vessel wall. The interaction of endothelium and parenchymal cell has profound consequences for the pathogenesis of atherosclerosis and represents an important focus for drug development.

We are studying the expression of lipoprotein lipase and hepatic triglyceride lipase activities in a mouse model in which a single autosomal recessive mutation, cld, produces a combined deficiency of these lipase activities. Our recent work suggests that the cld mutation affects postsynthetic cellular processes by which these lipolytic enzymes gain functional expression of the vascular endothelial surface. The plasma lipolytic activities regulate the levels of the atherogenic and antiatherogenic lipoproteins. Understanding the detailed cellular mechanisms that regulate these crucial functions can provide a rationale for the development of agents that may be effective against cardiovascular disease.
Pharmacokinetics and tissue distribution of astemizole in the dog
Authors: Michiels Marcel , van Peer Achiel , Woestenborghs Robert , Heykants Jozef
Published: January 2005

The pharmacokinetics of a single oral dose of 3H‐astemizole (AST) of 1 mg/kg was studied in Beagle dogs and compared with that of a tracer dose superposed at the end of a subchronic experiment. Single and superposed doses were equally well absorbed, and elimination half‐lives of AST and of its metabolites were similar at both occasions (t1/2ß = 3–5 d). Steady‐state was reached after 2–3 weeks of daily dosing. AST and its metabolite desmethylastemizole (DES‐AST) were extensively distributed, mainly to well perfused tissues but only poorly to brain, muscle, and fat. All tissue levels were many times higher than the corresponding plasma concentrations. The superposed tracer dose was well stirred in the tissue compartments and showed instantaneous equilibrium with pretreatment levels. Tissue/plasma level ratios of AST and DES‐AST remained constant with time, indicating that the elimination from tissues proceeded at a similar rate to that from plasma. The extensive distribution of AST and DES‐AST is explained by a strong, but reversible tissue binding that appears to be rate‐limiting for the elimination from the body.
Therapeutic effect of astemizole and terfenadine in students suffering from seasonal allergic rhinitis: A double‐blind comparison
Authors: Rombaut Niekol E. I. , van Roy Jean P. , Bracke Emmanuel , Vanden Bussche Gabriel
Published: January 2005

Ninety‐seven university students presenting with hay fever symptoms were evaluated in a double‐blind randomized study comparing astemizole 10 mg o.d. with terfenadine 60 mg b.i.d. Patients were seen at bi‐weekly intervals by their treating physician and scored their symptoms daily for a period of 4 weeks. Breaking the code revealed that 45 patients had received astemizole and 52 terfenadine. Both groups were comparable with regard to age, sex, weight, duration of disease, and symptom severity at start. At the end of treatment, symptom ratings showed a significant improvement of all typical hay fever symptoms in both treatment groups except for blocked nose. Global evaluation of treatment, however, was significantly in favour of the astemizole group of which 71% of the patients were considered as excellent or good responders, as compared to 55% in the terfenadine group. Neither of the two compounds was associated with sedative effects; other side effects were virtually absent in both groups.
Treatment of chronic myopathies in horses with the serotonin S2‐antagonist R 50970: A preclinical study
Authors: Ooms Leo A. A. , Degryse Anne‐Dominique A. Y. , Fransen Jan L. A. , van Mol Kris A. C.
Published: January 2005

In a preclinical study, R 50970, a potent serotonin S2‐antagonist with weak α1‐adrenoceptor blocking activity, was tested in 46 trotters, 11 riding horses and five ponies with chronic muscle problems as diagnosed by clinical examination, serum CPK values, and histopathology of the medial gluteal muscle. CPK values were of little value in the diagnosis of chronic myopathies. Oral treatment, varying from 14 to 60 days with a dose of 0.1 mg/kg of R 50970, resulted in clincial improvement of all animals except two trotters. The muscle biopsies revealed an overall histopathological improvement of 60%.
The in vivo antifungal activity of broad‐spectrum azoles
Authors: van Cutsem Jan , van Gerven Frans
Published: January 2005

The antifungal activities (topical and oral) of miconazole, ketoconazole, and itraconazole were compared in laboratory animals. Miconazole at concentrations of 1 and 2% was an effective antifungal agent in the topical therapy of microsporosis and at 2% in vaginal candidosis. Ketoconazole was superior to miconazole in potency and efficacy, a concentration of 1% producing a 100% cure. With itraconazole the same efficacy was reached as with ketoconazole but at concentrations 4 to 8 times lower. Miconazole, administered orally, was marginally active in dermatophytosis and, after long‐term treatment, in candidosis. In contrast, ketoconazole was found to be a broad‐spectrum antifungal agent of high efficacy at 10 mg/kg. Itraconazole again was more potent (doses 1.25 to 2.50 mg/kg) and more effective than ketoconazole in dermatophytosis, candidosis, and mycoses due to dimorphic fungi. Moreover, itraconazole constitutes an important therapeutic progress in the oral treatment of aspergillosis and cryptococcosis. The three compounds were free of side effects in the present experimental conditions.
Itraconazole (R 51 211): A clinical review of its antimycotic activity in dermatology, gynecology, and internal medicine
Authors: Cauwenbergh Geert , De Doncker Piet
Published: January 2005

Itraconazole was highly effective in skin infections caused by dermatophytes and yeasts. In addition, vaginal candidosis responded well to oral itraconazole therapy. Treatment periods for superficial mycoses ranged from 2 to 3 days in vaginal infections to up to 2 months in tinea pedis. The daily dose in superficial mycoses ranged from 50 mg to 200 mg (median 100 mg). In systemic mycoses, itraconazole is the first compound active in sporotrichosis since the advent of potassium iodide in 1901. It has also been shown to be active in aspergillosis and chromomycosis in man. The median daily dose of itraconazole administered in systemic mycoses was 100 mg (50–800 mg). The median treatment length in systemic mycoses was 6 months (15 days‐2.5 years).
Structural damage of the ischemic brain: Involvement of calcium and effects of postischemic treatment with calcium entry blockers
Authors: van Reempts Jos , Haseldonckx Marc , van Deuren Bruno , Wouters Luc , Borgers Marcel
Published: January 2005

The consequences of acute cerebral ischemia and the protective effects of post‐treatment with flunarizine and nimodipine were morphologically studied in an experimental rat model allowing simple quantification of delayed neuronal damage. Global incomplete ischemia was induced by temporary clamping of both carotid arteries combined with severe hypotension. Selective damage to CA1 hippocampal neurons was quantified 7 days later. Cytochemical visualization of subcellular Ca2+ in this model revealed a correlation between irreversible cell necrosis and toxic cytosolic Ca2+‐overload, the latter being a relatively slow process originating late in the reoxygenation period. Treatment with Ca2+‐entry blockers started at 5 min after restoration of cerebral blood flow. Flunarizine significantly protected against ischemic hippocampal damage, whereas nimodipine had no effect.
Comparative studies on cardiovascular, respiratory and gastrointestinal effects of the sedatives R 51163 and xylazine in cattle
Authors: Degryse Anne‐Dominique A. Y. , Ooms Leo A. A.
Published: January 2005

R 51163 and xylazine are rougly equipotent sedative agents in cattle. The effects of i.v. injections of R 51163 and xylazine on acid‐base status, arterial and venous blood gas tension, cardiovascular parameters, and rumen motility were compared in adult healthy cattle. With R 51163 heart rate increased and respiratory rate decreased. Xylazine decreased both heart rate and respiratory rate. Both drugs caused minor changes in arterial and venous blood parameters and blood pressure. The overall cardiovascular and respiratory changes produced by either drug remained within physioloical limits of normal awake cattle. After injection of R 51163, rurnination was inhibited but recurred within 45 min. Antegrade and retrograde contractions were slightly inhibited. Xylazine completely blocked rumination for at least 2 hr. Antegrade contractions were absent for 40 min. Antegrade and retrograde contractions were decreased during both the first and second 60‐min follow‐up period. Both R 51163 and xylazine produced modest cardiovascular and respiratory effects. Xylazine, when compared to R 51163, produced a profound depression of rumen motility. These effects have limited consequences in normal fasted cattle, but should be taken into account in diseased non‐fasted cattle with impaired cardiovascular functions.
Analgesia and motor activity following administration of THIP into the periaqueductal gray and lateral ventricle of rats
Authors: Retz Konrad C. , Holaday Lisa M.
Published: January 2005

Intracerebral microinjections of THIP (4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol), a GABAergic agonist that produces analgesia when administered systemically, were made to investigate the central sites of action of this agent. Comparisons were also made with intracerebral microinjections of morphine and with systemic administration of each agent. Injections into the ventral lateral periqueductal gray (PAG) produced analgesia on the 55°C hot‐plate test following a 2.0 μg dose, but were without effect at the other doses examined (0.5–20.0 μg). In the tail‐flick test, hyperalgesia was seen following the 5.0‐ and 20.0‐μg doses. Motor activity was increased following the 1.0‐, 2.0‐, and 10.0‐μg doses and was accompanied by ipsilateral turning. Injections into the lateral cerebral ventricle (ICV) were without effect at doses of less than 50 μg. No significant effects were observed in the hot‐plate test following 50 μg produced severe ataxia, precluding testing. Following 50 μg, hyperalgesia was seen in the tail‐flick test. THIP at both doses decreased motor activity. The present findings further demonstrate some novel aspects of the pharmacology of THIP and suggest that much of the drug's analgesic activity is produced by interaction with GABAergic receptors outside the PAG and structures easily accessed by ICV administration.
Effect of etodolac on the prostaglandin concentrations in the kidney of the normal rat
Authors: Lee David K.H.
Published: January 2005

The effect of acute and subchronic dosing with etodolac on the renal PGE2 and 6‐keto‐PGF1α concentrations in the normal rat were studied. Etodolac and other nonsteroidal antiinflammatory drugs (NSAIDs) were administered orally, at equieffective antiinflammatory doses, to normal rats either as a single dose or as seven daily doses. Whole kidney prostaglandin (PG) concentrations were measured. In the acute study, etodolac (3 mg/kg) did not significantly lower the PGE2 levels for up to 4 hr postdosing. In contrast, naproxen (3 mg/kg) and piroxicam (0.5 mg/kg) significantly decreased the PGE2 levels to about 20% and 60% of control, respectively. Similar reductions in 6‐keto‐PGF1α concentrations were observed. In the subchronic study, etodolac (3 mg/kg/day) did not lower either PGF2 or 6‐keto‐PGF1α concentrations whereas naproxen (3 mg/kg/day), piroxicam (0.5 mg/kg/day), indomethacin (1 mg/kg/day), and aspirin (300 mg/kg/day) significantlydecreased both PGs. In both studies, the effect of etodolac was significantly different from that of the NSAIDs. It is concluded that etodolac possesses only a very weak capacity to lower renal PGs, and therefore is unlikely to cause any renal complications related to PG biosynthesis inhibition.
Nomifensine enantiomers: Psychopharmacological effects in mice and rats in comparison with D,L‐nomifensine
Authors: Kruse Hansjoerg , Scholtholt J.
Published: January 2005

The D‐ and L‐enantiomers of nomifensine (8‐amino‐2‐methyl‐4‐phenyl‐1,2,3,4‐tetrahydrois‐oquinoline) were tested for psychopharmacological effects in mice and rats with D,L‐nomifensine hydrogen maleate as a reference drug. In tests on antidepressant activity (antagonism of tetrabenazine ptosis, reserpine hypothermia, oxotremorine hypothermia, “behavioral despair,” and potentiation of yohimbine toxicity), the D‐enantiomer was on average 1.7 or 2.8 times more potent than the racemate with the intraperitoneal (i.p.) or oral route of administration, respectively. The L‐enantiomer displayed slight ativity only when injected i.p. and was on average ≥ 30 times less potent than the racemate. In tests on dopaminergic acivity, D‐nomifensine was about 3 times (motor stimulation in mice) or 1.5–1.9 times (induction of stereotyped behavior in rats) more potent than the racemate. The L‐enantiomer was devoid of stimulant or stereotypic activity and had a rather sedative effect. In acute (24 h) toxicity studies, D‐nomifensine proved 2.9 or 4.5 times more toxic, and L‐nomifensine was 1.6 or 1.3 times less toxic than the racemate (i.p. or p.o., respectively). The results indicate that nomifensine acts by stereospecific mechanisms and that the D‐enantiomer is the active component.
Yohimbine‐induced seizures in mice: A model predictive of potential anxiolytic and GABA‐mimetic agents
Authors: Dunn Robert W. , Fielding Stuart
Published: January 2005

Yohimbine potentiation of lethality in mice has been used as a model for the prediction of antidepressant agent [Quinton, 1963]. However, prior to death or at sublethal doses, yohimbine induces clonic convulsions. In Swiss‐Webster mice (20–28 g) individually placed in clear plastic cylinders, the CD50 (median convulsive dose) for yohimbine‐induced seizures was 22.7 (18.9−27.3) mg/kg sc (subcutaneously). For anticonvulsant screening, compounds were administered intraperitoneally at appropriate pretreatment times prior to the CD95 dose of yohimbine (45 mg/kg sc). The following anxiolytic and GABA‐mimetic agents administered intraperitoneally dose‐dependently antagonized yohimbine‐induced clonic convulsions: diazepam (ED50) = 0.26 mg/kg); chlordiazepoxide (2.0 mg/kg); CGS 9896 (0.82 mg/kg); CL 218,872 (3.7 mg/kg); zopiclone (19.0 mg/kg); tracazolate (61.3 mg/kg); clonazepam (0.02 mg/kg); phenobarbital (9.0 mg/kg); valproic acid (81.1 mg/kg); trimethadione (163.0 mg /kg); muscimol (0.82 mg/kg); AOAA (16.0 mg/kg); clonidine (0.22 mg/kg); and baclofen (4.0 mg/kg). On the other hand, the antiepileptic agents diphenylhydantoin, ethosuximide, and carbamazepine as well as the benzodiazepine antagonists CGS 8216 and RO 15 1788 were inactive. The neuroleptics haloperidol, chlorpromazine, and thioridazine were inactive, while clozapine displayed anticonvulsant activity (ED50 = 30.4 mg/kg). Other inactive compounds include phenotolamine, propranolol, atropine, alpha‐methyltyrosine, PCPA, reserpine, buspirone, DMI, and imipramine. Since yohimbine has been reported to be anxiogenic in animals and man, this assay may be relevant for the prediction of anxiolytic agents. Furthermore, compounds active in this test have shown anxiolytic activity in behavioral conflict paradigms.
Enzymic biomedical research and new drug development
Authors: Tegeler John J. , Kim Kwon H.
Published: January 2005

The proceedings of a symposium on current trends in enzyme‐guided biomedical research and its relation to potential new drug discovery are reviewed. Topics under discussion include current concepts in enzyme inhibition, the mechanism and inhibition of phopholipase A2, 5‐lipoxygenase and inflammation, the protease/antiprotease hypothesis of emphysema, carbonic anhydrase and glaucoma, GTP‐binding proteins and adenylate cyclase, and the calpain hypothesis of memory storage.
5‐Lipoxygenase, leukotrienes, and regulation of inflammatory responses
Authors: Parker Charles W.
Published: January 2005

5‐Lipoxygenses are enzymes in leukocytes and mast cells that oxidize arachidonic acid to 5‐hydroperoxyeicosatetraenoic acid, which is in turn converted to a variety of products including leukotriene B4and the sulfidoleukotrienes (LTC4, LTD4and LTE4). These substances exert a broad range of biologic actions including effects on cell migration, enzyme secretion, smooth muscle contraction in the respiratory and gastrointestinal tracts, and vascular permeability. Considerable evidence now implicates these products in a variety of acute and chronic inflammatory responses in vivo as well as in acute allergic reactions affecting the airway and skin.
Interoceptive stimuli produced by cocaine are blocked during diazepam withdrawal
Authors: Wood Douglas M. , Ranschaert Erik R. , Lal Harbans
Published: January 2005

Rats were trained to select one lever after an intraperitoneal (ip) injection of cocaine (10 mg/kg), and an alternate lever after saline injection under a FR10 schedule of food reinforcement. Following chronic administration of cocaine (20 mg/kg/8hr), but not diazepam (80 mg/kg/8hr) for 7 days, the dose‐effect curve for the generalization of cocaine shifted twofold to the right. Subsequently, in the rats receiving chronic diazepam, RO 15‐1788, a drug known to precipitate diazepam withdrawal, failed to substitute for cocaine: however, the discriminability of cocaine (5 mg/kg) was reduced from 83% to 13% selection of cocaine‐appropriate lever after 72 hr following the last diazepam, injection. These data suggest that chronic administration of cocaine, but not diazepam, produced tolerance to the discriminative stimulus properties of cocaine, and following chronic diazepam administration and withdrawal, the stimulus properties of cocaine are antagonized.
Evaluation of oral skeletal muscle relaxants in the morphine‐induced straub tail test in mice
Authors: Pong Schwe Fang , Sweetman Janet Mary , Pong Amy Sue , Carpenter John Franklin
Published: January 2005

Morphine is known to produce a characteristic and reproducible elevation of the tail in mice (Straub tail response). The morphine‐induced Straub tail response in mice has been used to evaluate skeletal muscle relaxant (SMR) activity of compounds administered intraperitoneally (i.p.). This model was used to evaluate the oral (p.o.) efficacy of a number of SMRs and other pharmacological agents. Male mice (n ≥ 5) were given test drugs p.o. followed by morphine sulfate [15 mg/kg subcutaneously (s.c.)] 15 min later. The mice were scored all or none for a Straub tail reaction 45 min later. Graded doses of active compounds were further evaluated for ED50 estimation by probit analysis. ED50 values (mg/kg) were estimated for the following compounds: baclofen (6.4), chlorpromazine HCl (3.8), cyclobenzaprine HCl (24.6), dantrolene Na (14.4), diazepam (8.3), haloperidol (6.2), naloxone HCl (8.7), phenoxybenzamine HCl (47.6), phentolamine HCl (265), and trifluoperazine HCl (25.4). These ED50 values appeared to correlate with initial adult human daily oral doses for muscle relaxation. The following compounds inhibited the Straub tail response in ≤ 40% of the mice tested at the doses indicated (mg/kg): carisoprodol (300), lidocaine (100), mephenesin (300), phenytoin (100), procainamide HCl (100), procaine HCl (100), propranolol HCl (100), quinidine sulfate (100); and all selected calcium‐channel blockers (30), antidepressants (30), and neuromuscular blocking agents (> 10 times the literature i.p. ED50 values with the exception of gallamine triethiodide at 30 mg/kg) that were tested. Pentobarbital Na was active only at doses that impaired the righting reflex. This animal model was thus determined to be useful for evaluating SMR efficacy and in predicting.
Preliminary analysis of the discriminative stimuli induced by the calcium channel “agonist” BAY K 8644
Authors: Gladstein Laura , Traber Jörg , Spencer David G.
Published: January 2005

Rats were trained in a drug discrimination paradigm to press one of two levers for food reward after injection of the racemic dihydropyridine (DHP) Ca2+ ‐channel activator BAY K 8644 (2.5 mg/kg) and to press the other after vehicle injection. The discrimination was reliably attained in an average of 48 sessions. Thereafter, tests with various doses of BAY K 8544 yielded a dose‐dependent selection of the BAY K 8644 lever, with an ED50 of 0.74 mg/kg. The (−)‐enantiomer of BAY K 8644 generalized dose‐dependently (ED50 = 1.04 mg/kg), while the (+)‐enantiomer showed no generalization up to 10 mg/kg. Furthermore, nifedipine pretreatment fully antagonized the BAY K 8644 stimulus. These data indicate that BAY K 8644 produces physiological effects that can readily serve as discriminative stimuli in rats. The results also support the mediation of the BAY K 8644 stimulus through agonistic interaction with the calcium channel DHP receptor.
Potential antipsychotic BMY 14802 selectively binds to sigma sites
Authors: Taylor Duncan P. , Dekleva Jennifer
Published: January 2005

BMY 14802 presents a pharmacologic profile which, from behaviral testing, suggests potential as an antipsychotic agent with fewer side effects than currently available drugs. In marked contrast to these agents, BMY 14802 appears to have a “nondopaminergic” site of action. In view of the suggestion that antagonists of the so‐called s̀ site (labelled with high affinity by N‐allylnormetazocine and sensitive to haloperidol) may represent a new approach in the development of potential antipsychotic agents, we investigated the interaction of BMY 14802 with this site. We report that BMY 14802 selectively inhibited binding at this site, displaying stereospecificity, with the dextrorotatory form more potent than the levorotatory enatiomer, and that (+) BMY 14802 inhibited binding at this site in a competitive fashion.
General neuropharmacology of vinpocetine: A putative cerebral activator
Authors: Keim Kevin L. , Hall Pauliana C.
Published: January 2005

Results from a series of standardized tests in rodents were used to describe the general neuropharmacology of vinpocetine, a putative cerebral activator. Vinpocetine was tested at doses ranging from 5 to 100 mg/kg p.o.; these doses are greater that its behaviorally active doses (i.e., 1 to 5 mg/kg p.o.). Vinpocetine did not impair rotarod performance or produce ataxia in mice. Vinpocetine antagonized electroconvulsive shock (ECS)‐induced convulsion in rats (ED50 = 28 mg/kg p.o.); however, neither ECS‐ nor pentylenetetrazol (PTZ)‐induced convulsions in mice were prevented by vinpocetine. The compound did not attenuate aggressive behavior in isolated mice. Vinpocetine decreased spontaneous loco‐motor activity (SLA) without affecting the rectal temperature in rats at doses greater than 25 mg/kg p.o., but the decrease was not dose‐related. Neither 10 nor 50 mg/kg p.o. of vinpocetine antagonized amphetamine‐induced stereotypy and exophthalmos in rats. In mice, vinpocetine (up to 100 mg/kg p.o.) did not antagonize reserpine‐induced catalepsy and ptosis or protect against tremorine‐induced lacrimation, tremor, salivation, or hypothermia. The lack of effect in these tests demonstrates that vinpocetine has little, if any, propensity to produce central nervous system (CNS) side effects.
Human safety profile of tolrestat: An aldose reductase inhibitor
Authors: Ryder Steven , Sarokhan Brenda , Shand David G. , Mullane John F.
Published: January 2005

The safety of tolrestat use in the diabetic patient was demonstrated by data from 14 double‐blind and open‐label studies conducted in 1,300 patients with diabetic neuropathy; the results were supported by data from earlier bioavailability, pharmacokinetic, and clinical pharmacology trials. There was a generally comparable frequency of complaints in the tolrestat dose groups and placebo groups. In a year‐long double‐blind study, the only complaint considered to by “possibly” drug‐related that occurred with a significantly greater incidence in patients treated with tolrestat than in those on placebo was dizziness. Laboratory test values recorded during the trials supported the positive safety findings of tolrestat. A review of blood urea nitrogen and serum creatinine values did not suggest any potential for tolrestat‐induced renal dysfunction. Infrequently, significant elevations in serum hepatic enzyme (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) levels occurred, accounting for 27 of 42 possibly drug‐related patient withdrawals following tolrestat administration. On review of these cases, it was concluded that tolrestat may cause hepatocellular damage with coincident elevations in AST and ALT in approximately 2% of patients. Importantly, the abnormalities were reversible after discontinuing the drug, commonly within 8–16 weeks. There was no evidence of a hypersensitivity syndrome in any patient in any study. These results support a favorable safety profile for tolrestat.
Investigations of the cardiac actions of SK&F 86466 in the rabbit
Authors: Macia Richard A. , Molyvdas Paschalio‐Adam , Poyatzi Afroditi , Sperelakis Nicholas , Matthews William D.
Published: January 2005

The cardiac effects of SK&F 86466, an α2‐adrenoceptor antagonist currently under evaluation in humans as an antihypertensive agent, were investigated in rabbits. In the isolated working rabbit heart, SK&F 86466 had no effect on spontaneous heart rate, contractility, coronary flow, aortic flow, or left ventricular pressure at concentrations from 10−7 to 3 × 10−5 M. At higher concentrations, SK&F 86466 lowered heart rate, contractility, aortic flow, and left ventricular pressure to such an extent that the heart failed to perform work. Electrophysiologic studies of spontaneous actions potentials of sino‐atrial node cells revealed that from 10−9 to 10−5 M, SK&F 86466 had no effect on action potential generation. At 3X 10−5 M, a 25% decrease in the rate of spontaneous action potentials was observed. This effect was accompained by a 1.3 V/sec decrease in + Vmax and a 25% increase in APD50. These results suggest that: 1) SK&F 86466 has no direct cardiodepressant action in rabbits at pharmacologically relevent doses, and 2) the actions of SK&F 86466 on the heart are most likely due to an effect on inward calcium current.
Pharmacological characterization of CGS 17867A as a benzodiazepine receptor agonist devoid of limiting behavioral effects
Authors: Bennett Debra A. , Amrick Caryl L. , Wilson Douglas E. , Boast Carl A. , Loo Patricia , Bernard Patrick S. , Schmutz Markus , Gerhardt Susan C. , Braunwalder Albert , Klebs Klaus , Yokoyama Naokata , Liebman Jeffrey M.
Published: January 2005

CGS 17867A (2‐(4‐chlorophenyl)‐2,5,6,7,8,9,‐hexahydor‐3H‐pyrazolo [4,3,‐c]quinoline‐3‐one‐hydrochloride salt) is a tetrahydorpyrazoloquinoline related to the benzodiazepine (BZ) receptor agonist, CGS 9896. The compound is an effective inhibitor of [3H]flunitrazepam binding to the central BZ receptor (IC50 = 1.0 nM). Activity at the GABA‐A receptor and chloride channel components of the BZ receptor complex indicate a profile predictive of a partial agonist. CGS 17867A is orally active, block PTZ discriminative stimuli, produces an increase in conflict responding, and generalizes to CGS 9896 discriminative stimuli, indicating potential anxiolytic efficacy comparable to that of diazepam. This compound is more potent than diazepam in protecting rats against pentylenetetrazol‐induced convulsions and is effective in delaying the development of kindled seizures. Only moderate protection is noted against picrotoxin‐induced convulsions and no effect is produced by CGS 17867A against maximal electroshock‐ or strychnine‐induced convulsions. An absence of muscle relaxant properties is suggested by the inability of CGS 17867A to impair rotorod performance or to generalize to diazepam discriminative stimuli. Unlike CGS 9896, CGS 17867A does not antagonize diazepam‐induced rotorod deficit or diazepam discriminative stimuli. CGS 17867A potentiates ethanol‐induced rotorod impairment only at doses
in excess of those producing therapeutic efficacy, in contrast to the BZs, which induce both effects at comparable doses. Mice treated chronically with CGS 17867A do not show any tolerance or withdrawal effects upon subsequent testing. CGS 17867A produces a preclinical profile indicative of a partial BZ receptor agonist. The compound has anxiolytic and anticonvulsant potential and a reduced propensity to produce the limiting effects of the classical BZs.