bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractEU‐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

AbstractThe 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

AbstractThe 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

AbstractThe 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

AbstractWith 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

AbstractOvariectomized 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

AbstractCGS 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

AbstractThe 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

AbstractWe 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

AbstractA 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

AbstractCurrent 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

AbstractThe 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

AbstractNinety‐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

AbstractIn 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

AbstractThe 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

AbstractItraconazole 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

AbstractThe 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

AbstractR 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

AbstractIntracerebral 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

AbstractThe 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.