bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of protocatechualdehyde, a metabolite of the novel antirheumatic agent ACP, on chondrocyte metabolism
Authors: Watanabe Koju , Hayashi Haruhisa , Mori Yo 
Published: January 2005

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 production. ©1993 Wiley‐Liss, Inc.
Effect of calcium binding protein modulators on myofibrillar MgATPase activity and cGMP‐inhibitable phosphodiesterase activity from human cardiac muscle
Authors: Pagani Edward D. , O'Connor Bernard , Allen Paul D. , Hille Darcy , Silver Paul J. 
Published: January 2005

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 IC50 values 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 questionable. © 1993 Wiley‐Liss, Inc.
Pharmacology of cyanodothiepin (BTS 56 424), a selective 5‐hydroxytryptamine reuptake inhibitor
Authors: Luscombe Graham P. , Buckett W. Roger 
Published: January 2005

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 antidepressants. © 1993 Wiley‐Liss, Inc.
8‐(3‐Isothiocyanatostyryl)caffeine is a selective, irreversible inhibitor of striatal A2‐Adenosine receptors
Authors: Ji Xiao‐Duo , Gallo‐Rodriguez Carola , Jacobson Kenneth A. 
Published: January 2005

Abstract8‐(3‐Isothiocyanatostyryl)caffeine (ISC) was synthesized and shown to inhibit selectively the binding of [3H]CGS 21680 (an A2a‐selective agonist) at adenosine receptors in striatal membranes. The Ki value at A2a‐receptors was found to be 110 nM (rat), with selectivity ratios for A2a versus A1‐receptors in rat, guinea pig, bovine, and rabbit striatum of >100‐fold. Preincubation of membranes with ISC caused a dose‐dependent, irreversible antagonism of the binding of [3H]CGS 21680, with an IC50 value of 3 μM. The irreversibility is likely due to the presence of the chemically reactive isothiocyanate group, since the binding of the corresponding analogue in which the isothiocyanate was replaced with a chloro group was completely reversible. The potency of ISC to irreversibly inhibit the binding of [3H]CGS 21680 in several species varied in the order rat ≈︁ guinea pig > bovine ≈︁ rabbit. In all four species, binding of the A1‐selective agonist [3H]R‐N6‐phenylisopropyladenosine was not diminished by pre‐treatment with 2 μM ISC. The kinetics of irreversible inhibition of rat A2a‐receptors by 2 μM ISC gave a t1/2 of approximately 3 min. Following partial inactivation, the remaining rat A2a‐binding sites retained the same Kd value as in control membranes for saturatin by [3H]CGS 21680. Thus, ISC appears to be a selective affinity label for A2a‐ versus A1‐receptors in the brain. © 1993 Wiley‐Liss, Inc.
MS‐551: Pharmacological profile of a novel class III antiarrhythmic agent
Authors: Kamiya Joji , Ishii Masaaki , Yoshihara Kanji , Oyabe Akihiro , Banno Hitoshi , Katakami Tstutomu 
Published: January 2005

AbstractThe class II antiarrhythmic agent properties of the novel compound MS‐551 (1,3‐dimethyl‐6‐{(2‐[N‐(2‐hydroxyethyl‐3‐(4‐nitrophenyl)propylamino]ethylamino} ) 2,4 (1H3H)‐pyrimidinedione hydrochloride) have been characterized in vitro and in vivo. Using isolated canine Purkinje fibers, the effect of MS551 on the action potentials was studied. MS‐551 (0.1‐10μg/ml) caused a uniform and concentration‐dependent increase in action potential duration without changing parameters of action potential depolarization. IN anesthetized open‐chested dogs. MS‐551 (0.1‐10 mg/kg i,v.) produced a dose‐dependent increase in both atrial and ventricular effective refractory periods 9ERP) with QTc prolongation. At 0.3 mg/kg i.v., atrial and ventricular ERP were significantly increased 28 ± 4 mec and 12 ± 2 msec, respectively, and the minimum e4ffective plasma concentration of MS‐551 for atrial ERP prolongation was approximately 0.1 μg/ml. However, MS‐551 did not slow intracardiac conduction time (A‐H, H‐V) even at the highest dose studied (30 mg/kg i.v.). These data suggest that MS‐551 has a “pure” class III electrophysioloigcal property in dogs. Furthermore, we compared the effects of MS‐551 on the hemodynamics in anesthetized dogs with those of d‐sotalol. MS‐551 (0.1‐3 mg/kg) produced dose‐dependent decrease in heart rate with QTc prolongation and slight increase in LVdP/dtmax. In contrast d‐sotalol (0.1‐10 mg/kg i.v.) depcreased heart rate, mean arterial pressure, LVdP/dtmax and aortic flow in a dose‐dependent manner. Moreover, we reassessed in anesthetized dogs the cardiovascular toxicity of continuously infused MS‐551 (2 mg/kg/min for 50 min). Ath the end of the infusion (total dose: MS‐551 100 mg/kg), LVdP/dtmax was decreased 23%, but QTc prolongation never exceeded 30%. Thus, arrhythmias, such as torsade de pointes, were not seen. In conclusion, MS‐551 appears to be a pure and potent class III antiarrhythmic agent with a favourable hemodhynamic profile. © 1993 wiley‐Liss, Inc.
Comparison of acute and repeated treatment with the 5‐HT1A receptor ligands 8‐OH‐DPAT and ipsapirone in animal models of anxiety and depression
Authors: De Vry Jean , Schreiber Rudy 
Published: January 2005

AbstractThe present study compared the 5‐HT1A receptor ligands 8‐OH‐DPAT and ipsapirone with diazpepam and imipramine in the shock induced ultrasonic vocalization anxiety test and the forced swimming depression test in the rat. Acutely, 8‐OH‐DPAT induced anxiolytic and antidepressive effects (ED50: 0.12 and 1.4 mg/kg, i.p., respectively), whereas ipsapirone induced anxiolytic (ED50: 0.6 mg/kg) and moderate antidepressive effects (33% at 3‐10 mg/kg). Virtually no tolerance developed for the anxiolytic effects after 2 weeks of treatment with 0.03‐1 mg/kg 8‐OH‐DPAT or 0.1‐10 mg/kg ipsapirone (i.p., b.i.d.), with 10 mg/kg/day ipsapirone (s.c., mini‐pumps), or with 1.5 μg/rat/hr 8‐OH‐DPAT (local infusion in the dorsal raphe nucleus, mini‐pumps). However, some tolerance developed for the antidepressive effects of 8‐OH‐DPAT (ED50: 0.6, 1.4, 2.5 and >3 mg/kg, after 2 weeks of pretreatment with vehicle, 0.3, 1, and 3 mg/kg 8‐OH‐DPAT, respectively, i.p., b.i.d.). In the case of ipsapirone, the dose‐effect curve in the forced swimming test was shifted to the left after 2 weeks of pretreatment with ipsapirone (0.3‐10 mg/kg, i.p., b.i.d.). Acutely, diazepam induced an anxiolytic effect (ED50: 3.6 mg/kg, i.p.), but failed to induce an antidepressive effect; whereas imipramine induced an antidepressive effect (ED50: 20.5 mg/kg) and a moderate anxiolytic effect (max. efficacy: 47% at 30 mg/kg). Upon repeated administration (2 weeks), diazepam (5 mg/kg) showed t0olerance for its anxiolytic effects and weak antidepressive effects emerged, whereas imipramine (20 mg/kg) showed weak sensitization for both effects. It is concluded that (a) with all compounds, tolerance, as well as sensitization can be observed, depending on the behavioral test, the dose and the type of compound; and (b) compared with the other compounds tested, relatively low doses of 5‐HT1A drugs offer the most attractive profile of mixed anxiolytic/antidepressive activity. © 1993 wiley‐Liss, Inc.
Tretinoin: A review of preclinical toxicological studies
Authors: Cohen Marvin 
Published: January 2005

AbstractTretinoin (all‐trans‐retinoic acid) has shown efficacy in the treatment of acute promyelocytic leukemia. The preclinical toxicological profile of tretinoin was similar to that of other retinoids. The compound had a relatively low acute toxicity; repeated doses resulted in a substantial increase in toxicity that was a function of dose and duration of exposure. Bone fractures, elevated alkaline phosphatase, and testicular degeneration were produced by repeated doses of tretinoin. Teratogenicity was demonstrated in several species. Tretinoin was inactive in the Ames test but appeared to induce sister‐chromatid exchanges in human diploid fibroblasts. Insufficient data are available to evaluate the carcinogenic potential of tretinoin. © 1993 wiley‐Liss, Inc.
Neurochemical mechanisms mediating the behavioral and cognitive effects of nicotine
Authors: Gray Jeffrey A. , Mitchell Stephen N. , Joseph Michael H. , Grigoryan Grigory A. , Dawe Sharon , Hodges Helen 
Published: January 2005

AbstractData are reviewed, largely from experiments in the authors'laboratory, that suggest three modes of action of systemic nicotine in producing three different types of effect upon behavior and cognitive function. (1) Preexposure of a stimulus without consequence makes it harder subsequently to form associations to that stimulus, a form of selective attention known as latent inhibition. Latent inhibition is blocked by nicotine, an effect that is apparently mediated by a nicotine‐induced increase in dopamine release in the nucleus accumbens. (2) A single dose of nicotine proactively increases the partial reinforcement extinction effect measured several weeks later: that is, resistance to extinction is decreased by nicotine in animals that have been trained on a continuous reinforcement schedule, and increased in animals trained on a partial reinforcement schedule. This effect appears to be due to increased synthesis of tyrosine hydroxylase in the cell bodies of noradrenergic neurons in the locus coeruleus, followed by axonal transport to the hippocampus and increased synthesis and release of noradrenaline in that structure. (3) Nicotine improves vigilance in animals with cognitive deficits due to destruction of the forebrain cholinergic projection system, either as a consequence of excitotoxic lesions of the nuclei of origin of this system or after prolonged alcohol consumption; and also in human subjects with Alzheimer's disease (in which this system undergoes degeneration). This effect is most likely due to an action at denervated cholinergic synapses in the hippocampus and neocortex. © 1994 Wiley‐Liss, Inc.
Biochemical evidence for the involvement of central serotonergic neurotransmission in the action of the antidepressant drug Medifoxamine
Authors: Gillon Jean‐yves , Vitte Pierre‐Alain , Lemonnier Francoise , Kato Gabor 
Published: January 2005

AbstractMedifoxamine, an antidepressant agent which has an original chemical structure, has been shown through in vitro studies, utilising radioligand binding in tissue homogenates, to bind with moderately high affinity to 5‐HT1c and 5‐HT2 receptor subtypes and to 5‐HT uptake sites (IC50 950, 980, and 1,500 nM, respectively). It has been shown to bind in vivo to rat brain 5‐HT2 receptors after acute treatment with high dose (50 mg/kg, i.e., 133.9 μmol/kg). After 14 days continuous treatment with low dose (20 mg/kg, 53.6 μmol/kg), a decrease in the capacity of [3H]‐5‐HT uptake and a dose‐dependent down‐regulation of 5‐HT2 receptors in rat cerebral cortex were observed. These results indicate that medifoxamine, which has been shown previously to act through dopaminergic systems, interacts also with central serotonergic neurotransmission and particularly with the 5‐HT2 receptors, which could contribute to its antidepressant effect.
Attenuation of experimental hypertension with agents that increase insulin sensitivity
Authors: Kotchen Theodore A. 
Published: January 2005

AbstractBoth in the human and in several experimental models, hypertension is associated with insulin resistance. Thiazolidinedione derivatives are a novel group of oral hypoglycemic agents that increase insulin sensitivity without stimulating endogenous insulin secretion. These agents have been shown to attenuate the development of hypertension in the following experimental rat models: the Dahl salt‐sensitive rat, the one‐kidney, one‐clip hypertensive rat, the obese Zucker rat, and blood pressure increases in rats fed high carbohydrate or high fat diets. Clofibrate, a lipid lowering agent that also increases insulin sensitivity, also prevents the development of hypertension in Dahl salt sensitive rats. Additional studies will be required to determine if attenuation of hypertension by these agents is specifically related to their capacity to increase insulin sensitivity.
Diabetic nephropathy, renal hemodynamics, and aldose reductase inhibitors
Authors: Oates Peter J. 
Published: January 2005

AbstractDiabetic kidney disease or diabetic nephropathy is the leading cause of renal failure in the United States today. This review presents a brief overview of diabetic nephropathy—its current statistics, histopathology, natural history, and main risk factors, including hyperglycemia, hyperfiltration, and hypertension. Pathogenic mechanisms by which hyperglycemia, severe hyperfiltration, and capillary hypertension might cause renal injury are discussed. Evidence is reviewed indicating a potentially useful role for aldose reducatase inhibitors (ARIs) to normalize or reduce the impact of two possible risk factors for diabetic nephropathy, namely, elevated polyol pathway metabolism and severe hyperfiltration. Measurements in experimental models of whole kidney blood flow (57Co‐microspheres, clearance methods), superficial cortical blood flow (laser Doppler flowmetry), and single nephron hemodynamic parameters (renal micropuncture) concordantly indicate that the beneficial effect of ARIs on hyperfiltration is based on protection or restoration of normal renal microvascular resistance. Since ARIs affect neither blood sugar levels nor mean arterial pressure, ARIs have no increased risk attributable to hypoglycemia or hypotension. It is concluded that ARIs warrant further experimental and clinical research in early diabetic nephropathy.
Effect of 5‐HT2 receptor antagonist ergolines and their desisopropyl metabolites on rabbit platelet aggregation in vitro and ex vivo
Authors: Cohen Marlene L. , Bloomquist William 
Published: January 2005

AbstractAmesergide and LY215840 are potent and long‐lasting 5‐HT2 receptor antagonists after oral administration to animals. In animals, these ergolines are metabolized to their desisopropyl ergoline congeners which have lower affinity (40–60 nM) at 5‐HT2 receptors in the rat relative to higher 5‐HT2 receptor affinity (2–3 nM) at the cloned human 5‐HT2 receptor. Because amesergide and LY215840 are effective in rabbit models of thrombosis, we asked whether their efficacy in the rabbit was related in part to the activity of both the parent and desisopropyl metabolites at rabbit platelet 5‐HT2 receptors. Platelet aggregation responses were first optimized to ADP and the combination of ADP and serotonin with regard to platelet number (300,000 platelets/μl of plasma) and time (70 to 140 min after platelet harvest). In ex vivo studies, both amesergide and LY215840 (3.0 mg/kg p.o.) showed similar and marked antagonism of rabbit platelet 5‐HT2 receptors at 1 and 24 h after their oral administration to rabbits. Furthermore, the desisopropyl ergoline metabolites of both amesergide and LY215840 inhibited serotonin‐amplified platelet aggregation responses in vitro as did amesergide and LY215840. Thus, these studies add support to the hypothesis that the desisopropyl metabolites of amesergide and LY215840 may contribute to the oral antithrombotic efficacy of the parent molecules in rabbits.
Regulatory considerations on the role of general pharmacology studies in the development of therapeutic agents
Authors: Proakis Anthony G. 
Published: January 2005

AbstractIn contrast to the well‐defined regulatory requirements for the conduct of animal toxicology studies, FDA regulations and guidelines for nonclinical pharmacodynamic studies are relatively general and do not require that any specific studies be conducted. General pharmacology studies are conducted to identify actions of a new agent in addition to those associated with the primary therapeutic utility. General pharmacology studies aimed at determining drug effects on cardiovascular, central nervous system, gastrointestinal, respiratory and pulmonary, renal, endocrine and metabolism, autonomic nervous system, and drug‐receptor functions were among the types of general pharmacology studies included in a sample of recent investigational new drug application (IND) and new drug application (NDA) submissions. Assessment of drug effects on cardiovascular, autonomic nervous system, and drug‐receptor interactions were given the greatest individual importance in identifying drug effects relevant to the assessment of a product's safety at the initial IND stage. At the NDA stage, general pharmacology studies find their greatest value in predicting drug‐drug interactions, defining mechanisms of action, characterizing the pharmacological correlates of drug‐overdose, identifying dose‐limiting effects for the chronic toxicity studies, and associating animal toxicity findings with known pharmacotoxic effects. General pharmacology studies provide valuable information to complement animal toxicity studies for evaluating a drug's potential risk to humans.
Surface of synergistic interaction between dipyrone and morphine in the PIFIR model
Authors: López‐Muñoz Francisco J. 
Published: January 2005

AbstractThe analgesic effects of dipyrone and morphine administered either separately or in 24 different combination were determined in the “Pain‐Induced Functional Impairment in the Rat” (PIFIR analgesic model). This allowed the detection of the profile of analgesic interaction of the various combinations. Furthermore, the optimal degree of potentiation obtained with a specific combination of the above drugs was determined by means of the “Surface of Synergistic Interaction” (SSI) of the combinations. This parameter was calculated from the total analgesic effect produced by the combination after having subtracted the analgesic effect produced by each drug alone. Over the dose‐ranges used, the analgesic activities of either dipyrone or morphine tended to be smaller than those of their respective combinations. Furthermore, 11 combinations showed various degrees of potentiation (P < 0.05), while the remainder (13) exhibited additive analgesic effects. The combination of dipyrone (562 mg/kg, sc) and morphine (5.6 mg/kg, sc) produced the maximum analgesic effect. However, dipyrone (178 mg/kg) with morphine (3.2 mg/kg) produced the highest potentiation effect (P < 0.001). The surface of synergistic interaction clearly showed which combination of analgesic drugs produced the highest degree of potentiation in the rat. This represents the first study to show that a specific ratio of combination of analgesic drugs can produce an optimal potentiation of their analgesic effects. These findings may have important implications for the treatment of pain. © 1994 Wiley‐Liss, Inc.