bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adenosine A1 receptors in mammalian brain: Species differences in their interactions with agonists and antagonists
Authors: Ferkany John W. , Valentine Heather L. , Stone George A. , Williams Michael 
Published: January 2005

AbstractThe binding of the selective ligand [3H]cyclohexyladenosine (CHA) to adenosine A1 receptors was studied in brain membrane from six species; cow, rabbit, rat mouse, human, and guinea pig. Saturation analysis gave evidence for a single binding site in each species. The number of binding sites (2.6–4.7 pmol/mg protein), based on saturation analysis, was virtually identical in each species. The Kd values were, however, different; whereas rat, rabbit, and mouse A1 receptors had similar affinities (Kd=1–2 nM), the binding site in bovine tissue had three to four times greater affinity (Kd=0.59 nM). Adenosine binding sites in human and guinea pig brain had two to three times less affinity, with Kd values 3.7 and 6.6 nM, respectively, than those in rat, rabbit, and mouse brain. Examination of the binding of five agonists, the R and S diastereomers of N6‐phenylisopropropyladenosine (PIA), CHA, 5′N‐ethylcarboxamido adenosine (NECA), and 2‐chloroadenosine, and of five xanthine antagonists, PACPX [1,3,dipropyl‐8‐(2‐amino‐4‐chloro)phenylxanthine], 1,3 diethyl‐8‐phenylxanthine (DPX), 8‐phenyltheophylline (8PT), 8‐parasulfophenyl‐theophylline (8PST), and theophylline, showed that across the species N6‐substituted adenosine analogs showed consistent differences in rank order activity. R‐PIA ≥ CHA >S‐PIA, with the compounds being most active in bovine tissue and least active in guinea pig, showing an 18‐fold difference. In contrast, the 2‐substituted analog, 2‐chloroadenosine was most active in guinea pig and human brain membranes, and least active in rat and bovine brain. The 5′‐substituted analog NECA had similar activity in all species studied. PACPX was the most potent of the xanthines studied, being most active in bovine brain tissue and least active in guinea pig; the difference in activities was 393‐fold. The interaction of the remainder of the xanthines studied was complex. In general, the rank order of potency was PACPX > DPX=8 phenyltheophylline > 8PST >> theophylline. However, in human and rabbit brain 8PT was more active than DPX, and in guinea pig 8PT was twofold less active than DPX. In addition, in human and guinea pig brain, 8PST had comparable activities. These differences in pharmacological profiles may be attributable to differences in the adenosine systems studied as previously noted by Murphy and Snyder [Mol. Pharmacol. 22:250–257, 1982], which may in turn reflect distinct differences in A1 receptors or the presence of different subtypes of adenosine receptor in the various species. While these interspecies studies need to be extended to both A2 receptors and to coupled, i.e., adenylate cyclase, systems, they underline the need for care in choosing the mammalian species in which structure activity relationships are generated. Some caution is necessary in the use of bovine brain tissue in development programs targeted towards therapeutic entities in the adenosine A1 antagonist area.
Cardiovascular pharmacology of the cardiotonic, imazodan (Cl‐914)
Authors: Evans D.B. , Potoczak R.E. , Steffen R.P. , Burmeister W.E. , McNish R.W. , Schenden J.A. , Kaplan H.R. 
Published: January 2005

AbstractImazodan is a novel pyridazinone derivative. It was evaluated in excised cardiac tissue, anesthetized dogs and monkeys, and conscious dogs. Imazodan, 10−5–10−3M, produced dose‐dependent increases in guinea pig atrial and rabbit papillary muscle contractility. In ansthetized dogs and rhesus monkeys, imazodan, 0.001–1.0 mg/kg IV, produced dosedependent increases of 10–150% in myocardial contractility (dP/dt max of left ventricular pressure), and decreases of 1–31% in aortic blood pressure. Heart rate increases were minimal (0–34%) in comparison to the changes in contractility and they occurred only at the higher doses. The positive inotropic action of imazodan was not blocked by β‐adrenoceptor blockade with propranolol. Forelimb perfusion studies in the anesthetized dog demonstrated that imazodan produces a dose‐dependent direct peripheral vasodilator action. This agent was also demonstrated to be a highly effective cardiotonic when administered orally (0.1–1.0 mg/kg) to conscious dogs. The results of these studies indicate that imazodan is an orally effective cariotonic that possesses balanced positive inotrophic and peripheral vasodilator activities and possesses a wide margin of cardiac safety.
Buspirone attenuates learned helplessness behavior in rats
Authors: Drugan Robert C. , Crawley Jacqueline N. , Paul Steven M. , Skolnick Phil 
Published: January 2005

AbstractRats pretreated with either chlordiazepoxide (5 mg/kg) or buspirone (5 mg/kg) did not develop the shuttlebox escape deficit typically observed 24 hours after a session of inescapable tailshock. In contrast, the buspirone analog gepirone (MJ 13805) (2 or 5 mg/kg) did not block this shock‐induced learning deficit. These results demonstrate that the nonbenzodiazepine anxiolytic buspirone, like chlordiazepoxide, attenuates the learned helplessness syndrome.
Prevention of postsurgical peritoneal adhesion formation by intraperitoneal administration of ibuprofen
Authors: Orita Hiroyuku , Girgis Wefki , diZerega Gere S. 
Published: January 2005

AbstractPreviously, we reported a reduction in the formation of post‐surgical peritoneal adhesions accompanying the use of systemically administered ibuprofen in validated animal models. Since the use of systemic ibuprofen requires high doses, we evaluated intraperitoneal drug delivery to assess the effects of locally administered low doses of ibuprofen on adhesion formation. Adhesion formation was evaluated after (a) parietal peritoneal excision, (b) abrasion of large bowel serosal, and (c) both (a + b) performed together. Adhesions formed in 2/15 rabbits with parietal peritoneal excision only, 3/15 with serosal abrasion only, and 11/15 with both procedures performed in the same rabbit. To further validate the parietal peritoneal excision + adjacent serosal abrasion technique for adhesion induction, a second group of 23 rabbits was similarly treated; 20/23 were found to have adhesions. The minimum dose of ibuprofen delivered into the intraperitoneal cavity via Alzet pump which reduced adhesions was 5 μg/10 μl/5 cm2 test site/hr. No more than 4–5 days of postoperative treatment were required to achieve a significant reduction in adhesion formation. In the 2‐kg rabbits used here that would provide a total daily dose of 60 μg/kg/day. The minimum effective dose reported by this laboratory via systemic administration of ibuprofen for reduction of postsurgical peritoneal adhesions using a similar model was 35,000 μg/kg/day. The potential utility of these findings is enhanced by the ongoing development of biodegradable drug delivery systems which can administer ibuprofen within the peritoneal cavity.
Preclinical and clinical studies on the cardiovascular and renal effects of fenoldopam: A DA‐1 receptor agonist
Authors: Lokhandwala Mustafa F. 
Published: January 2005

AbstractRecent research in the area of peripheral dopamine (DA) receptors has led to the identification of two distinct subtypes of DA receptors, activation of which results in marked changes in the cardiovascular and renal function consisting of hypotension, bradycardia, diuresis, and natriluresis. Peripheral DA receptors mediating these effects are subdivided into DA‐1 and DA‐2 subtypes. The development of selective DA‐1 and DA‐2 receptor agonists and antagonists has made it possible to furhter characterize DA receptors located at various sites within the cardiovascular system. It is now established that activation of DA‐1 receptors located on blood vessel produces vasodilation, whereas stimulation of DA‐2 receptors on postganglionic sympathetic nerves results in the inhibition of norepinephrine release. The renal effects of DA receptor agonists either involve activation of specific DA receptors at various sites in the kidney and/or result from renal hemodynamic changes produced by these compounds. The concept of developing selective DA receptor agonists as therapeutic agents in the treatment of cardiovascular disorders has been proposed by several investigators. Fenoldopam (SK&F 82526) represents one of these new orally active DA receptor agonists developed for potential use in the treatment of hypertension and ischemic renal disease. In animal experiments fenoldopam was shown to produce hypotension and increase renal blood flow. It produced natriuresis and diuresis, and these effects were due to the activation of DA‐1 receptors. Recent clinical studies show that fenoldopam decreases blood pressure and renal vascular resistance and causes diuresis and natriuresis in hypertensive patients. The antihypertensive action of fenoldopam is mediated by a decrease in total peripheral resistance. There are increases in heart rate and plasma renin activity in hypertensive patients. Fenoldopam also improves left ventricular performance in patients suffering from congestive heart failure. These initial studies with fenoldopam show that peripheral DA‐1 receptor stimulation may represent an effective approach in the treatment of cardiovascular diseases. Future research in this area should be aimed toward developing DA‐1 receptor agonists that have longer duration of action and do not evoke renin release, while maintaining the beneficial effects on the kidney.
On the central effects of the GABA agonist fengabine: Psychometric and pharmaco‐EEG studies utilizing imaging methods
Authors: Saletu B. , Anderer P. , Kinsperger K. , Grünberger J. , Musch B. 
Published: January 2005

AbstractIn a double‐blind, placebo‐controlled study the pharmacokinetic, encephalotropic, and psychotropic properties of fengabine (FEN)‐a novel GABA receptor agonist–were studied in 15 normal subjects utilizing gas chromatography, quantitative pharmaco‐EEG, and topographical analysis methods as well as psychomeric and psychophysiological techniques. The subjects received randomized and, in weekly intervals, single oral doses of placebo; 200, 400, and 800 mg FEN: as well as 75 mg imipramine (IMI) as reference compound. Blood sampling, EEG recordings, and evaluation of pulse, blood pressure, and side effects were carried out at 0, 1, 2, 4, 6, and 8 hr, with psychometric tests at the same times except the first hour.Pharmacokinetic analyses demonstrated rapid absorption of FEN, with plasma peaks in the second hour, dose‐dependent Cmax, and areas under the plasma concentration time curves. Computer‐assisted spectral analysis of the EEG detected from 17 scalp regions and topographical mapping of the drug‐induced Q‐EEG changes demonstrated significant but subtle central effects of FEN, which resembled in certain aspects the marked CNS effects of 75 mg IMI, such as the increase of theta and concomitant beta‐1 activity in the frontocentral and frontotemporal regions, as well as a decrease of fast alpha activity in the frontocentral and frontotemporal regions, as well as a decrease of fast alpha activity and the centroid over the frontotemporal and centroparietal to occipital regions, respectively, specifically after 800 mg FEN. On the other hand, there was a lack of delt augmentation seen after IMI in the occipitotemporoparietal region, lack of theta increase after the two lower doses of FEN, increase of slow alpha rather than a decrease after IMI, and an augmentation of total power (which declined with increasing doses) rather than an attenuation after IMI.Regional differences were obtained also in regard to dose/treatment‐efficacy and time‐efficacy relations. Both compounds exhibited the peak encephalotropic effect in the second hour and a gentle decline thereafter. Behavioral dose‐ and time‐efficacy relations were only observed in the thymopsyche after FEN. These were characterized by an improvement in mood and affectivity after 400 and 800 mg FEN, respectively, as compared to placebo, while a deterioration occurred after the reference compound. On the other hand, 800 mg FEN also induced sedation, reflected by an increase of drowsiness and decrease of drive, which was observed to a much greater extent after 75 mg IMI. Noopsychic changes occurred only in singular variables. Evaluation of pulse, blood pressure, and side effects demonstrated good tolerability of FEN quite in contrast to IMI. Our findings suggest that the GABAergic compound should be studied in affective disorders.
Role of cyclic AMP in regulating cardiac muscle contractility: Novel pharmacological approaches to modulating cyclic AMP degradation by phosphodiesterase
Authors: Weishaar Ronald E. , Kobylarz‐Singer Dianne C. , Quade Mary M. , Kaplan Harvey R. 
Published: January 2005

AbstractThe role of cyclic AMP in modulating the contractile function of cardiac muscle has been the subject of intensive investigation for more than two decades. These studies have shown that the positive inotropic response to cyclic AMP involves multiple components, including adenylate cyclase, the enzyme that catalyzes the conversion of ATP to cyclic AMP, activation of cyclic AMP‐dependent protein kinases, which are responsible for phosphorylating key intracellular proteins, and phosphodiesterase, the enzyme that hydrolyzes cyclic AMP, thereby terminating the response. Several reports have shown, however, that increases in intracellular cyclic AMP are not always accompanied by increases in myocardial contractility, suggesting that cyclic AMP may be compartmentalized within cardiac cells and that only certain compartments are involved in modulating contractility. In addition, although cardiac muscle contains only one form of adenylate cyclase, multiple forms of phosphodiesterase have been identified in ventricular muscle, which vary in their substrate specificity and their response to allosteric effectors such as calmodulin. Recent studies have also shown that these various forms of phosphodiesterase can be located in different regions within the cardiac cell and that only certain forms of the enzyme are involved in modulating the inotropic response to cyclic AMP. This review summarizes the current state of knowledge regarding the involvement of cyclic AMP with cardiac contractile function and also explores several controversial aspects of this involvement.
Mechanisms of cholinesterase inhibition in senile dementia of the alzheimer type: Clinical, pharmacological, and therapeutic aspects
Authors: Becker Robert E. , Giacobini Ezio 
Published: January 2005

AbstractSenile dementia of the Alzheimer type (SDAT) is a degenerative disease of the brain that affects up to 20% or more of individuals who live beyond 80 years of age. A deficiency of cholinergic function is expected to play a major role in the development of SDAT psychopathology. Possible existence of an underactive cholinergic system has led to clinical trials of cholinomimetic drugs to attempt to reverse the deficit in SDAT. Some improvement in memory function has followed the administration of cholinesterase (ChE) inhibitors, but in general the affected individuals have not been returned to normal or mildy impaired mental functions or activities of daily living functioning. This paper is a critical review of results of acute and chronic trials performed with ChE inhibitors in experimental animals and humans. We also review and discuss mechanisms of decvelopment of pharmacological behavioral tolerance to ChE inhibitors. Behavioral changes following ChE inhibition appear to coincide with predicted peak levels of acetulcholine (ACh) concentration in the brain. Yet we find an inconsistent relationship among the degree of ChE inhibition, changes in brain acetylcholine concentrations, and behavioral changes, both therapeutic and adverse effects, following administration of ChE inhibitors. ChE inhibition is associated with distressing adverse effects. The therapeutic effects of increased ACh levels in the brain may be masked by these side effects. We suggest that an adequate test of the efficacy of ChE inhibition may await the use of new and improved ChE inhibitors that produce significantly fewer side effects and greater therapeutic effects than drugs presently being tested for efficacy in the treatment of SDAT patients.
Celiprolol: A beta‐1 partial agonist in isolated cat cardiac tissue
Authors: Smith Ronald D. , Cobuzzi Agnes M. , Wolf Peter S. 
Published: January 2005

AbstractThe cardiostimulatory effects of celiprolol were evaluated in isolated cat cardiac tissue to elucidate the contributions of beta versus alpha adrenoceptor mechanisms. Racemic celiprolol increased the spontaneous rate of cat right atria and the developed tension of paced left hemi‐atria and papillary muscle 44% ± 7%, 36% + 5% and approximately 23% of the maximum response to isoproterenol, respectively. In both left and right atrial preparations, celiprolol (d‐, l‐, and racemic) produced a concentration‐related cardiostimulatory effect. The l‐ and racemic celiprolol were approximately 50 times more potent than the d‐isomer. The cardiostimulatory effects of celiprolol in cat right atria were either not changed, or only slightly reduced, by catecholamine depletion with reserpine or chemical sympathectomy with 6‐hydroxydopamine or by alpha blockade with prazosin (3 × 10−7 M) alone or in combination with propranolol. Beta‐1 blockade with atenolol 10−6 M alone produced a parallel rightward shift of the celiprolol concentration‐response curve of 1.7 log units. By contrast, beta‐2 blockade with ICI 118, 551 10−6 M shifted the celiprolol response curve only 0.6 log units. It is concluded that celiprolol has a limited but significant cardiostimulatory effect in isolated cat cardiac tissue due primarily to a partial agonist action on postsynaptic beta‐1 receptors and does not involve noradrenergic mechanisms either preor postsynaptically.
Cardiovascular properties of bemarinone: A new orally active quinazolinone cardiotonic agent
Authors: Falotico Robert , Moore John B. , Bandurco Victor , Bell Stanley C. , Levine Seymour D. , Tobia Alfonso J. 
Published: January 2005

AbstractThe cardiovascular properties of bemarinone (5, 6‐dimethoxy‐4‐methyl‐2‐(1H)‐quinazolinone), a new chemical entity with positive inotropic and vasodilator activity, were investigated. Bemarinone (10−6−10−3M) selectively increased contractile force 144 ± 15% in electrically paced guinea pig left atria while marginally affecting sinus rate (16 ± 13%, peak effect) in spontaneously beating right atria. In anesthetized dogs, bemarinone (0.125–0.875 mg/kg, i.v.) increased myocardial contractile force (21–114%) and left ventricular dP/dtmax (7–45%) in a dose‐related manner. Selective inotropic activity was observed in vivo since no significant change in mean arterial pressure or heart rate occurred at a 50% increase in contractile force (ED50 = 0.23 mg/kg). In conscious instrumented dogs, oral administration of bemarinone (2.5–10 mg/kg) produced peak increases in left ventricular dP/dtmax ranging from 28% to 87% (ED50 = 3.7 mg/kg). The onset of positive inotropic activity after 10 mg/kg p.o. occurred within 5 min, and the duration exceeded 3 hr. Bemarinone decreased mean arterial blood pressure (0.4–16%) via a reduction in total peripheral resistance. Direct vascular effects were observed in vitro since bemarinone relaxed rabbit aortic strips contracted with phenylephrine or KCl. In an acute model of ischemic left ventricular failure, bemarinone increased cardiac output (41%) and stroke volume (34%) while reducing left ventricular end diastolic pressure (63%) and total peripheral resistance (29%) without significantly changing mean arterial pressure or heart rate. The positive inotropic effect of bemarinone was not antagonized by propranolol and atropine pretreatment. The compound selectively and competitively inhibited cyclic AMP phosphodiesterase fraction III from canine ventricle (Ki = 15.8.μM). In summary, bemari none is an orally active, positive inotropic and vasodilator agent with potential clinical utility in the management of congestive heart failure.
Prenatal ethanol exposure: Correlation of neurobehavioral changes with mother's blood ethanol level
Authors: Pradhan Sikta , Briggs Felicia , Philips Don 
Published: January 2005

AbstractDifferent liquid diets were tested as vehicles for ethanol administration in order to maximize the blood ethanol level (BEL) in rats. This was done since maternal BEL during the gestation period is believed to be the determining factor for behavioral and neurochemical changes in the offspring. A comparative study with three different liquid diets indicated that the Sustacal and Lieber‐DeCarli diets were more effective in elevating the BEL than the Bio‐Mix diet. Furthermore, it was observed that prenatal ethanol exposure affected to a varying extent the neuromuscular abilities (detected by rotarod test) and maze‐learning in the offspring of mothers that receive ethanol through Lieber‐DeCarli diet. No significant (P < 0.01) behavioral changes were observed in the offspring of mothers that received the Bio‐Mix diet containing ethanol.
Energy metabolism in the conscious gerbil during recirculation following transient ischemia: Effects of RU 24722 and vincamine
Authors: Formento Maria Luisa , Barzaghi Fernando , Mantegazza Paolo 
Published: January 2005

AbstractIn the present study, cerebral energy metabolism and the alanine/glutamate ratio were evaluated in gerbils at the end of or 6, 24, or 48 hr after ischemia (10 min) induced by clamping both common carotid arteries. At the end of ischemia, the energy substrates were dramatically reduced, while lactate and pyruvate levels and the alanine/glutamate ratio were increased. During 48 hr of recirculation, the high‐energy phosphate increased but never to normal values; lactate, which is low in the early postischemic period, progressively increased; pyruvate fell but without returning to normal; the alanine/glutamate ratio decreased without reaching normal value. RU 24722 (vindeburnol) or vincamine were administered subcutaneously 15 min, 10, 24, and 34 hr after ischemia. RU 24722 completely inhibited the increase in lactate levels observed 24 and 48 hr after ischemia, improved pyruvate recovery, and normalized the alanine/glutamate ratio, but vincamine did not. Neither compound had any effect on the tissue concentrations of phosphocreatine, ATP, ADP, or AMP. The ability of RU 24722 to prevent the postischemic lactate accumulation associated with the normalization of the alanine/glutamate ratio indicates that it should improve the capacity for postischemic cerebral metabolic recovery and that it also has a different biochemical profile from that of vincamine.
Psoriasis: Hyperproliferative/inflammatory skin disorder
Authors: Ziboh Vincent A. 
Published: January 2005

AbstractThe skin lesions in psoriasis are characterized by epidermal thickening (acanthosis), by a sustained inflammatory reaction that is evident in the dermis and epidermis, by altered epidermal differentiation (histologically characterized by para‐ and hyperkeratosis), and by the absence of granular layer. The development of future pharmacological agents for psoriasis, therefore, must recognize these various aspects of the disease activities. Chemical agents that are targeted toward only one aspect of the disease are unlikely to be totally beneficial. Although in its infancy, the possibility of therapeutic management via dietary manipulation by varying ratios of polyunsaturated fatty acids derived from vegetable and marine oils is promising. Furthermore, the possible beneficial effect of the dihydroxy metabolite of vitamin D3 (1α,25(OH)2D3), a naturally occurring substance, in the management of psoriasis is exciting and deserves to be fully explored. It is likely that this naturally occurring vitamin D3 metabolite may function to modulate keratinocyte differentiation.