bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of propentofylline on the micromechanical properties of red blood cells
Authors: Seiffge Dirk , Nagata L. Katsuyoshi 
Published: January 2005

AbstractThe hemorheological effects of the xanthine derivative propentofylline (HWA 285) were investigated in vitro and ex vivo. The following micromechanical methods were used: (1) Nuclepore filtration test; (2) Filtrometer MF 4 [Teitel, 1977]; (3) Singlepore Erythrocyte Rigidometer (SER) [Kiesewetter et al., 1982b] (4) Mini‐Aggregometer [Schmid‐Schönbein et al., 1973a]. A protective effect of HWA 285, starting at a dose of 10−5 mol/liter, against red blood cell (RBC) rigidification, induced by lactacidosis (pH 6.9) in the Nuclepore filtration test could be demonstrated. RBC deformability was shown to decrease in adjuvant arthritis (AA) in rats. We tested HWA 285 (1, 5.01, 10.0, 15.8, 31.5, and 50.0 mg/kg p.o. for 21 days) in AA rats for its effect on hemorheology. The drug neither had an effect on inflammation with respect to hematological parameters and plasma proteins nor caused a reduction in the increased RBC aggregation in AA rats. However, we could show with the first three methods that HWA 285 has a significant effect on improvement of RBC deformability.
A review: Diabetic retinopathy—pathophysiologic and therapeutic approaches
Authors: Tso Mark O. M. 
Published: January 2005

AbstractOf the five million known diabetics in the United States, 5,000 become blind each year because of diabetic retinopathy. While the pathologic changes in the retina are well defined, the pathogenetic and pathophysiologic factors are not clear, and therapeutic approaches are empirical. The disease may be classified clinically and pathologically into four stages:(1) preretinopathy, characterized by disruption of the blood‐retinal barrier; (2) background retinopathy, exhibiting typical microangiopathic changes; (3) diabetic macular edema, resulting in gradual loss of central vision; (4) proliferative retinopathy, ending in retinal detachment and blindness. Many associated pathophysiologic factors have been described, but the critical pathogenetic mechanisms have not been established. The contributing factors include: (1) hyperglycemia and insulin control; (2) disruption of the blood‐retinal barrier; (3) retinal microangiopathy, including changes of pericyte and endothelial cell basement membrane; (4) formation of microaneurysms; (5) systemic diseases, including hypertension, blood alteration, hormonal changes, and genetic abnormalities; (6) ocular disorders such as optic atrophy, alteration in intraocular pressure, and eye surgery; and (7) retinal and vitreal neovascularization. A number of therapeutic approaches are being actively tested. Treatment with panretinal photocoagulation has been helpful to some patients, and the control of contributing systemic factors may delay progression of the disease. Vitrectomy with or without endoscopic panretinal photocoagulation has been useful in some advanced cases. Pituitary ablation has been effective for treatment of severe diabetic retinopathy, but severe complications have forced its abandonment. Aldose reductase inhibitors and other medications are currently being tested.
The pharmacology of ketanserin, the first selective serotonin S2‐antagonist
Authors: Awouters Frans 
Published: January 2005

AbstractThe quinazolinedione derivative ketanserin was studied in many known and newly introduced tests to obtain its detailed pharmacological profile. Ketanserin was a potent, orally very effective antagonist of endogenous serotonin (5‐HT): 0.15 mg/kg (ED50 s.c. and p.o.) protected rats from the gastric lesions induced by the mast cell activator compound 48/80. Many other in vivo observations, such as antagonism of tryptamine‐induced cyanosis in rats (ED50 s.c., 0.056 mg/kg), inhibition of mescaline‐induced head twitches in rats (ED50 s.c., 0.097 mg/kg), and inhibition of 5‐HT‐induced effects in various species, revealed the potent antagonist activity of ketanserin on vasoconstrictor and bronchoconstrictor actions of serotonin. When compared to other compounds with 5‐HT‐antagonist activity, the pharmacological profile of ketanserin corresponds to that of a potent, peripherally acting serotonin antagonist with weak associated α‐adrenergic blocking and antihistamine activity. In addition, binding experiments and studies on isolated tissues and platelets disclosed the high selectivity of ketanserin's serotonin antagonism. Serotonin S2‐receptors of the rat frontal cortex were labeled by low concentrations of ketanserin (Ki = 0.39 nM), and affinity of drugs for S2‐receptors highly correlated with their activity against serotonin‐induced contractions of blood vessel preparations (e.g., of the rat caudal artery, A2‐value of ketanserin: 0.83 nM) and serotonin‐induced platelet aggregation. In these experiments, ketanserin was devoid of serotonin! ‐binding, of agonist activity on vascular smooth muscle, of inhibition of 5‐HT uptake into platelets, and of 5‐HT antagonism on gastrointestinal smooth muscle. The absence of all these secondary activities is pharmacologically characteristic for ketanserin when compared to known serotonin‐antagonists. On the basis of this profile of pure and selective serotonin S2‐antagonism, ketanserin was studied in experimental hypertension and in many spontaneous and induced circulatory dysfunctions. A prolonged antihypertensive effect can be obtained with ketanserin in the absence of distinct compensatory mechanisms. Vascular dysfunction can start at low, sensitizing concentrations of serotonin and be almost completely corrected by ketanserin, despite the involvement of other mediators. Ketanserin is a very effective antagonist of the mixture of vasoactive substances released by aggregating platelets. In experimental thrombosis, sustained ketanserin treatment prevents the impairment of blood flow and the associated organ deficiency. When deviations from normal hemorrheology are long‐standing, as in aged spontaneously hypertensive dogs, acute ketanserin administration is distinctly antihypertensive and reduces hemorrheological abnormalities. At the conclusion of these extensive studies, serotonin appears to act at peripheral S2‐receptors as the primary pathological mediator of vascular congestion.
Effect of propentofylline on cerebral metabolism of rats
Authors: Stefanovich V. 
Published: January 2005

AbstractPropentofylline (HWA 285) [3‐methyl‐1‐(5′‐oxohexyl)‐7‐propylxanthine] is in in vitro experiments a good inhibitor of cAMP and cGMP phosphodiesterases in the rat brain and cerebral microvessels. In in vivo experiments it modulates cAMP and cGMP systems and GABA concentration in four examined structures of rats: cortex, hypothalamus, cerebellum, and striatum. Propentofylline (5 mg/kg i.v.) doesn't influence levels of cerebral energy reserves in normal rats but prevents to a significant degree some of the changes in metabolite levels caused by anoxia (30 s of nitrogen breathing). This antianoxic effect occurs at 5 min and disappears 20 min after administaration of the drug. Caffeine (5 mg/kg i.v.) shows a trend toward further aggravation of anoxia. The modulating effect of propentofylline on cAMP and cGMP systems, GABA levels, and especially cererbral enery metabolism in anoxia is possibly related to the potential therapeutic effect of this drug.
Biochemical evidence for a new benzodiazepine receptor antagonist
Authors: Kenneth Koe B. , Kondratas Elena , Lebel Lorraine A. , Minor Katherine W. 
Published: January 2005

Abstract1‐(3‐Chlorophenyl)‐3‐diethylcarbamoyl‐1 H‐1,2,4‐triazole (CP‐32,961) inhibited [3H]diazepam binding to rat cortical membrances and [3H]flunitrazepam binding to mouse brain in vivo. Its inhibition of the binding of [3H]Ro 15‐1788 (benzodiazepine receptor antagonist) to these membranes was not facilitated by added GABA; CP‐32,961 exhibited a GABA ratio of 0.84 compared to 2.44 for diazepam. Cerebellar cyclic GMP content in rats was raised by CP‐32,961, which also further elevated the increased cyclic GMP levels induced by isoniazid. These neurochemical actions are similar to those shown by ethyl β‐carboline‐3‐carboxylate (β‐CCE) and suggest that CP‐32,961 is a benzodiazepine receptor antagonist with inverse agonist activity.
Levocabastine (R 50547): The prototype of a chemical series of compounds with specific H1‐antihistaminic activity
Authors: Stokbroekx Raymond A. , Luyckx Marcel G. M. , Willems Johan J. M. , Janssen Marcel , Bracke Johan O. M. M. , Joosen Robert L. P. , van Wauwe Jean P. 
Published: January 2005

AbstractThe synthesis and the histamine H1 antagonism of four racemates of 1‐[cyano‐4‐(4‐ fluorophenyl)cyclohexyl]‐3‐methyl‐4‐phenyl‐4‐piperidinecarboxylic acid, termed R 48756, R 49389, R 49429, and R 49549, are described. R48756 (cabastine) was found to be the most potent compound, with oral ED50 values of 0.002–0.003 mg/kg in both the histamineinduced lethality test (guinea pigs) and the compound 48/80 assay (rats). Upon resolution of cabastine into its two optical isomers, levocabastine (R 50547) after oral administration in guinea pigs was about four times (1 hr) to 90 times (24 hr) more potent than dextrocabastine (R 50554). Protection from dyspnea, induced by histamine aerosols, was obtained with 0.005 mg/kg of levocabastine, whereas a dose of 2.5 mg/kg, failed to protect guinea pigs from dyspnea induced by serotonin or acetylcholine aerosols.
Comparative pharmacological profile of ritanserin and ketanserin
Authors: van Nueten Jan M. , Schuurkes Jan A. J. , De Ridder Walter J. E. , Kuyps Jan J. M. D. , Janssens Walter J. 
Published: January 2005

AbstractThe effect of ritanserin was determined on a variety of isolated smooth muscle tissues. The compound is a potent antagonist of serotonin‐induced contractions of isolated blood vessels (IC50‐, Ah‐ or A2−value between 5.6 × 10−11 and 3.3 × 10−10M) and trachea (IC50 = 1.6 × 10−8M) and of serotonin−induced bronchospasms in anaesthetised guineapigs (ED50 = 0.026 mg/kg i.p.). In most tests ritanserin was more potent than ketanserin (IC50‐ or A2‐value between 5.1 × 10−10 and 2.6 × 10−9M) as a serotonergic antagonist. In these vascular and tracheal preparations, serotonin induced contractions via S2‐serotonergic receptor sites. Ketanserin acted as a competitive antagonist. In contrast, ritanserin was un unsurmountable, apparently non‐competitive S2‐serotonergic antagonist, except at the rabbit femoral artery where the serotonergic antagonism was of the competitive type. Its resistance to wash‐out suggests a long duration of action. Both compounds had little or no effect on serotonergic responses mediated through M‐ or D‐receptors in gastrointestinal tissues. In the femoral artery of the rabbit, ritanserin and ketanserin inhibited H1‐histaminergic responses at concentrations 20 times and 4 times higher, respectively, than those required for S2‐serotonergic antagonism. No other effects of ritanserin were observed unless at much higher concentrations. For instance, in the femoral artery of the rabbit, concentrations approximately 200 times higher (A2‐value = 2.8 × 10−8M) were needed for alpha1‐adrenergic antagonism than were required for S2‐serotonergic antagonism (A2‐ value = 1.3 × 10‐10M), while this ratio was 9 for ketanserin for the same preparation. In the rat tail artery, these ratios, based on IC50‐values, were 666 and 39 for ritanserin and ketanserin respectively.In conclusion, as an S2‐serotonergic antagonist, ritanserin is more potent and more specific than ketanserin. The mode of interaction with the S2‐serotonergic receptor and the relation between time and antiserotonergic activity are different for the two compounds.
Development and clinical use of the new gastrointestinal prokinetic drug cisapride (R 51 619)
Authors: Reyntjens André , Verlinden Marleen , Aerts Tonny 
Published: January 2005

AbstractCisapride is a new gastrointestinal prokinetic substance that is devoid of antidopaminergic and direct muscarinic activity. This was evidenced by a lack of effect on prolactin release and gastric secretion. In man, cisapride stimulates lower esophageal, gastric, small intestinal, and colonic motility. Accordingly, cisapride significantly improves esophageal reflux disorders, gastroparesis, and constipation and has been successfully used in the treatment of clinical conditions that result from a deficient motor coordination.
Nucleoside transport inhibition and the release of purine metabolites from hypoperfused isolated guinea pig hearts
Authors: van Belle Herman , Wynants Jozef , Goossens Frans 
Published: January 2005

AbstractHypoperfusion elicited a marked but transient release from isolated guinea pig hearts of inorganic phosphate, nosine, hypoxanthine, xanthine, and uridine, but had no effect on the release of uric acid, uracil, and adenosine. Lack of increased formation of adenosine, as well as a clearcut effect of hypoperfusion on uridine release, suggest that the purine catabolites did not originate from either cyclic AMP or from ATP released with catecholamines during ischemia. They merely point to a particular sensitivity of some cells to ischemia whereby the nucleotides are rapidly degraded and released into the interstitium.Inclusion at low concentrations (5 × 10−8 M) of a nucleoside transport inhibitor, such as the water soluble analogue of mioflazine, drastically reduced the basal release of most of the metavolites and completely suppressed the effect of hypoperfusion. This effect is specifically ascribed to nucleoside‐transport inhibition since no marked change was observed on the release of inorganic phosphate.
Selectivity of agonists and antagonists at D2dopamine receptors compared to D1 and S2receptors
Authors: Seeman Philip , Grigoriadis Dimitri E. , Niznik Hyman B. 
Published: January 2005

AbstractThe common dopamine agonists (dopamine, apomorphine, ADTN, and N‐propylnorapomorphine) are not selective D1 or D2 dopamine receptors, affecting both simultaneously. SK&F 38393 is selective for D1, while bromocriptine and (D2)D2LYD2171555 are selective for D2. The neuroleptic with the highest D2/S2 selectivity is eticlopride with an affinity 3,200‐fold higher for the D2 dopamine receptor compared to the S2 serotonin receptor. Such selective neuroleptics may be clinically useful and may also help in measuring the elevated D2 density in vivo by positron emission tomography in the brains of schizophrensis.
Evaluation of the cardiovascular effects of arecoline in the anesthetized dog
Authors: Beil Michael E. , Goodman Frank R. , Shlevin Harold H. , Smith Edward F. 
Published: January 2005

AbstractArecoline has been reported to improve memory deficits, but a relatively short half‐life and adverse cardiovascular effects have limited its use. The purpose of this study was to compare the cardiovascular effects of a bolus administration with those of an infusion of arecoline in anesthetized beagle dogs. Arecoline was administered either as a 15 sec bolus (group I), as a constant infusion (group II), or as an infusion after pretreatment with 0.1 mg/kg methyl scopolamine (group III). In group I, mean arterial blood pressure (MABP) was immediately reduced (i.e., which 1 min) after each dose of arecoline, but had returned to the baseline value by 5 min after doses of 0.01 to 10 μg/kg, and by 20 min after a 30 μg/kg dose. However, blood pressure was still depressed 20 min after a 100 μg/kg dose of arecolin. Cardiac output (CO) was significantly reduced only after the 30 or 100 μg/kg doses. In group II, MABP, heart rate (HR), and CO were unchanged after a 0.3 or 1.0 μg/kg/min infusion of arecoline. An infusion of 3.0 or 10 μg/kg/min produced dose‐dependent decreases in MABP (–15 and –56%, respectively) and HR (–13 and –71%, respectively). CO was unchanged at 3 μg/kg/min but was reduced by 50% at 10 μg/kg/min (P < 0.05). Plasma levels of arecoline were 46.9 ± 5.5 ng/ml after an arecoline infusion of 10 μg/kg/min. Pretreatment with methyl scopolamine significantly attenuated the cardiodepression produced by 10 μg/kg/min arecoline. Moveover, infusions of 30 and 100 μg/kg/min of arecoline produced less than 40% reductions in MABP, HR, and CO. After pretreatment with methyl scopolamine, plasma arecoline levels were 29 ± 4 and 259 ± 38.7 ng/ml with an infusion of 10 or 100 μg/kg/min, respectively. These data indicate that the continuous administration of a low dose of arecoline may minimize the undesired cardiovascular effects. Pretreatment with methyl scopolamine further attenuated the cardiovascular responses produced by arecoline, suggesting that a greater therapeutic ratio may be achieved in the presence of a peripheral muscarinic blocking agent.
Lethal drug interaction: Isoniazid and methylxanthines
Authors: Harris Cynthia M. , Springfield Angela C. , Ranschaert Erik R. , Lal Harbans 
Published: January 2005

AbstractNonlethal doses of methylxanthines (caffeine or theophyline) produced dose‐dependent lethality in rats pretreated with isoniazid. Isoniazid pretreatment did not alter theophylline concentration in blood or brain, suggesting that the drug interaction was not due to altered distribution or metabolism of theophylline. Death was associated with tonic‐clonic seizures and pulmonary congestion. The toxicity of the drug combination was blocked by the anticonvulsants diazepam, barbital, and trimethadione, but not by chlorpromazine, a sedative drug which lacks anticonvulsant activity. Thus, there is a fatal drug interaction between isoniazid and theophylline which may be due to convulsions that trigger a shock lung syndrome.
Carbonic anhydrase: General perspective and advances in glaucoma research
Authors: Maren Thomas H. 
Published: January 2005

AbstractThe chemistry and physiology of carbonic anhydrase are reviewed in relation to pharmacological progress in the development of sulfonamide inhibitors. The major organ systems are briefly dicussed. From the medical point of view, the major thrust is now for the treatment of glaucoma. The physiology of aqueous humor formation with respect to ion transport is discussed, and it is shown that a key event is the catalytic formation of HCO3− from CO2 and OH−. The newly formed HCO3− is linked to NA+ and fluid movement to produce aqueous humor. Inhibition of HCO3− sunthesis sulfonamides reduces aqueous formation and lowers pressure in normals and in glucoma.Four sulfonamides have been used sytemically, the chief being acetazolamide. None of these works topically; they do not reach the ciliary process in adequate concetrations. New programs have begun, searching for sulfonamides of different properties that cross the cornea in effective concetrations to inhibit carbonic anhydrase in the ciliary porcess. The key to the problems seems to be to search for a balance between water and lipid solubility, maintaining high activity against the enzyme. This has been achieved, and new structures described from this and other laboratories lower pressure in the rabbit nearly as well as systemic sulfonamides.Corneal permeabilities to test compounds (in vitro) in rabbit and man are similar, but accession to the auqeous (in vivo) is less in man. This may make the goal difficult, and the reasons for this difference are being explored.
Immunology and skin disorders
Authors: Bergstresser Paul R. 
Published: January 2005

AbstractConcepts of the function of skin have changed in the last decade from that of a barrier against microbiologic and chemical invasion to include its important role in immunity. This transition began with the recognition that skin could serve as a sensitive target of immunologic injury, typified by diseases such as lupus erythematosus and cutaneous vasculitis. Recently, a more complicated picture has emerged as investigators have established a role for skin in the initiation and regulation of immune responsiveness. Considerable effort in this area has focused on Langerhans cells and Thy‐1+ dendritic epidermal cells, both of which reside as bone marrow‐derived immigrants in normal epidermis. Not only do these cells contribute to immune processes in skin, but their function, in turn, is modified by the keratinocytes that surround them. More importantly, pharmacologic and physical manipulation of one cell or one structure in skin often has impact on its neighbors. This phenomenon may be documented by the wide‐reaching cutaneous effects of ultraviolet radiation, bone marrow transplantation, and drugs such as cyclosporine. Our changing concepts of the function of skin also create for us a model for the current evolution in science; our problem and our fortune lie in the mutual interdependence of cells, tissues, systems, and disciplines.
Lipids are major components of human immunodeficiency virus (HIV): Modification of HIV lipid composition, membrane organization, and protein conformation by AL‐721®
Authors: Crews F. T. , McElhaney M. R. , Klepner C. A. , Lippa A. S. 
Published: January 2005

AbstractThe lipid composition of human immunodeficiency virus (HIV) was investigated. Several strains of HIV were found to contain considerable amounts of lipid. The major lipid constituents were cholesterol and phospholipid with a molar ratio close to one. This lipid composition and membrane apparent microviscosity, as determined by diphenylhexatriene fluorescent polarization, indicate that the HIV envelope is an extremely rigid membrane. A previous in vitro study and two recent clinical reports have indicated that AL‐721®, a lipid mixture designed to alter membrane lipid composition and organization by extraction of membrane cholesterol, has anti‐HIV activity. We found that AL‐721® modifies the lipid composition of HIV, reducing the cholesterol content and the cholesterol to phospholipid molar ratio. Both DPH fluorescent probe and endogenous protein fluorescent studies suggest that AL‐721® alters HIV envelope organization and/or apparent microviscosity. Membrane perturbation of HIV by AL‐721® may represent a new approach to AIDS therapy.
Tissue specificity of cAMP‐phosphodiesterase inhibitors: Rolipram, amrinone, milrinone, enoximone, piroximone, and imazodan
Authors: Pang David C. , Cantor Elinor , Hagedorn Alfred , Erhardt Paul , Wiggins Jay 
Published: January 2005

AbstractThe effects of nine cAMP‐phosphodiesterase inhibitors, including amrinone, milrinone, enoximone, piroximone, imazodan (Cl‐914), CK‐2438 (4,5‐dihydro‐6‐[pyridin‐4‐yl]‐3‐[2H]pyridazinone), rolipram, ZK‐73433 4[(3,4‐dimethoxy‐phenyl)methyl]‐2‐pyrolidinone), and IBMX (3‐isobutyl‐1‐methylxanthine) were determined on crude enzyme fractions prepared from heart, brain, and thoracic aorta of dogs. Inhibitors, such as amrinone, milrinone, enoximone, piroximone, imazodan, and CK‐2438, were found to be specific for the enzyme from the heart, but not that from the brain and thoracic aorta. On the other hand, rolipram and ZK‐73433 were potent inhibitors of the brain enzyme, but not of enzymes from the heart and thoracic aorta. None of these compounds effectively depressed cGMP‐phosphodiesterase from the thoracic aorta. Conversely, IBMX was nonspecific because it was equally active on the cAMP‐phosphodiesterases from all three tissues and the cGMP‐phosphodiesterase from the thoracic aorta. The abilities of these compounds to inhibit the cAMP‐phosphodiesterase from the three tisses were not a function of their different lipid solubilities. It is concluded that most inhibitors exhibited tissue specificity on the cAMP‐phosphodiesterases from various organs of one animal species. These data also suggest the existence of isoforms of cAMP‐phosphodiesterase (PDE‐III) in different tissues.