bluuebunny/crossref_metadata_2025 huggingface dataset:
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

Senile 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

The 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

The 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

Different 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

In 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

The 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.
Psoriasis: In vivo models for topical drug evaluation
Authors: Lowe Nicholas J.
Published: January 2005

Psoriasis is a common skin disease characterized by scaling erythematous skin plaques, which in severe cases can cover the entire skin. It affects about 2% of the population of the USA. The etiology is unknown, but the diseased skin shows a benign epidermal hyperplasia and abnormal differentiation plus dermal inflammation. There is no reproducible naturally occurring animal model for psoriasis. As a result, a variety of simulated animal models have been produced that possess some of the characteristic features, e.g., epidermal hyperplasia. These have been used to study epidermal kinetics and biochemical abnormalities associated with epidermal hyperplasia. Some of these models have also been used to study and screen for potentially effective and antipsoriatic drugs. There will always be, however, the need to study effects of new agents in carefully conducted studies on psoriasis patients to confirm efficacy.
Percutaneous drug penetration: Choosing candidates for transdermal development
Authors: Flynn Gordon L. , Stewart Barbra
Published: January 2005

There is currently a high level of interest in using the skin as a route for delivering drugs. One hears the questions: What are the attributes of a drug that make it a serious candidate for transdermal delivery? By what a priori analysis might one zero in on the best transdermal candidate within a family of drugs? Answers to these questions lie in understanding the molecular factors that make a drug a facile permeant of the skin. Among other properties, it must have a high absolute affinity for the skin's phases, which provide for its diffusive conduction. Other factors in evaluation are the potency of the drug and the relative efficiency of the drug's systemic presentation once it has gained access to the body. One also considers the potential for the drug to elicit adverse responses in the skin. Fortunately, parallels between the drug's ability to partition between oil and water and its ease of mass transfer across the skin can be used to ferret out a working mass transfer coefficient. If not already known, solubilities are easily experimentally deduced. The extent of first‐pass metabolism by the oral route, presumed to be a known quantity, is compared with the relative amount of metabolism of the drug in the course of its diffsion through the skin, an experimentally determined quantity, in order to set the transdermal dose. These bits of information can then be used to form an early, reasonably faithful picture of the feasibility of delivering a particular drug transdermally and to make a first estimate of the size of patch required for the drug.
Restoration of microsieve filterability of human red cells after exposure to hyperosmolarity and lactacidosis: Effect of vinpocetine
Authors: Schmid‐Schönbein H. , Grebe R. , Teitel P. , Artmann G. , Eschweiler H. , Schröder Susanne
Published: January 2005

A new technique has been utilized to assess quantitatively the filterability (i.e., the ability to pass restricted pores) of leukocyte‐free red blood cell (RBC) suspensions by means of computer‐assisted conductometry of novel precision metal microsieves with uniform pore diameters of 4.2 μm (MyNiPore®). RBCs were exposed to adverse conditions of chemical “stress” (400 mOsmol/liter, pH 6.8), thereafter, the effects of vinpocetine (Methyl‐Apo‐Vipamin, Thiemann‐Arzneimittel GmbH, Waltrop, FRG) were tested. When added in concentrations between 10−5 and 10−2 mol/liter to the “stressed” RBCs, vinpocetine restored the red cell microrheological performance (or behavior) when tested under low shear stresses. The present results suggest that in interpreting vinpocetine's effects in low flow situations, a possible protective microrheological action should be taken into consideration.
Pharmacologic corrections of cerebral blood flow and CO2‐reactivity in cerebrovascular insufficiency
Authors: Weinstein G. B. , Parfenov V. E. , Bodo M. , Gaidar B. V.
Published: January 2005

Experiments in brain‐ischemic rabbits were performed in order to study the effects of dimethylaether oxybutric acid (Dimephosphone), chloralhydrate oxypiridin (Emoxipine), and trimethyl hydrasine propionate (THP). These compounds proved to be antihypoxic in measures of cerebral blood flow and CO2‐reactivity.
Correlations between memory, language, gnosia, and praxia in 80 patients with senile dementia of the alzheimer type
Authors: Roudier M. , Marcie P. , Podrabinek N. , Lamour Y. , Davous P.
Published: January 2005

A global neuropsychological study has been carried out with 80 in‐patients presenting a syndrome of senile dementia of the Alzheimer type (SDAT):60 scored less than 20 (mild dementia) on the Mini‐Mental Test Examination (MMSE); 20 scored less than 10 (severe dementia). The test battery included a set of tasks exploring memory, language, abstract nonverbal thought, gnosias, and praxias. In patients with mild dementia, the overall MMSE score was statistically correlated with the scores for memory, nonverbal thought, language, and gnosias, but not with the score for praxia. Language score was correlated with the scores for the other higher functions. It is suggested that the SDAT syndrome has to be considered as a unique syndrome affecting every higher function quite similarly, with no evidence of clinical subgroups. With this in mind, new studies should be designed to delineate further the role of the mnesic, linguistic, and/or perceptual factors involved in the dementia process.
Calcium antagonist activity of vinpocetine and vincamine in several models of cerebral ischaemia
Authors: Lamar Jean‐Claude , Poignet Hervé , Beaughard Michèle , Dureng Georges
Published: January 2005

The potency and selectivity (i.e., the central vs. peripheral vascular smooth muscle activity) of the calcium antagonist (CA) effects of vinpocetine and vincamine have been compared with those of the standard CAs: flunarizine, verpamil, diltiazem, and nimodipine in rabbit basilar and splenic artery preparations. The cerebral antiischemic activity of these substances also was evaluated in five well‐documented in vivo models, i.e., hypobaric and normobaric hypoxia, global cerebral ischemia to MgCl2, cytotoxic anoxia with KCN, and cerebral edema induced by triethyl tin. Both vinpocetine and vincamine possess only weak CA activity, the potency order being: nimodipine > diltiazem > flunarizine = verapamil > vinpocetine > vincamine, with vinpocetine and flunarizine, in contrast to other compounds, showing a clear, 6‐ to 13‐fold selectivity for cerebral vascular smooth muscle. In the in vivo models, vinpocetine and flunarizine, together with vincamine, proved most active and had a larger spectrum of activity than the other CAs. These results suggest that the cerebrally selective CA effects of vinpocetine are at most only partly responsible for the effects of this compound in the in vivo models of cerebral ischemia.
Effect of vinpocetine on age‐related differences in brain function of aged fischer rats
Authors: Notvest Ronald R. , Emrey Tracey A. , Inserra John J.
Published: January 2005

Vinpocetine, an eburnamenine derivative, is under clinical investigation as a cerebral activator for use in Alzheimer's and other diseases characterized by symptomatic cognitive and attentional deficits. In this study, vinpocetine was evaluated by examining its effect on the electrocorticogram (ECoG) of aged (26‐month‐old) Fischer‐344 rats. Significant age‐related differences were apparent for all ECoG parameters examined, suggesting a cerebral deficit in aged rats. Vinpocetine, administered orally (p.o.) over the dose range of 0.3 to 30 mg/kg/day p.o. for 5 days, diminished the age‐related differences in the ECoG. These findings provide evidence that vinpocetine may serve as a useful therapeutic agent in diseases characterized by cerebral deficits.
Animal models for evaluation of age‐related changes in behaviour
Authors: Schulze Gert , Coper Helmut , Jänicke Bernhard
Published: January 2005

A larger degree of deterioration of the centrally controlled physiological, motor, and cognitive functions is characteristic of an organism's aging process. This restricted adaptation can be monitored on various organizational and functional levels. Mazes permit registration of cognitive performance in controlled motivation such as memory, spatial orientation, ability to learn, and speed of learning. The total running time is a composite parameter determined by a number of time‐dependent and time‐independent factors. With time‐dependent factors, age‐related differences remain after five repetitions, even when slight effects of training are evident. In most time‐independent factors, age‐related differences can be nearly eliminated by training. An example of the method “testing the limits” is to measure compensative responses under 10% normobaric hypoxia over a period of several days. Young as well as old rats reacted with the same reduction in feed intake and spontaneous activity. Adaptation to normal levels concerning motility and food consumption is accomplished less effectively and more slowly by the old rats than by the young ones. There were no differences between age groups in comparing the blood gas values of O2, CO2, and pH values. If the animals have to learn an operant conditioning schedule (fixed ratio/differential reinforcement of low rates), there are age‐related divergences of performance. Under hypoxic conditions, 27‐month‐old animals need twice as long to reach the test criterion in the “fixed ratio” as 4‐ and 20‐month‐old rats. Only the young and middle‐aged groups accomplished the task called “differential reinforcement of low rates”.
Influence of nootropic drugs on the stimulus‐release relationship of dopaminergic structures
Authors: Wustmann Christian , Fischer Hans‐Dieter , Rudolph Erika , Schmidt Joachim
Published: January 2005

Brain slices labelled with radioactive neurotransmitters are a well established system for the investigation of transmitter secretion. The basal outflow of transmitter in the absence of external stimuli is largely due to a passive diffusion from nerve endings. The potassiumstimulated overflow represents a quasiphysiological release with a well defined correlation between stimulus intensity and fractional efflux rate. Upon long‐term exposure of rats to mild hypobaric hypoxia (10 day, 20 hr daily) the stimulus‐release relationship shows a marked ascent in the gradient in comparison to naive animals. Twenty‐four hours after long‐term treatment with piracetam, pyritonol, meclofenoxate, or vinpocetine (twice a day for 3 weeks) only the pretreatment with piracetam (100 mg/kg, twice a day) leads to changes of the stimulus‐release relation comparable to that seen in rats that were exposed to a long‐term hypoxia. These effects continued until 10 days after the last injection of the drug or after cessation of hypoxia. Meclofenoxate, pyritinol, and vinpocetine were without marked effects on the stimulus‐release relation.
Metoprolol monotherapy in the treatment of mild hypertension
Authors: Mahapatra Rajat K. , Mahapatra Dipta , Paul Subir K. , Lal Harbans , Hunter Kenneth W.
Published: January 2005

Metoprolol tartrate (MT) as monotherapy was administered orally in 17 patients with mild hypertension. All other drugs were discontinued 2 weeks prior to MT therapy. The present study group consisted of 10 men and 7 women within the age range of 42 to 71 years (mean ± S.D. = 55.8 ± 8). MT was administered at an initial dose of 50 mg twice daily. Subsequently, the dose of MT was titrated on a biweekly basis for a period of 12 weeks until the diastolic blood pressure was < 90 mmHg or a maximum daily dose of 300 mg was administered. The blood‐pressure‐lowering effect of MT was found to be clinically satisfactory and statistically significant (P< 0.05). Mild fatigue and swelling of the extremities were seen in two patients each. Mild headache, transient diarrhea, and mild cloudiness of mind were seen in one patient. From this study it is concluded that MT is a safe and effective first‐step antihypertensive agent. The long‐term effect of MT as a monotherapy in the treatment of mild hypertension needs further clinical evaluation.
Stage‐specific behavioral, cognitive, and in vivo changes in community residing subjects with age‐associated memory impairment and primary degenerative dementia of the Alzheimer type
Authors: Reisberg Barry , Ferris Steven H. , de Leon Mony J. , Franssen Elia Sinaiko Emile , Kluger Alan , Mir Pervez , Borenstein Jeffrey , George Ajax E. , Shulman Emma , Steinberg Gertrude , Cohen Jacob
Published: January 2005

Stage‐specific relationships between the seven‐stage Global Deterioration Scale (GDS) for age‐associated memory impairment and primary degenerative dementia of the Alzheimerapos;s type and behavioral, cognitive, and neuroradiologic changes were examined in community residing subjects with normal aging or Alzheimerapos;s disease (AD). The results revealed significant decrements between GDS stages 2 and 3; 3 and 4; 4 and 5; and 5 and 6 for most behavioral measures. No decrements were noted between GDS stages 1 and 2. Consequently, the subjective complaints of cognitive decrement, which characterize GDS 2 subjects and which commonly accompany aging, do not appear to be accompanied by objective behavioral or cognitive change. Floor effects for most behavioral and cognitive measures occurred by GDS 6, with nearly uniform bottom scores by GDS stage 7. Computerized tomographic (CT) assessments of brain change revealed significant relationships with global severity on the GDS, but few significant consecutive stage decrements were noted. The magnitude of the relationship between CT assessments of brain change and GDS scores was notably less than the magnitude of the relationship noted between various behavioral measures and GDS. Although behavioral and neurcradiologic measures studied did not reveal decrements in the GDS 2 subjects in comparison with age‐matched GDS 1 subjects who do not have subjective decrements, previous studies of a neuroimmunologic measure (brain reactive antibody levels) do appear to have indicated significant differences between these groups. Consequently, there is some current preliminary evidence for the hypothesis of a physiologic substrate for the subjective deficits characteristic of the GDS 2 stage, as well as clear‐cut behavioral data distinguishing each of the subsequent GDS stages of aging and AD.
Does the brain possess an independent immune compartment?
Authors: Blumenthal Herman T.
Published: January 2005

An immunoregulatory feedback circuit exists between the CNS and the immune system comparable to other feedback systems that maintain homeostasis in mammals. Moreover, the brain “enjoys” certain privileges and autonomies. The privileges include a redistribution of blood flow, which provides additional blood to the brain under conditions of anoxia, and a redistribution of nutrients so that the brain preferentially receives an additional supply under conditions of starvation. The so‐called immunologic privilege of the brain serves to shield it from systemic immune reactions that may be damaging to neural structures. An example of an autonomy is the independent endocrine capacity of the CNS; but does it also possess an independent immune capacity? Studies on neuron‐binding immunoglobulins (lgs) have revealed that some of these lgs are directed against antigens shared between neural structures and tissues outside the CNS, such as the Thy‐1 antigen of thymic lymphocytes. Other lgs appear to be specific for neural antigens. This suggests that the blood‐brain‐barrier (BBB) may protect neural structures from cross‐reacting with extraneural antibodies. But the BBB would also provide a barrier to the systemic immune system when aberrant antigens are generated within the CNS. Observations such as these have given rise to the hypothesis that antibodies to neural antigens might be generated within the CNS. Evidence is provided here from studies on monkeys, as well as a review of relevant literature, that the CNS contains structures that can provide an independent immune capacity. These include perivascular and glial cells and elements of the choroid plexus. Some of these structures also display markers similar to those displayed by immunocytes. It is proposed here that neuronophagia and the resultant loss of neurons with age may be due to immune reactions confined to the CNS. It is also proposed that certain CNS phenomena associated with Alzheimerapos;s disease may be due to parallel age‐related autoimmune reactions not causally related to AD.
Development of the hippocampal formation in mutant mice
Authors: Nowakowski R. S.
Published: January 2005

The highly laminated structures of the hippocampal formation provide an ideal location for the assessment of the effects of mutant genes on the development of the central nervous system. Presently seven different mutations and one genetic variant (NZB/BINJ) are known to affect the developing hippocampal formation. Each of them affects neuronal migration and/or cell proliferation in a different constellation of cell types and produces a distinct pattern of reorganization. The fact that different mutations, which map to different chromosomal locations, can affect neuronal migration in the hippocampal formation indicates that there is a variety of developmental processes that influence the ultimate destination of a migrating neuron. In addition, the fact that the different mutations do not uniformly affect all populations of migrating cells indicatesd that, in some cases, migrating neurons with different destinations may use different cues to find their final position. Conversely, the overlap in the phenotypes of the various mutations provides insight into the extent of common gene expression during neuronal migration. For example, six of the mutations have ectopic CA3 pyramidal cells. These same six mutations also have ectopic granule cells in the molecular layer of the cerebellar cortex. This association may reflect the existence of common gene expression during the migration of these two diverse cell types. Also, NZB/BINJ mice and four of the single gene mutations have immune system dysfunctions. Thus, there may be common gene expression during the differentiation of the immune system and neuronal migration. These genetic tools provide a significant new way to explore cerebral cortical development, in general, and neuronal migration, in particular.
Peptide t sequences prevent neuronal cell death produced by the envelope protein (gp 120) of the human immunodeficiency virus
Authors: Brenneman Douglas E. , Buzy Jeanine M. , Ruff Michael R. , Pert Candace B.
Published: January 2005

Peptide T, an octapeptide sequence found in the external evelope protein (gp 120) of the ARV isolate of human immunodeficiency virus (HIV), was investigated for its action in preventing neuronal death observed in mouse hippocampal cultures treated with purified gp 120. Cell counts of neuronspecific enolase‐identified neurons revealed that peptide T application completely and potently antagonized gp 120‐induced death. Analogs of the core pentapeptide sequence of pepptide T, TTNYT, found in the second variable region of all gp 120 isolates sequenced to date, were also tested and found to be similarly active. Investigations of structure activity relationships of related peptides suggested that the second and fourth positions in the core pentapeptide sequence were critical for biological activity in the neuronal survival assay. Antiserum against the peptide T sequence found in the the ARV isolate was found to prevent neuronal cell death in cultures treated with purified gp 120 from the IIIB isolate of HIV. These data indicate that the peptide T sequence is effective in preventing neuronal cell death associated with the envelope protein and provide a rationale for peptide T to be evaluated as a potential therapeutic agent for the neuropsychiatric and neurological sequelae of acquired immune deficiency syndrome.
Perceptual masking of drug stimuli
Authors: Gauvin David V. , Young Alice M.
Published: January 2005

Three separate drug‐discrimination experiments, using pigeon subjects, were designed to assess the modification of a morphine (MS) stimulus by d‐amphetamine (AMPH). Experiment 1 examined the drug mixture in a two‐choice discriminative procedure in three groups of subjects trained to one of three doses of MS (1.0, 3.2, or 10 mg/kg) vs. saline (SAL). Blockade of the MS stimulus by concomitant AMPH administration was training dose‐dependent. Complete blockade was found in the high‐MS (10 mg/kg) training dose (TD) group; partial blockade was found in the intermediate‐TD (3.2 mg/kg) group; and complete generalization was found in the low‐TD (1.0 mg/kg) group. Experiment 2 was designed to assess whether the MS‐AMPH mixture resulted in the creation of a functionally new stimulus. With a three‐choice drug‐discrimination procedure, two new groups were trained to discriminate between 3.2 mg/kg MS, SAL, and 1.8 mg/kg AMPH. Once training criteria were met, subjects were divided into two groups and one group's MS training dose was faded up to 10 mg/kg. Data clearly indicated that MS‐AMPH combinations did not produce novel stimuli. Experiment 3 was designed to assess the MS‐AMPH combinations in a three‐choice quantitative discrimination using 1.8 mg/kg MS vs. SAL vs. 10 mg/kg MS as discriminative stimuli. Data suggested that if masking does occur, it is a result of shifting the dose‐response function to the left (i.e., to a nondiscriminable dose). We conclude that perceptual masking of drug stimuli can occur, but the phenomenon seems dependent on training dose and/or drug and behavioral history.
A pentylenetetrazol‐like stimulus during cocaine withdrawal: Blockade by diazepam but not haloperidol
Authors: Wood Douglas M. , Laraby Patrick R. , Lal Harbans
Published: January 2005

In the present experiment, rats were trained to discriminate the stimulus properties of an anxiogenic drug, pentylenetetrazol (PTZ), 20 mg/kg, from saline using a food‐rewarded two‐lever choice task. Following training, substitution tests were performed, and rats selected the PTZ‐appropriate lever after PTZ in a dose‐dependent manner. Cocaine (5–20 mg/kg) did not substitute for PTZ. Subsequently, testing and training were halted, and cocaine, 20 mg/kg/8 hr, was administered to three groups of ten rats per group for 3, 7, and 14 days. Withdrawal from cocaine produced a PTZ‐like stimulus that increased in intensity proportionally to the duration of chronic cocaine exposure. The selection of the PTZ lever by these subjects during withdrawal was reversed following administration of diazepam, 5 mg/kg, but not by haloperidol, 0.64 mg/kg. Stimulus control tests performed 2 weeks following the last withdrawal test demonstrated a return to baseline responding, with no significant loss of stimulus control. These data demonstrate the development of a PTZ‐like interoceptive stimulus during withdrawal from cocaine, which suggests the possibility of an anxiety‐like stimulus during cocaine withdrawal. This anxiety‐like component appears to be influenced by the duration of cocaine exposure.
Neuropharmacological assessment of the discriminative stimulus properties of the novel anxiolytic ipsapirone
Authors: Cunningham Kathryn A.
Published: January 2005

The novel anxiolytic ipsapirone appears to interact selectively with 5‐hydroxytryptamine1A (5‐HT1A) receptors. The present study investigated (1) the discriminability of ipsapirone using a two‐lever, water‐reinforced task and (2) the importance of 5‐HT1A and catecholamine systems in the ipsapirone cue. To this end, rats were trained to discriminate ipsapirone (7.5 mg/kg; N = 14) from saline. Dose‐response tests indicated that the ipsapirone cue was dose dependent. Buspirone and 8‐OH DPAT substituted while the dopamine (DA) D1 agonist SKF 38393, the DA D2 agonist quinpirole, and the α2‐adrenoceptor agonist clonidine engendered saline responding. Furthermore, the D1 antagonist SCH 23390, the D2 antagonist sulpiride, and the putative 5‐HT1A antagonist spiroxatrine did not block or mimic the ipsapirone cue. This research suggests that catecholamine systems do not play a prominent role in mediating the stimulus properties of ipsapirone. Moreover, while the substitution profile for ipsapirone suggests that this novel anxiolytic may be a selective 5‐HT1A agonist, blockade of the ipsapirone cue by a 5‐HT1A antagonist remains to be established.
General pharmacology of diprafenone, a new class lc antiarrhythmic agent, and 5‐hydroxydiprafenone, an active metabolite
Authors: Greenberg Stanley , Luisi Alan
Published: January 2005

This study compareo the effects of diprafenone, a new class lc antiarrhythmic agent, and 5‐hydroxydiprafenone (5‐OHDP), an active metabolite of diprafenone, to standard class l antiarrhythmic agents (propafenone, flecainide, or lidocaine), in several pharmacologic models, to ascertain the potential for side effects relative to the currently available class l antiarrhythmic agents. Diprafenone and propafenone decreased blood pressure and heart rate in anesthetized rabbits at 3 and 7 mg/kg, i.v., respectively. Neuromuscular transmission in rabbit gastrocnemius muscle was partially (38%) inhibited after 3 mg/kg of diprafenone and 7 mg/kg of propafenone. Diprafenone and 5‐OHDP (10−4M), but not lidocaine, inhibited aggregation of human platelets evoked by sodium arachidonate and adenosine diphosphate. Diprafenone, fleoainide, and 5‐OHDP (10−4M) inhibited the contractile responses of guinea pig vas deferens to norepinephrine and spontaneous and bradykinin‐evoked contractions of the guinea pig uteri. Diprafenone and 5‐OHDP, but not flecainide, relaxed rabbit bronchial smooth muscle contracted by acetylcholine. Diprafenone, 5‐OHDP and propafenone (10−5M and 10−4M) also depressed the contractile responses of canine mesenteric arteries to transmural nerve stimulation. Thus, high concentrations of diprafenone (10−5M and 10−4M) depress smooth muscle and neural function. The depressant effects occur with 4ndash;40 times the antiarrhythmic concentration of diprafenone and are shared by propafenone and, in part, by 5‐OHDP and flecainide. It is unlikely that major peripheral side effects will occur with therapeutic doses of diprafenone in man.
Phencyclidine acts as an N‐methyl‐D‐Aspartate agonist in vitro
Authors: Taylor Duncan P. , Behling Susan H.
Published: January 2005

The in vitro binding of the tricyclic compound (+)‐[3H]MK‐801 to membranes from rat brain cerebral cortex has been shown to be enhanced by L‐glutamic acid and inhibited by the noncompetitive N‐methyl‐D‐aspartate (NMDA) antagonist phencyclidine (PCP) and the competitive NMDA antagonist 3‐[(±)‐2‐carboxypiperazin‐4‐yl] propyl‐1‐phosphonic acid (CPP). We characterized these interactions in ligand saturation experiments. As noted by others, the KD was decreased by L‐glutamic acid. In addition, we noted a slight but significant increase in Bmax in the presence of the excitatory amino acid. PCP increased the KD in a fashion characteristic of competitive inhibition, but it also increased Bmax in a fashion which mimicked L‐glutamic acid. That this effect might be mediated by a direct action of PCP at the NMDA binding site was confirmed by the ability of CPP to block the PCP‐induced increase in Bmax. These data suggest that the chemical structure of PCP may represent a new starting point for the development of agents which interact with the NMDA receptor.
Effects of H2‐receptor antagonists on the central nervous system
Authors: Berlin Roger G.
Published: January 2005

Histamine functions as a neurotransmitter in the central nervous system (CNS), and H2‐receptor activation can modulate the activity of the CNS. H2‐receptor antagonists are known to penetrate the blood‐brain barrier and to cause neuropsychiatric effects. It appears that interactions with CNS H2‐receptors may account for many of these effects, although receptor interactions unique to certain H2‐antagonists may also play a role.
Loreclezole (R 72 063): An anticonvulsant chemically unrelated to prototype antiepileptic drugs
Authors: Wauquier Albert , Fransen Joannes , Melis William , Ashton David , Gillardin Jean‐Marie , Lewi Paul J. , Van Clemen Gust , Vaught Jeffrey , Janssen Paul A. J.
Published: January 2005

This study reports on the anticonvulsant profile of a chemically and pharmacologically new compound, loreclezole, as compared to prototype antiepileptics. The compound was tested in different species (mice, rats, guinea pigs, and dogs), in different seizure models, following p.o. or i.p. drug administration, and at different time intervals. Loreclezole was found to be active in a genetic model of reflex epilepsy (audiogenic seizures in mice) and in all models where seizures were elicited by chemical or electrical stimulation. In addition, loreclezole was active against both tonic (TON) and clonic (CLON) seizures and increased the threshold for behavioral as well as electroencephalographic (EEG) seizures. Loreclezole has a rapid onset of action (15 min in the quinolinic acid‐induced CLON seizures and barrel rotations) and a duration of action, in certain tests, of more than 24 hr (allylglycine test and s.c. pentylenetetrazol test in rats). There is a dissociation between the anticonvulsant doses and the induction of neurological side effects (in dogs, ratio > 25.5). Chronic administration for 5–7 days did not lead to tolerance to the anticonvulsant action of loreclezole. Also, as based on spectral map analysis, loreclezole both valproate and ethosuximide, suggesting that it might be effective against both grand mal and petit mald epilepsy.
Effect of exercise on disposition and pharmacokinetics of drugs
Authors: Somani Satu M. , Gupta Sundeep K. , Frank Stuart , Corder Clinton N.
Published: January 2005

The effect of various drugs on exercise in man and animal has been reported but there are very few reports which evaluate the effect of exercise on the disposition and pharmacokinetics of drugs. Exercise in general decreases the absorption after oral administration and increases absorption after intramuscular and subcutaneous administration. Exercise decreases the distribution and excretion of flow‐limited drugs and increases the distribution and excretion for capacity‐limited drugs. Treadmill or running wheel, but not swimming exercise diminishes or elevates the Phase I metabolism and glucuronidation. The effect of exercise on drug metabolism may be substrate specific, suggesting alterations in isozymes of Cyt P‐450. Exercise also decreases glutathione concentration. Effect of exercise on drug disposition is also related to the other factors including temperature, pH, drug permeability, and barometric pressure; the most critical factor, however, appears to be altered blood flow which occurs with exercise. There is a wide inter‐ and intraindividual variation in the metabolism and pharmacokinetics of drugs due to exercise. It remains to be determined what factors play a major role in drug disposition as a consequence of exercise. Exercise influences the amount of drug reaching the receptor site, which has significant affect on pharmacodynamic activity. This aspect of pharmacology has great implications in therapeutics particularly for drugs which have a low margin of safety.
Human immunodeficiency virus protease: A target for aids therapy
Authors: Debouck Christine , Metcalf Brian W.
Published: January 2005

Human immunodeficiency virus, also called HIV, is the etiologic agent of acquired immune deficiency syndrome (AIDS). This retrovirus produces a small, dimeric aspartyl protease which specifically cleaves the precursor forms of the structural proteins and enzymes of the virus. This proteolytic activity is absolutely required for the production of mature, infectious viral particles and is therefore an attractive target for therapeutic intervention. Peptide analogues containing transition‐state mimics were synthesized and shown to inhibit the activity of the purified HIV protease in vitro to various extents. Most interestingly, the most potent inhibitors were shown to effectively block the protease in HIV‐infected cells and to impair the viral life cycle. Other approaches to interfere with the viral protease activity or production are also discussed.
Pharmacology of Cl‐966: A potent GABA uptake inhibitor, in vitro and in experimental animals
Authors: Taylor Charles P. , Vartanian Mark G. , Schwarz Roy D. , Rock David M. , Callahan Michael J. , Davis M. Duff
Published: January 2005

Experiments were performed to assess the pharmacology of a novel inhibitor of GABA uptake, Cl‐966 ([1‐[2‐[bis 4‐(trifluoromethyl)phenyl]methoxy]ethyl]‐1,2,5,6‐tetrahydro‐3‐pyridinecarboxylic acid, HCl salt; the molecular weight of the free acid is 473.8). Cl‐966 potently inhibits tritiated GABA uptake into rat hippocampal slices in vitro (lC50 = 304 nM). It has no appreciable effect on the uptake of other neurotransmitters tested (aspartate, dopamine, norepinephrine, serotonin) and has low activity in a broad range of neurotransmitter receptor binding assays. When given orally to mice, Cl‐966 prevents tonic extensor seizures from low‐intensity electroshock and prevents pentylenetetrazole‐induced clonic seizures (ED50 = 0.4–1.0 mg/kg). In addition, the hippocampal afterdischarge threshold in kindled rats is increased markedly (ED50 = 2.6 mg/kg p.o.). Despite anticonvulsant effects, higher doses of Cl‐966 reduce the intravenous dose of pentylenetetrazole needed to produce clonus in mice. In mice, rats, dogs, and monkeys, Cl‐966 interferes with normal behavior, causing ataxia, reduced responsivenes and myoclonus. In the hippocampus of anesthetized rats, Cl‐966 increases inhibition measured electrophysiologically. Overflow of endogenous GABA in the striatum (measured with in vivo microdialysis) was also increased. All of these observed effects with Cl‐966 may be explained by its inhibitory effect on GABA uptake.
Comparison of Somatuline (BIM‐23014) and somatostatin on endocrine and exocrine activities in the rat
Authors: Moreau Sylviane C. , Murphy William A. , Coy David H.
Published: January 2005

The actions of Somatuline (BIM‐23014), an Octapeptide analogue of somatostatin, and somatostatin have been compared on several endocrine and exocrine activities in the rat. A substantial difference exists between these two compounds with respect to potency, duration of action, and tissue‐selectivity. With regard to endocrine activities, Somatuline was about 300 times more potent than somatostatin in inhibiting growth hormone (GH) release 15 min after intravenous injection, and about 4 to 6 times more potent 15 min after subcutaneous administration. The inhibitory activity of subcutaneously‐administered Somatuline on D‐ALa2‐GRF‐stimulated GH release lasted for about 6 hr, whereas an action of somatostatin was not detected 30 min after injection. Somatuline was also more potent than somatostatin in inhibiting insulin‐stimulated glucagon secretion when both substances were administered intravenously, whereas they were about equipotent when given by the subcutaneous route. However, Somatuline was only about half as potent as somatostatin by the intravenous route in inhibiting glucose‐stimulated insulin release and inactive by the subcutaneous route. With regard to exocrine activities, Somatuline was about 300–500 times more potent than somatostatin in inhibiting the increase in plasma α‐amylase activity following ligation‐induced pancreatitis when both compounds were administered subcutaneously concurrently with pancreatic duct ligation. Somatuline was also about 20–400 times more potent that somatostatin in inhibiting gastric acid secretion when both compounds were administered subcutaneously prior to, or concurrently with, pentagastrin challenge, and about 100 times more potent than somatostatin when administered after pentagastrin challenge. Somatuline had a very weak inhibitory effect on the development of ethanol induced gastric ulcers, it did not induced diarrhea, and it had no effect on the course of diarrhea in rats subjected to castor oil gavage. The differences that have been shown to exist between Somatuline and somatostatin indicate that Somatuline may be more useful in treating certain disease states, such as diabetes mellitus, pancreatitis, and possible gastritis or bleeding gastric ulcers.
Cardioprotective effects of nicorandil on isoproterenol‐induced injury
Authors: Ohta Hideyuki , Azuma Junichi , Tanaka Yuya , Takihara Keiko , Hamaguchi Tomoyuki , Awata Nobuhisa , Sawamura Akihiko , Sperelakis Nicholas , Kishimoto Susumu
Published: January 2005

Nicorandil, a new anti‐anginal drug, exerts a coronary vasodilation effect by mechanisms different from either nitrates or slow channel Ca+ + entry blockers. This agent has been demonstrated to increase membrane K+ conductance, elevate cyclic guanosine monophosphate content, and inhibit Ca+ + kinetics in vascular smooth muscle cells. In the myocardium, however, the direct effects of the agent have not been elucidated. We examined whether nicorandil could antagonize myocardial injury in chick hearts induced by a toxic dose of isoproterenol. Isoproterenol treatment (240 mg/kg subcutaneously twice a day for 4 days) caused a significant increase in heart/body weight ratio and induced a remarkable histological perturbation. A substantial accumulation of Ca+ + and a profound decrease of creatine kinase and lactate dehydrogenase activity were observed in the myocardium from isoproterenol‐treated chick. Oral administration of nicorandil (4 mg/day for 4 days, 15 min prior to each isoproterenol treatment) attenuated the deterioration induced by isoproterenol. The present study suggests that nicorandil partially protects the myocardium from the isoproterenol‐induced injury.