bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigation of the acute and chronic anti‐inflammatory properties of diphosphonates using a broad spectrum of immune and non‐immune inflammatory reactions
Authors: Dunn Colin J. , Doyle David V. , Willoughby Derek A.
Published: January 2005

Diphosphonates are known to affect skeletal and soft tissue mineralization; however, several studies have shown that these compounds effectively suppress adjuvant‐induced polyarthritis in the rat, reducing the edematous inflammatory component as well as skeletal changes. Therefore, we investigated the specific anti‐inflammatory potential of two diphosphonates, ethane‐1‐hydroxy‐1,1 diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl2MDP), using several different models of acute, non‐immune‐ and immune‐driven inflammation in the pleural cavity of rats and guinea pigs which afforded both a qualitative and quantitative assessment of leukocyte infiltration and exudate fluid (edema) formation. EHDP and Cl2MDP, administered at doses which suppressed the chronic inflammatory lesions induced in adjuvant arthritis, failed to inhibit acute inflammation regardless of the stimulus used (carrageenan; calcium pyrophosphate dihydrate crystals; hydroxyapatite crystals; immune complexes (Arthus reaction); delayed‐type hypersensitivity to purified protein derivate). At the highest dose tested (15 mg/kg subcutaneously [sc]) both EHDP and Cl2MDP exacerbated hydroxyapatite‐ and delayed‐type hypersensitivity‐induced leukocyte infiltration; hydroxyapatite crystals precoated with EHDP or Cl2MDP caused a small but significant inhibition of the chronic inflammatory response to sc cotton pellet implantation. We conclude that EHDP and Cl2MDP may be effective in chronic rather than acute inflammation. Our observations suggest that further studies are warranted on the potential of diphosphonates as novel therapeutics for chronic inflammatory disease. © 1993 Wiley‐Liss, Inc.
Adenosine receptors in the human heart: Pharmacological characterization in nondiseased and cardiomyopathic tissue
Authors: Böhm Michael , Ungerer Martin , Erdmann Erland
Published: January 2005

The purpose of the present study was to characterize adenosine receptors in human atrial and ventricular preparations as well as in nonfailing and failing human ventricular myocardium. Using the antagonist radioligand 3H‐DPCPX, A1‐adenosine receptors were identified in human atrial and ventricular myocardial membranes. The rank order of potency of agonists and antagonists as well as the influence of Gpp(NH)p on agonist high affinity binding were similar in atrial and ventricular myocardium, indicating that the same receptor type probably couples in a similar guanine nucleotide‐dependent way to different effectors producing the “direct” or “indirect” effects on myocardial force on contraction. The density and coupling of ventricular adenosine receptors as well as the antiadrenergic, “indirect” effect following their stimulation were not different in failing human myocardium, despite an increase in Giα‐proteins. Thus, enhanced antiadrenergic effects of A1‐adenosine receptors do not contribute to the reduction of cAMP‐dependent positive inotropic effects in heart failure. © 1993 Wiley‐Liss, Inc.
Hypoxia, endothelium, and purines
Authors: Burnstock Geoffrey
Published: January 2005

The article focuses on the events involving purine nucleotides and nucleosides during the initial responses of the cerebral vascular bed to ischaemia. In particular, the role of ATP released from endothelial cells which acts on P2Y‐purinoceptors, leading to production of nitric oxide and subsequent vasodilatation, will be considered. A relation between these events and the involvement of purines in the longer term degenerative consequences of ischaemia seems unlikely. © 1993 Wiley‐Liss, Inc.
Purinergic responses in the feline pulmonary vascular bed
Authors: Neely Constance F.
Published: January 2005

Adenosine and ATP produce dose‐dependent, tone‐dependent response in the pulmonary vascular (PV) bed, under conditions of controlled pulmonary blood flow and constant left atrial pressure in vivo in intact‐chest, spontaneously breathing cats. At low, resting PV tone, adenosine produces dose‐dependent vasoconstrictor responses by acting on “A1‐like” adenosine receptors which activate a phospholipase and thromboxane release. ATP Produces dose‐dependent vasoconstrictor responses, in part, following its metabolism to adenosine, by acting on “A1‐like” adenosine receptors and by acting on P2x receptors. At elevated PV tone, data to date support that adenosine and ATP produce dose‐dependent vasodilator responses by acting on A2 and P2Y receptors, respectively. Mechanisms to explain how a change in vascular tone alters the response of the vascular bed to a substance are not known. Moreover, the role of purinoceptors in pulmonary vascular disease is not known. Identification of selective pharmacological probes for purinoceptors in the pulmonary vascular bed is necessary to investigate their role in the development of pulmonary hypertension of acute and chronic lung disease. © 1993 Wiley‐Liss, Inc.
Prolonged agonist exposure induces imbalance of A1 and A2 receptor‐mediated functions in rat brain slices
Authors: Abbracchio Maria P. , Brambilla Roberta , Rovati G. Enrico , Cattabeni Flaminio
Published: January 2005

Agonist‐induced desensitization of A1 and A2 adenosine receptors was studied in brain slices obtained from either rat striatum or cortex, exposed to the adenosine analogue N6‐cyclopentyl adenosine (CPA) for selected time periods (15–60 min), and repeatedly washed at the end of agonist exposure. Adenosine receptor function in control and agonist‐exposed slices was evaluated by measuring coupling with the cAMP producing system in striatum and with membrane phosphoinositide metabolism in cortex. In rat striatum, exposure to the adenosine analog resulted in a rapid, time‐and dose‐dependent desensitization of cyclase‐linked A1 receptors, as shown by a gradual loss of A1 receptor‐mediated inhibition of basal cAMP formation. Binding studies with [3H]cyclo‐hexyl‐adenosine (CHA) showed no changes of A1 receptors for the shortest agonist exposure periods utilized (i.e., 15 and 30 min), indeed suggesting an initial uncoupling of receptors from their transduction system. After a 60 min exposure to the adenosine analogue, a significant change of [3H]CHA higher affinity component was instead detected, probably reflecting later agonist‐induced receptor changes related to irreversible receptor loss. The initial agonist‐induced loss of A1 receptor function was also confirmed in rat cortex, where A1 receptor‐mediated modulation of phosphoinositide breakdown was dose‐dependently impaired by pre‐exposure of slices to the adenosine analogue. A2 receptors seemed resistant to agonist‐induced desensitization, at least for the exposure periods utilized. In striatum, changes of A1 receptor function were indeed accompanied by a concomitant increase of A2 receptor mediated stimulation of adenylate cyclase activity, suggesting an “unmasking” of A2 stimulatory receptors as a consequence of inhibitory receptors. These result therefore indicate that the over‐exposure to adenosine analogues can result in a functional unbalance between A1 and A2 adenosine receptors, which might be at the bases of changes of adenosine neuroprotective activity in brain pathological conditions characterized by an increased release of the nucleoside. © 1993 Wiley‐Liss, Inc.
Depression of synaptic transmission and evoked NMDA Ca2+ influx in hippocampal neurons by adenosine and its blockade by LTP or ischemia
Authors: Schubert Peter , Keller Franz , Rudolphi Karl
Published: January 2005

Neuronal Ca2+ influx in response to repetitive synaptic activation was determined in rat hippocampal slices by measuring the evoked decreases of the extracellular Ca2+ concentration with ion‐sensitive electrodes in the synaptic layer (ΔCaSpad) and in the CA1 pyramidal cell layer (ΔCaSpyr). The generation of NMDA receptor‐mediated Ca2+ fluxes (NMDA Ca2+ fluxes) was uncovered by measuring the proportion of ΔCa blocked by the NMDA receptor antagonist 2‐amino‐5‐phosphonovalerate (APV); 1 μmol adenosine increased the critical input frequency required to generate synaptic MNDA Ca2+ influx. This effect is apparently exerted by limiting the postsynaptic membrane depolarization and is no longer seen, if the NMDA Ca2+ channels have lost their Mg‐dependent voltage sensitivity. It has been recently reported by Ben‐Ari and co‐workers [(1992) Trends Neurosci 15:333–339] that such a loss of voltage sensitivity, leading to an “upregulation” and persistent generation of NMDA Ca2+ currents, Can be elicited by an activation of the protein kinase C (PKC) and may be responsible for the initiation of synaptic long‐term potentiation (LTP) and for ischemia‐induced nerve cell damage. Consistent with this hypothesis, we found that the depressive effect of 1 μmol adenosine on the generation of NMDA Ca2+ influx or synaptic transmission can be no longer elicited in hippocampal slices after LTP and after preceding transient brain ischemia in vivo. These findings suggest that the mosaic of different adenosine actions includes some which are related to PKC activation. Accordingly, we observed a synaptic modulation by adenosine which was characterized by a reduced Mg‐sensitivity and blocked by phorbol ester treatment. © 1993 Wiley‐Liss, Inc.
An inhibitory postsynaptic potential in spinal nociceptive neurones is mediated by adenosine through activation of ATP‐sensitive K+ channels
Authors: Salter Michael W. , De Koninck Yves , Henry James L.
Published: January 2005

Inhibitory processes within the dorsal horn participate in regulating the transmission of nociceptive information. Spinal nociceptive neurones are inhibited by cutaneously applied vibration and we have characterized this inhibition physiologically and pharmacologically [Salter et al., 1993]. This inhibition is evoked by activation of Pacinian corpuscle afferents and is mediated in the spinal cord by adenosine acting through P1‐purinergic receptors. The adenosine‐mediated inhibition of nociceptive neurones by vibration is the result of an inhibitory postsynaptic potential (IPSP) produced by activating a K+ conductance. Adenosine is known to activate K+ currents in a number of different types of cell [Greene and Haas, 1985; Proctor and Dunwiddie, 1987; Segal, 1982; Trussell and Jackson, 1987; Gerber et al. 1989] and it has been reported that in cardiac muscle cells the + channels [Kirsch et al., 1990]. Therefore, we investigated the possibility that these channels might mediate the IPSP we have observed in nociceptive dorsal horn neurones upon vibratory stimulation applied to the skin. We found that the inhibition of nociceptive neurones by this stimulation is abolished by glibenclamide, a blocker of ATP‐sensitive K+ Channels [Ashcroft, 1988; Schmid Antomarchi et al., 1987a,b]. In addition, the IPSP evoked by vibratory stimulation was blocked by direct intracellular injection of AYP. These results suggest that the adenosine‐mediated IPSP in nociceptive spinal neurones results from activating ATP‐sensitive K+ channels in these neurones. As this inhibition of nociceptive dorsal horn neurones may be the physiological basis for the analgesia produced by vibratory stimulation in humans [Bini et al., 1984; Lundeberg, 1984; Lundeberg et al., 1984; Ottoson et al., 1981], We suggest that activation of ATP‐sensitive K+ channels ion nociceptive neurones may mediate this analgesia. A diversity of drugs exists which act on ATP‐sensitive K+ channels and we further suggest that such drugs might be therapeutically useful in enhancing the analgesia produced by vibration or in producing analgesia on their own. © 1993 Wiley‐Liss, Inc.
Opportunistic infections: Treatment and developmental therapeutics of cryptosporidiosis and isosporiasis
Authors: St. Georgiev Vassil
Published: January 2005

Cryptosporidium sp. and Isospora sp. are coccidian protozoans taxonomically related to Toxoplasma gondii and Plasmodium sp. Although associated with many animal species, these pathogens are also the causative agents of cryptosporidiosis and isosporiasis, 2 invasive opportunistic infections in humans. In immunocompetent hosts, the infections are usually self‐limited, flu‐like gastrointestinal disorders which resolve spontaneously. In immunocompromised patients, however, cryptosporidiosis is a severe, debilitating, and prolonged illness, with high morbidity and no known therapy effective against it. Spiramycin has been proven largely ineffective. In recent years, however, the use of immunotherapy is being actively pursued as one potentially useful approach for the treatment of cryptosoporidiosis. Azithromycin, a new macrolide antibiotic, has also shown promise in preclinical studies. In the case of isosporiasis, the combination of trimethoprim and sulphamethoxazole has been found to be effective, although AIDS patients have shown a high rate of relapse and, therefore, the need for suppressive maintenance therapy. © Wiley‐Liss, Inc.
In vitro evaluation of the antiviral activity of SP‐303, an euphorbiaceae shrub extract, against a panel of respiratory viruses
Authors: Wyde Philip R. , Meyerson Laurence R. , Gilbert Brain E.
Published: January 2005

The antiviral dn cytotoxic activity of SP‐303, a naturally occurring polyphenolic polymer (average M.W. = 2,100 daltons) isolated from a Euphorbiaceae shrub, was evaluated in tissue culture. The compound exhibited selective antiviral activity (ratio IC50/EC50 ≥10) against parainfluenza virus type 1, respiratory syncytial virus, influenza A viruses, and influenza B viruses; marginal selective antiviral activity (IC50/EC50 ratio >2 to <10) against parinfluenza virus type 3; and no selective antiviral activity (IC50/EC50 ratio ≤1) against measles virus or adenovirus type 5. Hemagglutination and other studies suggested that SP‐303 may at least partially inactivate virus by direct interaction with virus or host cell lipid membranes. © Wiley‐Liss, Inc.
Transdermal penetration of physostigmine: Effects of oleic acid enhancer
Authors: Meshulam Yacov , Kadar Tamar , Wengier Ada , Dachir Shlomit , Levy Aharon
Published: January 2005

The efficiency of the transdermal penetration of physostigmine through the guinea‐pig skin, in a vehicle containing propionic acid, was studied in the course of developing a transdermal physostigmine pad for the potential treatment of Alzheimer's disease patients. In an attempt to improve drug penetration, the addition of various concentrations of oleic acid(0.5–5%) was tested. The study included histological examination of skin biopsies from application site. The addition of 0.5% oleic acid to the vehicle enhanced the permeation of physostigmine and shortened the time needed to reach steady state levels of blood cholinesterase inhibition, without any damage to the skin. Stable values of physostigmine concentration and of cholinesterase inhibition were measured both in blood and in brain up to 72 h. A high correlation was found between physostigmine concentration in the plasma and cholinesterase inhibition in whole blood samples (r = 0.99 for the values measured up to 48 h). A lower correlation was found between physostigmine concentration and cholinesterase inhibition in the brain (r = 0.57). In a vehicle containing up to 1% oleic acid, physostigmine was stable for at least one month. Oleic acid concentrations higher than 1%, while increasing the flux of the drug through the skin, resulted in considerable skin damage. © Wiley‐Liss, Inc.
Determinants of angiotensin II‐induced hypertrophy versus hyperplasia in vascular smooth muscle
Authors: Owens Gary K.
Published: January 2005

There is clear evidence implicating a role for angiotensin II in control of hypertrophic growth of vascular smooth muscle cells in vivo. However, the specific mechanisms whereby angiotensin II influences smooth muscle cell growth have not been defined. The focus of this mini‐review is to consider how angiotensin II contributes to control of hypertrophic vs. hyperplastic growth of vascular smooth muscle in vivo, and in particular how the differentiated state of the smooth muscle cell may influence growth responsiveness to angiotensin II. © 1993 Wiley‐Liss, Inc.
Endothelin‐1 modulates vascular smooth muscle structure and vasomotion: Implications in cardiovascular pathology
Authors: Ohlstein Eliot H. , Douglas Stephen A.
Published: January 2005

Endothelin‐1 modulates vascular smooth muscle tone by exerting potent vasoconstrictor actions through the ETA receptor subtype located on the membranes of vascular smooth muscle cells. This receptor subtype also mediates the growth‐promoting actions of this peptide in vascular smooth muscle cells. The ETA receptor is distinct, however, from the endothelin receptor subtype located on the endothelium; the anatomically and functionally distinct ETB receptor mediates the release of the endothelium‐derived factor nitric oxide, a labile substance which not only produces potent vasodilation but also possesses anti‐mitogenic activity. This report describes the interaction between these two vasoactive factors in the control of cardiovascular function. Under normal conditions the endothelium serves to modulate the contractile and proliferative actions of endothelin‐1. However, many cardiovascular disorders (e.g., hypertension, atherosclerosis, vascular restenosis, subarachnoid hemorrhage, etc.) are associated with both abnormal endothelial cell function, resulting in an inability to synthesize and/or release nitric oxide, and elevated circulating levels of endothelin‐1. Since the resultant loss/inhibition of nitric oxide will augment both the contractile and proliferative actions of endothelin‐1, this has the potential to promote vasoconstriction and smooth muscle hyperplasia/hypertrophy at the site of any such lesion. Since evidence is accumulating that both endothelin‐1 and nitric oxide play pivotal roles in the control of both vascular smooth muscle tone and growth, any imbalance between these two counter‐regulatory systems is likely to have profound pathological consequences within the cardiovascular system. © 1993 Wiley‐Liss, Inc.
The dilemma of biotechnology
Authors: Sapienza Alice M.
Published: January 2005

The 1988 decision by the U.S. Health Care Financing Administration (HCFA) not to accord special reimbursement treatment to Genentech's tissue plasminogen activator (Activase™) was a signal event in the growing dilemma of biotechnology. In the U.S. (and to a degree in Japan and major Western European nations as well), therapeutic biotechnology investment appears to be on a collision course with health care cost containment efforts. During this time of renewed political interest in pharmaceutical pricing, there is urgent need for dialogue among the affected parties. Otherwise, repercussions of a collision could damage both private and public sector biotechnology innovation. The purpose of this article is to outline the nature of, and clarify the reasons for, the dilemma of biotechnology. ©1993 Wiley‐Liss, Inc.
Effect of a novel monamine oxidase‐a inhibitor, bw 1370U87, on urinary 3‐methoxy‐4‐hydroxyphenylglycol in normal volunteers
Authors: Hedeen Kevin M. , White Helen L. , Cooper Barrett R. , Conner Gary W. , Norton Ronald M.
Published: January 2005

Urinary 3‐methoxy‐4‐hydroxyphenlglycol (MHPG) levels were measured in 14 normal volunteers during a Phase I study of the novel, reversible monoamine oxidase‐A (MAO‐A) inhibitor BW 1370U87 targeted for the treatment of depression. baseline MHPG excretion (day 0) showed a significant diurnal increase (n = 14, P < 0.05) between 1200 and 2000 h. Oral administration of BW 1370U87 produced significant (35‐45% maximal, P < 0.05) decreases from these basal levels during the same 1200‐2000 h time interval Twenty‐four hours after the dose (dose was given at 0800 h), urinary MHPG levels returned to baseline, consistent with a reversible mechanism of inhibition by BW 1370U87. Decreases in urinary MHPG did not appear to be dose‐dependent between 200‐800 mg BW 1370U87 per day, suggesting that maximal MAO‐A inhibition was achieved at the 200 mg dose. These effects on MHPG excretion may be helpful in predicting the efficacy of BW 1371370U87 in the treatment of depression. © 1993 wiley‐Liss, Inc.
Effect of mannitol treatment on soman‐induced brain and heart lesions in the rat
Authors: Filbert Margaret G. , Dochterman Leland W. , Smith Catherine D. , Forster Jeffry S. , Phann Sorabe , Cann Frank J.
Published: January 2005

The effect of intravenous mannitol on soman‐induced neuropathology and cardio‐myopathy was studied in rats. Soman, an organophosphorus agent, irreversibly inhibits total body acetylcholinesterase and induces a cholinototoxic syndrome in rats which results in the development of sezures, brain damage, and degenerative cardiomyopathy. The severity of the cardiomyopathy parallels the severity of the neuropathology. When mannitol at a dose of 1.5 g/kg was administered at the onset of sezures and followed by a second dose 5 h later, there was a significant increase in 24 h survival. Moreover, the severity of brain lesions was reduced in the piriform cortex, thalamus, amygdala, and the caudate putamen. The same treatment schedule also provided almost complete protection against the concomitant development of degenerative cardiomyopathy. The finding that the mannitol treatments reduced both the severity of the neuropathology and the degenerative cardiomyopathy reinforces the concept of a possible central neurogenic mechanism for the development of the cardiomyopathy. These results suggest that mannitol may be useful to reduce the severity of sezure‐related neuropathology and to provide additional protection to other vital organs which may be secondarily susceptible to neurogenically mediatd pathologic change, such as the heart in rats which develop cardiomyopathy following soman‐induced seizures. © 1993 wiley‐Liss, Inc.
Transient agonist‐like action of the thromboxane A2 receptor antagonist S‐1452 (d‐s‐145 Ca) and its reduction by gradual injection or oral administration
Authors: Asanuma Fujio , Jyoyama Hirokuni , Kurosawa Atsushi
Published: January 2005

The thromboxane A2 receptor antagonist S‐1452, d‐S‐145 Ca, calcium 5(Z)‐1R,2S,3S,4S‐7‐[3‐phenylsulfonylaminobicyclo[2.2.1]hept‐2‐yl]‐5‐heptenoate dihydrate, is a partial agonist and transiently alters platelet shape and smooth muscle contraction in vitro [Hanasaki et al., Biochem Pharmacol 38:2007‐20017, 1989; Otani et al.: Folia Pharmacol Jpn 94:319‐328, 1989: Kakushi et al.: Folia Pharmacol Jpn 98:113‐120, 1991]. A water soluble preparation of the compound d‐S‐145 Na caused transient apnea in mice by a bolus injection through the tail vein. This agonistic effect was seen in the dose range similar to that observed for TXA2 antagonism, which was evaluated as a preventive activity of U46619‐induced sudden death [ED50: 55 μg/kg, iv, for the apnea appearance and 15 μg/kg, iv, for prevention of the U46619‐induced sudden death]. The agonistic and antagonistic effects of d‐S‐145 Na were more marked than those of the l‐enantiomer, 1‐S‐145 Na. d‐S‐145 Na was also agonistic in guinea pigs. Bolus injection through the jugular vein at doses above 10 μg/kg of d‐S‐145 Na caused a transient increase in airway resistance. However, the response disappeared completely or was markedly reduced by gradual injection of the compound at the same dose. The gradual injection of d‐S‐145 Na did not cause a marked alteration in the TXA2 antagonistic activity, which was evaluated as a prevention of U46619‐induced increase in airway resistance. The separation of the agonistic and antagonistic effects of S‐1452 was much more remarkable in dosing S‐1452 through an oral route. In conclusion, the intrinsic agonistic action of S‐1452 can be reduced significantly by gradual injection or oral administration of the compound, without severe reduction of the antagonistic activity against TXA2. © 1993 wiley‐Liss, Inc.
Surviving as a niche player in the pharmaceutical industry: Reflections from the field
Authors: Jorgensen Stig , Jensen Ivan , Edwards Martin
Published: January 2005

The pharmaceutical industry can be divided into a top tier of about 30 major league companies and a second tier (minor league) comprising several thousand. This paper focused on the second tier and the particular challenge of minor league companies—especially niche players—to balance operating requirements and strategic ambitions within limited and limiting resources. In the authors' experience, survival as a niche player requires not only that the company stays on the technology frontier but also that risk willingness and innovative behavior be characteristic of managers' mindset. To this end, the authors share 13 “ground rules” to perform appropriately as a niche player. © 1993 wiley‐Liss, Inc.
Serotonin mechanisms in alcohol drinking behavior
Authors: McBride William J. , Murphy James M. , Yoshimoto Kanji , Lumeng Lawrence , Li Ting‐Kai
Published: January 2005

Rat lines selectively bred for disparate alcohol‐drinking behaviors exhibit innate differences in the contents of serotonin (5‐HT) in several CNS limbic regions, e.g., nucleus accumbens (ACB), frontal cortex, hypothalamus, and olfactory tubercles. In these regions, the selectively bred alcohol‐preferring (P) line has levels approximately 20% (P > 0.05) lower than values obtained for the alcohol‐nonpreferring (NP) line. In addition, in some limbic regions, the densities of (1) 5‐HT1A receptors are higher by approximately 30% and (2) 5‐HT1B and 5‐HT2 receptors are lower (by 25‐40%) in the P than in the NP line. systemic administration of agents that increase synaptic levels of 5‐HT, such as fluoxetine (a 5‐HT uptake inhibitor), d‐fenfluramine (a 5‐HT releaser) and D, L‐5‐hydroxytryptophan (an immediate precursor of 5‐HT), significantly decreased alcohol consumption of the P line of rats. Systemic (1.0 and 2.0 g/kg ip) administration or local perfusion (100 mM) of ethanol significantly increased the extracellular levels of 5‐HT in the ACB of unselected Wistar rats. An interaction of the dorsal raphe nucleus (DRN) 5‐HT system with the ventral tegmental area (VTA) dopamine (DA) pathway projecting to the ACB was indicated by the findings that DA release in the ACB increased and decreased following stimulation and inhibition, respectively, of DRN 5‐HT neurons. Moreover, an involvement of 5‐HT in mediating alcohol‐stimulated DA release in the ACB is indicated by the observation that local application of a 5‐HT3 antagonist can attenuate this stimulated release. Overall, the data suggest that an innate 5‐HT deficiency in certain limbic structures of the P rat may be a major neurobiological factor underlying their high alcohol drinking characteristics. © 1993 wiley‐Liss, Inc.
Tretinoin: A review of in vivo pharmacological studies
Authors: Cohen Marvin
Published: January 2005

Tretinoin (all‐trans‐retinoic acid), a metabolite of retinol, has shown efficacy in the treatment of acute promyelocytic leukemia. Preclinical studies in rodents indicated that tretinoin inhibited or prevented chemically‐induced skin papillomas or carcinomas. However, tretinoin had no effect on several types of transplantable tumors. Studies of tretinoin's pharmacodynamic profile indicated a lack of central nervous system or cardiovascular activity. Effects of tretinoin on the immune system were dependent on the animal model employed, both enhancement and suppression being reported. Tretinoin appeared to increase serum triglycerides and lower serum as well as liver cholesterol levels. Additional preclinical studies are needed to establish minimal effective doses and quantitation of the time course of changes induced by this retinoid. © 1993 wiley‐Liss, Inc.
In vivo agonist properties of 7‐hydroxy‐N,N‐di‐n‐propyl‐2‐aminotetralin, a dopamine D3‐selective receptor ligand
Authors: McElroy John , Zeller Kim , Amy Kelly , Ward Kathryn , Cawley James , Mazzola Amie , Keim William , Rohrbach Kenneth
Published: January 2005

The selective dopamine D3 receptor ligand 7‐hydroxy‐N,N‐di‐n‐propyl‐2‐aminotetralin (7‐OH‐DPAT) produced stereotypical sniffing and climbing, increased locomotor activity, and caused 6‐hydroxydopamine‐lesioned animals to rotate in a contralateral direction, behavioral effects highly predictive of dopamine agonist activity. In contrast, 7‐OH‐DPAT was inactive in the conditioned avoidance response, catalepsy, and anti‐apomorphine test, animal models highly predictive of dopamine antagonist activity. These results indicate that 7‐OH‐DPAT is an agonist at dopamine receptors in vivo. © 1993 wiley‐Liss, Inc.
Antagonism of diazepam's anticonflict effects in rats by nicotine, but not by arecoline
Authors: Porter Joseph H. , Heath Gregory F. , Rosecrans John A.
Published: January 2005

The purpose of the present study was to determine the possible role of cholinergic mechanisms in the anticonflict effects of the anxiolytic diazepam. Male Sprague‐Dawley rats were tested with a modified Geller‐Seifter procedure using a multiple reinforcement schedule in which unpunished responding in one component was reinforced according to a fixed‐interval 60‐sec schedule, and punished responding in the other component resulted in both food and a brief electric shock presentation according to a fixed‐ratio 1 schedule. In Experiment 1 (−)‐nicotine antagonized the increase in punished responding that was produced by diazepam. In Experiment 2 diazepam produced selective increases in punished responding that again was antagonized by (−)‐nicotine, a nicotinic cholinergic agonist, whereas arecoline, a muscarinic cholinergic agonist, did not antagonize diazepam's increase in punished responding. Neither drug produced any significant changes in unpunished responding. In Experiment 3 it was shown that the centrally acting nicotinic antagonist, mecamylamine, was able to block nicotine's antagonism of diazepam. These results suggest that there is an interaction between central nicotinic cholinergic mechanisms and diazepam's anticonflict effects in this animal model for anxiolytics, and support clinical observations that smoking can reduce some effects of benzodiazepines. © 1994 Wiley‐Liss, Inc.
Structure‐activity studies of N,N‐dialkyl and cycloalkyl carbamate esters of dimethylethanolamine and choline with nicotinic and muscarinic cholinergic properties
Authors: Saraswati Manda , Lerner‐Marmarosh Nicole , Wang David X. , Sheu Shey‐Shing , Sharma Viranda , Abood Leo G.
Published: January 2005

Structure‐activity studies were performed on a series of newly synthesized N‐sub‐stituted carbamate esters of choline and dimethylethanolamine which exhibited either or both nicotinic and muscarinic cholinergic properties. Substitutions on the carbamyl N consisted of varying lengths of dialkyls, diphenyl, and various heterocycles. The compounds were evaluated for their nicotinic and muscarinic receptor binding properties in rat brain membranes, their effect on muscarinic receptor‐activated phosphoinositide (PI) turnover in rat cortical slices, and for muscarinic receptor‐mediated intracelluar Ca release in a mouse adrenal carcinoma cell line transfected with an m1 muscarinic cholinergic receptor gene. N,N‐diethylcarbamylcholine had the highest affinity for nicotinic cholinergic receptors; the Ki value of 1 × 10−9 M approached that of nicotine and being 1/5 that for the dimethyl analogue. With increasing chain length of the dialkyl substituents the nicotinic affinity progressively decreased, while muscarinic affinity increased. N,N‐diphenylcarbamylcholine had a Ki value of 1 × 10−7 M for nicotinic receptors and exhibited nicotinic antagonist activity. Contrary to the results with [3H]‐N‐methylcarbamylcholine binding, the tertiary derivatives exhibited higher Ki values for [3H]‐3‐quinuclidinyl benzilate binding than the quarternaries; the tertiary dibutyl and diphenyl had the highest affinities with Ki values of 4 × 10−7 M. The inhibition of muscarinic receptor‐mediated PI turnover and release of intracellular calcium were related to the muscarinic antagonist potency of the compounds. © 1994 Wiley‐Liss, Inc.
Antidiabetic and antiobesity effects of a highly selective β3‐adrenoceptor agonist (CL 316,243)
Authors: Largis Elwood E. , Burns Michael G. , Muenkel Helen A. , Dolan Jo Alene , Claus Thomas H.
Published: January 2005

A third β‐adrenoceptor subtype has been cloned form the rat, mouse, and human genomes. The presence of these receptors primarily on adipose tissue has raised the possibility that β3‐adrenoceptor selective agonists may be useful antiobesity agents. CL 316,243 is a highly selective β3‐agonist; it has a <30,000 to 1 β3‐to‐β1‐adrenoceptor selectivity ratio and a 10,000 to 1 β3‐to‐β2‐adrenoceptor selectivity ratio in in vitro functional assays. In vivo, animals were treated with CL 314,698, a diester prodrug of CL 316,243, which is rapidly converted to CL 316,243. In obese (ob/ob) and diabetic (db/db) mice, treatment with CL 314,698 reduced their hyperglycemia to the euglycemia of their lean littermates, and decreased plasma insulin levels. In obese mice, the compound also caused decreased weight gain despite increased food consumption, and the decreased weight was due to loss of fat while lean body mass was spared. CL 314,698 treatment also improved both glucose and insulin tolerance in obese mice, suggesting that it decreased insulin resistance. CL 314,698 also prevented further weight gain, without affecting food consumption, in rats previously made obese by feeding a high fat diet. The compound reduced plasma insulin and triglyceride levels, and reduced fat pad weights, while having no effect on plasma glucose, cholesterol, thyroxine, or T3 levels or on skeletal muscle weight. Decreased weight gain without decreased food consumption suggested that CL 316,243 stimulated thermogenesis. Treatment of obese mice for 3 weeks with CL 316,243 increased thermogenesis by 45% as measured by indirect calorimetry. Thus, CL 316,243 is a potent, β3‐adrenoceptor selective agonist with thermogenic, antidiabetic, and antiobesity properties in several models of non‐insulin dependent diabetes and obesity.
Developmental aspects of the Adipose tissue renin‐angiotensin system: Therapeutic implications
Authors: Crandall David L. , Herzlinger Helen E. , Saunders Brian D. , Kral John G.
Published: January 2005

Adipose tissue possesses considerable growth potential, and excess adipose tissue mass is associated with noninsulin dependent diabetes mellitus (NIDDM). Adipose tissue is a significant source of angiotensinogen, the precursor of angiotensin II (All), a vasoactive peptide with in vitro mitogenic effects. The renin‐angiotensin system remains only partially identified in adipose tissue, however, and knowledge of whether All has a physiologic role in this tissue is dependent in part upon other components of the system being characterized. We have chosen to further investigate aspects of the renin‐angiotensin system in separate adipose tissue depots of rats during growth and development of the tissue. Either epididymal or retroperitoneal adipose tissue was examined in young lean, or adult obese male Sprague‐Dawley rats. Adipose tissue was subjected to collagenase digestion, yielding separate vascular and fat cell fractions. Each fraction was analyzed for angiotensin converting enzyme (ACE) activity and All receptor binding capacity. ACE activity was significantly greater when expressed per gram of adipose tissue in the young lean rats. Vascular and fat cell fractions exhibited All receptors of high affinity, with a greater density of receptors observed in the epididymal adipose tissue fractions. Incubation of adipocytes with exogenous All was associated with the release of prostaglandin into the medium, and analyses of adipocyte cytosol indicated the presence of angiotensinogen. Growing rats given oral losartan, an All receptor antagonist, once daily (15 mg/kg) for 2 weeks exhibited reductions in body weight gain, fat mass, fat cell volume, and All receptor number. These data further document the presence of a peripheral renin‐angiotensin system in anatomically distinct adipose tissue depots at different stages of growth. While the characterization of the effects of All upon adipose tissue development remains incomplete, future investigations with agents affecting the adipocyte renin‐angiotensin system could provide additional information on the role of this system in adipose tissue growth.
Effect of glycosides of Streblus asper on motility, glucose uptake, and certain enzymes of carbohydrate metabolism of Setaria cervi
Authors: Singh Som N. , Chatterjee Ranjit K. , Srivastava Arvind K.
Published: January 2005

The in vitro effects of two pure glycosides, i.e., asperoside (K029) and strebloside (K030) isolated from a traditionally used medicinal plant Streblus asper on the bovine filarial parasite Setaria cervi females were studied. Both K029 and K030 caused death of the worms within 2 to 3 hours at concentrations of 10 μg/ml (1.7 pmoles) and were found to inhibit motility and glucose uptake of the parasites at lower concentrations (0.1 μg/ml; 0.17 pmoles). These glycosides also inhibited the incorporation of [U‐14]C‐glucose into macromolecules of S. cervi females. Parasites preincubated with either K029 or K030 had lowered profiles of glucokinase (EC 2.7.1.2), malate dehydrogenase (EC 1.1.1.37) and succinate dehydrogenase (EC 1.3.99.1) activities, suggesting that the lethal effects of the glycosides were due to effects on glucose metabolism.
Interrelationship of general pharmacology studies with drug discovery and development, clinical medicine, and regulatory affairs
Authors: Fossa Anthony A. , Allan Buchholz R.
Published: January 2005

General Pharmacology/Safety Pharmacology studies are being used increasingly to support registration of clinical drug candidates. The value of these studies and the possible impact on the drug discovery and development processes is being recognized as evidenced by the increasing number of companies implementing formal General Pharmacology/Safety Pharmacology groups. The interactions of other departments such as Discovery, Drug Metabolism, Toxicology, Clinical Medicine, and Regulatory Affairs with General Pharmacology are highly dependent on the positioning within the particular organization and the goals set for General Pharmacology studies. The nature of these interactions and how they can be used to the advantage of drug discovery and development programs are discussed.
General pharmacology, the international regulatory environment, and harmonization of guidelines
Authors: Lumley Cynthia E.
Published: January 2005

The performance of general pharmacology procedures on new drug candidates supports both drug discovery and safety assessment activities; however, the potential contribution of general pharmacology to safety assessment has had less attention than other aspects of non‐clinical testing. Pharmaceutical companies are divided as to whether or not general pharmacology is integrated with the rest of toxicology testing or carried out as part of the discovery program, and, recently, discussions have taken place within Europe as to whether or not these studies should be subject to Good Laboratory Practice (GLP) conditions. All three regions (the United States, Europe, and Japan) require data on the pharmacological properties of new drugs to be included in a marketing application. This should cover primary and secondary pharmacological effects, and should provide information concerning potential adverse reactions. In addition, Europe and the United States request non‐clinical data on potential drug interactions. However, the most detailed requirements are described in the Japanese guidelines. This paper reviews the current regulatory environment in the European Community (EC), Japan, and the United States, highlighting some general features of the three regulatory systems which are relevant to general pharmacology, and summarising the specific guidelines for these studies in the three regions. Although there are significant differences between the detailed Japanese general pharmacology requirements and the more flexible Western approach, it is not clear that it is appropriate to include general pharmacology within the international harmonization discussions. Rather, deregulation in this area is a desirable goal for the future.
In vitro screens and functional assays to assess receptor pharmacology
Authors: Sills Matthew A.
Published: January 2005

In the drug discovery process, compounds that demonstrate therapeutic potential must be free of undesirable side effects in order to reach the clinic. Compounds that interact with more than one target, such as a receptor, have the potential to elicit side effects, in comparison to those compounds that are selective for a single target. One predictive measure of whether a compound demonstrates specificity is to profile a compound's activity through a series of receptor binding assays in what is termed a safety screen. If a compound demonstrates activity, further studies are subsequently performed in functional assays in order to determine whether the compound possesses agonist or antagonist activity at that receptor. This article discusses some of the basic tenets of receptor pharmacology and their application to safety assessment.
Thrombolytic activity of YM866, a novel modified tissue‐type plasminogen activator, in a rabbit model of jugular vein thrombosis
Authors: Kawasaki Tomihisa , Kaku Seiji , Sakai Yumiko , Takenaka Toichi
Published: January 2005

The thrombolytic activity of a novel modified t‐PA analog, YM866, was compared with that of recombinant t‐PA (t‐PA) in rabbits with experimental jugular vein thrombosis. Thrombus was induced in an isolated segment of the jugular vein from a mixture of whole autologous blood and thrombin. Thirty minutes after the induction of thrombus, YM866 was administered by iv bolus injection, while t‐PA was given by the same method or by a 60‐min iv infusion. Thrombi were removed 70 min after iv bolus injection or 10 min after the termination of iv infusion, and thrombus size was measured by total protein content in the isolated thrombus. Both YM866 and t‐PA exhibited dose‐dependent thrombolysis; the thrombolytic activity of YM866, however, was 4 times greater than that of t‐PA. The improved thrombolytic activity of YM866 correlated with its relatively higher antigen levels in plasma, which result from its prolonged biological half‐life. Depletion of plasma fibrinogen to less than 20% of baseline levels was observed in all groups. Template bleeding time was not significantly altered in any group. These results suggest that YM866 offers the potential for clinical use in thrombolytic therapy by iv bolus injection for patients with venous thromboembolic diseases. © 1994 Wiley‐Liss, Inc.
Sub‐library composition of peptide libraries: Potential application in screening
Authors: Furka ÁrpáD
Published: January 2005

Peptide sub‐libraries and omission sub‐libraries derived from parent peptide libraries synthesized with the portioning‐mixing method are defined. They can be distinguished by their order, i.e., the number of non‐varied positions or omission positions in the molecules. The number of types of sub‐libraries as well as the number of their components depend on both the order and the number of residues. Sub‐libraries belonging to a given residue number and a given order altogether form a kit. The paper outlines the potential use of sub‐libraries and other kinds of partial libraries in identification of the bioactive components of peptide and other kinds of biooligomer libraries. © 1994 Wiley‐Less, Inc.
Dopamine uptake inhibitory activity of novel tryptamine 5‐HT1 receptor ligands
Authors: Lebel Lorraine A. , Nowakowski Jolanta T. , Macor John E. , Fox Carol B. , Kenneth Koe B.
Published: January 2005

In the search for novel serotonin receptor ligands, a series of 5‐thiazolyl‐N,N‐dimethyltryptamine derivatives was synthesized which exhibited high affinity binding to 5‐HT1A, 5‐HT1B, and 5‐HT1D receptors and the functional characteristics of receptor agonists. One member, 5‐(4‐anilnomethyl‐2‐thiazolyl)‐N,N‐dimethyltryptamine (CP‐110,330), was found also to be a potent and selective inhibitor of dopamine uptake in rat striatal synaptosomes. This activity was confirmed by its potent displacement of [3H]N(1‐[2‐benzo(b)thiophenyl]cyclohexyl piperidine (BTCP) binding to the dopamine transporter in striatal membranes. A limited structure‐activity study indicated that optimal dopamine uptake blocking activity was obtained when the thiazole C4 substituent consisted of phenyl with a 2‐atom spacer. The potent effect of these 5‐HT1 receptor ligands on dopamine uptake can be rationalized by the observation that the flexibility of these tryptamine molecules allows the superimposition of the phenyl ring and amino group of the side chain with the corresponding moieties of tametraline, a known catecholamine uptake inhibitor of fixed conformation. A related compound, 3‐(R‐N‐methyl‐2‐pyrrolidinylmethyl)‐5‐(4‐benzyl‐2‐thiazolylamino)‐1H‐indole (CP‐146,662) showed similar potent binding affinity to 5‐HT1 receptors and the dopamine transporter. Compounds with this dual serotonergic and dopaminergic activity may have utility as antidepressant agents. As potent dopamine uptake inhibitors, they may also have application in the treatment of cocaine addiction. © 1994 Wiley‐Liss, Inc.
Inhibition of gastric mucosal damage by santonin pretreatment in rats
Authors: Al‐Harbi Mohammed M. , Qureshi Shoeb , Ahmed Mohammad M. , Raza Muhammad , Miana Ghulam A. , Afzal Mohammad , Shah Arif H.
Published: January 2005

The effect of santonin pretreatment on gastric mucosal injuries caused by 80% ethanol, 25% NaCl, 0.2 M NaOH, indomethacin, and combined treatment of ethanol and indomethacin was investigated in rats. The effects caused by ethanol on gastric mucus secretion, gastric levels of non‐protein sulfhydryl groups, and malondialdehyde and histopathological effects were also investigated. Santonin pretreatment at oral doses of 30, 60, and 120 mg/kg (121.8, 243.6, and 487.2 μmol/kg) provided a dose‐dependent protection against the ulcerogenic effects of different necrotising agents used. Further pretreatment with santonin afforded a dose‐dependent inhibition of ethanol‐induced depletion of stomach wall mucus, proteins, nucleic acids, non‐protein sulfhydryl groups, and an increase in malondialdehyde levels in gastric tissue. The histopathological lesions induced by ethanol in the gastric mucosa were also protected by santonin pretreatment. The protective effect of santonin against alcohol damage to the gastric‐wall mucosa may be mediated through its effects on mucus production, nucleic acids, and non‐protein sulfhydryl generation and its free‐radical scavenging. © Wiley‐Liss, Inc.
Ras farnesylation as a target for novel antitumor agents: Potent and selective farnesyl diphosphate analog inhibitors of farnesyltransferase
Authors: Manne Veeraswamy , Ricca Carolyn S. , Brown Johnni Gullo , Tuomari Anne V. , Yan Ning , Patel Dinesh , Schmidt Robert , Lynch Mark J. , Ciosek Carl P. , Carboni Joan M. , Robinson Simon , Gordon Eric M. , Barbacid Mariano , Seizinger Bernd R. , Biller Scott A.
Published: January 2005

Protein prenylation is increasingly recognized as an important mechanism by which functional association of proteins to membranes is mediated. Ras proteins, regulators of cell proliferation and differentiation, are among the proteins that undergo farnesylation, one of the two prenylation modifications known. Since ras proteins are activated into hyperactive oncogenic versions in a wide variety of human cancers, agents that down modulate ras activity could be antineoplastic. Therefore, inhibitors of farnesyltransferase have the potential to be of therapeutic value as anticancer agents due to their ability to block ras processing and hence its function. We describe the identification of two farnesyl pyrophosphate (FPP) analogs that are potent and selective inhibitors of farnesyltransferase. While showing no toxicity to untransformed cells, a pivaloyloxymethyl ester of one of these inhibitors blocked ras mediated transformation of NIH 3T3 cells. In addition, both the ester and its parent acid inhibited ras farnesylation as measured by incorporation of labeled mevalonate into ras proteins in whole cells. Thus, this is the first report of an FPP analog to show biological activity by inhibiting ras processing in whole cells. © 1995 Wiley‐Liss, Inc.