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At least 1,099 records · Page 61Linked to original sources
PubMed2006

Pharmacological characterization of psychosis-like behavior in the MPTP-lesioned nonhuman primate model of Parkinson's disease.

Investigation of the pathophysiology of psychosis in Parkinson's disease (PD), as well as the assessment of potential novel therapeutics, has been limited by the lack of a well-validated animal model. MPTP-lesioned primates exhibit abnormal behaviors that are distinct from dyskinesia and parkinsonism and may represent behavioral correlates of neural processes related to psychosis in PD. Here we assess four types of behavior--agitation, hallucinatory-like responses to nonapparent stimuli, obsessive grooming, and stereotypies that are termed "psychosis-like"--and define their pharmacology using a psychosis-like behavior rating scale. By assessing the actions of drugs known to enhance or attenuate psychosis in PD patients, we find that the pharmacology of these behaviors recapitulates, in several respects, the pharmacology of psychosis in PD. Thus, levodopa and apomorphine elicited psychosis-like behaviors. Amantadine significantly decreased levodopa-induced dyskinesia but exacerbated psychosis-like behaviors. Haloperidol reduced psychosis-like behaviors but at the expense of increased parkinsonian disability while the atypical neuroleptics clozapine and quetiapine reduced psychosis-like behaviors without significant effect on parkinsonian disability. The response of different components of the psychotomimetic behavior suggested the involvement of both dopaminergic and nondopaminergic mechanisms in their expression.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

Review of postoperative pharmacological infusions in ischemic skin flaps.

No single drug has yet been found which can overcome the inflammatory and microvascular changes which occur in a skin flap after ischemia-reperfusion. Nevertheless, the continued failure of approximately 7% of all free flap transfers clinically suggests that there may be a place for pharmacological intervention at the time of threatened flap failure. To date, plastic and reconstructive microsurgeons have been reluctant to use drugs because of the mass of conflicting evidence emanating from the plastic surgery literature. However, scientists and surgeons now have a clearer understanding of the problems arising in ischemia-reperfusion. Multi-acting drugs which can inhibit most of the important inflammatory changes would be the ideal. This review considers some of the historical developments in the pharmacological treatment of ischemic flaps in the past decade and looks to the future when pharmacological infusions may be part of the routine for salvaging failing skin flaps.

Adenosine Triphosphate↗
PubMed2005

Measuring the contribution of pharmacological treatment to advice to stay active in patients with subacute low-back pain: a randomised controlled trial.

PURPOSE: In clinical guidelines for acute and subacute low-back pain, pharmacological treatment is recommended for short-term symptomatic relief. The objective was to study the effect of the guidelines' advise to remain active, alone and with the addition of the drug adenosine tri-phosphate (ATP), in patients with subacute low-back pain. METHODS: A drug-guidelines effectiveness trial was undertaken simultaneously to an experimental drug efficacy placebo controlled trial in subacute (4-12 weeks) non-specific low-back pain patients. The 132 participating primary care physicians across France were randomised to participate to either trial. In the drug-guidelines trial, all physicians received a quick consultation card containing the key elements of the clinical guidelines and a brochure that gave their patients practical tips to remain active. Patients were then randomised to receive Atepadene, containing 90 mg of ATP by mouth daily for 30 days (guidelines plus ATP group), or nothing beside the rescue drug that was made available to all patients (guidelines alone group). The principal outcome was functional improvement on the Roland-Morris Disability Questionnaire (RDQ) at 90 days. RESULTS: In the drug-guidelines effectiveness trial, 157 patients were randomised. The rate of improvement in the RDQ over the 90 days of follow-up was superior in the group guidelines plus ATP (8.3 points, 95% confidence interval (CI): 7.3-9.3) than in the group guidelines alone (6.5 points, 95%CI: 5.3-7.7) (p = 0.02). In terms of probability of improving between two to five points on the RDQ at 90 days this difference translated in a 2 to 13 times higher probability compared to the group guidelines alone (odds ratios ranging from 2.1, 95%CI: 0.9-5.0 to 12.9, 95%CI: 1.6-103.4). Patients in the group guidelines plus ATP were also three times less likely to report a condition that had worsened or remained unimproved at 90 days (p = 0.02). CONCLUSION: This drug-guidelines effectiveness trial showed a modest advantage of combined specific pharmacologic and non-pharmacological treatments on absolute improvement on the RDQ. A threefold reduction in the risk of chronicity was observed, an important goal in low-back pain guidelines.

Adenosine Triphosphate↗
PubMed2003

Ionic and pharmacologic characteristics of epithelial cells in a semi-intact preparation of the rat ventral prostate gland.

BACKGROUND: The essential ionic and pharmacologic characteristics of epithelial cells within the ducts of the prostate gland are not well known. METHODS: Experiments were carried out on segments of ventral prostate glands from adult male rats. By using sharp microelectrodes, intracellular epithelial cell and transepithelial (lumen) potentials were recorded in response to ionic substitution and application of ion channel blockers, hormones, and other pharmacologic agents related to prostatic function. RESULTS: Membrane permeabilities to K(+), Na(+), and Cl(-) were found to account for approximately 43% of the resting membrane potential, whereas some 39% was likely to be metabolic in origin. The membrane potential also responded to adrenaline, acetylcholine, insulin, prolactin, testosterone, nerve growth factor, and nitric oxide. The lumen potential was found to be particularly sensitive to citrate, prolactin, and testosterone. CONCLUSION: It was concluded that the basal membrane potential of prostatic epithelial cells is associated with a relatively high Na(+):K(+) permeability ratio and metabolic dependence. The hormonal and pharmacologic sensitivity observed is consistent with the functional characteristics of the prostate gland.

Animals↗
PubMed2005

Phytochemical, pharmacological and toxicological aspects of Hibiscus sabdariffa L.: a review.

This article reviews the reported phytochemical, pharmacological and toxicological properties of Hibiscus sabdariffa L. (English: roselle, red sorrel; Arabic: karkade), the calyces of which are used in many parts of the world to make cold and hot drinks. Nutritionally, these contain ascorbic acid (vitamin C). In folk medicine, the calyx extracts are used for the treatment of several complaints, including high blood pressure, liver diseases and fever. The pharmacological actions of the calyx extracts include strong in vitro and in vivo antioxidant activity. In rats and rabbits, the extract showed antihypercholesterolaemic, antinociceptive and antipyretic, but not antiinflammatory activities. In rat and man a strong antihypertensive action has been demonstrated. The effects of the calyx extracts on smooth muscles in vitro are variable, but they mostly inhibit the tone of the isolated muscles. In healthy men, consumption of H. sabdariffa has resulted in significant decreases in the urinary concentrations of creatinine, uric acid, citrate, tartrate, calcium, sodium, potassium and phosphate, but not oxalate. Oil extracted from the plant's seeds has been shown to have an inhibitory effect on some bacteria and fungi in vitro. The plant extracts are characterized by a very low degree of toxicity. The LD50 of H. sabdariffa calyx extract in rats was found to be above 5000 mg/kg. A single report has suggested that excessive doses for relatively long periods could have a deleterious effect on the testes of rats. In view of its reported nutritional and pharmacological properties and relative safety, H. sabdariffa and compounds isolated from it (for example, anthocyanins and Hibiscus protocatechuic acid) could be a source of therapeutically useful products.

Animals↗
PubMed2007

Phytochemical, pharmacological and ethnobotanical studies of Rhazya stricta Decne.

Rhazya stricta Decne. is an important medicinal species that is rich in alkaloids containing anticancer alkaloids also. This paper reviews phytochemical, pharmacological and ethnobotanical studies of R. stricta. Phytochemical and pharmacological aspects of the species have been thoroughly explored. Over 100 alkaloids have been isolated from R. stricta, but the pharmacological activities are known for only a few of these compounds. Very few ethnobotanical studies of R. stricta have been done, and there is a particular need for such studies in various regions of South Asia and in Middle Eastern countries where the species grows. These ethnobotanical studies should investigate herbal recipes of R. stricta and their use for curing diseases. The genetic diversity, chemotaxonomy and allelopathy of R. stricta have not yet been explored, and these studies are recommended, with the ultimate goal of benefiting local communities in regions where R. stricta grows. This should be achieved by sharing knowledge and through the manufacture of herbal drugs from R. stricta's active chemical constituents, while protecting intellectual property rights and following the World Health Organization's guidelines for safety and efficacy.

Animals↗
PubMed1995

Distinct pharmacological regulation of evoked dopamine efflux in the amygdala and striatum of the rat in vivo.

The pharmacological regulation of evoked extracellular dopamine was compared in the basolateral amygdaloid nucleus (BAN) and caudate-putamen (CP) of the urethane-anesthetized rat. The effects of drugs, which alter dopamine uptake, release or degradation, were examined. Dopamine efflux was elicited by electrical stimulation of ascending dopamine fibers and was monitored by fast-scan cyclic voltammetry at Nafion-coated, carbon-fiber microelectrodes. Dopamine uptake inhibitors, nomifensine (25 mg/kg) and cocaine (20 mg/kg), and the dopamine receptor antagonist, haloperidol (0.5 mg/kg), robustly increased evoked extracellular dopamine in the CP. In sharp contrast, these drugs were much less effective in the BAN. The relative potencies of the uptake inhibitors varied between the two regions. Nomifensine was more potent than cocaine in the CP, whereas cocaine was more potent that nomifensine in the BAN. The monoamine oxidase inhibitor, pargyline (75 mg/kg), and the catechol-O-methyltransferase (COMT) inhibitor, Ro 40-7592 (40 mg/kg), had small or negligible effects in either region. No electrochemical evidence was found for the formation of 3-methoxytyramine, the dopamine metabolite formed by the action of COMT on released dopamine, on the time scale of the measurements in control or after pharmacological manipulation of the degradative enzymes for dopamine. The conclusions reached are: (1) potent mechanisms for uptake and autoreceptor inhibition of release, which exist in the CP to tightly control the concentration of extracellular dopamine, are considerably weaker in the BAN; (2) the extracellular clearance of evoked dopamine in the BAN and CP is the result of cellular uptake and not degradation; and (3) these results support the view that the pharmacological regulation of extracellular dopamine is regionally distinct in the brain.

Amygdala↗
PubMed2001

[(3)H]-serotonin release from bovine iris-ciliary body: pharmacology of prejunctional serotonin (5-HT(7)) autoreceptors.

In the present study, we investigated the pharmacological characteristics of electrically stimulated [(3)H]-serotonin release from mammalian iris-ciliary bodies. Isolated bovine and human iris-ciliary bodies were loaded with [(3)H]-serotonin, superfused with Krebs buffer solution and then stimulated with trains of 300 direct current (d.c.) pulses to initiate the release of the transmitter. The modification of this [(3)H]-serotonin release process by various serotonergic agonists and antagonists was studied in order to define the pharmacology of serotonin receptor(s) present in the iris-ciliary body. In bovine iris-ciliary body, electrically-evoked [(3)H]-serotonin release was calcium-dependent, tetrodotoxin-sensitive and was enhanced by serotonin (EC(50) = 200 n M) and 5-carboxmidotryptamine (EC(50) = 4 n M). The rank order of potency of agonists in enhancing field-stimulated [(3)H]-serotonin release was: 5-carboamidotryptamine > m-chlorophenylbiguanide > 2-methyl-5-hydroxytryptamine = 5-methoxy-dimethyltryptamine > serotonin > 5-methoxy-tryptamine > L-694,247 = alpha-methyl-5-hydroxytryptamine > CGS 12066A = 8-hydroxy-2-(di- n -propylamino)tetraline. Serotonin and m-chlorophenylbiguanide also enhanced electrically-evoked [(3)H]-serotonin release from human iris-ciliary bodies with EC(50)s of 3 microM and 30 n M, respectively. The pharmacological profile displayed by serotonin receptor agonists was supported by the potent antagonism of the serotonin-induced enhancement of [(3)H]-serotonin release by 5HT(7)receptor antagonists SB-258718 (IC(50) = 18.6 +/- 1.2 nM; n = 4) and mesulergine (IC(50) = 0.26 +/- 0.05 nM; n = 4). However, antagonists at 5HT(6)and 5HT(3)receptors exhibited a relatively weak blockade of serotonin induced enhancement of field-stimulated [(3)H]-serotonin release. These studies have shown the presence of functionally active prejunctional 5HT(7)autoreceptors regulating the release of [(3)H]-serotonin from bovine iris-ciliary bodies. Excitatory prejunctional 5-HT autoreceptors also exist in human iris-ciliary bodies. It is possible that these serotonin autoreceptors may have relevance to the regulation of aqueous humor dynamics in the anterior uvea.

Adult↗
PubMed1997

Problems with current pharmacologic treatment of Parkinson's disease.

For the past 30 years levodopa (LD) has been the pharmacologic standard of care for treating idiopathic parkinsonism (Parkinson's disease or PD), a neurodegenerative disease of the central nervous system. LD is a pharmacologically inactive precursor, which is converted enzymatically to the neurotransmitter dopamine by a declining population of neurons in the substantia nigra, the most important site of the pathology of PD. Most patients experience a smooth, lasting response to small amounts of LD during the early years of treatment, but as the underlying disease gets worse, treatment-related problems arise. Motor fluctuations, which slowly emerge after 3-5 years of chronic LD therapy, gradually replace the smooth pattern of response, and more frequent dosing is required. Abnormal involuntary movements (dyskinesia), wearing-off of the motor response after a few hours, organic psychosis (confusion and hallucinations), and progressive loss of independence characterize the complicated interaction between the drug and the disease. Despite its problems, including the theoretical potential for harming neurons by inducing oxidant stress, and the recent development of other antiparkinson drugs, LD remains the most effective pharmacologic agent available for the relief of symptoms in patients with PD.

Antiparkinson Agents↗
PubMed2000

Cloning and expression, pharmacological characterization, and internalization kinetics of the pituitary GnRH receptor in a metatherian species of mammal.

Gonadotropin-releasing hormone receptors (GnRH-Rs) expressed in the pituitary of eutherian species of mammal are unique in lacking the cytoplasmic C-terminal tail characteristic of GnRH-Rs of nonmammalian vertebrates and other G protein-coupled receptors. To further investigate evolutionary relationships among vertebrate GnRH-Rs, a full-coding region cDNA of the pituitary GnRH-R was cloned from a metatherian marsupial mammal, the Australian brushtail possum (Trichosurus vulpecula). We have determined the pharmacological characteristics and internalization kinetics of this GnRH-R from an early evolved, metatherian species of mammal and compared it with the corresponding receptors in eutherian species of mammal and nonmammalian vertebrates. The predicted GnRH-R protein from the possum pituitary has high homology with the other mammalian GnRH-Rs (80% identity) and, in common with other mammals, lacks an intracellular C-terminal tail. The ligand selectivity of the possum GnRH-R transfected into COS-1 cells, assessed using inositol phosphate assays and radioreceptor binding assays, was similar to that of the other mammalian GnRH-Rs, and distinct from those of the nonmammalian GnRH-Rs. The pharmacological characteristics of the possum GnRH-R were similar to those of other mammalian GnRH-Rs, for a selection of agonists (including naturally occurring GnRH ligands and superagonists) and antagonists. Receptor-mediated internalization of GnRH agonist by the possum GnRH-R was slightly more rapid than that of the human GnRH-R, while the internalization kinetics of the chicken GnRH-R, in which a cytoplasmic C-terminal tail is present, was considerably more rapid. In terms of the evolution of the GnRH-R in vertebrates, the possum (a metatherian mammal) GnRH-R has a striking resemblance, in both structure and pharmacological characteristics, to GnRH-Rs in eutherian mammals, which are quite distinct from the nonmammalian vertebrate GnRH-Rs, and are unique among G protein-coupled receptors in lacking an intracellular C-terminal tail. The distinct structure of the pituitary GnRH-R in mammalian vertebrates is likely to have important functional consequences in the reproductive physiology of mammals.

Amino Acid Sequence↗
PubMedDate not supplied

Evaluation of pharmacological induction of fatty acid beta-oxidation in X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is an inherited neurometabolic disorder associated with elevated levels of saturated unbranched very-long-chain fatty acids (VLCFA; C > 22:0) in plasma and tissues, and reduced VLCFA beta-oxidation in fibroblasts, white blood cells, and amniocytes from X-ALD patients. The X-ALD gene (ABCD1) at Xq28 encodes the adrenoleukodystrophy protein (ALDP) that is related to the peroxisomal ATP-binding cassette (ABCD) transmembrane half-transporter proteins. The function of ALDP is unknown and its role in VLCFA accumulation unresolved. Previously, our laboratory has shown that sodium 4-phenylbutyrate (4PBA) treatment of X-ALD fibroblasts results in increased peroxisomal VLCFA beta-oxidation activity and increased expression of the X-ALD-related protein, ALDRP, encoded by the ABCD2 gene. In this study, the effect of various pharmacological agents on VLCFA beta-oxidation in ALD mouse fibroblasts is tested. 4PBA, styrylacetate and benzyloxyacetate (structurally related to 4PBA), and trichostatin A (functionally related to 4PBA) increase both VLCFA (peroxisomal) and long-chain fatty acid [LCFA (peroxisomal and mitochondrial)] beta-oxidation. Isobutyrate, zaprinast, hydroxyurea, and 5-azacytidine had no effect on VLCFA or LCFA beta-oxidation. Lovastatin had no effect on fatty acid beta-oxidation under normal tissue culture conditions but did result in an increase in both VLCFA and LCFA beta-oxidation when ALD mouse fibroblasts were cultured in the absence of cholesterol. The effect of trichostatin A on peroxisomal VLCFA beta-oxidation is shown to be independent of an increase in ALDRP expression, suggesting that correction of the biochemical abnormality in X-ALD is not dependent on pharmacological induction of a redundant gene (ABCD2). These studies contribute to a better understanding of the role of ALDP in VLCFA accumulation and may lead to the development of more effective pharmacological therapies.

Adrenoleukodystrophy↗
PubMed1997

Sponge-induced angiogenesis in mice and the pharmacological reactivity of the neovasculature quantitated by a fluorimetric method.

Sponge-induced angiogenesis in mice and pharmacological reactivity of the neovasculature have been determined by a fluorimetric method. Pharmacokinetic studies following subcutaneous, intradermal, and intraimplant administration of sodium fluorescein resulted in a biphasic curve from which estimation of t1/2 for absorption and elimination of the dye were possible. Following topical injection of the dye at days 1, 4, 7, 10, and 14 postimplantation, measurement of fluorchrome generated emission in the systemic circulation reflected the development of blood flow in and around the implants and the interaction of the angiogenic site with the systemic circulation. The t1/2 values for the fluorescence peak in the bloodstream decreased steadily from an initial value of 6.41 +/- 0.28 min (avascular implant) to 2.78 +/- 0.23 min in fully vascularized implants (day 14). The reactivity of the neovasculature to ET-1 was dose-dependent and similar to the skin vasculature. By contrast, no reactivity to histamine was detected in the implant blood vessels, whereas it was present in the skin. These results show that the pharmacological response of the neovasculature differs from the response of mature blood vessels. The angiogenic stimulus (bFGF, 300 ng daily) decreased t1/2 for the fluorescence peak, whereas dexamethasone (1 mg/kg) increased it. Parallel histological studies corroborated the functional findings. These observations indicate the suitability of this assay to study angiogenesis, functional and pharmacological characterization of the neovasculature, and the interaction of the angiogenic site with the systemic circulation.

Animals↗
PubMed2002

Pharmacology of acute lung injury.

The acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a clinical syndrome that affects both medical and surgical patients. To date, despite improved understanding of the pathogenesis of ALI/ARDS, pharmacological modalities have been unsuccessful in decreasing mortality. However, several pharmacological agents for ARDS are in development and have shown great promise. In addition to the anti-inflammatory category including late corticosteroids, inhaled nitric oxide, alveolar surfactant, and vasodilators are being evaluated. Replacements of anticoagulation mediators have also suggested beneficial effects on the patient outcome. This article provides an overview of pharmacological treatments of ALI/ARDS.

Adrenal Cortex Hormones↗
PubMed2005

New pharmacological treatment approaches for anxiety disorders.

New developments in the pharmacological treatment of anxiety disorders will have distinct backgrounds: characterization of pathophysiological processes including evolving techniques of genomics and proteomics will generate new drug targets. Drug development design will generate new pharmacological substances with specific action at specific neurotransmitter and neuropeptide receptors or affecting their reuptake and metabolism. New anxiolytic drugs may target receptor systems that only recently have been linked to anxiety-related behavior. This includes the N-methyl-D-aspartate (NMDA), S-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and the cannabinoid receptors. In addition, signal transduction pathways, neurotrophic factors, and gases such as nitric oxide or carbon monoxide may be new drug targets. Combining psychopharmacological and psychotherapeutical interventions is a further field where benefits for the treatment of anxiety disorders could be achieved. Although the road of drug development is arduous, improvements in the pharmacological treatment of anxiety disorders are expected for the near future.

Anti-Anxiety Agents↗
PubMed1990

Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus.

The present study was designed to further characterize the muscarinic receptors mediating contraction of the guinea-pig uterus. The affinities of various selective muscarinic antagonists were determined and compared with those obtained at M1 (rabbit vas deferens), M2 (guinea-pig atria) and M3 receptors (guinea-pig ileum). The contractile responses of uterine smooth muscle from immature guinea-pigs to carbachol (pD2 = 5.73) were competitively antagonized by pirenzepine (pA2 = 7.04), AF-DX 116 (11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11- dihydro-6H-pyrido[2,3-b][1.4]benzo,diazepin-6-one) (pA2 = 6.96), himbacine (pA2 = 7.92), methoctramine (pA2 = 7.52), 4-DAMP (4-diphenylacetoxy-N-methylpiperidine methiodide) (pA2 = 8.87) and sila-hexocyclium (pA2 = 8.81). A comparison of affinity values indicates that the muscarinic receptors present in guinea-pig uterus display a novel pharmacological profile which is not consistent with the presence of either an M1, M2 or M3 receptor. The affinities determined for the different antagonists rather showed a close similarity to those obtained at muscarinic receptors present in rat striatum and NG108-15 cells which are considered pharmacological equivalents (M4 receptors) of the m4 gene product. We thus hypothesize that the guinea-pig isolated uterus preparation may serve as a simple functional assay system to study the pharmacology of M4 receptors.

Animals↗
PubMed1995

Localization and pharmacological characterization of somatostatin sst2 sites in the rat cerebellum.

Radioligand binding studies were performed in membranes of rat cerebellum using [125I]-[Tyr3]octreotide ([125I]204-090) to characterize the nature of cerebellar somatostatin receptors. Saturation experiments suggest the presence of a single class of binding sites with high affinity, pKd = 9.53 +/- 0.11, but low receptor density, Bmax = 12.7 +/- 1.0 fmol/mg protein. The pharmacological profile of [125I]204-090 sites in cerebellar membranes was established using a range of ligands known to interact with SSTR-2 (now called sst2) and other somatostatin (SRIF) receptors. SRIF analogues such as octreotide (SMS 201-995), seglitide (MK 678) and somatuline (BIM 23014) displayed very high affinity for cerebellar [125I]204-090 binding sites. The data were compared to results obtained using the same ligand in rat cerebral cortex membranes known to represent sst2 binding. The pharmacological characteristics of the cerebellar sites were in close correlation with those of the cerebral cortex (r = 0.976, n = 19, p < 0.001) and CHO-cells expressing human recombinant sst2 receptor (r = 0.977, n = 19, p < 0.001). By contrast, there was very little correlation between cerebellar binding and published affinities for rat sst5 receptors (r = 0.465), for which octreotide has also high affinity. In vitro autoradiographic studies performed in cerebellar slices using [125I]204-090 demonstrated the presence of binding sites in the molecular layer of the rat cerebellum. In situ hybridization studies using sst2 receptor mRNA selective oligoprobes confirmed the presence of sst2 receptor mRNA in the rat cerebellum. Together, the present data demonstrate the presence of a low density of SRIF receptors in the molecular layer of the adult rat cerebellum which are best characterized as sst2. This is the first pharmacological characterization and localization of sst2 receptors in the adult rat cerebellum.

Amino Acid Sequence↗
PubMed1996

Biochemistry and pharmacology of glycinamide ribonucleotide formyltransferase inhibitors: LY309887 and lometrexol.

Lometrexol, a tight-binding antifolate inhibitor of the purine de novo enzyme glycinamide ribonucleotide formyltransferase (GARFT), was the first GARFT inhibitor to be investigated clinically. Unexpected observations of delayed cumulative toxicity prompted a search for a second generation antimetabolite with a more favorable biochemical, pharmacological and toxicological profile. LY309887, 6R-2',5'-thienyl-5, 10-dideazatetrahydrofolic acid, had 9-fold greater potency to inhibit GARFT (Ki = 6.5 nM) compared to lometrexol. Like lometrexol, LY309887 was activated by folpolyglutamate synthetase, however, it had a lower first order rate constant. In vitro and in vivo data were consistent with these observations: polyglutamation of LY309887 was less extensive compared to lometrexol and livers of mice accumulated fewer polyglutamates of LY309887 than polyglutamates of lometrexol. The affinities of these two compounds for isoforms of human folate receptors (FR) were compared. Lometrexol had a 6-fold higher affinity for FR alpha than LY309887 and both compounds had higher affinity for the alpha isoform compared to the beta isoform. The selectivity of LY309887 for FR alpha (beta (Ki)/ alpha (Ki) = 10.5) was twice that of lometrexol's (beta / alpha = 5.0). Lometrexol and LY309887 were potent cytotoxic compounds against the human leukemia cell line CCRF-CEM with IC50's of 2.9 nM and 9.9 nM, respectively. In vivo, LY309887 was more potent than lometrexol at inhibiting tumor growth in the C3H mammary murine tumor model and several tumor xenografts. Excellent efficacy was achieved by both compounds in several colon xenografts. In two pancreatic human xenografts, LY309887 achieved greater efficacy than lometrexol. In summary, the biochemical and pharmacological properties of lometrexol and LY309887 support the hypothesis that these antifolates will have clinical activity against human solid tumors. LY309887 is a second generation GARFT inhibitor with biochemical and pharmacological properties which distinguish it from lometrexol and suggest that it will have broad antitumor activity, a different pharmacokinetic profile and produce less toxicity than lometrexol in cancer patients.

Acyltransferases↗
PubMed1988

Normal pharmacological and morphometric parameters in the noradrenergic hyperinnervated mutant mouse, "tottering".

Pharmacological and anatomical analyses of central monoaminergic and cholinergic neurons were performed in the "tottering" mouse, an autosomal recessive neurologic gene mutation that results in an overproduction of axons of the locus coeruleus and an increase in norepinephrine content in specific terminal fields. Except for the previously reported increase in norepinephrine content, all pharmacological parameters measured, including tyrosine hydroxylase activity, norepinephrine turnover, serotonin content, and choline acetyltransferase activity, in targets hyperinnervated by the locus coeruleus were normal. Immunocytochemical staining for tyrosine hydroxylase demonstrated the pronounced hyperinnervation in the "tottering" brain, whereas both serotonin and choline acetyltransferase immunostaining were similar between "tottering" and wild type. The volume of 3 target areas that are hyperinnervated by the locus coeruleus in the "tottering" mouse, the hippocampus, cerebellum, and cochlear nuclei, were normal. In addition, neuronal number and somal size in the locus coeruleus were found to be unchanged in the mutant genotype. These data demonstrate several features of the effects of the "tottering" gene: 1) compensatory changes in several adrenergic pharmacological parameters do not occur in response to the hyperinnervation of targets by locus coeruleus axons; 2) neither direct effects of the "tottering" gene on, nor compensatory changes in, the extent of cholinergic or serotonergic innervation of several targets of the locus coeruleus appear to occur; and 3) the lack of changes in size of the targets of the locus coeruleus suggest that the hyperinnervation in the "tottering" mouse is due to a direct genetic alteration of axonal growth by the locus coeruleus neurons, rather than to selective shrinkage of targets in the presence of normal terminal arbors.

Animals↗