dironyl and Disease-Models--Animal

The past three decades have witnessed a welcome expansion of the therapeutic armamentarium for the management of pulmonary arterial hypertension (PAH). However, against this backdrop, there have been some notable disappointments in drug development. Here we use these as case studies to emphasize the importance of informed drug target selection, the early evaluation of dose-response relationships in human studies, and the value of the deep phenotyping of patients in clinical studies to better understand inter-individual variation in patient response. The integration of "omics" technologies and advanced clinical imaging offer the potential to reduce the risk, and so cost, of drug development in PAH and bring much needed new medicines to those patients most likely to benefit with greater efficiency.

Topics: Animals; Biomarkers; Clinical Studies as Topic; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Pulmonary; Lisuride; Phenotype; Phentolamine; Protein-Tyrosine Kinases; Vasoactive Intestinal Peptide

Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited responsiveness to available treatments. It is characterised by epithelial cell injury, fibroblast activation and proliferation and extracellular matrix deposition. Serotonin (5-hydroxytryptamine; 5-HT) induces fibroblast proliferation via the 5-HTR(2A) and 5-HTR(2B) receptors, but its pathophysiological role in IPF remains unclear. A study was undertaken to determine the expression of 5-HT receptors in IPF and experimental lung fibrosis and to investigate the effects of therapeutic inhibition of 5-HTR(2A/B) signalling on lung fibrosis in vivo and in vitro.. Quantitative RT-PCR showed that the expression of 5-HTR(1A/B) and 5-HTR(2B) was significantly increased in the lungs of patients with IPF (n=12) and in those with non-specific interstitial pneumonia (NSIP, n=6) compared with transplant donors (n=12). The expression of 5-HTR(2A) was increased specifically in IPF lungs but not in NSIP lungs. While 5-HTR(2A) protein largely localised to fibroblasts, 5-HTR(2B) localised to the epithelium. To assess the effects of 5HTR(2A/B) inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced lung fibrosis and treated with the 5-HTR(2A/B) antagonist terguride (or vehicle) in a therapeutic approach (days 14-28 after bleomycin). Terguride-treated mice had significantly improved lung function and histology and decreased collagen content compared with vehicle-treated mice. Functional in vitro studies showed that terguride is a potent inhibitor of transforming growth factor β(1)- or WNT3a-induced collagen production.. The studies revealed an increased expression of 5-HTR(2A) specifically in IPF. Blockade of 5-HTR(2A/B) signalling by terguride reversed lung fibrosis and is thus a promising therapeutic approach for IPF.

Topics: Animals; Bleomycin; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Humans; Lisuride; Lung; Male; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2B; Serotonin 5-HT2 Receptor Antagonists; Serotonin Plasma Membrane Transport Proteins

Glucose tolerance, total plasma cholesterol and plasma triglycerides were studied in the genetically hypertensive obese Koletsky rats (SHR/N-cp) and in their lean siblings. The initial part of the glucose tolerance curve was substantially elevated in both obese and lean Koletsky animals compared to normotensive Wistar rats. The abnormal glucose tolerance in hypertensive rats was accompanied by increased total plasma cholesterol and plasma triglycerides. Long-term treatment with dopaminergic agonists terguride or bromocriptine (0.2 and 2.0 mg/kg/day, respectively) exerted similar effects on lipid metabolism but both drugs differed in their influence on glucose tolerance. Terguride lowered plasma lipids and normalized glucose tolerance in both obese and lean Koletsky rats. Bromocriptine reduced hyperlipidaemia but did not attenuate the abnormalities of glucose tolerance in either lean or obese Koletsky animals.

Topics: Animals; Blood Pressure; Body Weight; Bromocriptine; Disease Models, Animal; Female; Glucose Intolerance; Hyperlipidemias; Hypertension; Insulin; Lipids; Lisuride; Male; Obesity; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Rats, Wistar; Sex Factors

Eight Cebus apella monkeys were treated with haloperidol for 2 years. Five monkeys had developed mild oral tardive dyskinesia and all were primed for neuroleptic induced dystonia, thus serving as a model for both chronic and acute extrapyramidal side effects. In this model, the partial dopamine D2 receptor agonists SDZ HDC-912, SDZ HAC-911, terguride, (-)-3-(3-hydroxyphenyl)-N-propylpiperidine) ((-)-3-PPP) and SND 919 were tested for extrapyramidal side-effect liability. Their antipsychotic potential was also tested, using a dose of dextroamphetamine producing mild stereotypy and moderate motoric unrest. For comparison, the dopamine D2 receptor agonist, LY 171555 and antagonist, raclopride were used. In contrast to the other drugs tested, SDZ HAC-911 consistently reduced oral activity, P < 0.05 (at doses from 0.005 to 0.025 mg/kg). The relative dystonic potencies were raclopride > SDZ HDC-912 > SDZ HAC-911 = terguride. Neither (-)-3-PPP nor SND 919 produced dystonia, but had observable dopamine D2 receptor agonistic effects, (-)-3-PPP producing emesis at 1-4 mg/kg and SND 919 producing motoric unrest and stereotypy at 0.05-0.25 mg/kg. Comparing the antiamphetamine effects of the more antagonist-like drugs with raclopride, the relative potencies were terguride = SDZ HAC-911 > SDZ HDC-912 > raclopride. Comparing the antiamphetamine effects of the more agonist-like drugs with LY 171555, the relative potencies were SND 919 > (-)-3-PPP > LY 171555 in relation to motoric unrest, while neither (-)-3-PPP nor LY 171555 produced inhibition of stereotypy.

Topics: Administration, Oral; Amphetamine; Animals; Antipsychotic Agents; Behavior, Animal; Benzothiazoles; Cebus; Disease Models, Animal; Dopamine Agents; Dopamine D2 Receptor Antagonists; Dyskinesia, Drug-Induced; Dystonia; Ergolines; Female; Haloperidol; Lisuride; Male; Piperidines; Pramipexole; Quinpirole; Raclopride; Salicylamides; Thiazoles

The mixed dopamine (DA) agonist/antagonist terguride acts as a DA antagonist on normosensitive receptors but shows DA agonistic properties at supersensitive DA receptors. Such a compound could offer an alternative to the treatment of Parkinson's disease with indirect or direct DA agonists. The present study compares the actions of terguride, 4-12 mg/kg i.p., in naive common marmosets with its effects in animals rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 2 months or 10 months previously, in order to test its antiparkinsonian efficacy. Terguride reduced locomotor activity in naive common marmosets, similar to its effects in rodents and in line with the DA antagonistic activity of the compound. In marmosets treated with MPTP 2 months previously and exhibiting pronounced behavioural motor deficits, terguride stimulated locomotor activity, showing DA agonistic properties under these conditions. In contrast, the locomotor activity of animals that had recovered from MPTP treatment 10 months previously was not altered by terguride. It is concluded that terguride has anti-akinetic efficacy in this primate model of Parkinson's disease. In addition, terguride offers a unique opportunity to differentiate, pharmacologically, the extent of dopaminergic recovery from MPTP treatment in this primate species.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Callithrix; Disease Models, Animal; Dopamine Agents; Female; Lisuride; Male; Motor Activity; Parkinson Disease, Secondary; Time Factors

The partial dopamine agonist terguride (transdihydrolisuride) administered to four 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned hemiparkinsonian monkeys (at a dose of 4 mg/kg orally) induced marked contralateral turning that lasted 3.5 h. The 6-n-propyl derivative of terguride (proterguride) given to two monkeys (at a dose of 0.4 mg/kg orally) caused contralateral turning which lasted for more than 24 h but produced side effects such as dyskinesia and stereotype. After terguride treatment, cerebrospinal fluid concentrations of 3-methoxy-4-hydroxy-phenylglycol (MHPG) were increased, whereas concentrations of the metabolites dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were not significantly altered.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Disease Models, Animal; Ergolines; Female; Lisuride; Macaca fascicularis; Parkinson Disease, Secondary; Pyridines; Receptors, Dopamine

Terguride, an analogue of lisuride, decreased locomotor activity, produced cataplexy, and blocked apomorphine-induced stereotypic behavior. It did not induce stereotypies in rodents or emesis in dogs. However, in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra, terguride produced contralateral rotation. Terguride bound to D-2 striatal dopamine receptors. Terguride has both agonist and antagonist actions at striatal dopamine receptors, but chronic administration did not produce behavioral supersensitivity. These pharmacologic properties differ from those of other antiparkinsonian agents; terguride may be effective for the chronic treatment of Parkinson's disease.

Topics: Amphetamine; Animals; Apomorphine; Behavior, Animal; Brain; Disease Models, Animal; Ergolines; Levodopa; Lisuride; Male; Motor Activity; Parkinson Disease; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereotyped Behavior