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Biomedical subjects

J Brownell

Publications and source records attributed to J Brownell.

At least 37 records · Page 2Linked to original sources
PubMed1990

Postpartum return of pituitary and ovarian activity during lactation inhibition with the new dopamine agonist CV 205-502 and during normal lactation.

The new nonergot dopamine agonist CV 205-502 appears to be a promising alternative in the treatment of hyperprolactinemia. Regarding the potential use of CV 205-502 in infertility practice, we studied the influence of CV 205-502 on the return of endocrine fertility parameters during the physiological hyperprolactinemia of the puerperium. The resumption of pituitary and ovarian activity in 18 CV 205-502 treated women was compared with that in 10 bromocriptine-treated women. LH was measured by a new specific assay, which does not cross-react with hCG. This assay was also used in a second part of the study in which the pituitary function of 10 breast-feeding women was investigated. Both dopamine agonists adequately suppressed PRL. Pituitary secretion returned in the second week and was initially characterized by a high FSH/LH ratio. There were no major differences between CV 205-502 and bromocriptine. Ovulations occurred from day 18 on. The PRL rebound at the end of treatment seemed to play a role in the ovulation process. An acute increase of PRL just before midcycle was able to prevent ovulation. Breastfeeding women showed a delayed return of pituitary secretion: after a hypogonadotropic period, FSH returned in the third week and was followed by a period with a high FSH/LH ratio and follicular inactivity.

Aminoquinolines↗
PubMed1989

The effectiveness, safety, and tolerability of CV 205-502 in hyperprolactinemic women: a 12-month study.

Forty-one hyperprolactinemic women (prolactin [PRL] greater than 2,000 mU/L) were treated between 12 and 52 weeks with the new nonergot, long-acting dopamine agonist octahydrobenzo [g] quinoline (CV 205-502). The treatment resulted in normalization of PRL secretion in 71% of the women at a once-daily dose of less than or equal to 0.100 mg. All women responded with a significant decrease in serum PRL. Menstrual function normalized in all women except 1, whereas galactorrhea disappeared in all but 2 patients. During the observation period, four pregnancies were recorded with an additional three in the immediate posttreatment period. Until now, four healthy children have been born. Regarding tolerability, women with fair or poor response bromocriptine (Parlodel) in the past tolerated CV 205-502 better. Two women with no PRL decrease while on Parlodel responded with a decrease while on CV 205-502. All safety parameters remained normal while on treatment, and no significant changes were observed in blood pressure (supine and standing), pulse rate, or electrocardiogram (ECG) recordings. CV 205-502 therefore seems to be a valuable new compound in the management of patients with hyperprolactinemia.

Aminoquinolines↗
PubMed1989

Specific effect of CV 205-502, a potent nonergot dopamine agonist, during a combined anterior pituitary function test.

CV 205-502, an octahydrobenzo[g]quinoline, is a dopamine agonist compound that is not an ergot or ergoline derivative. To investigate the site of action of CV 205-502, three groups of five men were given single daily doses of CV 205-502 (0.04, 0.06, or 0.08 mg/day, doses that suppress plasma PRL by 60-80% for 24 h) for 5 days; on day 6 a combined anterior pituitary function test using iv administration of four hypothalamic releasing hormones (TRH, 200 micrograms; GHRH, 100 micrograms; CRH, 100 micrograms; LHRH, 100 micrograms) was performed. One month later the challenge tests were repeated to obtain control values. The following hormones were measured by RIA in plasma: TSH, ACTH, cortisol, PRL, GH, LH, FSH, and testosterone. With the exception of plasma PRL levels, basal and releasing hormone-stimulated values were similar after CV 205-502 administration and after the 1-month washout period. Basal plasma PRL was lower after CV 205-502 administration, and the response to TRH was attenuated by all three doses of CV 205-502 (the mean percent inhibition values were 76%, 93%, and 94%, respectively). All three doses of CV 205-502 were well tolerated, and another group of men well tolerated 0.1 mg daily. The results confirm that CV 205-502 is a potent dopamine agonist, which directly inhibits lactotropic cells but has no effect on other pituitary cell types.

Adult↗
PubMed1988

Potent and selective activity of a new carbocyclic nucleoside analog (carbovir: NSC 614846) against human immunodeficiency virus in vitro.

Carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine (Carbovir: NSC 614846), a novel nucleoside analog, emerged as a potent and selective anti-HIV agent from a large screening program conducted by the National Cancer Institute and its contractors. Its hydrolytic stability and its ability to inhibit the infectivity and replication of HIV in T-cells at concentrations of approximately 200- to 400-fold below toxic concentrations make carbovir a top-priority candidate for development as a potential antiretroviral agent in the treatment of AIDS patients.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Hormonal effects of CV 205-502, a novel octahydrobenzo [g] quinoline with potent dopamine agonist properties.

Following the success of ergot alkaloids and their synthetic derivatives in treating a variety of pathophysiological disturbances, efforts have been concentrated on the synthesis of new derivatives and partial structures with the aim of dissecting out a specifically dopaminomimetic pharmacophore. Accordingly CV 205-502, a structure which superposes the linear benzo [g] quinoline segment of apomorphine on the substituted pyrrolo [3,4- g] quinoline moiety of the ergolines was designed. This study was performed in normal young volunteers to investigate the effect of single oral doses of CV 205-502 on plasma prolactin levels and on other endocrine parameters (GH, LH, FSH, TSH and cortisol) as well as on tolerability. 10 volunteers participated in a dose-ranging study. They received single oral doses of 0.01 to 0.09 mg CV 205-502, in order to assess the prolactin suppressant action. 6 volunteers were given a dose of 0.06 mg CV 205-502 in order to determine the endocrine profile of the compound. The duration of action of 0.06 mg CV 205-502 was investigated in 6 subjects by measuring plasma PRL and GH levels for 48 h. The results show strong dose-dependent suppression of PRL appearing following doses between 0.04 and 0.09 mg of CV 205-502. PRL was markedly suppressed for more than 24h. and the peaks of the normal sleep profile were abolished. Intermittent transient GH increases occurred during the first 6 hours; sleep profiles were normal. Compared with placebo values, no changes were seen in the levels of any other hormone except TSH, which decreased. Tolerability was good and no drug attributable changes in safety measures occurred. This study demonstrates that CV 205-502 is a potent and long acting PRL suppressant compound and suggest that this novel octahydrobenzo [g] quinoline will prove to be a therapeutically useful dopaminomimetic compound.

Adult↗
PubMed1988

Long-term treatment with a new non-ergot long-acting dopamine agonist, CV 205-502, in women with hyperprolactinaemia.

Twenty-four hyperprolactinaemic women were treated for 6 months with the new, non-ergot, long-acting dopamine agonist, CV 205-502. The treatment resulted in normalization of PRL secretion in 17 of the 24 women at once-daily doses of 0.05 to 0.15 mg of the drug. Sixteen of these women as well as 4 of those who remained hyperprolactinaemic had regular menstrual bleeding. Five of the patients had previously discontinued bromocriptine therapy because of adverse effects but had no problems tolerating CV 205-502. Of three bromocriptine-resistant women, two responded partially while one also remained unresponsive to CV 205-502 treatment. Mild to moderate galactorrhoea was recorded at baseline in 19 of the 24 women. After 6 months' treatment mild galactorrhoea was still present in six patients, four of whom had attained normal PRL levels. Side-effects were mild and transient. CV 205-502 seems to be a valuable compound in the management of patients with hyperprolactinaemia.

Adult↗
PubMed1988

CQP 201-403, a new dopamine agonist in the treatment of hyperprolactinemia.

Current drugs used for hyperprolactinemia may have severe side effects. Effects and side effects of a new propylergoline derivate (CQP 201-403 SANDOZ) have been evaluated. Twenty-four otherwise healthy women (21-44 years) with hyperprolactinemia (35-318 micrograms/l) without extrasellar extension of pituitary adenomas took part in a randomized, double-blind study. Fasting prolactin levels measured on day 7 was significantly decreased when compared with day 1 (P less than 0.05) in all CQP groups, to 78% with 0.005 mg daily, to 40% with 0.015 mg daily, and to 27% with 0.025 mg CQP per day for one week. The levels in the control group did not change (96%). The area under the curve of the prolactin day curve (1-8 h after drug administration) decreased significantly (P less than 0.05) at all doses when day 7 was compared with day 1, to 77% with 0.005 mg, to 51% with 0.015 mg, and to 37% with 0.025 mg CQP. No change was seen in the control group (96%). Four patients (one on 0.005 mg, one on 0.015 mg, and two on 0.025 mg) experienced orthostatic hypotension while standing blood pressure was to be measured on the first day of treatment, and they had to lie down. CQP 201-403 lowers prolactin levels in hyperprolactinemic women at all doses employed. The effect was seen after the first dose of treatment, and lasted for at least 24 h. The adverse reactions are few and tolerable, and might be less than with current bromocriptine therapy.

Adult↗
PubMed1988

Hormonal effects of CQP 201-403, a new dopamine agonist.

CQP 201-403 is a propylergoline derivative with strong dopamine stimulant properties in animals models. It was developed in order to meet the need for a dopamine agonist compound which would offer longer action and improved tolerability. In this study, we tested CQP 201-403 m healthy male volunteers in order to assess its PRL suppression action and other hormonal effects as well as its duration of action and tolerability. Twenty-one volunteers participated in a dose-range study conducted according to a double-blind cross-over design with placebo control. The PRL suppression effect of single oral doses ranging from 0.05 mg to 0.035 mg were investigated. The duration of action of CQP 201-403 was tested in 6 other volunteers receiving a single oral dose of 0.025 mg or placebo. Blood was sampled over 48 h for PRL and GH measurements. An endocrine profile was performed in 6 volunteers receiving either 0.025 mg CQP 201-403 as a single oral dose or placebo. Blood was sampled over 8 h for measuring plasma PRL, GH, LH, FSH, TSH and cortisol. The results show strong dose-dependent PRL suppression (P less than 0.001) beginning 2 h after ingestion. PRL suppression lasted for more than 24 h and the normal sleep PRL surges were abolished. GH was transiently stimulated during the first few hours; the GH sleep profile was normal. All other hormones were not affected by the administration of CQP 201-403. Tolerability was good and no drug attributable changes in safety measures occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Endocrine effects of CV 205-502, a new dopamine agonist, in hyperprolactinemic women.

CV 205-502 (CV) is a potent dopaminergic compound which exerts a strong and sustained suppression of prolactin secretion in healthy volunteers. In a prospective double-blind, randomized, placebo-controlled trail, 12 hyperprolactinemic women (greater than or equal to 2000 mU/l), divided into 2 groups of 6 women each, were treated for 4 weeks. Combined pituitary challenge tests (GnRH, TRH, CRH and GHRH) were performed before and after treatment. The 6 CV-treated women (0.05 micrograms daily) showed approximately a 64% decrease of their initial prolactin serum concentrations after 4 weeks of capsule intake. Placebo-treated women showed no change in their prolactin serum level. After TRH administration, a blunted prolactin response was present in all women before treatment. After CV treatment a trend towards normalization of the prolactin response to TRH was seen, whereas the response pattern in the placebo group remained unaltered. The responses of GH, TSH, LH and ACTH to their releasing hormones and cortisol showed no significant changes after administration. FSH, however, showed a significant decrease in response to LH-RH, which could be explained by an increase in estradiol (E2) as ovarian function normalized in CV-treated women. In conclusion, CV shows strong dopamine agonistic properties in hyperprolactinemic women treated with 0.05 micrograms daily. The profile of this new quinoline compound, as judged from the pituitary challenge tests, does not differ from that of dopamine agonists of the ergoline type.

Adult↗
PubMed1987

CV 205-502: a new long-acting drug for inhibition of prolactin hypersecretion.

CV 205-502, an octahydrobenzo(g)quinoline, is a new non-ergot long-acting prolactin inhibitor. The substance was given to 24 hyperprolactinaemic women for 7 d. The women were randomized to one of three dose regimens, 0.01 mg, 0.03 mg or 0.06 mg daily. Two patients in each group were given placebo. Frequent blood samples were obtained during days 1, 7 and 8. The prolactin levels in serum were depressed dose-dependently in all patients given active substance. In group 1 (0.01 mg) the dose was insufficient to induce normal serum prolactin levels except in one woman, while two women in group 2 (0.03 mg) and four in group 3 (0.06 mg) became normoprolactinaemic. The depressant effect on prolactin secretion lasted for 24 h in group 2 and 3. Side-effects were mild and transient. No change in blood pressure was observed. CV 205-502 was an effective and long-acting drug for treatment of patients with hyperprolactinaemia in this short-term study and this new drug deserves investigation of its usefulness in long-term treatment.

Adolescent↗
PubMed1987

Effects of two novel dopaminergic drugs, CV 205-502 and CQP 201-403, on prolactin and growth hormone secretion by human pituitary tumours in vitro.

Two novel dopaminergic drugs, designated CV 205-502 and CQP 201-403 have recently been developed by Sandoz Pharmaceuticals Ltd (Basle, Switzerland). The effects of these drugs on PRL and GH secretion by normal rat and tumorous human pituitary cells in vitro have been investigated. Low doses of both CV 205-502 and CQP 201-403 immediately and profoundly suppressed PRL secretion, which failed to recover up to 7 h after removal of the drugs. Similarly, CQP 201-403 significantly suppressed basal GH secretion by human pituitary somatotropic tumours in culture, and both drugs significantly reduced the stimulatory effect of GHRH. These effects are more potent and longer acting than the previously described in vitro effects of bromocriptine. It is concluded that CV 205-502 and CQP 201-403 hold potential for the treatment of patients with hyperprolactinaemia and, possibly, also in patients with acromegaly.

Aminoquinolines↗
PubMed1987

Prolactin suppressant effect of CQP 201-403, a new dopamine agonist, in hyperprolactinemic women.

To meet the need for a dopamine agonist compound which would offer longer action and improved tolerability, CQP 201-403 has been developed. CQP is a propyl-ergoline which has shown specific and strong 24-hour prolactin suppression in healthy volunteers at oral doses from 0.01 mg and higher. In the study 24 hyperprolactinemic women were given once daily doses of 0.01 mg, 0.02 mg or 0.03 mg CQP 201-403, or placebo for 7 days in a double-blind study to assess the prolactin suppressant action and tolerability of the compound. The results show dose-dependent prolactin suppression following the initial CQP dose which was sustained in steady state, when a clear 24-hour action was seen. Tolerability was good and no drug attributable changes in safety measures occurred. On the basis of its facility to suppress prolactin at well tolerated once daily doses, CQP would offer an advantage over currently available drugs. Long-term therapeutic studies in hyperprolactinemia are therefore warranted.

Clinical Trials as Topic↗
PubMed1986

Carbocyclic puromycin: synthesis and inhibition of protein biosynthesis.

The carbocyclic analogue of puromycin was prepared by the coupling of N-(benzyloxycarbonyl)-p-methoxy-L-phenylalanine to the racemic aminonucleoside (+/-)-9-[3 beta-amino-2 beta-hydroxy-4 alpha-(hydroxymethyl)cyclopent-1 alpha-yl]-6-(dimethylamino)purine, followed by separation of the diastereomers and subsequent removal of the Cbz blocking group. Kinetic studies indicate that carbocyclic puromycin is an excellent substrate for the peptidyltransferase reaction with both prokaryotic and eukaryotic ribosomes. A comparison of carbocyclic puromycin with previously synthesized analogues indicate that the furanosyl ring oxygen and the hydroxymethyl group of puromycin do not contribute to ribosomal binding, but both moieties contribute to the rate of product formation from the enzyme-substrate complex. Carbocyclic puromycin was equal to puromycin when evaluated for cytotoxicity using P-388 mouse lymphoid leukemia cells in culture.

Animals↗
PubMed1986

Description of the time course of the prolactin suppressant effect of the dopamine agonist CQP201-403 by an integrated pharmacokinetic-pharmacodynamic model.

Six male volunteers (mean age 24 years) received a single oral dose of 0.025 mg CQP201-403 and placebo in a randomised double-blind crossover design. Fifteen plasma samples were collected over 48 h and were assayed by radioimmunoassay for drug substance and prolactin (PRL). Three of the samples were drawn during sleep on the first study day. The pharmacological effect (E%) of CQP201-403 was expressed as reduction in plasma PRL levels. The pharmacokinetic (PK)-pharmacodynamic (PD) model consisted of two kinetic compartments and an effect compartment linked to the central compartment. A sigmoid Emax model (Hill equation) described the relationship between the drug concentration in the effect compartment and E%. Curve-fitting of PK and PD data provided individual parameter estimates which served to generate computer-simulated PK and PD profiles after single and multiple doses in order to: investigate the in vivo concentration-effect relationship; evaluate the consequence of dosage reduction on the steady-state PD profile; and study the robustness of the response to changes in drug potency and bioavailability.

Adult↗
PubMed1984

Carbocyclic analogues of xylofuranosylpurine nucleosides. Synthesis and antitumor activity.

(+/-)-4 alpha-Amino-2 alpha,3 beta-dihydroxy-1 alpha-cyclopentanemethanol (6), the carbocyclic analogue of xylofuranosylamine, was synthesized from the previously reported 4 alpha-acetamido-2 alpha,3 alpha-epoxycyclopentane-1 alpha-methanol. Amine 6 was converted to (+/-)-4 alpha-[(5-amino-6-chloro-4-pyrimidinyl)amino]-2 alpha,3 beta-dihydroxy-1 alpha-cyclopentanemethanol (7) by condensation with 5-amino-4,6-dichloropyrimidine. From 7, the carbocyclic analogues of xylofuranosyladenine and xylofuranosyl-8-azaadenine were prepared. In contrast to 9-beta-D-xylofuranosyladenine and its 8-aza analogue, the corresponding carbocyclic nucleosides were resistant to deamination by adenosine deaminase. The carbocyclic 8-aza derivative 10 exhibited significant in vivo antitumor activity which varied according to treatment schedule.

Adenosine Deaminase↗
PubMed1980

Characterization of ergot and non-ergot serotonin antagonists by prolactin and growth hormone profiles during wakefulness and sleep.

In order to further clarify the involvement of serotonin in the control of secretion of pituitary lactogens, diurnal and sleep prolactin (PRL) and growth hormone (GH) profiles were investigated in healthy subjects treated with ergot and non-ergot serotonin antagonists. A group of 10 subjects received a single oral dose of 2 mg each of pizotifen, methysergide, and the dopaminergic drug bromocriptine as reference substance, in comparison with placebo. Blood was collected at hourly intervals for 6 h. Another group of 10 individuals received either a placebo, 2.5 mg bromocriptine (n = 6) twice daily for 4 days or pizotifen (n = 10) 0.5 mg 3 times daily for 12 days before undergoing EEG recording and blood sampling during night sleep. The diurnal plasma profiles of PRL and GH were not modified by pizotifen, a non-ergot drug. Methysergide and bromocriptine, two ergot derivatives, significantly (P < 0.01 and P < 0.001 respectively) suppressed the basal secretion of PRL throughout the trial and increased plasma GH significantly (P < 0.01). The sleep profile of PRL was not modified by pizotifen but there was a moderate reduction in GH reaching the level of significance (P < 0.02) between hours 1 and 2 of sleep. Bromocriptine suppressed completely PRL secretion throughout the entire sleep period and significantly (P < 0.05) prolonged the secretory profile of GH. The results indicate the presence in the ergot molecule of a dopaminergic moiety responsible for PRL inhibition and GH stimulation. This effect is independent of the serotonin active component of the drug.

Adult↗
PubMed1980

Endocrine effect of a methionine-enkephalin derivative (FK 33-824) in man.

The endocrine profile of FK 33-824, 0.5 mg i.m., was determined in comparison with placebo or pretreatment with naloxone, 4 mg i.v., in 14 healthy men. Prolactin (PRL), growth hormone (GH), ACTH, cortisol, gonadotropins (LH, FSH), thyrotropin (TSH), thyroxine (T4), triiodothyronine (T3), insulin and glucagon were measured and free water clearance was calculated from urine volumes and osmolar clearances. FK 33-824 increased PRL and GH (p less than 0.001). ACTH was below assay sensitivity but cortisol was significantly lowered (p less than 0.001). Free water clearance was enhanced (p less than 0.01) and the remaining parameters were unchanged. Naloxone alone had no hormonal effect but abolished the increase in PRL and GH following injection of FK 33-824 without modifying the decrease in plasma cortisol or the increase in free water clearance following the same treatment. The results indicate that the effect of FK 33-824 on PRL and GH release is mediated by opiate receptors. Other mechanisms or naloxone nonsensitive receptors may be implicated in the effects recorded on cortisol and FWC.

Adrenocorticotropic Hormone↗