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J Brownell

Publications and source records attributed to J Brownell.

16 recordsLinked to original sources
PubMed1992

Synthesis and biological evaluation of 5'-sulfamoylated purinyl carbocyclic nucleosides.

The first series of 5'-sulfamoylated carbocyclic purinyl nucleosides was synthesized and tested for antitumor and antibacterial activities. The target compounds were formed by reacting the 2',3'-acetonide-protected carbocyclic nucleosides with sulfamoyl chloride, followed by deprotection. The agents were tested for cytotoxic activity against P388 mouse leukemia cells. Two compounds, 5'-sulfamoyl carbocyclic adenosine (2) and 5-sulfamoyl-8-aza carbocyclic adenosine (6) exhibited IC50 values as low as 62 and 15 nM, respectively. These analogs inhibited protein biosynthesis and slowed down DNA and RNA biosyntheses in the P388 cells. None of the target molecules were as potent against Escherichia coli as they were against the tumor cells. Also, in cell-free systems, agents 2 and 6 were more effective inhibitors of protein synthesis in rabbit reticulocyte lysate than in E. coli. These new carbocyclic derivatives appear to be somewhat selective for eukaryotic over prokaryotic cells in affecting translation.

AMP Deaminase↗
PubMed1992

The effect of two dopaminergic drugs on menstrual function and psychological state in hyperprolactinemia.

OBJECTIVE: To investigate the effect of dopaminergic drugs on the well being in hyperprolactinemic patients. DESIGN: A psychometric test for well being, the SCL-90, was applied at baseline and in the 24th week of a double-blind randomized prospective study comparing the effectiveness and safety of the new dopamine d2 agonist CV 205-502 with bromocriptine. SETTING: Outpatient department of a university clinic for obstetrics and gynecology. PATIENTS: Twenty-four women with hyperprolactinemia, 9 of whom had a prolactinoma. Twenty had been treated before, and 11 were known to react unfavorably to bromocriptine. RESULTS: The effectiveness of CV 205-502 was identical to bromocriptine: its tolerability appeared to be better, especially in the initial phase of treatment. At baseline, the mean scores of the SCL-90 were significantly elevated over the reference values. Sixteen patients had normal scores. The elevations were caused by 8 patients with scores in the range found in psychiatric disease (211 +/- 30 [SD] [CV 205-502] and 182 +/- 32 [bromocriptine]). They were depressed, anxious, and hostile. At 24 weeks, the patients treated with CV 205-502 scored better (130 +/- 23.5) in the SCL-90 than the patients treated with bromocriptine (149.5 +/- 20). CONCLUSION: The markedly increased well being in patients treated with CV 205-502 cannot be explained by its better tolerability and is probably caused by a specific central activity of CV 205-502. Further research into the antidepressive properties of this compound is warranted.

Adult↗
PubMed1992

Effects of the dopamine agonist CV 205-502 in human prolactinomas resistant to bromocriptine.

In 21 patients with prolactinomas resistant to bromocriptine, we studied the effects of CV 205-502 on PRL hypersecretion and tumor mass, as assessed by consecutive computed tomography examinations. Cell culture studies were performed in 9 of such tumors. In 11 patients (group I; 52%) with a mean baseline plasma PRL level of 468 +/- 160 micrograms/L (+/- SE), normal PRL values were achieved after 1-6 months of treatment with 0.1-0.5 mg/day CV 205-502. Tumor size was reduced by 25% or more in 6 of 11 patients. In group II (n = 10), PRL levels (948 +/- 538 micrograms/L at baseline) were reduced by 48% after treatment with 0.1 mg/day CV 205-502. A progressive increase in the daily dose up to 0.5 mg did not further improve the partial reduction of PRL. No reduction in tumor size was observed in this group. The cell culture studies showed that 1) a brief exposure to both drugs provoked PRL suppression lasting 3 days; 2) in group I, CV 205-502 suppressed PRL release more efficiently than bromocriptine, with a maximal inhibition of 72% at 10(-9) mol/L; and 3) in group II, CV 205-502 only achieved a 26% inhibition of PRL release at 10(-8) mol/L, superimposable to that of bromocriptine. These data indicate that in at least half of such adenomas resistant to bromocriptine, CV 205-502, probably due to its higher affinity toward the D2 dopamine receptor, can overcome such resistance.

Adult↗
PubMed1991

CV 205-502, a new dopamine agonist, versus bromocriptine in the treatment of hyperprolactinaemia.

Forty-seven hyperprolactinaemic patients with serum prolactin (PRL) concentrations persistently above 1500 mU/l were treated with the new dopamine agonist CV 205-502 or bromocriptine in a prospective, randomized and double-blind fashion during a 24-week period. Two women had to be excluded because of poor compliance in the first month. Therefore 45 patients remained for evaluation. 81% of the patients in the CV 205-502 group and 70% of the patients in the bromocriptine group normalized their prolactin levels within the study period with a treatment dose as permitted in this protocol. In general serum prolactin normalized within 8 to 12 weeks of treatment. There were no differences between the two tested drugs regarding restoration of the menstrual cycle or disappearance of galactorrhoea. Both drugs gave rise to adverse reactions, especially during the initiation of therapy. However, the adverse reactions reported during CV 205-502 treatment were less severe and persistent than those attributed to bromocriptine. Patient acceptance of the new drug with regard to tolerability was judged by 90% of the women in that treatment group as very good or good, while 75% of those treated with bromocriptine evaluated its tolerability as very good or good. We conclude that CV 205-502 is highly effective in the treatment of hyperprolactinaemia with concomitant restoration of gonadal function and prevention of galactorrhoea. The tolerability of the drug seems better than of bromocriptine and therefore this drug is of value in the treatment of hyperprolactinaemic patients.

Adolescent↗
PubMed1991

CV 205-502 treatment of macroprolactinomas.

CV 205-502, a benzoquinoline, is a new nonergot dopamine agonist compound which has been shown to be effective in lowering PRL levels in normal volunteers and in hyperprolactinemic women. Seven patients (4 men and 3 women) presenting with hyperprolactinemia due to macroprolactinoma were treated with CV 205-502 given as a single daily dose at bedtime for up to 12 months. Six patients presented with impaired gonadal function and 2 with galactorrhea. All patients but one had previously been treated with bromocriptine and 4 had undergone pituitary surgery (3 with complementary radiotherapy). Six patients responded within a few weeks to CV 205-502 treatment, PRL levels being normalized (4 patients, 0.075 to 0.150 mg/day) or significantly reduced to restore normal gonadal function (2 patients, 0.225 mg/day). The seventh patient, who had previously been resistant to bromocriptine, also failed to respond to CV 205-502 treatment even after high doses (0.450 mg/day). Under CV 205-502 treatment, follow-up with magnetic resonance imaging revealed a reduction in tumor size of up to 52% of the initial volume in the "PRL-responders" whereas an increase in tumor size was observed in the "nonresponding" patient. No biological disturbance appeared during CV 205-502 treatment and the drug tolerance was very good, with mild side-effects being reported by only 2 patients. In conclusion, CV 205-502, given once daily, appears to be a safe and effective alternative to other dopamine agonists in the treatment of macroprolactinoma, by reducing hyperprolactinemia and tumor size. It was, however, of no benefit in the one patient whose macroprolactinoma had been resistant to bromocriptine.

Adult↗
PubMed1991

Lactation inhibition by the dopamine agonist CV 205-502.

In an open pilot study with a parallel group design 30 bottle feeding women were randomly assigned in a two to one ratio to receive either the new dopamine agonist CV 205-502 or bromocriptine for lactation inhibition. Ten women who intended to breast feed served as normal controls. All treated women reached prepregnant prolactin levels within 72 h with once-daily 0.075 mg of CV 205-502 or twice-daily 2.5 mg of bromocriptine, at starting doses of 0.05 mg and 2.5 mg respectively. Fifteen of the 20 women treated with CV 205-502 reported breast symptoms, 50% occurring on days 3 and 4 of treatment. Three of the 10 women treated with bromocriptine had breast symptoms between days 2 and 28. Overall efficacy and tolerance in the two groups was very good. Side effects did not differ between the groups, with the exception of pulse rate in the standing position, which was significantly higher in the bromocriptine treated group than in either the CV 205-502 group (P = 0.02) or the breast feeding group (P less than 0.01). The coagulation tests (fibrinogen, AT III, PTT and APTT) showed no significant differences between the three groups.

Administration, Oral↗
PubMed1991

The efficacy and tolerability of CV 205-502 (a nonergot dopaminergic drug) in macroprolactinoma patients and in prolactinoma patients intolerant to bromocriptine.

We studied the effect of CV 205-502 in 12 patients with macroprolactinomas and 8 patients with PRL-secreting tumors, who were selected because of previous repeatedly shown intolerance to bromocriptine in even small doses. We also investigated serum insulin-like growth factor-I (IGF-I) levels before and during CV 205-502 therapy. In 12 macroprolactinoma patients followed for 1 yr, 0.075-0.450 mg CV 205-502 lowered PRL levels by 91.2 +/- 5.4%. Only 3 of the patients had transient side-effects of nausea, dizziness, or fatigue. In eight patients with PRL-secreting tumors who were bromocriptine intolerant, CV 205-502 (0.075-0.300 mg daily) lowered PRL levels by 80.2 +/- 6.3%. Four of these patients showed transient side-effects (nausea, fatigue, and/or tachycardia). None of the patients discontinued therapy. There was a close correlation between pretreatment circulating PRL levels and tumor size, expressed in cubic millimeters. The decrease in pituitary tumor size after 52 weeks of CV 205-502 therapy (-74 +/- 6%) was also correlated with the decrease in PRL levels (P less than 0.01). In four patients with hypopituitarism, lowered IGF-I levels did not change during CV 205-502 therapy. However, in seven previously untreated patients with macroprolactinoma and normal CV 205-502 is a potent dopaminergic drug, which effectively controls PRL secretion and induces tumor shrinkage. At the doses used in our study, it causes only mild and transient side-effects in a minority of patients and can also be used to treat hyperprolactinemic patients who have shown intolerance to bromocriptine therapy.

Adult↗
PubMed1991

Clinical response and prolactin concentration in hyperprolactinemic women during and after treatment for 24 months with the new dopamine agonist, CV 205-502.

Twenty-four hyperprolactinemic women of whom 23 previously had been given bromocriptine, were treated between 6 and 24 months with a new non-ergot dopamine agonist, CV 205-502 (quinagolide; Norprolac, Sandoz Ltd, Basle Switzerland). Twenty-four weeks of treatment resulted in normalization of prolactin secretion in 16 of the 24 women. All of these women as well as 4 of those who remained hyperprolactinemic had regular menstrual bleedings. Fifteen of the 24 women were treated for 24 months and all had normalized prolactin levels in serum at the end of this period. Regular menstrual bleedings were observed in 13 women. Mild to moderate galactorrhea was recorded at baseline in 14 of the 15 women. After 24 months of treatment, mild galactorrhea was still present in 3 women. All 15 women had been treated with bromocriptine or other dopamine agonists before they entered the study. In 9 of the women the tolerability had been judged to be fair (N = 4) or poor (N = 5). Five of the 15 women had previously discontinued bromocriptine treatment because of adverse effects but had few problems tolerating CV 205-502. Prolactin in serum increased in all the patients after discontinuation of the medication. The results confirm that CV 205-502 seems to be a valuable compound in the management of patients with hyperprolactinemia.

Adult↗
PubMed1990

A double-blind study comparing a new non-ergot, long-acting dopamine agonist, CV 205-502, with bromocriptine in women with hyperprolactinaemia.

Twenty-two hyperprolactinaemic women were randomly allocated to two groups and treated with bromocriptine or the new, non-ergot, long-acting dopamine agonist, CV 205-502. The study was double-blind for 6 months. Four patients in the bromocriptine group, but none in the CV 205-502 group, discontinued the study because of adverse reactions. Adverse reactions in those receiving the new drug were milder and more transient than with bromocriptine. With once-daily doses of 0.075 mg CV 205-502, eight of 11 women achieved normal PRL concentrations after 8 weeks treatment (median (95% confidence limits), 352 (70-987) mU/l) compared with two of nine receiving a divided daily dose of 5 mg bromocriptine (1802 (1205-4438) mU/l) (P less than 0.002). With doses of 0.075-0.15 mg of CV 205-502, 10 of 11 women achieved normal PRL concentrations at 24 weeks compared with three of the remaining seven women on doses of 5-10 mg of bromocriptine. Regular menstrual bleeding was restored and galactorrhoea relieved in the majority of patients, with marginally greater efficacy with CV 205-502. CV 205-502 is highly effective for the long-term treatment of hyperprolactinaemia. It is better tolerated than bromocriptine, is effective in a once-daily dose, appears to be safe, and provides a valuable alternative to the dopamine agonist drugs in use today.

Adult↗
PubMed1990

Treatment of macroprolactinomas with a new non-ergot, long-acting dopaminergic drug, CV 205-502.

Eleven patients with prolactin-producing pituitary adenomas were treated with the new non-ergot, long-acting dopamine agonist, CV 205-502, for a period of 2-18 months (mean 11 months). Tumour volumes ranged from 1.9 to 64 ml in seven patients who were newly diagnosed, and from 0.1 to 3.1 ml in four patients who had been treated for macroprolactinomas by oral bromocriptine or depot bromocriptine (Parlodel LAR). Plasma prolactin values ranged from 3.5 to 360 U/l before institution of CV 205-502 treatment in these 11 patients. The following observations were made: (1) plasma prolactin values fell dramatically in all patients, and values within the normal range were obtained in five patients at once-daily doses of CV 205-502 between 0.075 and 0.300 mg; (2) tumour size reduction was obtained in all patients with macroadenomas on pretreatment CT scans. Tumour reduction was associated with the development of a partial empty sella in five patients, and with visualization of the pituitary in six cases; (3) bitemporal hemianopia (five patients) disappeared in four patients and improved in one patient. Oculomotor palsy receded in one patient; (4) signs of anterior pituitary insufficiency improved or normalized in most cases affected; (5) mild nausea or dizziness during the first days of CV 205-502 treatment and/or during several days after a dose increase were observed in three patients. We conclude that CV 205-502 in a once daily dose is an effective and safe alternative in the long-term treatment of macroprolactinomas.

Administration, Oral↗
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↗
PubMed1979

Poly(2-fluoroadenylic acid). The role of basicity in the stabilization of complementary helices.

The polymerization of 2-fluoroadenosine 5'-diphosphate by polynucleotide phosphorylase to give high molecular weight poly(2-fluoroadenylic acid), poly(fl2A), is described. Both the single-stranded and double-stranded (acid) forms of poly(fl2A) exhibit strikingly similar ultraviolet and circular dichroism spectra to those of poly(A), and the enzymatic polymerization rates and thermal hyperchromicities of the two polymers are also very similar. However, the pKa of poly(fl2A) for protonation at N-1 is 2.9 compared to 5.9 for poly(A) under similar conditions. Poly(fl2A) forms a triple-stranded helix with poly(U) which has ultraviolet and cd spectra very reminiscent of poly(A) . 2 poly(U), but no conditions could be found which permitted the formation of a double helix. In the Escherichia coli ribosome system poly(fl2A) codes for the synthesis of polylysine, as does poly(A), although the rate and extent of incorporation were less in the former case. The role of basicity of adenine N-1 in these interactions is discussed.

Drug Stability↗
PubMed1979

Prolactin. I. Mechanisms of control, peripheral actions and modification by drugs.

The role of neurotransmitters in the release of prolactin (PRL) is reviewed. Special attention is paid to dopamine (DA) as the possible prolactin-inhibiting factor (PIF). Among other agents, estrogens alone can act directly on the pituitary galactotropes without involving hypothalamic factors. Peripherally, in addition to its stimulatory action on mammary tissue, PRL exerts a permissive role on ovarian steroidogenesis. A possible physiological action of this hormone on the regulation of adrenal function remains uncertain. The secretory rhythms of PRL are described and the mechanisms involved are discussed. A number of drugs can modify the secreting pattern of PRL mainly by acting on the dopaminergic control mechanisms. The usefulness of such agents in the clinical evaluation of galactotrope cell function is reviewed.

Adolescent↗
PubMed1978

Photoaffinity labeling of the ribosomal peptidyl transferase site with synthetic puromycin analogues.

A photoaffinity labeling puromycin analogue, Nepsilon-(2-nitro-4-azidophenyl)-L-lysinyl puromycin aminonucleoside (NAP-Lys-Pan), was synthesized and used for investigation of the peptidyl transferase center of 70S riobsomes. Visible light irradiation of NAP-Lys-Pan led to covalent linkage of the analogue with Escherichia coli ribosomes. In a subsequent step, poly(uridylic acid) was employed to direct Ac[14C]Phe-tRNA to the P sites of the photolabeled ribosomes. Transpeptidation of Ac[14C]phenylalanine to the bound NAP-Lys-Pan resulted in selective incorporation of radioactive label into the peptidyl transferase A site. Dissociation of the ribosomes into subunits, and digestion of the RNA components, indicated that the radioactive label was incorporated into a protein fraction of the 50S subunit.

Acyltransferases↗