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Biomedical subjects

J F Noble

Publications and source records attributed to J F Noble.

At least 19 recordsLinked to original sources
PubMed2001

Double-blind, placebo-controlled study of INN 00835 (netamiftide) in the treatment of outpatients with major depression.

This study was designed to determine the safety, efficacy and pharmacokinetics of the antidepressant netamiftide (previously designated name: INN 00835) after 5 or 10 daily doses administered to patients diagnosed with major depression. Netamiftide was administered subcutaneously at a fixed dose of 18 mg/patient per day. Of the 55 enrolled patients, 22 were dosed for 10 days with drug, 11 for 5 days with drug followed by 5 days with placebo and 22 for 10 days with placebo only. The effect of treatment with netamiftide was evaluated by the following psychometric tests: Hamilton Depression Rating, Montgomery-Asberg Depression Rating Scale, Carroll Self-Rating Depression and Clinical Global Impression scales. None of the patients experienced significant adverse effects. A pharmacodynamic correlation (P < 0.05) was found between plasma drug concentrations and response to treatment. Highest plasma concentrations (Cmax) of netamiftide averaging 45.7 ng/ml were observed at 0.25 h after dosing. There were 89% responders in the group with Cmax > or = 45.7 ng/ml (minimum therapeutic concentration) versus 40% in the group with Cmax < 45.7 ng/ml. Onset of action was observed within 48 h after treatment, peak effect was observed at approximately 1 week after treatment and efficacy lasted during a 4-week follow-up period. Netamiftide is a promising antidepressant with rapid onset of action and with an excellent safety profile.

Adolescent↗
PubMed2000

A double-blind, placebo-controlled, efficacy, safety, and pharmacokinetic study of INN 00835, a novel antidepressant peptide, in the treatment of major depression.

BACKGROUND: INN 00835 is a synthetic pentapeptide with a potential for rapid onset of action as an antidepressant. Its efficacy was investigated in a pilot study in patients diagnosed with major depression. METHODS: Fifty two patients received either active drug - INN 00835 (26 patients) - or placebo (26 patients), subcutaneously at 0.2 mg/kg for 5 consecutive days. The patients were evaluated for an additional 4 weeks after treatment. Efficacy was evaluated by the following psychiatric rating scales: HAMD, MADRS, CSRS, CGI, and VAS. The effect of treatment was also evaluated by using a biochemical marker: changes in blood platelet serotonin (5HT) uptake rates in drug-treated patients compared to those in the placebo group. Plasma concentrations of INN 00835 were measured by LC/MS. RESULTS: Statistical analysis indicated a strong pharmacodynamic correlation between plasma drug concentrations at 1 h after dosing and the reduction in the severity of depression as measured by the psychiatric rating scales. A minimum effective plasma concentration (MEC) of INN 00835 was 5 ng/ml. Statistically significant differences in response to treatment (P<0.05) were found between patients with plasma concentrations above MEC and those in the placebo group, as well as between subjects with plasma concentrations above and below the MEC. The peak effect was observed after the 5-day treatment and the response to treatment persisted during the 4-week follow-up period. The change of 5HT uptake rates after treatment was significantly larger in the drug-treated group than in the placebo group. LIMITATIONS: This was a pilot study conducted in a relatively small population (52 patients) and the limited number of blood sampling times did not allow a comprehensive pharmacokinetic analysis. There was a relatively large placebo response. The results have to be confirmed in future, large scale studies. CONCLUSIONS: INN 00835 appears to be a promising drug for the treatment of major depression.

Adult↗
PubMed1990

The structure of cDNA clones encoding the aromatase P-450 isolated from a rat Leydig cell tumor line demonstrates differential processing of aromatase mRNA in rat ovary and a neoplastic cell line.

The conversion of androgens to estrogens is catalyzed by a complex of enzymes that includes a specific cytochrome P-450 aromatase (P-450arom). In this paper we describe the high level expression of aromatase activity in the rat Leydig cell tumor line, R2C. We also report the isolation of cDNA clones encoding the rat aromatase P-450arom from a cDNA library prepared from this cell line. Analysis of these cDNA clones predicts a protein sequence with a high degree of sequence conservation when compared to the chicken and human P-450arom enzymes. Notably, four of the cDNA clones were found to lack the last coding exon that contains the heme-binding domain, a structural feature essential for aromatase activity. These clones were found to contain instead a segment of genomic DNA derived from an unspliced intron. Northern analysis using a fragment of the coding region of the rat P-450arom cDNA as probe revealed that three species of P-450arom mRNa are expressed in rat ovary that are similar to those identified in RNA samples prepared from the rat R2C cell line. Analysis of the same samples of RNA using a probe derived from the 3' terminal intron segment of the rat aromatase cDNA clones that lack the heme-binding domain indicates that two of the species of aromatase mRNA transcripts present in both rat ovary and R2C cell lack the heme-binding domain and thus must encode a nonfunctional aromatase protein. These findings have important implications for the measurement of aromatase mRNA and appear to explain why three sizes of rat P-450arom mRNA exist on Northern analysis and why previous studies failed to demonstrate a clear relationship between aromatase mRNA, protein, and enzymatic activity in the rat ovary.

Amino Acid Sequence↗
PubMed1989

The vaginal epithelium of immature rats metabolizes androgens through an aromatase-like reaction: changes during the time of puberty.

Testosterone (T) at physiological levels can induce precocious vaginal opening without advancing the time of first ovulation. The present experiments were undertaken to test the hypothesis that the vaginal epithelium has the ability to aromatize androgens to estrogens. Using standardized conditions, we estimated aromatase activity using both 3H2O-release from [1 beta-3H]T and thin-layer chromatographic (TLC) characterization of estrogen formed after incubations with [1,2,6,7-3H] testosterone. Vaginal aromatase-like activity, as measured by the 3H2O-release assay, increased between the juvenile and peripubertal phases of development and remained elevated throughout puberty. In contrast, ovarian aromatase increased markedly during the early proestrus (EP) and late (first) proestrus (LP) phases of puberty but declined after the first ovulation. Vaginal aromatase-like activity was induced in vivo by either stimulation of ovarian steroidogenesis with pregnant mare's serum gonadotropin (PMSG), or by producing EP levels of serum T via testosterone-containing Silastic capsules. 4-Hydroxy androstenedione, a potent aromatase inhibitor, decreased both vaginal and ovarian aromatase activity in vitro in a concentration-dependent manner. Although the principal product of ovarian aromatase derived from [1,2,6,7-3H] T was identified as estradiol (E2), the identity of the vaginal estrogen product could not be firmly established. The vaginal metabolite comigrated with 16-keto-E2 in two TLC systems before and one TLC system after acetylation but failed to recrystallize as 16-keto-E2 diacetate and failed to co-elute with 16-keto-E2 diacetate on high performance liquid chromatography. This vaginal metabolite does not correspond to any of 13 steroids tested, including 2-hydroxy-E2, and it does not represent a 5 alpha-reduced metabolite of T.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1988

The expression of a functional cDNA encoding the chicken cytochrome P-450arom (aromatase) that catalyzes the formation of estrogen from androgen.

A complementary DNA (cDNA) copy of the aromatase P-450 has been isolated from a chicken ovary library using as probe a partial cDNA believed to encode the human placental aromatase. The predicted amino acid sequence of the chicken aromatase cDNA possesses regions of homology to that of its human counterpart, but only limited homology to other cytochrome P-450 enzymes. The introduction of the cDNA clone into COS-1 cells results in the production of high levels of aromatase activity. The chicken enzyme is targeted to the appropriate subcellular fraction in the transfected COS cells, and the apparent Km of the chicken aromatase activity, measured in microsomes prepared from the transfected cells, is similar to that of the enzyme prepared from chicken ovary microsomes. These findings establish that the cDNA clone encodes chicken ovarian aromatase and demonstrate that this protein can catalyze the three successive oxidation reactions necessary to form estrogen from androgen.

Amino Acid Sequence↗
PubMed1988

Methotrexate: assessment of in vivo clastogenicity and carcinogenicity.

The genotoxic and oncogenic potentials of methotrexate were studied in Sprague-Dawley rats. The rats received 0.1, 0.2, or 0.4 mg/kg of methotrexate as dietary admixtures on a 5 days on, 9 days off, regimen for 23 months. In the females of the high-dose group, there was a significant increase in mortality starting at 18 months. Significant increases in the number of rats with focal pulmonary interstitial fibrosis were seen in both sexes at the high-dose level. At the mid- and high-dose levels of both sexes, there was a significantly increased number of rats with myeloid and erythroid bone marrow hypoplasia. There was no evidence of either early onset or increased incidence of any tumor type in the treatment groups. Therefore, it is concluded that methotrexate does not have oncogenic potential. Also, at terminal sacrifice, bone marrow cells were harvested from selected animals on the last day of the 5-day dosing cycle and cytogenetic evaluation was performed. No significant increase in chromosomal aberrations was seen in any dose group relative to the control group. This observation further substantiates the absence of oncogenic potential due to methotrexate in rats.

Animals↗
PubMed1987

5 alpha-reduced androgens in the human fetal testis.

The androgen content was measured in testes from 34 male and in ovaries from 30 female embryos that varied in age from less than 12 to approximately 20 weeks. The 5 alpha-reduced androgens dihydrotestosterone and 3 alpha-androstanediol were found in testes at a level of about a 30th of that of testosterone at all ages examined, whereas very little or no testosterone, androstenedione, or either of the 5 alpha-reduced androgens were detected in the ovaries. Whether dihydrotestosterone plays a role in the development of the testes is unknown.

Androstane-3,17-diol↗
PubMed1987

[Temporomandibular arthrography].

Results of 104 arthrotomography scans with contrast of temporomandibular joints of 71 patients are used to define normal arthrography criteria (15.4% of cases). Reducible anterior displacements represented 28.8% of cases, non-reducible displacements 40.4%, perforations 12.5% (5.8% associated with a reducible luxation, 6.7% with a non-reducible luxation). The failure rate was 2.9%. Arthrography provides important information on articular morphology and dynamics, the state and position of the meniscus and of the posterior brake, and the state of the joint capsule. Performed by an experienced operator it possesses few complications.

Adult↗
PubMed1987

The effect of mitoxantrone treatment in beagle dogs previously treated with minimally cardiotoxic doses of doxorubicin.

Low-grade chronic cardiotoxicity as determined by myocardial biopsy specimens was induced in beagle dogs after four courses of doxorubicin hydrochloride (1.64 mg/kg, 34.0 mg/sq m) given intravenously once every 3 weeks. After this initial treatment, these dogs were separated into three groups. Two groups received six courses of mitoxantrone (0.25 mg/kg, 5 mg/sq m) commencing at 7 weeks or 19 weeks after the final doxorubicin treatment. The third group was treated with six additional courses of doxorubicin after an interval of 7 weeks. Up to seven sequential endomyocardial biopsies were performed to monitor the myocardial changes which were observed after the initial doxorubicin treatment. The low-grade cardiotoxic changes progressed for at least 7-11 weeks without any additional doxorubicin treatment, and stabilized or even partially reversed after 19 weeks of a treatment-free period. Dogs that received additional doxorubicin demonstrated progressive cardiotoxicity, associated with clinical signs, that resulted in death after a total of seven to ten courses of treatment (12-16 mg/kg, 238-340 mg/sq m cumulative dose). In dogs treated with doxorubicin followed by mitoxantrone after a 19-week treatment-free period, myocardial changes were shown to have stabilized and/or partially regressed. This study indicated that in beagle dogs four courses of doxorubicin (7 mg/kg, 136 mg/sq m cumulative dose) are the threshold dose at which non-life-threatening cardiotoxicity occurs. Residual toxic effects of doxorubicin may be erroneously interpreted as adverse findings attributable to other agents given subsequently during the susceptible period, ie, prior to stabilization of the myocardium. Mitoxantrone given after stabilization of doxorubicin-induced low-grade myocardial changes did not show additive or synergistic effects.

Animals↗
PubMed1986

Solubilization and partial purification of aromatase from chicken ovary.

Aromatase, the cytochrome P-450 that converts androgen to estrogen, has been solubilized from chicken ovarian microsomes with the nonionic detergent Emulgen 913. Following chromatography on gel filtration, anion exchange, dye affinity, and hydrophobic media, ovarian aromatase is purified up to 27-fold with 10-15% recovery. Separation of the cytochrome P-450 aromatase from NADPH cytochrome P-450 reductase is achieved during the purification. The partially purified enzyme is stable for as long as 6 months when frozen in liquid nitrogen in buffer containing dithiothreitol, glycerol, Emulgen and 150 mM KCl.

Animals↗
PubMed1986

Genetic toxicology evaluation of the novel semi-synthetic antibiotic piperacillin.

Piperacillin (T-1220, Pipracil) a semi-synthetic antibiotic was evaluated in a battery of genetic toxicology assays. The assays employed were: the microbial assay, the host mediated assay, the microbial assay incorporating urine samples from mice dosed with piperacillin, the in vivo cytogenetic assay, and the dominant lethal assay. In all assays, piperacillin produced consistent negative results indicating that piperacillin does not have mutagenic potential.

Animals↗
PubMed1986

Genetic toxicology profile of the new antineoplastic drug mitoxantrone in the mammalian test systems.

As part of safety evaluation and drug development, 1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl) amino]-ethyl]amino]-9,10-anthracenedione dihydrochloride (mitoxantrone, NSC 301739, CL 232,315, Novantrone) was tested in the mammalian test systems to determine its mutagenic potential. Mitoxantrone produced significant clastogenic effect in bone marrow of rats treated for 5 days at greater than or equal to 0.5 mg/kg i.p. It produced apparent increases in DNA repair in the rat hepatocyte UDS (unscheduled DNA synthesis) test and increased SCEs (sister chromatid exchanges) in CHO cells and mutant frequencies in mouse lymphoma assay. In the cell transformation test using C3H/10T 1/2 cl 8 cells, mitoxantrone did not produce significant increases in type II or type III transformed foci. In the dominant lethal test in rats, mitoxantrone administered 2 mg/kg/d i.p. affected matings of treated males, however, total implantations as well as early deaths resulting from matings with surviving males were unaffected. These results show the potential of mitoxantrone to produce genetic activity in vitro and in the somatic cells in vivo but inability of the drug to cause morphological transformation in vitro or genotoxic effect in the germinal cells in vivo. The biological significance of findings such as above is uncertain. Examination of genetic end-points such as chromosomal assays in rodents on life time studies which are currently being completed will delineate the significance, if any, of these findings.

Animals↗
PubMed1984

Androgen receptors are similar in fetal and adult rabbits.

In an effort to explain the separate roles of testosterone and dihydrotestosterone (17 beta-hydroxy-5 alpha-androstan-3-one) in virilizing the male fetus, we compared the binding of these androgens to cytosolic receptors from urogenital tract tissues of fetal and adult male rabbits. As measured by a direct binding assay, fetal and adult androgen receptors are similar in respect to specificity, affinity, and amount of binding. Apparent dissociation constants for dihydrotestosterone binding averaged 1.1 nM for fetal receptor and 0.8 nM for adult androgen receptors. Average apparent dissociation constants for testosterone binding were 4- to 24-fold higher than those for dihydrotestosterone in fetal and adult tissues. Nonradioactive dihydrotestosterone and testosterone competed for [3H]dihydrotestosterone binding to the androgen receptor in both adult prostate and fetal urogenital sinus in a manner consistent with their affinity for binding, whereas estradiol, progesterone, and cortisol were weak competitors for [3H]dihydrotestosterone. On sucrose density gradients, both testosterone and dihydrotestosterone were bound to a protein with a sedimentation coefficient of approximately 8S. Although androgen receptors were detectable in urogenital tubercle and urogenital sinus of both male and female fetuses on days 18 and 29 of gestation, we were unable to characterize androgen binding in fetal Wolffian ducts. The nature of the androgen receptor in this tissue remains unresolved. These findings are consistent with the hypothesis that dihydrotestosterone formation acts to amplify the androgenic signal in both the fetus and adult, but is not absolutely required for virilization.

Animals↗
PubMed1983

Characterization of the increased estrogen synthesis in skin fibroblasts from the Sebright bantam.

We have utilized the Sebright bantam chicken as a model system to explore the regulation of estrogen formation in peripheral tissues. As the result of a gene mutation, Sebright males develop a female feathering pattern associated with an increase in estrogen synthesis in skin and in fibroblasts cultured from skin. To provide insight into the mechanisms by which estrogen synthesis is increased we examined several parameters of the aromatase reaction in homogenates from control ovaries, Sebright ovaries and fibroblasts grown from Sebright skin: the pH optima; the apparent Km's for testosterone, 19-nortestosterone, androstenedione, 16-hydroxyandrostenedione, and NADPH; the apparent Ki's for 4-hydroxyandrostenedione, aminoglutethimide, dehydroepiandrosterone, and 19-hydroxytestosterone; and the inactivation of the reaction by heating. No qualitative differences were identified in the enzyme from Sebright and control birds.

Androstenedione↗
PubMed1982

Safety assessment of a new anticancer compound, mitoxantrone, in beagle dogs: comparison with doxorubicin. I. Clinical observations.

Twenty-four adult beagle dogs were divided into four groups of three males and three females and received iv infusions of doxorubicin (36.05 mg/m2), mitoxantrone (2.58 or 5.15 mg/m2), or the vehicle (0.9% normal saline). All animals were given a single dose once every 3 weeks. The duration of the study was 30 weeks. Animals were observed for toxicologic and cardiotoxic signs. The methods used to evaluate the cardiotoxic potential of both mitoxantrone and doxorubicin were sequential endomyocardial biopsies, ECGs, blood pressure, and serum levels of the cardiospecific isoenzyme CPK-MB (MB band of CPK). Animals given mitoxantrone had signs of gastrointestinal toxicity and fluctuating decreases in wbc counts. Animals given doxorubicin had signs of gastrointestinal toxicity and cardiotoxicity, as well as alopecia, fluctuating decreases in wbc counts, and diffuse erythema. All three male animals given doxorubicin died during the study from apparent congestive heart failure. All dogs treated with doxorubicin had positive CPK isoenzyme elevation, ECG changes, or progressive cardiomyopathy prior to administration of the last dose. None of these signs was observed in dogs treated with mitoxantrone. One male dog given mitoxantrone died during the course of the study.

Animals↗
PubMed1982

Safety assessment of new anticancer compound, mitoxantrone, in beagle dogs: comparison with doxorubicin. II. Histologic and ultrastructural pathology.

Beagle dogs received either doxorubicin hydrochloride (1.75 mg/kg) or mitoxantrone (0.125 or 0.25 mg/kg) iv once every 3 weeks. These doses were equivalent to 36.05 mg/m2 of doxorubicin and 2.58 or 5.15 mg/m2 of mitoxantrone. Sequential endomyocardial biopsies were performed approximately 2 weeks after the fourth (or fifth), seventh, and ninth doses in order to monitor histopathologic and ultrastructural changes during the study. Myocardial lesions that progressed with time and dose were observed in heart samples from dogs that received doxorubicin, but not in dogs that received mitoxantrone. The myocardial lesions induced by doxorubicin were observed with cumulative doses as low as 144 mg/m2. Myocardial changes, which did not progress with time and cumulative dose, were observed in dogs that received either dose of mitoxantrone. The earliest observable evidence of doxorubicin-associated cardiotoxicity was seen morphologically in biopsy material before clinical signs of cardiotoxicity. No evidence of cardiotoxicity, either morphologic or clinical, was seen in dogs treated with the maximum tolerated dose of mitoxantrone during the course of treatment. The dog appears to be a suitable model for studying the chronic cardiotoxic effects of anthracyclines and for monitoring effects of compounds such as mitoxantrone, which show a spectrum of activity and mechanism of action similar to that of anthracycline compounds.

Animals↗