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Biomedical subjects

K Sundaram

Publications and source records attributed to K Sundaram.

171 records · Page 10Linked to original sources
PubMedDate not supplied

Nestorone: a progestin with a unique pharmacological profile.

Nestorone(R) (Nestorone 16-methylene-17alpha-acetoxy-19-norpregn-4-ene-3,20-dione), formerly referred to as ST 1435, is a potent progestin when given parenterally via sustained release formulations. The pharmacological profile of Nestorone was compared with that of levonorgestrel and 3-keto-desogestrel by steroid receptor binding studies and by in vivo bioassays in rats and rabbits. 3-Keto-desogestrel showed the highest binding affinity to progesterone receptors (PR) followed by Nestorone, levonorgestrel, and progesterone. The binding affinity of Nestorone to androgen receptors (AR) was 500- to 600-fold less than that of testosterone. However, both levonorgestrel and 3-keto-desogestrel showed significant binding (40 to 70% of testosterone) to AR. None of the progestins bound to estrogen receptors (ER). The progestational activity of Nestorone, levonorgestrel, and progesterone was compared using McPhail index in immature rabbits and pregnancy maintenance and ovulation inhibition tests in rats after subcutaneous (s.c.) administration. In all three tests, Nestorone was the most potent progestin. The progestational activity of Nestorone was also compared after oral and s.c. administration in rabbits. The potency of Nestorone was over 100-fold higher upon s.c. administration than via the oral route. The androgenic activity of progestins, based on the stimulation of ventral prostate (androgenic target) and levator ani (anabolic target) growth in castrated immature rats, showed good correlation with their binding affinity to AR. Nestorone showed no androgenic or anabolic activity. Nestorone did not bind to sex hormone binding globulin (SHBG), whereas both levonorgestrel and 3-keto-desogestrel showed significant binding to SHBG. The estrogenic/antiestrogenic activity of Nestorone was investigated in immature ovariectomized rats. In contrast to estradiol and levonorgestrel, Nestorone showed no uterotropic activity in ovariectomized rats. Despite significant binding to glucocorticoid receptors (GR), Nestorone showed no glucocorticoid activity in vivo. It is concluded that a strong progestational activity, combined with lack of androgenic, estrogenic, and glucocorticoid-like activities, confer special advantages to Nestorone for use in contraception and hormone replacement therapy.

Animals↗
PubMedDate not supplied

Outcome differences in younger and older patients with laryngeal cancer: a retrospective case-control study.

PURPOSE: Younger or older age has a significant impact on the outcome of patients with head and neck cancer. However, the data regarding outcomes based on age are conflicting. The aim of this article is to determine the impact of age on the outcome of laryngeal cancer. MATERIALS AND METHODS: A retrospective study was performed including all patients with squamous cell carcinoma of the larynx for over a 9-year period. The patients were divided into 3 groups based on age. The younger age group included patients 40 years of age and younger, the older group included patients over 80 years of age, and the remaining patients served as the control group. Descriptive statistics were used to summarize study data. Nonparametric quantitative and qualitative analyses were performed using the Mann-Whitney U test and Fisher's exact test, respectively. Survival analysis was performed using the generalized Wilcoxon test. The Cox proportional hazards model was used for multivariate analysis. RESULTS: Of the 209 patients with laryngeal carcinoma presenting to our institution over a 9-year period, 20 (10%) were < or =40 years and 15 (7%) were > or =80 years of age. No differences in TNM stage at presentation, treatment, or treatment-associated complications were observed based on age. However, younger patients were less likely to report tobacco (50%; P < .001) or alcohol (57%; P = .03) use and more likely to have human immunodeficiency virus infection (50%; P< .001). Older patients showed a trend toward having a worse baseline medical status. Recurrence was significantly more common in older patients (P = .02) and cause-specific survival significantly poorer for both younger and older patients (P = .002). CONCLUSIONS: The presentation and outcome of laryngeal cancer is influenced by the age at presentation. The differences may be related exact reason for the observed survival differences needs to be determined.

Adult↗
PubMedDate not supplied

Latissimus dorsi myocutaneous flap for secondary head and neck reconstruction.

PURPOSE: To review our experience and results with the use of pedicled latissimus dorsi myocutaneous flap (LDMF) for secondary reconstruction in head and neck surgery. METHODS: Twenty-two patients had LDMF, 17 of them for secondary reconstruction. Data were collected regarding the primary surgery, primary method of reconstruction, indication for secondary reconstruction, and outcome. RESULTS: Seventeen LDMF procedures were performed for secondary reconstruction. Flap success rate was 100%. Reconstructive goals were achieved immediately in 16 (94.1%) patients. CONCLUSION: LDMF is a thin flap with a large surface area and a long pedicle that allows it to reach any region in the head, neck, and scalp. Its main disadvantages are the need for lateral positioning of the patient and the fact that its pedicle is not protected with muscle. In our experience, LDMF provides an excellent reconstructive option especially in complicated cases of secondary reconstruction. It may be used in cases where a free flap is usually used, but with significantly reduced surgical time.

Adult↗
PubMedDate not supplied

The roles of estrogen and progestin in producing deciduosarcoma and other lesions in the rabbit.

The interactions of estrogens and progestins in producing decidualization, deciduosarcoma. and other lesions in the rabbit were explored. Steroids were delivered by silicone elastomer implants placed subdermally except for oral dosing in 1 experiment. Varying doses of levonorgestrel (LNG) were given with and without estradiol (E2) and varying doses of E2 with and without LNG. LNG alone delivered at an estimated mean dose of 233 microg/day did not result in endometrial decidualization or deciduosarcoma. Both conditions occurred when E2 was added to the regimen and increased as the dose of E2 was increased. Sixty microg of E2 per day produced endometrial decidualization in all test animals in a 2-month exposure, but deciduosarcoma occurred only when LNG was also supplied and increased as the LNG dose was increased. Progesterone given with E2 resulted in deciduosarcoma in most rabbits. Ethynylestradiol alone at 30 microg/day delivered by implants produced splenic and ovarian deciduosarcomas in 1 of 5 test animals. Adding LNG resulted in more numerous and widespread deciduosarcomas. These experiments indicate that exogenous estrogen is necessary for decidualization of the endometrium and to production of deciduosarcoma in the nonpregnant rabbit. Exogenous progestin promotes the process. Necrosis of the uterine wall tended to increase with increasing dose of estrogens.

Administration, Oral↗
PubMedDate not supplied

The antigonadotropic action of testosterone but not 7alpha-methyl-19-nortestosterone is attenuated through the 5alpha-reductase pathway in the castrated male rat pituitary gland.

The enzyme 5alpha-reductase plays a significant role in the prostate to amplify the action of testosterone (T) by converting it to a more potent androgen, dihydrotestosterone (DHT). The role of 5alpha-reductase in the testosterone feedback inhibition of gonadotropin secretion from the pituitary has not been elucidated. Therefore, we investigated the role of 5alpha-reductase on T action in in vitro and in vivo models. Castration has been reported to increase the 5alpha-reductase activity in pituitary glands. Hence, the effect of castration duration on the conversion of T to DHT by pituitary homogenates and the responsiveness of pituitary monolayer cell cultures to gonadotropin-releasing hormone (GnRH) challenge exposure were investigated. Incubation of [3H]-T with pituitary homogenates showed that the conversion of T to 5alpha-reduced metabolites was two- to threefold greater in pituitaries from rats who had been castrated for 14 days compared with those castrated for 1 day. In addition, the GnRH-stimulated release of LH from monolayer cell cultures of pituitaries from rats castrated for 1 day was twofold greater, whereas that from rats castrated for 2 weeks was six- to sevenfold greater compared with basal luteinizing hormone (LH) release. Hence we used rats castrated for 2 weeks to elucidate the role of 5alpha-reductase in T feedback inhibition. The inhibitory effects of the androgens T, 19-nortestosterone (19-NT), and 7alpha-methyl-19-nortestosterone (MENT) at 3 different concentrations (10(-9), 10(-7), and 10(-5) mol/L) on GnRH-stimulated LH release from monolayer cell cultures of pituitaries from rats castrated for 2 weeks were examined. All 3 androgens showed dose-dependent inhibition of LH release. MENT showed the greatest inhibition, followed by 19-NT and T. In the presence of finasteride (a 5alpha-reductase inhibitor), the inhibition of LH released by T and 19-NT were significantly greater. The inhibitory effect of MENT, which does not undergo 5alpha-reduction, was not altered by finasteride. In an in vivo study, rats castrated for 2 weeks received T with or without finasteride. There was a significantly greater suppression of serum LH in rats receiving T plus finasteride compared with those receiving T alone. These results suggested that 5alpha-reductase in the pituitary is not obligatory for the inhibitory action of T on gonadotropin secretion in the castrated rat. The action of MENT, a nonreducible androgen, on the pituitary is not affected by 5alpha-reductase.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMedDate not supplied

Effects on the spermatogonia of mice following treatment with sodium bisulfite.

The effect of sodium bisulfite on differentiating spermatogonia has been investigated. Adult mice were given either a single intraperitoneal injection (500, 600, 700, 800, 900 and 1000 mg/kg body weight) or repeated intraperitoneal injections (200 and 400 mg/kg body weight) of sodium bisulfite. In the latter case, the doses were administered 20, 30 and 40 times during 28, 42 and 56 days respectively. Different types of spermatogonia were enumerated from paraffin sections of tests stained with periodic acid--Schiff and Ehrlich's hematoxylin. No mortality was observed up to 700 mg/kg dose within 24 hours. At 1000 mg/kg dose 80% of the mice died within 24 hours post treatment. Cytotoxicity data showed that sodium bisulfite, at any of the dosage level tested after acute or repeated administration did not alter the population of various types of spermatogonia.

Animals↗
PubMedDate not supplied

Pharmacokinetics of 7 alpha-methyl-19-nortestosterone in men and cynomolgus monkeys.

Testosterone and its esters are widely used for androgen replacement therapy. In the prostate, testosterone ins 5 alpha-reduced to dihydrotestosterone (DHT), which leads to an amplification of its stimulatory activity in this and other tissues that have significant 5 alpha-reductase activity. While this amplification is essential during fetal development, it has potentially undesirable consequences during adult life. 7 alpha-Methyl-19-nortestosterone (MENT) is a potent synthetic androgen that does not undergo 5 alpha reduction and is therefore being investigated for long-term clinical use because it is expected to be less stimulatory to the prostate. Since we anticipate using MENT acetate (MENT Ac) rather than MENT as the form of this androgen in humans, the bioavailability of MENT following the administration of MENT and MENT Ac was investigated in cynomolgus monkeys. Equimolar concentrations of MENT or MENT Ac were administered as a continuous subcutaneous infusion via Alzet osmotic pumps. Serum MENT levels were measured by radioimmunoassay (RIA) in blood samples collected daily for 4 days during steady state. The serum MENT levels were not significantly different in the two groups (11.3 +/- 1.6 vs. 13.1 +/- 1.2 nmol/L). This suggested that MENT Ac was rapidly converted to MENT in circulation. The hydrolysis of MENT Ac to MENT was confirmed by the in vitro incubation of MENT Ac with blood or plasma and the demonstration of MENT in products following separation by high-performance liquid chromatography (HPLC). Following the demonstration of the safety of MENT Ac in subchronic toxicity studies in rats and rabbits, a pharmacokinetic study was performed in men. In normal men, a single intravenous bolus of 500 micrograms of MENT led to peak serum MENT levels at 3 minutes after dosing (when the first samples were collected), followed by an exponential decline, reaching undetectable levels by 180 minutes. The average terminal half-life and the metabolic clearance rate (MCR) were calculated to be 40 minutes and 2,360 L/day, respectively. The results of the pharmacokinetic studies show that in both men and monkeys, the MCR of MENT is much faster than the values reported for testosterone. The faster MCR can be attributed, in part, to the finding that, in contrast to testosterone, MENT showed no binding to sex hormone binding globulin (SHBG).

Adult↗