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PubMed1977

Microbiological degradation of bile acids, further degradation of a cholic acid metabolite containing the hexahydroindane nucleus by Corynebacterium equi.

1. The further degradation of a cholic acid (I) metabolite, (4R)-4-[4alpha-(2-carboxyethyl)-3aalpha-hexahydro-7abeta-methyl-5-oxoindan-1beta-yl]valeric acid (IIa), by Corynebacterium equi was investigated. This organism effected ring-opening and gave (4R)-4-[2alpha-(2-carboxyethyl)-3beta-(3-carboxypropionyl)-2beta-methylcyclopent-1beta-yl]valeric acid (VI). The new metabolite was isolated as its trimethyl ester and identified by partical synthesis. It was not utilized by C. equi. 2. (4R)-4[4alpha-(2-Carboxyethyl)-3aalpha-decahydro-8abeta-methyl5-oxa-6-oxoazulen-1beta-yl]valeric acid (IVa), which is a hypothetical initial oxidation product in the above degradation, was not converted by C. equi into the expected metabolite (VI), but into 3 - [2beta - [(2S) - tetrahydro - 5 - oxofur - 2 - yl] - 1beta - methyl - 5 - oxocyclopent - 1alpha - yl]-propionic acid (VIII), the structure of which was established by partial synthesis. 3. Both the possible precursors of the metabolite (VI), an isomer of the epsilon-lactone (IVa), the gamma-lactone (XIa), and the open form of these lactones, the hydroxytricarboxylic acid (V), were also not utilized by C. equi. 4. Under some incubation conditions, C. equi also converted compound (IIa) and 3-(3aalpha-hexahydro-7abeta-methyl-1,5-dioxoindan-4alpha-yl)propionic acid (IIb) into 5-methyl-4-oxo-octane-1,8-dioic acid (III), (4R)-4-(2,3,4,6,6abeta,7,8,9,9aalpha,9bbeta-decahydro-6abeta-methyl-3-oxo-1H-cyclopenta[f]quinolin-7beta-yl)valeric acid (VII) and probably a monohydroxy derivative of compound (IIa) and compound (III), respectively. 5. The possibility that an initial step in the degradation of compound (IIa) by C. equi is oxygenation of the Baeyer-Villiger type, yielding compound (IVa), is discussed. Metabolic pathways of compound (IIa) to compounds (III), (VI), (VII) and (VIII) are also considered.

Cholic Acids↗
PubMed2006

Effects on the male endocrine system of long-term treatment with gonadotropin-releasing hormone agonists and estrogens in male-to-female transsexuals.

We studied hormonal changes resulting from long-term treatment with gonadotropin-releasing hormone agonist and 17beta estradiol valerate in 40 healthy middle-aged male-to-female transsexuals over a period of two years. All of the participants received injections of 3.8 mg goserelin acetate every four weeks in combination with 6 mg oral 17beta estradiol valerate per day for cross-sex hormone treatment for male-to-female transsexuals. There was a significant reduction in the levels of serum luteinizing hormone and follicle-stimulating hormone to the hypogonadal stage. Mean testosterone levels decreased by 97% to 0.52 and 0.59 nmol/l after 12 months and 24 months, respectively. There was a significant reduction in dehydroepiandrosterone sulfate by 37% after 12 months and 43% after 24 months, and androstendione by 29% after 12 months and 27% after 24 months, respectively. Cortisol levels were reduced by 43% and 50%, respectively. Estrogen levels were significantly increased from 77.51 to 677 after 12 months and 661 pmol/l after 24 months. Sex hormone-binding globulin and corticoid-binding globulin levels were significantly increased after 12 and 24 months. There was a significant decrease in all measured androgen fractions and cortisol during long-term treatment with gonadotropin-releasing hormone agonist and 17beta estradiol valerate. Apart from suppression of testicular hormone production, one possible interpretation is that treatment with long-term gonadotropin-releasing hormone agonist and 17beta estradiol valerate influences adrenal hormone levels in healthy middle-aged male-to-female transsexuals. Cortisol serum levels may be decreased due to estrogen-induced increase in corticoid-binding globulin.

Adolescent↗
PubMed1996

Effects of tamoxifen on serum prolactin levels, pituitary immunoreactive prolactin cells and uterine growth in estradiol-treated ovariectomized rats.

Pituitary effects of the antiestrogen tamoxifen are not well established, although estrogen is known to have a stimulatory role in prolactin secretion. Effects of tamoxifen on serum prolactin levels, pituitary wet weight and number of prolactin cells were studied. Ovariectomized female Wistar rats were injected, subcutaneously, with estradiol valerate, 50 or 300 micrograms/rat per week for 2 or 10 weeks. Tamoxifen was injected during the last days of estrogen treatment. Data were compared with two other groups, treated with estradiol valerate alone or estradiol valerate plus the dopamine agonist bromocriptine. Serum prolactin levels were increased by estrogen treatment with all doses used. Furthermore, rats treated with 300 micrograms of estradiol valerate, for 2 and 10 weeks, showed a clear increase in pituitary weight and number of prolactin cells (p < 0.05). Bromocriptine decreased prolactin levels, pituitary weight and the number of prolactin cells (p < 0.05). Tamoxifen associated to subacute period of estrogen administration resulted in a significant reduction of serum prolactin levels and pituitary weight (p < 0.05). No effects on prolactin levels or number of prolatin cells were observed with tamoxifen associated to chronic estrogen treatment. Tamoxifen also presented a dose-related inhibitory effect upon estrogen-stimulated rises in uterine weight and DNA content. In conclusion, the results of the present paper showed that tamoxifen reduced estrogen-stimulated prolactin levels in some, but not in other hormonal conditions and that these effects were not mediated by an inhibition of lactotroph cell growth. Further studies are needed to define the exact role of antiestrogens at molecular level in hyperprolactinemic states and their eventual connection with dopamine and its agonists.

Animals↗
PubMed1995

Long oestradiol replacement in an oocyte donation programme.

The objective of this study was to optimize, in terms of endometrial receptivity (embryo implantation), the limits of unopposed administration of oestrogens beyond 35 days in an in-vitro fertilization (IVF) and ovum donation programme. Oocytes donated by 182 women undergoing IVF were distributed among 186 women treated by ovum donation. Five groups of recipients were established according to the duration of oestradiol valerate administration, in a 'prolonged follicular phase' protocol, before embryo replacement, employing oestradiol valerate at increasing doses up to 6 mg/day. Gonadotrophin-releasing hormone analogues (GnRHa) were simultaneously administered in ovulatory patients. The dosage of oestradiol valerate was maintained until oocytes were available for insemination and subsequent transfer. Donors and recipients were equally distributed among groups in terms of age and cause of infertility. There was no difference among groups in serum oestradiol concentration the day in which progesterone was added to obtain a secretory transformation of the endometrium. An analysis of the ovum donation cycles showed no difference among groups in pregnancy and implantation rates after the replacement of a similar number of embryos. Successful implantation was observed even after 100 days of unopposed oestradiol valerate administration. Break-through bleeding increasingly appeared according to the duration of oestrogen replacement. These clinical observations provide evidence that the concept of 'prolonged follicular phase' oestrogen replacement for ovum donation can be maintained, at least as long as 15 weeks. However, because of the high (> 44%) incidence of break-through bleeding after 9 weeks, it is advisable to stop oestrogen treatment at this point.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2005

Improvement of portal hypertension and hepatic blood flow in cirrhotic rats by oestrogen.

BACKGROUND: In this study, we investigated the effects of oestrogen on nitric oxide synthase activity and nitric oxide production using the cirrhotic rat liver. MATERIAL AND METHODS: Cirrhosis was induced by dimethylnitrosamine. Estradiol valerate was subcutaneously injected twice at week 4 after dimethylnitrosamine treatment. Furthermore, subcutaneous injection of an oestrogen receptor antagonist, ICI-182.780, was performed 2 days before administration of estradiol valerate. Portal pressure and hepatic blood flow were measured. Nitric oxide synthase activity was assessed by l-citrulline generation. Sinusoidal endothelial cells were isolated from the cirrhotic rat liver and cultured. The cells were incubated with estradiol and/or ICI-182.780 for 24 h. Images for nitric oxide in sinusoidal endothelial cells were obtained using diaminofluorescein-2 diacetate. RESULTS: Cirrhotic rats treated with estradiol valerate showed a significant decrease in portal pressure and a significant increase in hepatic blood flow compared with those of control cirrhosis rats. However, in cirrhotic rats treated with ICI-182.780, the reduction of portal pressure and elevation of hepatic blood flow were completely inhibited. In cirrhotic rats treated with estradiol valerate, nitric oxide synthase activity was increased compared with that in control cirrhotic rats. The fluorescent level of intracellular nitric oxide in estradiol-stimulated, cultured, sinusoidal endothelial cells was higher than that in nontreated sinusoidal endothelial cells. CONCLUSIONS: The present study indicated that oestrogen plays an important role in the enhancement of nitric oxide production in sinusoidal endothelial cells of cirrhotic liver and reduces the portal pressure in cirrhotic rats.

Animals↗
PubMed1985

Contractile effect of short-chain fatty acids on the isolated colon of the rat.

The contractile effect of short-chain fatty acids on proximal, middle and distal segments of the rat colon was studied in vitro. A single contraction of the longitudinal muscle of the everted preparation of the middle and distal but not the proximal colon was induced by mucosal application of propionate, butyrate or valerate. Sigmoid dose-responses were observed between contraction and log dose of propionate, butyrate and valerate. The threshold concentration of short-chain fatty acids was between 0.02 and 0.04 mM. A maximal contraction was induced with 0.1 mM-propionate, butyrate and valerate. While acetate (up to 10 mM) and lactate (up to 30 mM) had no contractile effect at all. Serosal application of short-chain fatty acids was without effect, while the contractile response with up to 10 mM-propionate was abolished in both the middle and distal colon by scraping away the mucosa. Cumulative addition of short-chain fatty acids to the organ bath (without wash-out of the first dose) caused adaptation of the contractile response; thus, the effect of propionate (1 mM) was abolished by prior addition of acetate (10 mM) or lactate (30 mM) or propionate (1 mM) or butyrate (1 mM) or valerate (1 mM). The contractile effect of propionate was also inhibited by atropine (1 microM), procaine (0.4 mM) and tetrodotoxin (3 microM); was unaffected by hexamethonium (0.1 mM) and enhanced by eserine (10 nM). The results suggest that short-chain fatty acids, which are normal constituents of the colon, have the ability to stimulate colonic contractions, probably via an enteric reflex involving local sensory and cholinergic nerves.

Adaptation, Physiological↗
PubMed1982

Prophylaxis of radiation dermatitis with a topical cortisone cream.

Nineteen cancer patients receiving radiation therapy to the head, neck, chest wall, or abdomen were evaluated in a double-blind study to determine the effectiveness of 0.2% hydrocortisone valerate vs. placebo in reducing acute radiation dermatitis. Patients applied hydrocortisone valerate to one-half of the irradiate area and the placebo to the other half beginning two weeks after the initiation of radiotherapy and continuing until three weeks after completion. Left and right sides were scored each week with respect to erythema, dry desquamation, moist desquamation, ulceration, and the duration and intensity of symptoms such as soreness, burning, and itching. No statistically significant difference was found between the 0.2% hydrocortisone valerate and the placebo in the acute skin response or the symptoms of radiation dermatitis. The patients were evaluated three months following radiotherapy for evidence of skin atrophy. There were no differences found between hydrocortisone valerate and the placebo with respect to the late effects of radiation therapy.

Administration, Topical↗
PubMed2003

Effects of long-term estrogen replacement therapy versus combined hormone replacement therapy on nitric oxide-dependent vasomotor function.

Postmenopausal hormone replacement therapy (HRT) with estrogen may increase production of the predominant endothelium-derived vasodilator nitric oxide (NO) and consequently improve vascular reactivity. In contrast, concurrent progestin therapy may oppose this beneficial effect. We studied the effect of long-term estrogen HRT and combined HRT on vasomotor function and on plasma nitrate, which reflects the amount of NO in the circulation. As lipid peroxidation affects NO production and impairs endothelial function, we also measured the amount of the in vivo lipid peroxidation marker urinary 8-iso-prostaglandin F(2 alpha). The study group comprised 15 women receiving estradiol valerate HRT (mean age, 56 yr; treatment duration, 10.5 yr) and 15 women receiving combined HRT with estradiol valerate and levonorgestrel (mean age, 58 yr; treatment duration, 11.3 yr). The peak flow velocity (PFV) and pulsatility index of the common carotid and internal carotid artery and the abdominal aorta were measured by ultrasonography after long-term HRT (baseline), after a 4-wk pause and again 3 wk after reintroducing HRT. A statistically significant interaction between the groups and time points was observed in the PFV of the internal carotid artery (P = 0.011). In women taking estradiol valerate, the PFV values decreased significantly after withdrawal of HRT (P = 0.007) and increased again to the baseline level after reintroduction of therapy (P < 0.001). In women receiving combined HRT, the PFV remained stable over all study periods. At baseline, the PFV of women taking estradiol valerate correlated with the plasma nitrate concentration in the common carotid artery (r = 0.646; P = 0.009) and in the abdominal aorta (r = 0.579; P = 0.024). For pulsatility index and urinary 8-iso-prostaglandin F(2 alpha) excretion, there were no significant differences between the groups. Our results suggest that the favorable effects of long-term estrogen treatment on blood flow are at least partly mediated through NO. The addition of levonorgestrel to the treatment regimen appears to abolish this effect.

Aged↗
PubMed1990

Analysis of the gonadotropin surges in patients with premature ovarian failure undergoing steroid replacement cycles.

Ovarian steroids regulate pituitary gonadotropin secretion in normal cycles. This regulation has also been demonstrated in hypogonadal women receiving exogenous drugs, and has been suggested in women with premature ovarian failure receiving cycles of steroid replacement for oocyte donation. The purpose of this study was to analyse the gonadotropin surges in patients with premature ovarian failure using different experimental protocols. Those protocols were planned to induce the surges with different combinations of estradiol valerate and progesterone. According to the first protocol, a typical sequential administration of estradiol valerate and progesterone was given as a control. Maximal estradiol levels were detected on day 12 of the artificial cycle. The negative feed-back of estradiol was evident, with a significant (p less than 0.05) reduction of FSH and LH from the initial values. The positive feed-back showed a moderate LH surge in 6 out of 8 patients. In addition, a mild FSH increase was detected in 4 women. Both surges occurred on day 15 and were coincident with a decreased estradiol valerate and increased progesterone intake. A second protocol was scheduled for 5 patients in order to identify a real LH surge. High-dose estradiol valerate administration was maintained and progesterone was not administered. The LH surge clearly appeared on day 15 in all subjects, but the peak value was again moderate. The third protocol was designed in order to demonstrate a real FSH surge in 4 patients. Progesterone administration was advanced by 5 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1998

Topical mometasone. A review of its pharmacological properties and therapeutic use in the treatment of dermatological disorders.

Mometasone, a synthetic 16 alpha-methyl analogue of beclomethasone, is classified as a 'potent' glucocorticoid for dermatological use. It is available as 0.1% cream, ointment and lotion formulations for the treatment of patients with inflammatory glucocorticoid-responsive dermatoses. In patients with atopic dermatitis, the effect of mometasone 0.1% applied once daily over 2 to 3 weeks were similar to those of other glucocorticoids of similar potency, such as betamethasone dipropionate 0.05% twice daily and methylprednisolone aceponate 0.1% once daily. Mometasone 0.1% was significantly superior to twice-daily application of less potent glucocorticoids such as clobetasone 0.05%, hydrocortisone 1.0%, hydrocortisone butyrate and hydrocortisone valerate 0.2%. In patients with seborrhoeic dermatitis, mometasone 0.1% was more effective than ketoconazole 2.0% and hydrocortisone 1.0% in trials lasting 4 or 6 weeks. In the management of scalp psoriasis and psoriasis vulgaris, mometasone 0.1% applied once daily for 2 to 8 weeks was generally more effective than other glucocorticoids of similar or weaker potency such as betamethasone valerate 0.1%, fluocinolone acetonide 0.025%, fluticasone propionate 0.005%, triamcinolone acetonide 0.1% and hydrocortisone 1.0% and as effective as diflucortolone valerate 0.1%. Alternate day application of mometasone 0.1% for 2 weeks was as effective as once-daily application in maintaining symptom control in a small number of patients with psoriasis vulgaris. Although mometasone demonstrates greater anti-inflammatory activity and a longer duration of action than betamethasone, it has low potential to cause adverse systemic effects such as suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Moreover, its atrophogenic potential is low and no greater than that of other glucocorticoids in its class, such as betamethasone valerate. Transient, mild to moderate, local adverse effects such as burning, stinging, folliculitis, dryness, acneiform eruptions and signs of skin atrophy have been reported with mometasone. Mometasone has shown a low risk of primary sensitisation and cross-reactions in preliminary patch test studies. Mometasone is a well tolerated topical glucocorticoid effective in the management of patients with atopic dermatitis, seborrhoeic dermatitis, scalp psoriasis and psoriasis vulgaris. In addition to its low potential for causing primary sensitisation and cross-reactions with other topical glucocorticoids, mometasone offers the convenience of once-daily administration.

Administration, Topical↗
PubMed1977

Bioavailability of natural estrogens in young females with secondary amenorrhea.

The bioavailability of 17 beta-estradiol valerate, free 17 beta-estradiol and Premarin was studied in 24 subjects suffering from secondary amenorrhea. 17 beta-estradiol and estrone were determined by specific radioimmunoassay systems. All estrogens were administered as single oral doses. The amounts applied were 2 and 10 mg of 17 beta-estradiol valerate or equivalent amounts of the free estradiol and Premarin, respectively. No elevations of 17 beta-estradiol serum levels were recorded at the lower dosages, whereas the increases of estrone serum levels were approximately tenfold over basal levels. Similar data were recorded in a group of 3 women with normal cycles after the ingestion of 2 mg of 17 beta-estradiol valerate. All subjects responded to the higher doses of estrogens with a moderate increase of 17 beta-estradiol serum levels, but with much higher elevation of estrone levels. These data suggest a rapid conversion of 17 beta-estradiol into estrone. The biological activity of 2 mg 17 beta-estradiol valerate is discussed on grounds of a possible metabolism of estrone sulfate at the target tissues.

Administration, Oral↗
PubMed1975

Nonequilibration of acetyl units from fatty acids and glucose in mammary glands of lactating mice.

Lipid synthesis by lactating mouse mammary gland slices from [1-carbon14] propionate, [1-carbon14] valerate, and [1-carbon-14] heptanoate, in the presence of glucose and from [uniformly labeled carbon-14] glucose in the presence of propionate, valerate, and heptanoate was studied. Regardless of the labeled substrate, almost all of the radioactivity incorporated into the total lipid fraction was in triglycerides. In experiments with labeled glucose and either the propionic. the valeric, or the heptylic acid, the carbon-14 fatty acids in triglycerides were almost exclusively composed of even-chain fatty acids. When the substrate was either [1-carbon-14] propionate, [1-carbon-14] valerate, or [1-carbon-14] heptanoate, in the presence of glucose, the pattern changed to one in which a larger proportion of the radioactivity was in the odd-chain fatty acids. These findings suggest that in mouse mammary gland, acetyl units produced via beta-oxidation of fatty acids may not equilibrate with those formed from oxidation of pyruvate which is derived from glucose.

Acetates↗
PubMed1988

Net portal absorption of volatile fatty acids and L(+)-lactate by lactating Holstein cows.

Net absorption of L-lactate and VFA from the portal drained viscera of first lactation Holstein cows was measured at 4, 8, (four cows), 12, 16, and 20 wk (two cows) of lactation. Chronic indwelling catheters were installed 7 to 14 d postpartum in appropriate vessels to measure blood flow and net nutrient absorption. Cows were fed a completely mixed, 60:40 (dry basis) corn silage:supplement diet and milked every 12 h. Average metabolizable energy intake was 2.8X maintenance and mean milk production was 24.0 kg. Net absorption of lactate, any of the VFA, or their total was not affected by week postpartum. Net absorption of L-lactate, VFA, and alpha-amino N accounted in sum for 53.6% of metabolizable energy intake; contributions of each component to energy in absorbed nutrients were acetate and propionate, 29.5% each; alpha-amino N, 23.4%; L-lactate, 5.4%; n-butyrate, 5.3%; 2-methylbutyrate, 2.8%, and i-butyrate, i-valerate, and n-valerate, 1.2 to 1.6% each. Comparison of paired samples of blood and plasma showed that blood cells contribute to the transport of acetate, propionate, i-butyrate, and 2-methyl-butyrate but not of n-butyrate, i-valerate, or n-valerate.

Animals↗
PubMed2006

Short term changes in melatonin and cortisol serum levels after a single administration of estrogen to menopausal women.

OBJECTIVES: It has been well-documented that serum melatonin levels are insensitive to estrous or menstrual ovarian steroid variations in the female rat or the human. However, a negative coupling has been already demonstrated between the nocturnal serum melatonin peak and serum E2 concentration during the late premenopausal period in the woman. The objection of the present study was designed to determine if diurnal serum melatonin values can be also lowered by a single administration of estrogen. METHODS: We performed a detailed analysis of variations of serum estradiol, LH, FSH, melatonin and cortisol after one single I.M. injection of 2 mg of a conjugated estrogen, delestrogen (estradiol valerate) in 0.1 ml of oil. A 15 ml blood collection was done at 8:00 a.m. before the injection, and at 8:30 a.m., 9:00 a.m., 10:00 a.m., 12:00 noon, and 4:00 p.m. 17beta-estradiol, LH and FSH were determined by microparticle enzyme immunoassays kits. Melatonin determination was made using a RIA kit and cortisol was assayed by a RIA method. RESULTS: A significant rise in serum 17beta-estradiol was already seen by one hour after the injection of estradiol valerate. Then, an almost linear increase was observed up to at last eight hours after the injection of estradiol valerate. A significant decrease in serum LH was not seen before four hours after the injection of estradiol valerate. Overall, there was a trend toward a decline in serum melatonin and cortisol concentration. The decreasing trend of cortisol serum level was tested as significant over time (p< 0.001). However, the decrease in serum concentration did not reach a significant level for melatonin. CONCLUSION: Overall, these results show that after menopause an acute administration of estrogen during the early diurnal period of the day leads to a significant rapid decrease in cortisol serum values, but to only a partial non significant decrease in melatonin serum values.

Estradiol↗
PubMed1979

[A fundamental study on a bioassay for the antiphlogistic effect of topically applied antiinflammatory agents (author's transl)].

To establish a reliable laboratory assay for quantitating topical anti-inflammatory efficacy, the method of Tonelli et al was modified by employing felt fixed forceps, felt and sharp punch in Wistar rats. Croton oil, applied topically to the rat ear, elicited an acute phlogistic response which was maximal 6 hr after the application. The phlogistic response elicited by a single topical application of croton oil (1, 2, 5 and 10%) was increased in a dose-dependent manner, and croton oil, 5%, induced 63.2% increase of ear weight and was the optimal concentration for the experiment. Using this procedure, the antiphlogistic potencies of two corticoids were assayed under conditions of a blind test. ED50 of betamethasone valerate and diflucortolone valerate was 0.26 mg/ml and 0.0097 mg/ml, respectively, in Wistar rats, and 0.86 mg/ml and 0.016 mg/ml in Sprague Dawley rats, suggesting that diflucortolone valerate has an antiphlogistic potency of 27-56 relative to that seen with betamethasone valerate with minor differences in the strain of the rat. Our method should prove to be a useful assay for rapidly quantitating antiphlogistic activities of topically applied corticoids.

Administration, Topical↗
PubMed1984

Odd-carbon fatty acid metabolism in hepatocytes from starved rats.

The metabolism of odd-chain fatty acids was investigated in hepatocytes from 24 h-starved rats. Rates of glucose and 14CO2 production from [1-14C]propionate, [1-14C]valerate and [1-14C]nonanoate were maximal at 0.1 mM. Glucose production was greater with propionate as substrate than with valerate or nonanoate. Ketone body, lactate and pyruvate release were not affected by addition of the odd carbon fatty acids. It is concluded that hepatic odd-chain fatty acid metabolism in starvation is partly oxidative and partly gluconeogenic. Vasopressin and angiotensin II stimulated 14CO2 production from [1-14C] valerate and [1-14C]nonanoate but not from [1-14C]propionate and [1-14C]oleate in hepatocytes from starved rats. Nonanoate and valerate generate acetyl-CoA and propionyl-CoA, whereas oleate or propionate produce acetyl CoA and propionyl-CoA respectively. Given this stoichiometry, it is inferred that in hepatocytes from starved rats there must be an input of a tricarboxylic acid cycle intermediate to permit expression of the hormonal sensitivity.

Angiotensin II↗
PubMed1981

Protein-associated DNA breaks and DNA-protein cross-links caused by DNA nonbinding derivatives of adriamycin in L1210 cells.

The effects of Adriamycin derivatives on L1210 mouse leukemia cells were studied with the DNA alkaline elution assay. The exposure of exponentially growing cells to approximately equitoxic concentrations of N-trifluoroacetyladriamycin-14-valerate (13.8 microM) and its metabolites, N-trifluoroacetyladriamycin (9.0 microM) and N-trifluoroacetyladriamycinol (43.7 microM), for 1 hr in vitro resulted in a high frequency of protein-associated DNA breaks and DNA-protein cross-links. These effects were comparable to those observed with Adriamycin (2.8 microM) and with adriamycinol (26.9 microM). In contrast to Adriamycin and its metabolite adriamycinol, N-trifluoroacetyladriamycin-14-valerate and its two major metabolites do not bind to DNA. Despite the absence of this direct interaction, N-trifluoroacetyladriamycin-14-valerate and its metabolites produce alterations in DNA comparable with the effects of intercalating agents. No evidence for conversion of N-trifluoroacetyladriamycin-14-valerate to Adriamycin or adriamycinol was found in L1210 cells. The similar effects on DNA macromolecules, observed between intercalating and non-DNA-binding anthracyclines, are consistent with the concept that mechanisms other than direct interaction with DNA play a role in the toxic effects of these compounds.

Animals↗
PubMed2003

The effect of the PDE-4 inhibitor (cipamfylline) in two human models of irritant contact dermatitis.

BACKGROUND: New therapeutic approaches have to be considered in the treatment of irritant contact dermatitis (ICD). Recently, phosphodiesterase 4 (PDE-4) inhibitors have been introduced as nonsteroidal, antiinflammatory agents. These agents inhibit the secretion of the cytokines thought to be involved in the pathogenesis of ICD. We investigated the effect of a new selective PDE-4 inhibitor (cipamfylline) in human models using single and repeated exposures to an irritant in a blind, randomized pilot study with healthy volunteers. We compared the effect of cipamfylline ointment with a strong corticosteroid (betamethasone-17-valerate) and with a placebo ointment. METHODS: Ten volunteers were patch tested at four investigation sites with sodium dodecyl sulphate (1%) for 24 h. In a model that simulates chronic damage, 11 volunteers were patch tested with sodium dodecyl sulphate (0.2%) for 4 h daily for four consecutive days. The investigation sites were treated once a day with the above-mentioned agents. One site was left untreated. We used erythema scoring, measurements of transepidermal water loss (TEWL) and several immunohistochemical markers for epidermal proliferation and differentiation. RESULTS: Repeated application revealed that betamethasone-17-valerate caused a statistically significant reduction in erythema and TEWL compared to cipamfylline and placebo. We also observed a significant suppression of proliferating cells and cytokeratin 16 expression at sites treated with betamethasone compared to the other sites. In the model for acute ICD, no significant differences were seen between the investigated sites. CONCLUSIONS: Our results show that betamethasone-17-valerate may modulate the response in ICD. In this human model of ICD we could not confirm the efficacy of cipamfylline. Clinical studies are needed before the effect of PDE-4 inhibitors in ICD can be refuted with certainty.

3',5'-Cyclic-AMP Phosphodiesterases↗