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Biomedical subjects

A Dupont

Publications and source records attributed to A Dupont.

At least 145 records · Page 8Linked to original sources
PubMed1985

Combination therapy with flutamide and castration (LHRH agonist or orchiectomy) in advanced prostate cancer: a marked improvement in response and survival.

Eighty-seven previously untreated patients with clinical stage D2 (bone metastases) prostate cancer have received the combination therapy with a pure antiandrogen and an LHRH agonist (or orchiectomy) as first treatment in a multicentre study for up to 34 months (average = 16.2 months). A positive objective response assessed according to the criteria of the US NPCP has been observed in all cases. Pain disappeared in all patients within 1 month and performance become normal in all (including 2 bedridden patients) within 4 months. Progression of the disease after a period of remission has been observed in only 8 patients. Only one patient has died from prostate cancer while 3 have died from other causes. The probability of continuing response and survival at 2 years for the patients who receive the combination treatment (Kaplan-Meier's method) is 81 and 91%, respectively. By contrast, in the randomized group who had orchiectomy alone, 4 of 7 have died from prostate cancer (P less than 0.05 as compared to combination therapy). In addition to a marked improvement in the remission rate and survival, combination therapy maintains a good quality of life, hot flashes and a decrease or loss of libido being the only side-effects.

Acid Phosphatase↗
PubMed1984

The effects of p-chlorophenylalanine (PCPA) treatment on the substance P content measured in discrete brain nuclei of normal and neonatally-induced hypothyroid rats.

Neonatal hypothyroidism is known to induce the accumulation of substance P and serotonin in many discrete brain nuclei of the rat. In this work, we have studied the effects of p-chlorophenylalanine (PCPA), a serotonin (5-HT) depleting drug, on the regional distribution of substance P in the brains of neonatally-induced hypothyroid and euthyroid rats. PCPA injections were given 48 and 24 h before sacrifice and the peptide content of discrete brain nuclei, removed by punches of frozen brain slices, was measured by radioimmunoassay. In hypothyroid animals, substance P levels were significantly increased in the n. paraventricularis, n. medialis thalami, n. arcuatus. n. mamillaris medialis, substantia nigra, area ventralis tegmenti, n. interpeduncularis, substantia grisea and n. dorsalis raphes. This hypothyroid-induced accumulation of substance P was completely abolished, and even reversed in some nuclei, by PCPA treatment. Interestingly, in normal rats, following PCPA treatment, the substance P level was increased in n. paraventricularis pars magnocellularis, n. ventromedialis (hypothalami), n. dorsomedialis pars dorsalis (hypothalami), n. amygdaloideus centralis, area ventralis tegmenti, substantia grisea, n. medianus raphes and n. dorsalis raphes. These results lend support to the existence of a physiological relationship between both substance P and serotonergic systems.

Animals↗
PubMed1984

Effect of neonatal hypothyroidism on the serotonin system of the rat brain.

The effects of neonatal thyroidectomy and thyroid hormone replacement therapy on the development of serotonin-containing neurons in discrete rat brain nuclei were studied. Newborn male rats were rendered hypothyroid by the injection of 125 mu Ci 131I, and, after 45 days, were compared with normal littermate controls and 131I-injected animals subsequently maintained by daily T4 injections. The serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) contents of discrete brain nuclei removed by punches of frozen brain slices were measured by HPLC with electrochemical detection. 5-HT and 5-HIAA contents were significantly increased in many nuclei of the hypothyroid rat brain. By blocking the biosynthesis of 5-HT with p-chlorophenylalanine we found that the activity of tryptophan hydroxylase is an important step in the stimulatory effect of hypothyroidism on the 5-HT and 5-HIAA contents. Furthermore, we demonstrated after blockage of monoamine oxidase activity with pargyline, a less pronounced decline of 5-HIAA in neonatal hypothyroid animals, thus causing a relative accumulation of this metabolite. These results demonstrate that there are important modifications of the 5-HT system in the brain of neonatal hypothyroid rats. This may have an important role in the development of hypothyroid-induced impairments of central nervous system function.

Animals↗
PubMed1984

Influences of both thyroid and bovine growth hormones on substance P, thyrotropin-releasing hormone, serotonin and 5-hydroxyindoleacetic acid contents in the lumbar spinal cord of developing rats.

Neonatal hypothyroidism was induced by injection of 131I on the first living day whilst neonatal hyperthyroidism was induced by daily administration of high doses of thyroxine (T4). Following decapitation, segments of the lumbar spinal cord were microdissected by a punch technique. We measured serotonin and 5-hydroxyindoleacetic acid (5-HIAA) contents by high performance liquid chromatography and both substance P and thyrotropin-releasing hormone (TRH) levels by radioimmunoassay. We demonstrated that: (1) neonatal hyperthyroidism decreased substance P and TRH levels in the dorsal and ventral horns respectively, without modifying serotonin and 5-HIAA contents; (2) neonatal hypothyroidism increased the concentration of substance P in dorsal horn, of TRH in ventral horn (confirming our previous work), of serotonin in ventral horn, and of 5-HIAA in both ventral and dorsal horns; (3) T4-replacement therapy abolishes hypothyroid effects on substance P, TRH, and 5-HIAA, but not on 5-HT accumulation; and (4) bovine growth hormone-replacement therapy has no therapeutic action on the hypothyroid-induced accumulation of substance P, TRH, serotonin and 5-HIAA.

Animals↗
PubMed1984

Serotonin, 5-hydroxyindoleacetic acid and substance P content of discrete brain nuclei in rats made hypo- or hyperthyroid in the neonatal period: effect of growth hormone treatment.

In order to determine the role of growth hormone (GH) in the therapeutic effect of thyroxine (T4), we measured the content of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and substance P in discrete brain nuclei of neonatally-induced hypothyroid rats and in neonatally-induced hypothyroid rats subsequently maintained on bovine growth hormone (b-GH) injections. Substance P was measured by radioimmunoassay whilst 5-HT and 5-HIAA levels were determined by HPLC with electrochemical detection. In neonatal hypothyroid rats, substance P concentration increased in 5 out of 11 brain nuclei dissected while 5-HT and 5-HIAA level increased in 7 out of 19 brain nuclei selected. Although b-GH-replacement therapy abolished the hypothyroid-induced accumulation of 5-HT and 5-HIAA in brain nuclei with exception of the substantia nigra zona reticulata, it did not influence the substance P accumulation. This suggests that the abnormal brain development observed during hypothyroidism may, in part, result from absence of growth hormone. We also observed that neonatal hyperthyroidism induced very little modification of 5-HT, 5-HIAA and substance P concentrations in discrete nuclei of the rat brain.

Animals↗
PubMed1984

Simultaneous administration of pure antiandrogens, a combination necessary for the use of luteinizing hormone-releasing hormone agonists in the treatment of prostate cancer.

Although castration levels of serum androgens are consistently achieved after 2-3 weeks of treatment with luteinizing hormone-releasing hormone (LHRH) agonists, the administration of these peptides alone in adult men is always accompanied by a transient increase in plasma testosterone and dihydrotestosterone levels, which lasts for 5-15 days at the beginning of treatment and is accompanied by disease flare-up in some cases, thus seriously limiting the acceptability of this otherwise efficient and well-tolerated treatment. The present data show that the simultaneous administration of a pure antiandrogen neutralizes the influence of the transient increase in serum androgens on prostate cancer, as indicated by the 60% decrease in serum prostatic acid phosphatase observed within 5 days of combined treatment with an LHRH agonist and a pure antiandrogen. The addition of a pure antiandrogen thus makes fully acceptable the use of LHRH agonists as an advantageous substitute for surgical castration and estrogens in the treatment of prostate cancer.

Acid Phosphatase↗
PubMed1984

Inhibition of basal and adrenocorticotropin-stimulated plasma levels of adrenal androgens after treatment with an antiandrogen in castrated patients with prostatic cancer.

The basal plasma levels of cortisol, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and testosterone were studied in 20 patients with advanced prostatic cancer receiving combined treatment with an LHRH agonist and an antiandrogen [5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl]-2 4-imidazolidinedione]. After 60 days of combined antihormonal therapy, plasma levels of testosterone decreased from 5.44 +/- 0.44 (SEM) to 0.136 +/- 0.052 ng/ml (2.5% of control). Somewhat unexpectedly, the plasma concentrations of the adrenal androgens DHEA and DHEA-S were reduced to 45 +/- 7 and 64 +/- 4% of control, respectively. The maximal reduction in plasma adrenal androgen levels occurred between 2 and 4 weeks of treatment. Whereas the increase in serum cortisol, 17-hydroxypregnenolone, and 17-hydroxyprogesterone concentrations 2 1/2 h after the injection of 0.25 mg human ACTH 1-24 was not affected by the combined treatment, the increment of DHEA and androstenedione after the same stimulus was reduced from 3.1 +/- 0.98 and 0.73 +/- 0.11 to 1.48 +/- 0.5 and 0.31 +/- 0.05 ng/ml, respectively. The reduced levels of serum DHEA and DHEA-S were not due to the LHRH agonist by itself, since similarly low levels of serum DHEA and DHEA-S were found in patients surgically castrated and receiving the same antiandrogen. These data suggest that treatment with an antiandrogen in castrated men inhibit the formation of adrenal androgens due to a blockade at the level of 17, 20-desmolase. The efficiency of the new combined antihormonal therapy (castration and antiandrogen) aimed at complete androgen neutralization in prostate cancer is thus further facilitated.

Adrenocorticotropic Hormone↗
PubMed1983

Limitation of access to highly palatable foods increases the norepinephrine content of many discrete hypothalamic and amygdaloidal nuclei of rat brain.

The norepinephrine (NE) concentration of 14 discrete brain nuclei of rats fed with either purina rat chow or highly palatable foods, given ad libitum or in a restricted quantity isocaloric with the Purina rat chow diet, was measured by high performance liquid chromatography with electrochemical detection. The NE level was significantly increased in the n. suprachiasmaticus, n. paraventricularis, n. arcuatus and n. amygdaloideus (medialis, corticalis, centralis, basalis pars lateralis, lateralis pars posterior) of rats fed with palatable foods given in restricted amount. The increased NE level seems to be associated with the limitation of access to highly palatable food whilst the regimen composition and the palatability of foods are not implicated in this phenomenon. Some hypothalamic and amygdaloid NE-containing neurones can be affected by food-restriction stress, suggesting a role of this neuronal system in feeding activity.

Amygdala↗
PubMed1983

Comparative effects of neonatal hypothyroidism and euthyroidism on TRH and substance P content of lumbar spinal cord in saline and PCPA-treated rats.

The effects of neonatal thyroidectomy and thyroid hormone replacement therapy on the content of substance P and TRH in the lumbar segment of the rat spinal cord were studied. The peptide content of discrete spinal cord regions removed by punches of frozen serial slices was measured by RIA. Animals receiving T4 replacement therapy were indistinguishable from normal littermates. In hypothyroid animals without PCPA-treatment, levels of TRH and substance P were significantly increased by 100% in the ventral and the dorsal lumbar spinal cord, respectively. Inhibition of serotonin biosynthesis by PCPA increased by 90% the substance P content in the dorsal horn of euthyroid rats and abolished completely the stimulatory effect of hypothyroidism on the TRH content of the ventral horn. These findings suggest the existence of a physiological relationship between substance P and TRH with the serotoninergic system in the rat spinal cord and that thyroid hormone is implicated in the normal development of the peptide-containing neurons in the rat spinal cord.

Animals↗
PubMed1983

New approach in the treatment of prostate cancer: complete instead of partial withdrawal of androgens.

To completely eliminate androgens of both testicular and adrenal origin, 37 previously untreated patients with advanced (stages C or D) prostatic cancer received the combination therapy using an LHRH agonist (HOE-766) and a pure antiandrogen (RU-23908). The response criteria developed by the National Prostatic Cancer Project were used. A positive response (assessed by bone scan and/or serum prostatic acid phosphatase measured by radioimmunoassay was observed in 29 of the 30 cases who could be evaluated by these objective criteria (97%). The objective response was parallel to a rapid and marked improvement of the clinical signs and symptoms related to prostate cancer (prostatism, bone pain, and general well being). In marked contrast, the same combination therapy applied to patients previously treated with high doses of diethylstilbestrol (13 patients) showed a positive objective response in only 55% of cases. In 23 previously castrated patients showing relapse, an objective response was seen in only 25% of cases after neutralization of adrenal androgens by the antiandrogen. Previous treatment with chlorotrianisene (TACE) had no detectable effect on prostatic cancer and patients having previously received such treatment had a rate of positive response similar to previously untreated patients (five of five). In the previously untreated patients receiving the combination therapy, a 60% fall in serum prostatic acid phosphatase was observed as early as five days after starting treatment, at a time when the serum androgen concentration was 100% to 200% above control. Combined treatment with the pure antiandrogen completely prevents flare-up of the disease, a complication previously found in a significant proportion of patients treated with an LHRH agonist alone. The present data show that complete withdrawal of androgens by combined hormonal therapy with the LHRH agonist (or castration) and a pure antiandrogen leads to a positive objective response in more than 95% of cases as opposed to 60%-70% as reported by many groups using the previous partial hormonal therapy (castration or high doses of estrogens). Adrenal androgens are most likely responsible for this difference. The present study also shows that the proportion of androgen-sensitive cells decreases from more than 95% in untreated patients to 25% to 55% after previous partial hormonal therapy. Such data clearly indicate that the previous partial hormonal therapy exclusively aimed at neutralizing testicular androgens left 25% to 55% of cancer cells having a relatively low sensitivity to androgens in a hormonal milieu compatible with their continuous growth. No clinical or biochemical side effect could be detected except those related to reduced serum androgen levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Acid Phosphatase↗