Biomedical subjects
Publications and source records attributed to N R Hall.
Bayesian methods are presented for assessing bioequivalence for studies in which a new formulation and a standard are administered simultaneously, and for Latin square designs which compare two or more new formulations to a standard. Two examples illustrate the application of the methods.
Endotoxin-free thymosin fraction 5 elevated corticotropin, beta-endorphin, and cortisol in a dose- and time-dependent fashion when administered intravenously to prepubertal cynomolgus monkeys. Two synthetic component peptides of thymosin fraction 5 had no acute effects on pituitary function, suggesting that some other peptides in thymosin fraction 5 were responsible for its corticotropin-releasing activity. In agreement with these observations, total thymectomy of juvenile macaques was associated with decreases in plasma cortisol, corticotropin, and beta-endorphin. These findings indicate that the prepubertal primate thymus contains corticotropin-releasing activity that may contribute to a physiological immunoregulatory circuit between the developing immunological and pituitary-adrenal systems.
The behavioral effects of the putative dopamine autoreceptor agonists, TL-99 and 3-PPP, were explored in animal procedures that reveal highly characteristic effects of neuroleptics currently in clinical use. Sidman avoidance responding in rats was not altered appreciably by doses up to 10 mg/kg TL-99 or 30 mg/kg 3-PPP. Higher doses of TL-99 attenuated Sidman avoidance performance in squirrel monkeys, although 3-PPP had no effect. Lever pressing for intracranial self-stimulation (ICSS) was attenuated in a dose-related fashion by TL-99 and 3-PPP, with relatively shallow dose-response relationships. A low dose of haloperidol (0.03 mg/kg) partly reversed the effects of 3-PPP (3 mg/kg) on lever pressing ICSS, but not those of TL-99 (3 mg/kg). Yohimbine (3 mg/kg) failed to alter the effects of TL-99 at a dose that abolished the suppressant effect of clonidine on ICSS. Analysis of within-session ICSS response decrement patterns indicated that TL-99 reduced ICSS to a greater extent towards the end of the session than during the first 5 min. No such within-session trend was produced by 3-PPP, suggesting that 3-PPP attenuates ICSS by virtue of a performance deficit. Similar conclusions were reached using a shuttlebox task that involved self-regulation of ICSS duration by rats. Therefore, the clinical profile of neuroleptics is unlikely to be mimicked precisely by 3-PPP or TL-99. Clinical trials of DA autoreceptor agonists for antipsychotic efficacy will indicate whether or not avoidance and ICSS behaviors are relevant to the detection of the intrinsic antipsychotic activity of drugs.
There is developing evidence that certain thymosin peptides and lymphokines produce a transient increase in steroid hormones when introduced systemically. Conversely, the repressive effect of adrenocortical steroids on the immune system is well documented. In the present study, the direct effect of certain components of the immune system on steroid output by rat adrenal fasciculata cells was tested. With this system, there was no direct steroidogenic effect of either the partially purified thymosin fraction 5, or any of the purified peptide components tested (thymosin alpha 1, alpha 7, or beta 4). These peptides also did not synergize the cellular response to ACTH, nor did they induce cAMP production by a ACTH- and NaF-responsive adrenal membrane preparation. Supernatants from Con A-stimulated spleen cells, which were demonstrated to contain lymphokine activity, and partially purified mouse interferon were also without a significant direct or synergistic effect on steroidogenesis by adrenocortical cells. These results suggest that the steroidogenic response to these peptides observed in vivo may be mediated by the central nervous system.
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Studies by many investigators have demonstrated that the immune system is subject to regular circadian fluctuation. Some rhythms that have been reported include circadian changes in components of the immune system, e.g., lymphocytes, and circadian variation in primary and secondary immune responsiveness. The observation that many of these rhythms are inversely correlated to the glucocorticoid rhythm has led to the suggestion that fluctuations in the immune system may be a result of the glucocorticoid circadian rhythm. This study was designed to see if thymosin-alpha 1 (Tsn-alpha 1), a 28-amino acid polypeptide isolated from bovine thymus that has been reported to influence thymocyte differentiation, might follow a circadian rhythm, and thus play a role in the periodicity of the immune system. In these experiments, groups of 10 C57BL/6 or Swiss Webster mice were sacrificed at 4- or 6-hr intervals over a 24-hr period. Serum Tsn-alpha 1 and corticosterone levels were determined by radioimmunoassay. Results from the first experiment showed that Tsn-alpha 1 undergoes a circadian rhythm (p less than 0.001) with an acrophase (time of peak levels) 1.5 hr after the onset of light, and an amplitude (amount of maximum variation from the 24-hr mean) of 0.493 ng/ml Tsn-alpha 1-like immunoreactivity. These results were confirmed in an experiment in which the animals were placed on a reversed light cycle. In a separate experiment, the Tsn-alpha 1 circadian rhythm persisted in mice thymectomized 6 mo. earlier. In this latter experiment, a significant increase in the amplitude of the corticosterone rhythm in the thymectomized relative to sham-operated controls was also observed. Although these experiments do not imply casuality, it is interesting that the time of peak Tsn-alpha 1 levels can be correlated with the time of optimal immune function.
Adult male mice were treated with various doses of 6-hydroxydopamine in order to assess the effects of this drug upon thymic dependent immunity. A consistent decrease in primary antibody titers to sheep erythrocytes was observed following treatment with this drug. Serum levels of thymosin alpha 1 were increased by day three after 6-OHDA with a return to normal by day five. Thymocyte terminal deoxynucleotidyl transferase changes were biphasic with an initial decrease after 6-OHDA followed by an increase. Changes in mitogen responsiveness were observed but were not consistently reproducible. Involvement of both catecholamines and corticosteroids in bringing about these observed changes was discussed.
Bioequivalence trials are carried out to compare two or more formulations of a drug containing the same active ingredient, in order to determine whether the different formulation give rise to comparable blood levels. We consider the 2 x 2 changeover experiment the compares two formulations, one of which is considered the standard. For a single univariate characteristic of the plasma concentration--time curve, a criterion for bioequivalence is proposed based on the posterior probability that the difference in formulation means is less than a specific percentage of the mean of the standard. The sensitivity of this posterior probability to alternative priors is investigated. Differences in carry-over effects can be incorporated within the Bayesian framework without restoring to the "all-or-nothing" approach implied by a preliminary test. The use of sequential experimentation is discussed.
Implants of crystalline PGE2 in the basal preoptic-anterior hypothalamic areas stimulates high levels of sexual receptivity in ovariectomized, estrogen-primed rats. Indomethacin, which blocks the synthesis of PGE2 failed to inhibit either estrogen- or estrogen plus progesterone-induced receptivity. Neither intracerebral nor subcutaneous administration of indomethacin diminished the display of steroid induced reproductive behavior without also causing a depression in open-field activity, and in some cases, causing gastrointestinal problems and even death. These results suggest the prostaglandin synthesis is not a required step in the mechanism by which estrogen and progesterone exert their behavioral effects. The possibility that PGE2 and LH-RH synthesis and/or release might contribute to a collateral mechanism for the induction of sexual receptivity was discussed.
A group of estrogen-primed, ovariectomized rats was adrenalectomized and tested for sexual receptivity following hypothalamic implantations of PGE2. The combination of PGE2 and adrenalectomy led to severe debilitation as manifested by greatly reduced open-field activity scores and inhibition of estrogen and progesterone induced sexual receptivity. Neither exogenous progesterone nor corticosterone was able to restore these behaviors to normal levels. A mechanism involving PGE2 and adrenalectomy-induced transient ischemia was discussed as a possible cause of the debilitation.
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In the first experiment gonadectomized male rats were injected daily with various combinations of vehicle (V), estradiol benzoate (E), dihydrotestosterone (D) and/or the anti-androgen cyproterone acetate (CA). The eight treatment combinations consisted of V, E, D, CA, E + D, E + CA, D + CA and E + D + CA. Only those males treated with both E and D were found to display ejaculations. Concurrent treatment with CA completely blocked ejaculatory behavior and it significantly reduced both mount and intromission frequencies. Examination of peripheral androgen target tissues indicated that following stimulation with D, CA effectively reduced seminal vesicle and penile weights, and penile lengths, but it did not reduce penile spines. In the second experiment gonadectomized female rats were treated with two daily injections of E, E + CA or E + the anti-estrogen CI-628. A second set of gonadectomized females received three daily injections of testosterone (T), T + CA or T + CI-628. On the day after completion of these injections all females received progesterone and were tested for sexual receptivity three hours later. Both E and T treated females were found to display the lordotic posture in response to mounting stimulation while both CI-628 and CA were found to block this behavior. In E treated females, CI-628 and CA were also found to reduce uterine weight. Thus, CA was shown to have anti-estrogenic as well as anti-androgenic properties. These results were discussed in terms of the aromatization and 5alpha reduction theories of testosterone action in sexual behavior.
A single 27 gauge implant of PGE2 into the periventricular region of the hypothalamus resulted in a significant increase in sexual receptivity in estrogen primed, ovariectomized female rats. Open field activity levels were only slightly decreased while rectal body temperature increased significantly over control values. It is postulated that the effects upon sexual receptivity might be mediated by PGE2 stimulated LRF release.
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The present study was designed to test the hypothesis that cyproterone acetate (C) might selectively block the actions of dihydrotestosterone (D) and via this action, function as an anti-androgen in male sexual behavior. Sexually experienced male SW mice, a strain previously shown to respond to D following castration, were divided randomly into six groups. Beginning on the day after castration, animals received SC injections for 21 days of either testosterone (T), (D), (C), (T+C), (D+C) or vehicle (V). C was found to significantly reduce seminal vesicle and body weights in all androgen treated groups. There was no evidence to support the contention that C selectively blocks the action of D. To the contrary, in sex tests C maintained palpations, thrust mounts, with intromissions and mounts with ejaculations. Indeed, only animals receiving C alone or in combination with T and D exhibited ejaculations throughout the testing. These results suggest that in the SW mouse, C can work like an androgen in the maintenance of male sexual behavior.
The conditions under which CCK-8-S may block opiate-induced analgesia were examined in detail. A U-shaped dose-response relationship was observed for the ability of CCK-8-S to attenuate (by approximately 50%, at most) morphine-induced tail flick analgesia. The analgesic effects of morphine in the hot plate or acetic acid-induced stretching tests were not altered by CCK-8-S at doses that antagonized morphine in the tail flick test. Tail flick latency elevations induced by meptazinol, a putative mu-1 receptor agonist, were also attenuated by CCK-8-S according to a U-shaped dose-response relationship, but those induced by U-50,488, a kappa agonist, were not antagonized by CCK-8-S doses that attenuated morphine analgesia. Thus, the ability of CCK-8-S to antagonize opiate analgesia does not follow a conventional dose-response relationship, does not extend to all tests of analgesia and may not extend to all opioid drugs. Analgesia mediated by the mu-1 opioid receptor subtype may be more amenable to antagonism by CCK-8-S than that mediated by the kappa receptor subtype.