Placebo Implants Research Articles

Improving Clinical Outcomes in Treating Heroin Dependence

Oral naltrexone hydrochloride effectively antagonizes heroin, but its utility is limited by patient noncompliance. Sustained-release preparations may overcome this limitation. To compare the safety and efficacy of a single-treatment sustained-release naltrexone implant with daily oral naltrexone treatment. Seventy heroin-dependent volunteers entered a randomized, double-blind, double-placebo controlled trial with a 6-month follow-up period. Eligibility criteria were DSM-IV opioid (heroin) dependence; age 18 years or older; willingness to be randomized; residing in the Perth, Western Australia, metropolitan area; and completion of preclinical screening and written consent. A total of 129 eligible participants were identified, and 70 (54%) provided informed consent and were randomized as per the study design. Participants received oral naltrexone, 50 mg/d, for 6 months (plus placebo implants) or a single dose of 2.3 g of naltrexone implant (plus placebo tablets). (1) Maintaining therapeutic naltrexone levels above 2 ng/mL; (2) return to regular heroin use (>or=4 d/wk); (3) other heroin use and abstinence; (4) use of illicit nonopioid drugs; (5) number of opiate overdoses requiring hospitalization; (6) treatment-related unexpected and expected adverse events; and (7) blood naltrexone levels (ie, pharmacokinetic profile) for recipients of active naltrexone implants. More participants in the oral vs the implant group had blood naltrexone levels below 2 ng/mL in months 1 (P < .001) and 2 (P = .01); in addition, more oral group participants had returned to regular heroin use by 6 months (P = .003) and at an earlier stage (median [SE], 115 [12.0] days vs 158 [9.4] days). There were 10 trial-related, unexpected adverse events. One serious adverse event, a wound hematoma, was associated with surgical implantation. Naltrexone blood levels in implant recipients were maintained above 1 and 2 ng/mL for 101 (95% confidence interval, 83-119) and 56 (39-73) days, respectively, among men and 124 (88-175) and 43 (16-79) days among women. The naltrexone implant effectively reduced relapse to regular heroin use compared with oral naltrexone and was not associated with major adverse events. Clinical Trial Registration anzctr.org.au Identifier: ACTRN12606000308594.

Corticosterone Treatment Has Subtle Effects on Thermoregulatory Behavior and Raises Metabolic Rate in the New Zealand Common Gecko, Hoplodactylus maculatus

Baseline concentrations of adrenal glucocorticoids often vary substantially in wild vertebrates in the field. In at least one ectotherm, females of the New Zealand common gecko, Hoplodactylus maculatus, this variation in baseline (not stress-induced) corticosterone appears to be correlated with variation in body temperature (T(b)). We tested the hypothesis that elevated corticosterone affects thermoregulatory behavior so as to raise T(b) and that, independently of an increase in T(b), corticosterone increases metabolic rate. Compared with geckos receiving placebo implants, those that received implants containing corticosterone displayed heat-seeking behaviors, had a higher mean T(b) in their home cages, and, at one time of day, selected a higher mean T(b) in a thermal gradient. At a constant T(b), corticosterone-treated geckos consumed oxygen at a rate approximately 50% higher than placebo geckos. This work has far-reaching implications for a variety of physiological and ecological processes in ectotherms and suggests that corticosterone should be considered as a variable influencing T(b) and metabolism in future studies.

Progesterone modulates aggression in sex-role reversed female African black coucals.

Testosterone is assumed to be the key hormone related to resource-defence aggression. While this role has been confirmed mostly in the context of reproduction in male vertebrates, the effect of testosterone on the expression of resource-defence aggression in female vertebrates is not so well established. Furthermore, laboratory work suggests that progesterone inhibits aggressive behaviour in females. In this study, we investigated the hormonal changes underlying territorial aggression in free-living female African black coucals, Centropus grillii (Aves; Cuculidae). Females of this sex-role reversed polyandrous bird species should be particularly prone to be affected by testosterone because they aggressively defend territories similar to males of other species. We show, however, that territorial aggression in female black coucals is modulated by progesterone. After aggressive territorial challenges female black coucals expressed lower levels of progesterone than unchallenged territorial females and females without territories, suggesting that progesterone may suppress territorial aggression and is downregulated during aggressive encounters. Indeed, females treated with physiological concentrations of progesterone were less aggressive than females with placebo implants. This is one of the first demonstrations of a corresponding hormone-behaviour interaction under challenged and experimental conditions in free-living females. We anticipate that our observation in a sex-role reversed species may provide a more general mechanism, by which progesterone--in interaction with testosterone--may regulate resource-defence aggression in female vertebrates.

Cerebral Hypoperfusion Increases Estrogen Receptor Abundance in the Ovine Fetal Brain and Pituitary

Background/Aims: Estrogen is an important component of fetal neuroendocrine function in late-gestation fetal sheep; however, little is known about the regulation of estrogen receptor abundance in the brain and pituitary of fetuses. The present study was performed to test the hypotheses that estrogen receptor abundance in the fetal brain and pituitary are influenced by circulating estradiol concentrations and that they are acutely regulated after cerebral hypoperfusion. Methods: We studied 16 time-dated fetal sheep (124–128 days gestation) that were chronically catheterized and instrumented at least 5 days before study. Four groups (n = 4 each) were studied in which fetuses received estradiol (0.25 mg/day, producing physiological increases in fetal plasma estradiol concentrations) or placebo implants, and in which fetuses received a 10-min period of brachiocephalic occlusion (BCO) or sham-BCO. One hour after BCO or sham-BCO, fetuses were euthanized and tissues rapidly removed for analysis of estrogen receptors (ER)-α and -β at the mRNA and protein levels. Results: Both BCO and estradiol treatment were effective in changing ER expression, although the effects were region-specific. BCO dramatically increased ER-α in the pituitary and both ER-α and ER-β in the brainstem, while decreasing ER-α expression in the hypothalamus. Estradiol treatment decreased ER-α expression in the hypothalamus, whereas it increased ER-α expression in the brainstem, cerebral cortex and hippocampus. Conclusions: We conclude that the expression of ER-α and ER-β in the brain and pituitary of fetal sheep are influenced by circulating estrogen concentrations and acutely regulated in response to cerebral hypoperfusion.

Chronic corticosterone elevation and sex‐specific augmentation of the hypoxic ventilatory response in awake rats

Perinatal stress disrupts normal development of the hypothalamo-pituitary-adrenal (HPA) axis. Adult male (but not female) rats previously subjected to a stress such as neonatal maternal separation (NMS) are characterized by chronic elevation of plasma corticosterone (Cort) levels and an abnormally elevated hypoxic ventilatory response through mechanisms that remain unknown. The present study tested the hypothesis that a chronic increase of plasma Cort levels alone augments the ventilatory response to hypoxia in adult rats. Three groups of Sprague-Dawley male and female rats were used (control, placebo and Cort implants). Rats subjected to chronic Cort elevation received a subcutaneous Cort implant (300 mg) 14 days prior to ventilatory measurements, whereas sham-operated rats received placebo implants. Controls received no treatment. Plasma Cort levels and body weight profiles were measured to assess protocol efficiency. Whole body plethysmography was used to measure ventilatory activity and metabolic indices during normoxia and following a 20 min period of moderate hypoxia (12% O(2)). Male rats implanted with Cort showed a ventilatory response to hypoxia higher than placebo-treated rats; this effect was mainly due to a larger tidal volume response. In females, Cort treatment increased the breathing frequency response but the effect on minute ventilation was not significant. Taken together, these data show that chronic elevation of Cort alone increases the ventilatory response to hypoxia, but in a sex-specific manner. These data raise important questions regarding the mechanisms underlying the sexual dimorphism of this effect and the potential link between HPA axis dysfunction and respiratory disorders related to abnormal ventilatory chemoreflex.

Chronic Treatment of Male Tammar Wallabies with Deslorelin Implants During Pouch Life: Effects on Development, Puberty, and Reproduction in Adulthood1

The present study evaluated the effects of chronic GnRH agonist (deslorelin) treatment on sexual maturation in the male tammar wallaby. Slow-release deslorelin or placebo implants were administered to male pouch young (n = 10/group) when they were between 180 and 200 days old, to determine if disruption of the pituitary-testicular axis during development altered the timing of sexual maturation or had long-term effects on adult reproductive function. Deslorelin treatment caused retardation of testicular growth and reduced the serum FSH and testosterone concentrations between 12 and 24 mo of age. Maturation of the hypothalamic-pituitary-testicular axis was also delayed in treated animals at 13 and 19 mo of age. Despite these alterations in the pattern and timing of neuroendocrine development, sexual maturation was not permanently blocked in these animals and deslorelin-treated animals reached sexual maturity at the same age as treated animals, as evidenced by a fully functional pituitary-testicular axis and proven fertility at 25 mo of age. The ability of the treated animals to reach puberty at the same time as control animals, despite delayed maturation of the hypothalamic-pituitary-testicular axis, suggests that puberty in the male tammar wallaby is additionally regulated by other, gonadotropin-independent factors.

CAN TESTOSTERONE INHIBIT GROWTH?

Ever since Darwin published The descent of man, and selection in relation to sex, people have been puzzled about the forces that drive sexual differences in body size. But as Robert Cox and Henry John-Alder point out in this issue of The Journal of Experimental Biology `relatively little is known about the proximate physiological mechanisms underlying sex differences in growth'. While males are large and females small in many vertebrate species, a few species buck this trend; female Sceloporus virgatus lizards are larger than their males. Knowing that testosterone promotes growth in many species, the team suspected that testosterone actually inhibits growth in S. virgatus males. Cox and John-Alder decided to test the effects of testosterone on S. virgatus males and compare the steroid hormone's effects on Sceloporus jarrovii lizards, whose males are larger then their females(p. 4679).Collecting juvenile males of both species from the Chiricahua Mountains in Arizona, the team divided both species into three further groups; one that was castrated and received a testosterone implant, another that was castrated and received a placebo implant and a control group that was not castrated and received a placebo implant. Having measured each male's length, the team released the males back into the wild, leaving them for just over 40 days before recapturing them again.Sure enough, the castrated S. virgatus males that didn't receive testosterone were larger than the males that were exposed to testosterone. On the other hand, the castrated S. jarrovii males that carried placebo implants were smaller than the castrated males whose implants carried testosterone. Testosterone inhibits growth in S. virgatus while stimulating it in S. jarrovii males.But why does testosterone have the opposite effect on S. virgatusmales than S. jarrovii males? Cox and John-Alder suspect that reproduction may be an energetically costly process for the S. virgatus males, so they may have traded a smaller stature for their higher reproductive costs.

Estradiol Regulates Angiopoietin-1 mRNA Expression Through Estrogen Receptor-α in a Rodent Experimental Stroke Model

Female, compared with male, animals are protected from cerebral ischemic injury. Physiological concentrations of 17beta-estradiol (E2) reduce damage in experimental stroke. E2 augments angiogenesis in reproductive organs and noncerebral vascular beds. We hypothesized that E2 protects brain in stroke through modulation of angiogenesis. We quantified molecular markers of angiogenesis and capillary density before and after unilateral middle cerebral artery occlusion (MCAO). Female animals were ovariectomized, treated with 25 microg E2 or placebo implants, and subjected to 2-hour MCAO and 22 hours of reperfusion. Brain angiopoietin-1 (Ang-1), Ang-2, Tie-1, Tie-2, vascular endothelial growth factor (VEGF), VEGF R1, and VEGF R2 mRNA levels were determined by RNAse protection assays, and CD31-positive vessels were counted. E2, but not ischemia, upregulated cerebral Ang-1 mRNA by 49%. Capillary density was higher in the brains of E2-treated animals. In estrogen receptor-alpha knockout (ERKO) mice, E2-mediated induction of Ang-1 mRNA was absent relative to wild-type littermates. These results suggest that E2 increases Ang-1 and enhances capillary density in brain under basal conditions, priming the MCA territory for survival after experimental focal ischemia.

Novel Slow- and Fast-Type Drug Release Round-Window Microimplants for Local Drug Application to the Cochlea: An Experimental Study in Guinea Pigs

Novel drug release microimplants (0.8 × 1.14 mm; custom-made by Leiras, now Schering OY, Finland) of slow- and fast-release types containing either 0.9 mg beclomethasone or no drug at all were placed unilaterally onto the round-window membrane (RWM) of 45 guinea pigs for a maximum duration of 28 days. The following parameters were tested on days 1, 14 and 28 after implantation: threshold levels of beclomethasone in the perilymph of the scala tympani, auditory brain stem responses (ABR thresholds and ABR threshold shifts), RWM morphology and hair cell loss (cytocochleograms). None of the animals in the non-implanted control group (n = 5) or placebo implant group (n = 15), but all animals in the slow-release-type implant group (n = 15) and fast-release-type implant group (n = 15) revealed the presence of beclomethasone on day 1 (34.9 and 64.3 pg/µl, respectively), day 14 (43.8 and 46.9 pg/µl, respectively) and day 28 after implantation (4.7 and 60.5 pg/µl, respectively). Histology of the RWMs appeared normal, and cytocochleograms revealed no inner hair cell loss and outer hair cell loss within normal ranges (from 0.5 ± 0.4 to 0.8 ± 0.2% per cochlea) in both ears in all experimental groups at any time during examination (days 1, 14 and 28). Initial values of ABR thresholds at 3, 6, 9 and 12 kHz did not differ significantly in any of the experimental groups. In non-implanted controls, no significant differences of ABR thresholds were observed in all frequencies tested in either ear on days 1, 14 and 28 compared to initial values, and ABR threshold shifts ranged from –3 ± 5 dB (min.) to +5 ± 7 dB (max.). On day 28 after implantation, there were no significant differences of ABR threshold shifts between this and the implant groups, except for 6 kHz of the slow-release device. Therefore, the placebo implants, the slow-release and the fast-release beclomethasone implants appear suitable for further experiments.

Pain Control Via Opioid Analgesic- Local Anesthetic Loaded IPNs

Relief of chronic pain is an important clinical problem requiring special care and approaches. The present study was designed for the construction of a controlled release system for local application of analgesics (hydromorphone (HM), morphine (M), and codeine (C)) and a local anesthetic, bupivacaine (BP). An interpenetrating network (IPN) drug release system was prepared by using a biocompatible, biodegradable copolyester, poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) and another biocompatible but synthetic, nondegradable polymer, poly (2- hydroxyethyl methacrylate), (PHEMA). In situ release kinetics of the IPN system was first order for BP but could not be fitted to any known equation for the other drugs. Complete release from the IPNs occurred within a considerably short time (24 h for 80 % of the drugs) most probably due to the significant hydrophilicity of PHEMA. In order to slow down the release rate these IPNs were coated with PHBV. Release from these coated IPNs (cIPN) resulted in rates that could be described by Higuchi's equations. In vivo measurement of antinociceptive efficacy was carried out in rats with tail flick and paw-withdrawal tests after inducing chronic pain created by sciatic nerve ligation at the right side. Control groups received placebo implants. In vivo studies showed potent, prolonged (2-3 days) antinociception at the site of injury (right paw) for strong opioids (HM and M) and about 2 days for the weak opioid (C) and local anesthetic (BP). In all cases the release rate was found to be as important as the antinociceptive potency. The weakest opioid analgesic of those evaluated (C) had a higher first day antinociception than its stronger counterpart M, probably due to its higher initial concentration that was expected from its faster release rate in the in situ experiments.

Antinociceptive effects of hydromorphone, bupivacaine and biphalin released from PLGA polymer after intrathecal implantation in rats

Intraspinal drug delivery, based on the concept of controlling pain by delivering drug to a nociceptive target rich in opioid and other relevant receptors is increasingly used clinically. The therapeutic ratio for opioids or other centrally acting agents is potentially greater if they are administered intrathecally (i.t.) than outside the central nervous system (CNS). The present study was designed with the ultimate goal of formulating a controlled release system for intrathecal analgesia characterized by effectiveness, rapid onset and few side effects for chronic pain control. A biodegradable copolymer poly( l-lactide-co-glycolide) (PLGA) was used to prepare a rod-shaped drug delivery system containing hydromorphone (HM), bupivacaine (BP), both HM and BP, or biphalin (BI). In vitro drug release kinetics of these systems showed a zero-order release rate for HM and BP from PLGA (85:15) rods. Drug-loaded rods were implanted i.t. Control groups received only placebo implants. Measurement of analgesic efficacy was carried out with tail flick and paw-withdrawal tests. In vivo studies showed potent, prolonged analgesia in comparison to controls for all active treatments. Analgesic synergy was observed with HM and BP. With further refinements of drug release rate, these rods may offer a clinically relevant alternative for intrathecal analgesia.

Quantitative estimates of angiogenic and anti-angiogenic activity by laser Doppler flowmetry (LDF) and near infra-red spectroscopy (NIRS)

The use of laser Doppler flowmetry (LDF) and near-infra-red spectroscopy (NIRS) for non-invasive in vivo measurements of angiogenic and anti-angiogenic activity in nude mice was evaluated. Angiogenic foci were induced in the skin by implantation of slow release pellets containing 200 ng basic fibroblast growth factor (bFGF). LDF and NIRS recordings from induced foci were significantly higher than placebo implants (P<0.05) and controls (P<0.001), proving that LDF and NIRS provide measures of angiogenic activity. Correspondingly, by these methods, an anti-angiogenic activity was significantly demonstrated in bFGF-stimulated animals treated with either the specific anti-angiogenic compound TNP-470 (P<0.05) or the anti-inflammatory agent dexamethasone (P<0.001). We conclude that LDF and NIRS, alone or in combination, are useful non-invasive tools for early evaluation of angiogenic and anti-angiogenic activity in vivo.

Assessment of hormone dependence of comedo ductal carcinoma in situ of the breast.

Ductal carcinoma in situ (DCIS) represents 20%-30% of breast cancers detected by clinical screening (i.e., mammography). More than 50% of DCIS lesions may be estrogen receptor negative and, therefore, hormone independent. However, the role of estrogen in the natural history of DCIS is unknown. A novel in vivo (i.e., xenograft) model was developed to determine to what degree DCIS lesions depend on estrogen for growth. Specimens of breast tissue were collected from 52 women during diagnostic or therapeutic surgical procedures. Portions of each specimen were randomly selected and analyzed by histology and thymidine labeling (to measure cell proliferation). The remainder of each specimen was implanted into five to 18 athymic BALB/c nu/nu mice (depending on the amount of tissue available), with eight pieces of approximately 2 mm x 2 mm x 1 mm implanted at different locations on the back of each mouse. Half of the mice received implants containing estrogen (2 mg 17 beta-estradiol), and the other half received placebo implants. Levels of cell proliferation in xenografts, recovered after 14, 28, 42, or 56 days in the mice, were measured by thymidine labeling or by immunohistochemistry through use of an antibody specific for the Ki-67 nuclear antigen. Immunohistochemistry was also used to measure the levels of estrogen receptor in the tissue specimens. Serum 17 beta-estradiol levels in the mice were measured by radioimmunoassay. Initial levels of cell proliferation were approximately 10-fold higher in 10 specimens with estrogen receptor-negative, comedo (i.e., more malignant in appearance) DCIS than in four specimens with estrogen receptor-positive DCIS (mean proliferation indices: 22% versus 1.9%, respectively; two-sided P < .001). Xenografts from the majority of specimens survived up to 56 days in the mice and maintained good architectural and cellular preservation. Estrogen treatment of the xenograft-bearing mice had no effect on the high level of cell proliferation observed in estrogen receptor-negative, comedo DCIS specimens (two-sided P = .89). In contrast, increased levels of cell proliferation in response to estrogen supplementation were measured in three estrogen receptor-positive, noncomedo DCIS specimens (two-sided P < .001). However, even with estrogen treatment, cell proliferation levels in estrogen receptor-positive DCIS specimens did not reach those seen in estrogen receptor-negative DCIS specimens. Estrogen receptor-negative, comedo DCIS lesions appear to be estrogen independent; therefore, antiestrogen (e.g., tamoxifen) therapy may not benefit patients with comedo DCIS.

Progesterone implants enhance SIV vaginal transmission and early virus load.

Simian immunodeficiency virus (SIV) can cross the intact vaginal epithelium to establish a systemic infection in macaques (mac). Using this SIVmac model, we found that subcutaneous progesterone implants, which could mimic hormonally based contraceptives, thinned the vaginal epithelium and enhanced SIV vaginal transmission 7.7-fold over that observed in macaques treated with placebo implants and exposed to SIV in the follicular phase of the menstrual cycle. Progesterone treatment also increased the number of SIV DNA-positive cells in the vaginal lamina propria as detected by in situ polymerase chain reaction analysis. Moreover, plasma viral RNA was elevated for the first three months in macaques with progesterone implants, and three of the progesterone-treated macaques developed relatively rapid disease courses. This study shows that SIV genital infection and disease course are enhanced by subcutaneous implants containing progesterone when compared with the rate of vaginal transmission in the follicular phase.

Thyroxine-Induced Changes in Metabolic Rate and Cytochrome Oxidase Activity in Thamnophis sirtalis: Effects of Nutritional Status

The effects of nutritional status on thyroxine-induced changes in standard metabolic rate (SMR), and the activity of hepatic cytochrome oxidase were examined in the garter snake Thamnophis sirtalis. Twelve snakes were fed ad libitum , and 12 more were fed a maintenance diet, which was half as many fish per gram of body weight as that eaten by ad libitum snakes. Snakes in the first group gained weight during the 3-week treatment, while individual snakes in the second group either maintained their original weight or showed a slight loss (less than 10%). Within each diet treatment, half of the snakes received a 5-mg thyroxine (T 4) pellet implant, and half received placebo implants. Plasma [T 4] was unchanged by treatment. Plasma [T 3] was elevated in T 4-supplemented snakes fed ad libitum , but the difference was not statistically significant ( P = 0.09). Standard metabolic rate and cytochrome oxidase activity at 25° were increased significantly (34 and 24%, respectively) only in the T 4-supplemented snakes on the ad libitum diet. Thus, T. sirtalis must be in a positive energy balance for thyroid hormones to have an effect on SMR or hepatic cytochrome oxidase activity.

Antihypertensive effect of 19-acetylenic-deoxycorticosterone in inbred salt-sensitive rats.

Rats susceptible to the hypertensive effect of dietary salt (SS/Jr) have excess 19-nor-deoxycorticosterone (19-nor-DOC) compared with salt-resistant control rats (SR/Jr). 19-Nor-deoxycorticosterone is a hypertensinogenic mineralocorticoid believed to contribute to the salt sensitivity of SS/Jr. 19-Acetylenic-deoxycorticosterone (19-Ac-DOC), an inhibitor of 19-nor-DOC biosynthesis, was evaluated for its antihypertensive effect in 20 hypertensive female SS/Jr rats. At 60 days of age, the rats were started on a high-salt diet (8% NaCl); then, at 120 days, the 10 surviving rats were divided into two groups. Group 1 included five animals with blood pressure +/- standard error (BP +/- SE) of 208 +/- 2 mm Hg that had 19-Ac-DOC implants (1 mg released over 10 days). Group 2 consisted of five animals with a BP of 204 +/- 2 mm Hg that had placebo implants (vehicle only). At 130 days, when another set of pellets was implanted, four rats were still alive in group 1 (BP 165 +/- 5 mm Hg) and none in group 2. At 140 days, the four surviving rats had a BP of 157 +/- 2 mm Hg. Finally, at 150 days, after 10 days off any 19-Ac-DOC, only two rats remained alive (BP 200 +/- 0 mm Hg). Urinary corticosterone +/- SE, DOC +/- SE, and 19-nor-DOC +/- SE before the first implant were 10 +/- 3, 16 +/- 5, and 42 +/- 14 micrograms/week, respectively, and 7 +/- 2, 13 +/- 5, 23 +/- 13 micrograms/week, respectively, after the second implant.(ABSTRACT TRUNCATED AT 250 WORDS)

Ovarian luteal activity and reproductive performance of heifers with norgestomet prototype implants

A 122-day trial was conducted with grazing beef heifers (N=120; 14 to 17 months of age) to determine the effects of a silastic Norgestomet prototype implant on heifer weight gain and on the suppression of ovarian luteal activity. The retention rate of the Norgestomet implants and of silastic placebo implants, which were either left untreated, or were topically treated with oxytetracycline, was determined. Medication of the placebo implants with oxytetracycline increased (P < 0.01) implant retention rate at both Day 56 and Day 122. Heifers with Norgestomet implants had higher body weight gains during the last 66 days (P < 0.05), and during the entire 122-day trial (P < 0.07) than heifers with placebo implants. Serum progesterone concentrations on Day 111 or Day 112 indicated a decrease (P < 0.01) in percentage of heifers with ovarian luteal activity on the Norgestomet treatment compared with heifers receiving placebos (23.8% vs 87.7%, respectively). The Norgestomet implant has the potential for suppressing ovarian luteal activity while improving weight gain in beef heifers.

A Double‐Blind Placebo Controlled Study of Healthy Volunteers Given a Subcutaneous Disulfiram Implantation

A study was carried out to elicit information of the pharmacological effect of implanted disulfiram (DS). Healthy volunteers were randomized to either of two groups; six were given 1 g DS implant and six subjects placebo (PL) implants. Each participant was subjected to one intravenous ethanol challenge before, and six intravenous ethanol challenges as well as one oral ethanol challenge after the implantation. No clinical signs of disulfiram-ethanol reactions (DER) were observed. The intravenous challenges did not result in any significant differences between pre- and post-implantation values for blood acetaldehyde concentrations in the DS group, and these values were not significantly different from the corresponding values in the PL group. However, somewhat higher blood acetaldehyde concentrations were recorded after an oral ethanol dose (0.8 g/kg) in the DS group. In a longitudinal study with oral ethanol challenges after implanted DS, one of three healthy volunteers had a significant higher blood acetaldehyde concentration three weeks after the implantation, while no such tendency was found in any subject tested earlier or later in the post-implantation period. The blood acetaldehyde levels after oral challenges were, however, far too low to produce a DER.

Effectiveness of chronic LHRH-analogue and 17 α-methyltestosterone therapy, administered at different times prior to the spawning season, on the maturation of milkfish ( Chanos chanos)

In this study, 100 milkfish were divided into two groups. In each group, 40 individuals were chronically exposed to the LHRH-a plus 17 α-methyltestosterone therapy and the 10 remaining individuals were implanted with placebos. The first group (Experiment I) was implanted in March 1986; the second (Experiment II) in April 1986. There was no significant difference between the percentage of males that matured in the treated and control groups. A significantly higher percentage of mature females was found among fish receiving hormone implants, however, by the onset of the natural spawning season. Eighty-five percent of the hormone-implanted females (34 of 40) reached a stage of maturity in which induced spawning trials could be initiated. Only 33.3% of the females receiving placebo implants matured to this stage. The data also suggested that the response of individuals to the therapy exhibits seasonal variation. Chronic exposure to the hormonal therapy appeared to be more effective when initiated closer to the start of the natural breeding season.

EFFECT OF OESTROGEN AND TESTOSTERONE IMPLANTS ON PSYCHOLOGICAL DISORDERS IN THE CLIMACTERIC

In a double-blind trial oestradiol, oestradiol/testosterone, or placebo implants were assessed for their effects on psychological symptoms in women attending a menopause clinic. After two months, women receiving active treatment scored better than the placebo group on a self-rating scale of distress, on anxiety, and on depression (p < 0·05). Postmenopausal but not perimenopausal women improved after placebo, and at 4 months the scores in the three groups no longer differed significantly.