Analgesic efficacy of orally administered buprenorphine in rats

The analgesic effect of orally administered buprenorphine was compared with that induced by a standard therapeutic injected dose (0.05 mg/kg of body weight, s.c.) in male Long-Evans rats. Analgesia was assessed by measuring pain threshold, using the hot-water tail-flick assay before and after administration of buprenorphine. The results suggest that a commonly used formula for oral buprenorphine in flavored gelatin, at a dose of 0.5 mg/kg, does not increase pain threshold in rats. Instead, oral buprenorphine doses of 5 and 10 mg/kg were necessary to induce significant increases in pain threshold. However, these doses had to be administered by orogastric infusion because the rats would not voluntarily eat flavored gelatin containing this much buprenorphine. The depth of analgesia induced by these infused doses was comparable to that induced by the clinically effective s.c. treatment (0.05 mg/kg).     

Ovarian responses to perphenazine-induced prolactin secretion in the rats: Effect of ovulation, stress, and steroids.

A single injection of 2.5 mg perphenazine (PH)/kg body wt to rats on the day of estrus (day 0) did not result in increased serum progesterone 24 hr later. Continued daily injections, however, resulted in a 2.5-fold increase in serum progesterone between days 1 and 3 and a 1.6-fold increase between days 3 and 5 to a final concentration of 58 plus or minus 4 ng/ml on day 5 in serially anesthetized and bled rats. Neither daily administration of 5.0 nor 10.0 mg PH/kg body wt to rats subjected to the stressful conditions of this regimen resulted in further increases in serum progesterone, but the 5.0 mg dose of PH in unstressed rats bled only on day 5 resulted in a highly significant increase in serum progesterone to 110 plus or minus 7 ng/ml. In unstressed rats the increase in serum progesterone over control values after five daily injections of 2.5 mg PH/kg body wt could be attributed to decreased 20alpha-reduction of progesterone, but when the dose of PH was increased to 5.0 mg/kg, a highly significant increase in both progesterone and total progestins occurred indicating that prolactin can increase steroidogenesis as well as reduce 20alpha-hydroxysteroid dehydrogenase activity. After inhibition of ovulation, the 5.0 mg daily dose of PH resulted in serum progesterone of only 25 plus or minus 8 ng/ml on day 5 in unstressed rats. Thus, serum progesterone in ovulating rats treated with PH originated primarily in the corpora lutea. Perphenazine, 5.0 mg/kg, administered only on estrus and the first day of diestrus was sufficient to induce pseudopregnancy of 14.5 plus or minus 1.6 days. No evidence for gonadotropin stimulation of the ovaries of any rats was observed. The effect of stress on the progesterone response was not mimicked by administration of cortisol acetate and is assumed to be medicated by suppression of prolactin secretion.     

Acute and Long-Term Effects of Chlorpromazine on Glutamine Synthetase and Glutaminase in Rat Brain

The effect of administration of chlorpromazine on the activity of glutamine synthetase and glutaminase and the content of glutamate and gamma-aminobutyric acid (GABA) in different regions of rat brain was studied in an investigation of the possible role of these amino acids in the lowering of the seizure threshold following prolonged administration of chlorpromazine. Chlorpromazine was administered at a dose of 20 mg/kg of body weight s.c. For the acute study, the animals were killed 20 min after a single injection. For the long-term study, the animals were treated every day with the same dose for 21 days and were killed 20 min after the last injection. The results showed an increase in glutamate level in each brain region investigated following long-term administration, but only in the cerebral cortex after a single dose. GABA levels showed an increase in the brainstem only in acute experiments. Glutamine synthetase activity was increased in all three regions after a single dose and only in cerebral cortex after long-term administration. Glutaminase activity showed a decrease in cerebral cortex only after long-term administration of the drug. These results suggest the possible occurrence of a state of increased excitability in the brain as a result of long-term administration of chlorpromazine, thus contributing to the known complication of seizures.     

Induction of thyroid hormone in changing Na+K(+)-ATPase activity in different organs of toad, Bufo melanostictus

Single injection of T3, at the doses of 0.5 and 1 micrograms/g body weight, stimulated Na+K(+)-ATPase activity of crude liver homogenate of toad in a dose dependent fashion. Lowering the dose of T3 to 0.25 micrograms/g had no effect on the enzyme activity. T3 at the dose of 2 micrograms/g showed the same level of enzyme activity at par with that of 1 microgram/g. Na+K(+)-ATPase activity of muscle increased with T3 at the doses of 1 and 2 micrograms/g, but without any dose dependent manner while T3 at the doses of 0.25 and 0.5 micrograms/g remained unresponsive in changing the enzyme activity. T4, after 3 consecutive injections, increased the enzyme activity in liver with 1 and 2 micrograms/g and in muscle with 2 micrograms/g only while the other doses of T4 (0.25 and 0.5 micrograms/g in case of liver and 0.25, 0.5, and 1 micrograms/g in case of muscle) had no effect on the enzyme activity. Brain showed no alteration to Na+K(+)-ATPase activity with the same doses of T3 and T4. Cycloheximide counteracted the T3 induced rise in enzyme activity. The reduced level of Na+K(+)-ATPase activity in the PTU treated toad was recovered and brought to the control level after 3 consecutive injections of T4 at the dose of 1 microgram/g.     

Demonstration of hepatic cytosolic malic enzyme activity as a thyroid hormone sensitive physiologic parameter in a teleost, Heteropneustes fossilis bloch

Single injections of various doses (0.1, 0.25, 0.5, 5 and 20 micrograms/g) of T3 significantly increased the cytosolic malic enzyme activity (delta OD/min/mg cytosolic protein) in liver of Singi fish Heteropneustes fossilis Bloch, in a dose-dependent nature, maximum up to 5 micrograms/g dose on the 3rd day in comparison to the control. There was no difference in the enzyme activity between 5 and 20 micrograms/g of T3 doses. When the enzyme activity was expressed per mg DNA, the dose-dependent increase in the malic enzyme activity was observed upto 0.5 microgram/g of T3, whereas a fall in the enzyme activity was noticed with 5 and 20 micrograms/g of T3 doses. Lowering the dose of T3 to 0.05 microgram/g was without any effect on the malic enzyme activity (delta OD/min/mg cytosolic protein or DNA). Hepatic cytosolic protein content showed a biphasic nature of variation, significant increase with single injections of 0.05, 0.1, 0.25 and 0.5 microgram/g and a fall with 5 and 20 micrograms/g of T3 doses in comparison to the untreated control. Cycloheximide treatments of the Singi fishes counteracted both the T3-induced rise in the hepatic cytosolic malic enzyme activity (delta OD/min/mg cytosolic protein or DNA) and the hepatic cytosolic protein contents. Thiourea-treated hypothyroid fishes showed significantly decreased level of malic enzyme activity (delta OD/min/mg cytosolic protein or DNA) and cytosolic protein content in liver. A single injection of T3 at 0.25 microgram/g to the thiourea-treated fishes not only recovered but also increased the enzyme activity and cytosolic protein content above the untreated control values.(ABSTRACT TRUNCATED AT 250 WORDS)     

Progesterone enhances ethanol-induced modulation of mesocortical dopamine neurons: antagonism by finasteride

The effect of endogenous 3α‐hydroxy‐5α‐pregnan‐20‐one (3α,5α‐TH PROG) on the modulation of mesocortical dopamine extracellular concentration by ethanol was investigated by microdialysis in rats. Intraperitoneal injection of progesterone (5 mg/kg, once a day for 5 days) increased the cortical content of 3α,5α‐TH PROG and potentiated the biphasic effect of acute intraperitoneal administration of ethanol on dopamine content. A dose of ethanol (0.25 g/kg) that was ineffective in naïve rats induced a 55% increase in dopamine extracellular concentration in rats pretreated with progesterone. This increase was similar to that induced by a higher dose (0.5 g/kg) of ethanol in naïve rats. Administration of ethanol at 0.5 g/kg to progesterone‐pretreated rats inhibited dopamine content by an extent similar to that observed with an even higher dose (1 g/kg) in naïve rats. The administration of the 5α‐reductase inhibitor finasteride (25 mg/kg, subcutaneous), together with progesterone, prevented the effects of the latter, both on the cortical concentration of 3α,5α‐TH PROG and on the modulation by ethanol of dopamine content. These data suggest that 3α,5α‐TH PROG contributes to the action of ethanol on the mesocortical dopaminergic system. They also suggest that physiological fluctuations in the brain concentrations of neuroactive steroids associated with the oestrous cycle, menopause, pregnancy and stress may alter the response of mesocortical dopaminergic neurons to ethanol.     

Behavioral effects of acute and chronic triazolam treatments in albino rats

Previous behavioral studies on triazolam (TZ), which are small in number, could only speculate about tolerance to the anxiolytic effect of TZ, as the experiments did not cover sufficient time (of 4 to 7 days) for tolerance to develop. Therefore longer time for chronic TZ administration is used. We investigated the effects of TZ on motor activity and exploratory behavior using plus maze and open field. Three experiments were conducted. In the first, five groups of rats were acutely treated with different doses of TZ (0.25 mg/kg-4.0 mg/kg). In the second set of experiments, rats were treated chronically with a single daily dose of TZ (started with 0.25 mg/kg and increased by time to 1.0 mg/kg) for 5 weeks (representing clinical use). In the third, rats were treated chronically with three daily doses of TZ (started with 0.25 mg/kg and increased by time to 0.5 mg/kg) for 20 days (mimicking drug abuse). Acute TZ administration produced dose dependent anxiolytic effects and a decrease in motor activity with higher doses. Chronically treated rats, either once daily or three times daily doses, showed tolerance to both anxiolytic and sedative effects of TZ. It may be concluded that tolerance to the anxiolytic and sedative effects of TZ would develop after chronic administration either with clinical use or its abuse.     

Mifepristone for the prevention of breakthrough bleeding in new starters of depo-medroxyprogesterone acetate

Depo-medroxyprogesterone acetate (DMPA) is an effective injectable contraceptive with worldwide availability. However, it is associated with a high incidence of breakthrough bleeding (BTB) during the first 6 months of use which often leads to discontinuation. Mifepristone is a progesterone receptor antagonist that has been demonstrated to decrease BTB caused by the levonorgestrel subdermal implant (Norplant). The purpose of this study was to determine if mifepristone would decrease BTB in new starters of DMPA. Twenty regularly cycling women who were new starters of DMPA were randomized to receive 50 mg of mifepristone or placebo every 2 weeks for 24 weeks. Percent days of BTB and number of cycles with bleeding intervals > or =8 and > or =14 days were evaluated using daily bleeding diaries. Ovulation was determined by measuring thrice-weekly urinary metabolites of estrogen and progesterone. Endometrial concentrations of ER and PR were determined by immunohistochemistry. Mifepristone significantly decreased the percent days of BTB and the number of cycles with prolonged bleeding intervals when compared to placebo. No subject ovulated in either group. ER immunostaining increased and PR immunostaining decreased after mifepristone treatment. In conclusion, a 50 mg dose of mifepristone taken every 2 weeks decreases the incidence of BTB in new starters of DMPA. This effect may be due to modulation of endometrial estrogen and progesterone receptors.     

金雀异黄酮通过减少卵巢切除大鼠心肌小凹蛋白-1的表达而增加一氧化氮的生成

观察金雀异黄酮(genistein)替代治疗对卵巢切除大鼠心肌中一氧化氮(nitric oxide,NO)和内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)的影响.成年雌性Sprague-Dawley大鼠经双侧卵巢切除术,假手术组作为对照,术后三周将行卵巢切除术的大鼠随机分为低剂量genistein(0.5 mg/kg·d1)、高剂量genistein(5.0 mg/kg·d-1)、17-β雌二醇(0.1 mg/kg·d-1)和模型组(100μl/d芝麻油),各组均皮下注射给药并给予不含大豆的饲料喂养6周,测定大鼠尾动脉血压、心率,麻醉后放血处死大鼠称量子宫重量;放免法检测血浆中总雌二醇,亚硝酸还原酶法检测心肌匀浆中NO,Western blot检测心肌中eNOS的表达以及eNOS的调节蛋白小凹蛋白-1(caveolin-1)和钙调素(calmodulin)的表达情况.结果显示各组间大鼠血压无显著性差异,同17-β雌二醇一样,genistein能呈剂量依赖性地增加心肌组织中eNOS表达量和NO生成,同时genistein能明显降低内源性eNOS活性抑制物caveolin-1的表达,而不影响eNOS活性正性调节蛋白钙调素的表达.与溶媒对照组比较,0.5 mg/kg·d-1的genistein不增加子宫重量,5.0 mg/kg·d-1的genistein增加子宫重量3倍,但较17-β雌二醇(增加6倍)的作用小(P＜0.01).上述结果提示,植物雌激素genistein剂量依赖性地上调心肌组织eNOS的活性并增加NO的生成,减少抑制eNOS活性的小凹蛋白-1表达.     

Effects of ovarian hormones on the behavior of captive Macaca fascicularis

To examine the effects of ovarian hormones on the behavior of female Macaca fascicularis and their male partners, daily 1-hr behavior tests were conducted while ovariectomized females were (1) untreated, (2) given estradiol benzoate (EB) (5 μg subcutaneously [s.c.]/day), (3) given estradiol benzoate together with increasing doses of progesterone (P) (5 mg, 10 mg, and 20 mg. s.c./day), and (4) given testosterone propionate (TP) (0.25 mg s.c./day) (six pairs, 540 tests). Weekly blood samples were analyzed by radioimmunoassay for plasma hormone levels (81 samples). Estrogen treatment produced plasma estradiol levels similar to those of intact females during the late follicular phase of the menstrual cycle. Additional progesterone at the lowest dose produced plasma progesterone levels similar to or somewhat higher than those during the midluteal phase, while higher doses produced supraphysiological levels. Androgen treatment resulted in plasma levels well above the physiological range. Hormone treatments produced highly significant effects on the sexual, social, and aggressive interactions of the pairs. As in rhesus monkeys, estrogen increased male and female sexual activity, and increasing doses of additional progesterone reversed these effects. Unlike in rhesus monkeys, testosterone propionate increased both female sexual motivation (invitations) and also male sexual activity and ejaculatory performance. The direction of the hormone-dependent changes in grooming and aggressive interactions confirmed earlier results with intact females and indicated that aggressive interactions and male grooming times were highest, and female grooming times were lowest, when copulatory activity was at its height.     

Inhibition of ovulation in PMSG/hCG-treated immature rats by rotenone, a specific inhibitor of mitochondrial oxidation

Immature Wistar rats were induced to ovulate by treatment with PMSG and hCG. Control animals ovulated 43.5 +/- 0.36 ova/rat. Intraperitoneal injection of rotenone doses of 0.125, 0.25 and 0.50 mg/kg reduced the ovulation rate to 24.0 +/- 3.08, 8.0 +/- 0.88 and 1.5 +/- 0.44 ova/rat, respectively. The rotenone significantly reduced ovarian cytochrome oxidase activity and progesterone production, but not production of oestradiol or testosterone. Thyroxine treatment at a dose of 5 mg/kg s.c. reversed the rotenone inhibition of ovulation. The results suggest that an increase in mitochondrial respiration is an essential feature of the ovulation process in mammals.     

Induction of micronuclei by vinyl acetate in mouse bone marrow cells and cultured human lymphocytes

A dose-dependent increase in micronucleated polychromatic erythrocytes was observed in the bone marrow of male C57B1/6 mice 30 h after a single intraperitoneal injection of vinyl acetate (250, 500, 1000 or 2000 mg/kg b.wt.; (9-14 animals per group). The effect was statistically significant at 1000 mg/kg (1.33 +/- 0.29% vs. 0.6 +/- 0.10% in olive oil-treated controls) and at 2000 mg/kg (1.57 +/- 0.19%) of vinyl acetate. These doses were fatal to 6 (1000 mg/kg) and 8 (2000 mg/kg) out of 14 animals in both groups. The ratio of polychromatic to normochromatic cells decreased as a function of vinyl acetate dose. Cyclophosphamide (20 mg/kg), used as a positive control chemical, induced a clear increase in micronucleated polychromatic erythrocytes (2.07 +/- 0.20%). None of the treatments affected the number of micronuclei in normochromatic erythrocytes. In human whole-blood lymphocyte cultures, micronucleus induction by a 48-h treatment with vinyl acetate (0.125, 0.25, 0.5, 1 and 2 mM; 24 h after culture initiation) was studied in lymphocytes with preserved cytoplasm from smear slides prepared by a method involving the removal of erythrocytes at harvest by sodium cyanide treatment to improve preparation quality. The frequency of micronucleated lymphocytes reached a peak at 0.5 mM (3.2 +/- 1.0% vs. 0.9 +/- 0.1% in control cultures) and 1 mM (3.1 +/- 0.7%), with a decline at 2 mM probably because of a toxic effect resulting in mitotic inhibition.     

Recovery of MAO-B enzyme activity after (-)deprenyl (selegiline) pretreatment, measured in vivo

The recovery of MAO-B activity after a single dose of 0.25 mg/kg s.c. (-)deprenyl was measured in rat, by following the time course of the changes in the PEA (phenyl-ethylamine)-induced hyperactivity. One hour after its administration (-)deprenyl enhanced both the PEA-induced locomotion and stereotypy, however, its effect on the latter was more marked. At 24 h and at later time-points only stereotype was enhanced. The results show that a single small dose of (-)deprenyl which selectively blocks MAO-B, causes a long-lasting inhibition of PEA metabolism, and the enzyme activity needs more than one week to restore completely.     

The antitumor mechanism of progesterone antagonists is a receptor mediated antiproliferative effect by induction of terminal cell death

The antiprogesterones Onapristone, ZK 112.993 (Schering AG), and Mifepristone (Roussel-Uclaf) proved to possess progesterone receptor-mediated antiproliferative effects in experimental mammary carcinomas. In this study, the potency and mechanism of the antitumor action of Onapristone and ZK 112.993 is characterized by ovariectomized, progestagen and/or estradiol substituted mice bearing hormone-dependent MXT(+) mammary tumours. Medroxyprogesterone acetate (MPA, 0.8 mg/mouse, 3 times weekly, s.c.) could only induce a poor stimulation of tumour growth (% T/C = 40; intact control % T/C = 100), which was only marginally inhibited (% T/C = 21) by Onapristone (0.2 mg/mouse, 6 times weekly, s.c.) during a 6-week therapy. Therefore, the antitumor mechanism of antiprogesterones cannot preferably depend on a classical progesterone antagonism. In contrary, the pronounced stimulation of tumor growth (% T/C = 152) by estradiol benzoate (EB, 0.33 microgram/mouse, 3 times weekly, s.c.) was completely inhibited (% T/C = 7) by the antiprogesterones. An even more stimulated tumour growth was achieved by a combination of EB and MPA (% T/C = 365 using 0.17 mg; % T/C = 225 using 0.8 mg MPA). Onapristone dramatically blocked tumor growth (% T/C = 7) at the lower dose of MPA; no inhibition (% T/C = 203), however, was detected at the higher dose of MPA. These data and a morphological analysis indicate that the potent antitumor activity of the progesterone antagonists depends on the binding to a number of available progesterone receptors high enough to trigger an antiproliferative effect via the induction of terminal differentiation associated with terminal cell death.     

Reversible suppression of pituitary-testicular function by a sustained-release formulation of a GnRH agonist (leuprolide acetate) in dogs

Pituitary-testicular function was studied in 15 dogs following treatment with a sustained-release formulation of a GnRH agonist, leuprolide acetate (LA). Adult male dogs were treated with a single subcutaneous injection of microencapsulated LA (0.1 or 1 mg/kg). Treatment with LA at a dose of 1 mg/kg resulted in decreased (P<0.001) ejaculatory volume and disappearance of morphologically normal spermatozoa within 8 wk and the effect persisted for 6 wk, while the 0.1 mg/kg dose was not adequate to effect suppression of spermatogenesis. The larger dose treatment (1 mg/kg) caused a transient rise in plasma levels of LH and testosterone followed by a marked decline to below the normal level by 2 wk, the low levels being maintained for at least 5 wk, indicating a prolonged effect of LA treatment on pituitary-gonadal axis. Twenty weeks after treatment with LA, a complete return to normal spermatogenesis was observed. The full reversibility of spermatogenesis in the dog after LA treatment suggests that this peptide could be used as a reversible method of male contraception.     

Nuclear activation by thyroid hormone in liver of Singi fish: changes in different ion-specific adenosine triphosphatases activities

Various ion-dependent (Na+K+, Ca++ and Mg++) ATPases activities in liver cell nuclear membrane have been determined after a single injection of different doses (0.01, 0.025, 0.05, 0.1, 0.25, 0.5, 1, 2 and 4 micrograms/g) of L-triiodothyronine (T3) in Singi fish, Heteropneustes fossilis Bloch. Administration of T3 at a minimum effective dose of 0.05 micrograms upto 4 micrograms/g induced a rise (14 to 43% over control value) in the Na+K+-ATPase activity in a dose-dependent fashion maximum upto 1 microgram/g dose, whereas Ca++-ATPase showed a dose-dependent increase (20 to 43% over control) with 0.25-1 microgram/g of T3, although the increase in the respective enzyme activity was maintained upto 4 micrograms/g of T3 dose. Mg++-ATPase activity in liver cell nuclear membrane was found to be increased at 1 microgram-4 micrograms/g of T3 dose, showing a similar magnitude of increase (7% over the control value) with these doses of T3. Other doses of T3 (0.01 and 0.025 micrograms/g) were ineffective in altering the different ion-specific ATPase activity. Treatment of Singi fish with thiourea (1 mg/ml) for 30 days caused a significant fall in Na+K+, Ca++ and Mg++-ATPase activities upto 21%, 17% and 5%, respectively, below the euthyroid control level. A single injection of T3 at the dose of 1 microgram/g in the hypothyroid fish raised the Na+K+ and Ca++-ATPase activities to about 36% over the control value, and the Mg++-ATPase activity was restored to only the control level. Thus a dose-dependent nuclear effect of T3 is evident from the present investigation.     

Immunosuppressive Activity of the Ethanol Extract of Sedum sarmentosum and Its Fractions on Specific Antibody and Cellular Responses to Ovalbumin in Mice

The immunosuppressive activity of the ethanol extract of Sedum sarmentosum (EESS) and its fractions was studied with respect to specific antibody and cellular response to ovalbumin (OVA) in mice. ICR Mice were immunized subcutaneously with OVA on days 0 and 14. Beginning on the day of immunization, the mice were administered intraperitoneally (ip) with EESS and it fractions at a single dose of 0.25, 0.5, and 1.0 mg, and cyclosporin A at a single dose of 0.1 mg at intervals of 7 days. On day 28, splenocyte proliferation and specific antibody level in serum were measured. EESS significantly suppressed concanavalin A (Con A)‐, lipopolysaccharide (LPS)‐, and OVA‐induced splenocyte proliferation in the immunized mice in a dose‐dependent manner. The OVA‐specific serum IgG, IgG1, and IgG2b levels in the immunized mice were also markedly reduced by EESS. Among four fractions of EESS, the BuOH fraction consisting mainly of flavonoid glycosides showed the highest suppressive activity. The results suggest that EESS could suppress the cellular and humoral immune response in mice, and deserve further research to be developed as immunosuppressant.     

Thermoregulatory responses of the unrestrained cat to acute and chronic intravenous administration of low doses of morphine and to naloxone precipitated withdrawal

Morphine in doses of 1, 2, and 4 mg/kg i.v. produced dose related elevations in cat body temperature while doses of 0.25 and 0.50 mg/kg had no such effect. Tolerance was found to develop to the hyperthermic response after seven days of daily morphine injection. Pretreatment with naloxone at a dose one-fourth the dose of morphine prevented the morphine induced rise in body temperature in all cats tested. When the cats received naloxone after twelve days of daily morphine a withdrawal syndrome resulted and was accompanied by a hypothermia that was proportional to the morphine maintenance dose and severity of withdrawal.     

Abortifacient and endocrine effects of metergoline in beagle bitches during the second half of gestation

The purpose of this study was to investigate the abortifacient effects of high doses of metergoline when administered to pregnant beagle bitches during the second half of gestation and to define the endocrine effects of this treatment as represented by plasma progesterone and estradiol concentrations. Previously, metergoline had been shown to be incompletely luteolytic and induced abortion in only one of eight pregnant bitches when 0.4-0.5 mg/kg were administered twice daily for 5 days from Days 18 to 20 of diestrus. Nine pregnancies in six beagle bitches were used for the present study. Three bitches were treated in each of two consecutive pregnant cycles. Metergoline was administered at a dose of 0.6 mg/kg per os twice daily, starting on Day 28 after the cytological onset of diestrus. Abortion was induced in eight of the nine treated pregnancies and started after 3-23 days of treatment (mean 12.5 days, S.D. 6.4 days). The abortions were completed within 0.5-8 days (mean 2.2 days, S.D. 2.7 days). There were no side effects associated with metergoline treatment and none of the abortions was associated with complications that required intervention. In the single bitch that did not abort, an ovarian granulosa cell tumor was discovered when the single fetus had to be removed surgically at term. Plasma progesterone concentrations declined after the start of metergoline administration in all pregnancies but levels below 4.8 nmol/l were required for successful abortions. Plasma estradiol concentrations showed a tendency to decline and fluctuate concurrently with the plasma progesterone levels. However, suppression of plasma estradiol concentrations by metergoline was not as complete as the suppression of progesterone and did not seem a prerequisite for abortion. The hormone profiles and treatment period required for abortion tended to be similar for both cycles of the three bitches that were treated during two consecutive pregnancies. This suggests a bitch effect on the factors that determine the efficacy of metergoline to induce abortion. The large variation and length of the treatment period that was required until abortion commenced was probably related to the relatively early start of treatment compared to other studies. The results of this investigation suggest that, similar to other prolactin suppressing ergot derivatives, metergoline causes complete luteolysis and can be used to reliably induce abortion only during the last 3 weeks of gestation.     

Comparison of the pharmacokinetics of subcutaneous and intravenous administration of a phosphorothioate oligodeoxynucleotide in cynomolgus monkeys

The pharmacokinetics of subcutaneous (s.c.) administration of a phosphorothioate oligodeoxynucleotide (PS-ODN) was evaluated in cynomolgus monkeys. In a single dose study, monkeys were injected s.c. or intravenously (i.v.) with doses of either 1 or 5 mg/kg ISIS 2302. The bioavailability of s.c. injection ranged from 26% to 55% and appeared to be dependent on the concentration of the dosing solution rather than the dose. The bioavailability of a subcutaneously administered 5 mg/kg dose of ISIS 2302 was 55% using a 50 mg/ml dosing solution and only 26% using a 10 mg/ml dosing solution. Slow absorption from the s.c. injection site significantly blunted the maximal concentration (Cmax) compared with i.v. administration. The time to peak plasma concentration (Tmax) increased slightly with increasing dose, from 0.5 to 1 hour for the 1 mg/kg dose to 1 to 2.5 hours for the 5 mg/kg dose. Plasma half-lives were prolonged after s.c. administration, indicating more dependence on absorption than elimination. The half-lives after s.c. administration averaged 3 hours, whereas after i.v. administration, the half-lives were <1 hour. Metabolism of the ISIS 2302 after s.c. injection was consistent with exonucleolytic cleavage, as previously observed after i.v. administration. In summary, s.c. administration of PS-ODN resulted in prolonged and extensive absorption of the ODN.