Suppression of postprandial glucose, insulin, C-peptide, and glucose-dependent insulinotropic peptide (GIP) in man by oral administration of a prostaglandin analogue (enprostil)

Enprostil, a long-acting, orally active dehydroprostaglandin E2 with cytoprotective and gastric antisecretory properties, is a potent inhibitor of meal-stimulated gastrin release. Recent data have suggested suppression of additional other gastrointestinal peptide hormones following single doses of enprostil. The current investigation was conducted to further clarify the effects of enprostil administration on gastrointestinal hormones and glucose metabolism under physiologic conditions and to determine whether these effects were present following multiple doses of the agent. Enprostil 70 mcg/d and its placebo were each administered for 7 1/2 days to eight normal male subjects in a study of crossover design, each treatment period lasting 7 1/2 days and separated by a 7 day washout period. Subjects received a test meal on days 1 and 8 and an oral glucose challenge on day 3 of each treatment period following enprostil or its placebo. Following the test meal, there was a delay and suppression of the maximum measured serum glucose levels. Mean overall peak glucose concentrations were lower during the enprostil phase compared to placebo (112 vs. 121 mg/dd, P = 0.025) with a trend toward delay in the time to achievement of peak glucose concentrations. Mean overall peak levels for insulin, C-peptide, and glucose-dependent insulinotropic peptide (GIP) were significantly suppressed by 36%, 16% and 60%, respectively by enprostil when compared to placebo. The overall integrated postprandial responses for insulin, C-peptide, and GIP were significantly reduced by 42%, 39% and 90%, respectively while that for glucose above baseline was reduced by 44% (P = 0.098). Similar effects were present following the oral glucose challenge.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of protective effect of oral enprostil, a synthetic prostaglandin E2, on intestinal transport and morphology following abdominal irradiation in the rat

Previous studies have demonstrated that abdominal irradiation alters intestinal uptake of nutrients. The purpose of this study was to determine the effect of an orally administered synthetic prostaglandin E2, enprostil, given on three occasions shortly prior to a single exposure to 600 cGy external abdominal irradiation, on intestinal active and passive transport processes and villus morphology measured 7 days later. Animals were sham-irradiated (CONT) or were exposed to a single dose of 600 cGy external abdominal irradiation (RAD); two and one mornings before the day of irradiation or sham irradiation, and 1 h before irradiation or sham irradiation enprostil was administered. One half of CONT and RAD groups were dosed orally with enprostil, 5 micrograms/kg body weight, and the other half of the CONT and RAD groups were dosed with placebo. Seven days later the in vitro uptake of glucose, galactose, long-chain fatty acids, and cholesterol was determined in the four groups (CONT with and without enprostil, and RAD with and without enprostil). In CONT, enprostil was associated with increased jejunal uptake of glucose and ileal uptake of galactose. In RAD given enprostil, there was increased jejunal uptake of galactose but reduced ileal uptake of glucose and galactose. The expected radiation-associated decline in jejunal galactose uptake was prevented with enprostil. In CONT given enprostil, there was increased jejunal uptake of fatty acid (FA) 14:0 and 16:0 but reduced uptake of FA 18:0, 18:1, and 18:2; enprostil had no effect on lipid uptake in the ileum in CONT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic effects of oral contraceptives in monkeys fed adequate protein & low proein diets

The effects of 2 oral contraceptives, Ovulen and Norlestrin, were studied in monkeys fed adequate protein and low protein diets. The experiment was carried out in parts. In the first one, the administration of contraceptives was cyclic and similar to that employed in human subjects. In the other experiments, the contraceptives were given continuously and an attempt was made to exaggerate the deleterious effects of the oral contraceptive on the liver by including small doses of a known hepatotoxic agent, aflatoxin (AT). In Experiment 1, 45 female monkeys were divided into 2 groups of 20 and 25 and received an adequate protein (16%) and low protein diet (4%) respectively. Each monkey was fed 1/5 of a tablet of Ovulen or Norlestrin orally for 3 weeks, and then administration was discontinued for 1 week. In Experiment 2, 35 female monkeys were divided into 7 groups of 5 each. All the animals recieved 4% protein diet. 5 groups were tube fed at the rate of 100 cal/kg body weight, while 2 groups were given diet ad libitum. Group I received the diet alone while groups II-V received 10 mcg AT, 25 mcg AT, 10 mcg AT plus 1/5 Ovulen tablets, and 25 mcg AT plus 1/5 Ovulen tablet respectively daily. Groups VI and VII received the diet ad libitum but were orally fed 75 mcg AT and 75 mcg AT plus 1/5 Ovulen tablet respectively. Serum glutamic-oxalacetic transaminase activity and alkaline phosphatase activity were studied at regular intervals after the administation of oral contraceptives in the experiments. Serum proteins and hemoglobin were also determined. Monkeys fed oral contraceptives showed increased serum glutamic-oxalacetic transaminase and alkaline phosphatase activities irrespective of the level of protein in the diet. Livers of animals receiving oral contraceptives were morphologically similar to the controls fed respective diets. The experiments were conducted for a period of almost 2 years.     

Prostaglandins,indomethacin and dysmenorrhea

Uterine contractility was recorded during the period of menstruation in six dysmenorrheic women. A variable high tonus was observed in each case. Uterine recordings were repeated during the subsequent menstruation following pre-treatment with indomethacin at an oral dose of 75 mg or 200 mg per day beginning one day before the expected onset of menstruation. A lower uterine tonus was found in all indomethacin-treated cycles. Complete alleviation of spasmodic pain was obtained in the six subjects. The endogenous concentration of 15-keto-13,14-dihydro PGF_2α was determined by the gas chromatography-mass spectrometry method and observed to be relatively high in women with dysmenorrhea.     

Comparison of chloroquine,pyrimethamine and sulfadoxine,and chlorproguanil and dapsone as treatment for falciparum malaria in pregnant and non-pregnant women,Kakamega District,Kenya.

OBJECTIVE--To compare treatment and protection against falciparum malaria in pregnant and non-pregnant women with three drug regimens. DESIGN--Prospective intervention study with six weeks'' follow up. Patients received one of three drug regimens in order of entry. SETTING--Primary care hospital and secondary girls'' school in rural western Kenya. PATIENTS--158 of 988 pregnant women (89 primigravid and 69 multigravid) in the third trimester and 105 of 1488 non-pregnant schoolgirls of reproductive age were parasitaemic (more than 500 asexual forms/microliter. These women were divided into three treatment groups by gravid state. INTERVENTIONS--Women were treated with chloroquine base 25 mg/kg over three days or pyrimethamine 75 mg and sulfadoxine 1500 mg as a single dose or chlorproguanil 1.2 mg/kg and dapsone 2.4 mg/kg as a single dose. MAIN OUTCOME MEASURES--Parasitaemia and haemoglobin concentrations measured at seven day intervals for six weeks. RESULTS--Primigravid women were more likely to be parasitaemic on follow up than multigravidas or nulligravidas, whose response was about the same. Parasites did not clear by day 7 in primigravidas in six (20%) of 30 who received chloroquine, three (8%) of 35 treated with pyrimethamine and sulfadoxine, and none of 23 treated with chlorproguanil and dapsone. At day 28, 83%, 19%, and 67% of primigravidas in these treatment groups were parasitaemic. Haemoglobin concentrations rose in all women, but improvement was sustained only in women who remained free of parasites. CONCLUSIONS--Clearance of parasites was better with either pyrimethamine and sulfadoxine or chlorproguanil and dapsone than with chloroquine. Longest protection was obtained with pyrimethamine and sulfadoxine.     

Stimulation of HCO3- secretion by the prostaglandin E2 analog enprostil: studies in human stomach and rat duodenum

This study investigated the action of enprostil, a synthetic analog of PGE2, on gastric HCO3- secretion in humans and on duodenal HCO3- secretion in the anesthetized rat. A previously validated 2-component model was used to calculate gastric HCO3- and H+ secretion in 10 human subjects. Compared to placebo, a single 70 micrograms oral dose of enprostil increased basal gastric HCO3- secretion from 1810 +/- 340 to 3190 +/- 890 mumol/hr (P less than 0.05). In addition, enprostil reduced basal gastric H+ secretion from 5240 +/- 1140 to 1680 +/- 530 mumol/hr (P less than 0.02). Enprostil also increased HCO3- secretion and reduced H+ secretion during intravenous pentagastrin infusion. In the rat, duodenal HCO3- secretion was measured by direct titration in situ using perfused segments of duodenum just distal to the Brunner gland area and devoid of pancreatic and biliary secretions. Addition of enprostil (10 micrograms/ml) to the duodenal bathing solution increased duodenal HCO3- secretion from 6.3 +/- 1.3 to 15.1 +/- 2.0 mumol/cm X hr (P less than 0.01, n = 6). The stimulatory action of enprostil on duodenal HCO3- secretion at 10 micrograms/ml was comparable in magnitude and duration to that of 10 micrograms/ml natural PGE2. In summary, the PGE2 analog enprostil stimulated gastroduodenal HCO3- secretion, effects which may be beneficial in protection of the gastroduodenal mucosa against luminal acid.     

Single dose cabergoline versus bromocriptine in inhibition of puerperal lactation: randomised,double blind,multicentre study. European Multicentre Study Group for Cabergoline in Lactation Inhibition.

OBJECTIVE--To compare the efficacy and safety of a single dose of 1 mg of cabergoline with that of bromocriptine 2.5 mg twice daily for 14 days in the inhibition of puerperal lactation. DESIGN--Prospective, randomised, double blind, parallel group, multicentre study. SETTING--University of hospital departments of obstetrics and gynaecology in different European countries. SUBJECTS--272 puerperal women not wishing to lactate (136 randomised to each drug). INTERVENTIONS--Women randomised to cabergoline received two 0.5 mg tablets of cabergoline and one placebo tablet within 27 hours after delivery and then placebo twice daily for 14 days. Those randomised to bromocriptine received 2.5 mg of bromocriptine and two placebo tablets within 27 hours and then 2.5 mg of bromocriptine twice daily for 14 days. MAIN OUTCOME MEASURES--Success of treatment (complete or partial) according to milk secretion, breast engorgement, and breast pain; rebound symptomatology; serum prolactin concentrations; and number of adverse events. RESULTS--Complete success was achieved in 106 of 136 women randomised to cabergoline and in 94 of 136 randomised to bromocriptine and partial success in 21 and 33 women respectively. Rebound breast symptomatology occurred respectively in five and 23 women with complete success up to day 15 (p less than 0.0001). Serum prolactin concentrations dropped considerably with both drugs from day 2 to day 15; a prolactin secretion rebound effect was observed in women treated with bromocriptine. cabergoline and 36 receiving bromocriptine (p = 0.054), occurring most during the first treatment day. CONCLUSION--A single 1 mg dose of cabergoline is at least as effective as bromocriptine 2.5 mg twice daily for 14 days in preventing puerperal lactation. Because of the considerably lower rate of rebound breast activity and adverse events and the simpler administration schedule cabergoline should be the drug of choice for lactation inhibition.     

Atenolol,sustained-release oxprenolol,and long-acting propranolol in hypertension.

The effect of once-daily atenolol, sustained-release oxprenolol (a new formulation of oxprenolol presented as a compressed tablet in a waxed matrix), and long-acting propranolol (a new formulation presented as spheriods in a capsule) was studied in a double-blind crossover trial in 23 carefully selected hypertensive outpatients. After a run-in period with matching placebo each patient received atenolol (100 mg/day), sustained-release oxprenolol (160 mg/day), long-acting propranolol (160 mg/day), and placebo according to a randomised sequence. After four weeks'' treatment with sustained-release oxprenolol blood pressure in the two to four hours before the next dose was not significantly lower than after placebo. The effectiveness of atenolol and of the new formulation of propranolol in reducing blood pressure was confirmed. These results suggest that the present formulation of sustained-release oxprenolol should be reconsidered.     

Efficacy in asthma of once-daily treatment with fluticasone furoate: a randomized,placebo-controlled trial

Background

Fluticasone furoate (FF) is a novel long-acting inhaled corticosteroid (ICS). This double-blind, placebo-controlled randomized study evaluated the efficacy and safety of FF 200 mcg or 400 mcg once daily, either in the morning or in the evening, and FF 200 mcg twice daily (morning and evening), for 8 weeks in patients with persistent asthma.

Methods

Asthma patients maintained on ICS for ≥ 3 months with baseline morning forced expiratory volume in one second (FEV₁) 50-80% of predicted normal value and FEV₁ reversibility of ≥ 12% and ≥ 200 ml were eligible. The primary endpoint was mean change from baseline FEV₁ at week 8 in pre-dose (morning or evening [depending on regimen], pre-rescue bronchodilator) FEV₁.

Results

A total of 545 patients received one of five FF treatment groups and 101 patients received placebo (intent-to-treat population). Each of the five FF treatment groups produced a statistically significant improvement in pre-dose FEV₁ compared with placebo (p < 0.05). FF 400 mcg once daily in the evening and FF 200 mcg twice daily produced similar placebo-adjusted improvements in evening pre-dose FEV₁ at week 8 (240 ml vs. 235 ml). FF 400 mcg once daily in the morning, although effective, resulted in a smaller improvement in morning pre-dose FEV₁ than FF 200 mcg twice daily at week 8 (315 ml vs. 202 ml). The incidence of oral candidiasis was low (0-4%) and UC excretion was comparable with placebo for all FF groups.

Conclusions

FF at total daily doses of 200 mcg or 400 mcg was significantly more effective than placebo. FF 400 mcg once daily in the evening had similar efficacy to FF 200 mcg twice daily and all FF regimens had a safety tolerability profile generally similar to placebo. This indicates that inhaled FF is an effective and well tolerated once-daily treatment for mild-to-moderate asthma.

Trial registration

NCT00398645     

CANCER OF THE LUNG IN WOMEN

Cancer of the lung in women has the same signs and symptoms as in men, but the disease seems to advance more rapidly. Of 35 female patients, half were under radiation therapy (for inoperable tumor) within four months after the first manifestation. In three of the five who had no symptoms, the cancer when diagnosed was inoperable.Scalene node biopsy confirmed metastasis in nine of the eleven cases in which it was used, and this procedure should be used after diagnosis whenever metastasis is not evident.Of the 35 women, two received only chemotherapy, 32 radiotherapy. Only four were alive at the time of report—one without evidence of disease at 20 months, one with symptoms of disease at 11 months, two under chemotherapy at two months, For 29 who received palliative or radical irradiation to the primary tumor site, the median survival time was 26 weeks.     

Response of the midpregnant human uterus to systemic administration of 15(S)-15-methyl-prostaglandin F2alpha

The contractile response of the midpregnant human uterus to a new (PG) prostaglandin analogue, 15(S)-methyl-PGF2alpha (15-me-PGF2alpha), was investigated and compared to the effect of natural PGF2alpha. It was found that the threshold dose of 15-me-PGF2alpha was around 10 mcg when given as a single intravenous injection, which is approximately 1/10 of the corresponding dose of PGF2alpha. It was also found that higher intravenous doses of 15-me-PGFalpha resulted in a uterine response of longer duration than that following PGF2alpha. Intramuscular injection of the analogue at doses of 1.0-1.5 mg induced a marked uterine stimulation sustained for 5-7 hours without causing local reaction. Intravenous infusion of 5 mcg/min of 15-me-PGF2alpha stimulated a level of uterine activity equivalent to that of 75 mcg/min of PGF1alpha. The incidence of gastrointestinal side effects was the same in the 2 treatment groups. However, there seemed to be a tendency toward a significantly higher abortion rate with the analogue.     

Study of immunological and virological parameters during thalidomide treatment of SIV-infected cynomolgus monkeys

The potential therapeutic utility of thalidomide (Thd), an effective inhibitor of tumor necrosis factor (TNF)-α in vitro , was investigated in cynomolgus monkeys ( Macaca fascicularis ) at 10 months after infection with simian immunodeficiency virus (SIV). Thd-treated macaques (n=8) received an oral dose (10 mg) daily for 7 days, followed by a wash-out period of 5 weeks. A 2nd cycle of treatment was performed on the same animals at higher doses (20 mg Thd/day) for 14 days. The control monkeys (n=7) received a placebo for the same period of time. In the present study, we show that Thd, in addition to inhibiting TNF-α production after in vitro mitogen stimulation of peripheral blood mononuclear cells (PBMCs), was able to restore the proliferative responses to SIV peptides in monkeys that were infected with SIV. Interestingly, we found that such effects are associated with an increased expression of CD28 cell surface receptors on CD4⁺ T-cells paralleled by a decrease on CD8⁺ T-cells. At the same time, significant reduction in either cell-associated viral load or plasma viral RNA was not observed among the SIV-infected monkeys during the two treatment cycles, when compared with the placebo group.     

SCE in lymphocytes of patients treated with single, large doses of diazepam

When using the SCE test for evaluation of exposure in vivo to potential mutagens/carcinogens, it is necessary to consider possible confounding factors. In studies of possible mutagenic effects of pharmacological treatment the effect of concomitant administration of other agents such as sedatives may have to be considered. In order to assess whether diazepam per se influences SCE we have examined SCE in peripheral lymphocytes in 34 persons before and after oral administration of a single large dose of diazepam. 18 men and 16 women undergoing minor surgery of the hand received diazepam 0.2 mg kg-1 body weight orally on the day of operation, and venous blood samples were drawn on the day before the operation and again 2-5 h after the administration of diazepam. Both within cigarette smokers and non-smokers there was no statistically significant change of SCE following diazepam. It was concluded that there was no indication, from the SCE test, of an immediate mutagenic effect of a single large dose of diazepam and that such medication is not a confounding factor in studies by the SCE test.     

Effect of enprostil on plasma glucose, insulin and lipid metabolism in patients with non-insulin-dependent diabetes mellitus

Measurements of various aspects of glucose, insulin and lipid metabolism were made before and after the administration of enprostil (a synthetic dehydroprostaglandin E2) for one week to ten patients with non-insulin-dependent diabetes mellitus (NIDDM). Both fasting (P less than 0.01) and postprandial (P less than 0.001) plasma glucose concentrations were significantly lower after one week of enprostil, and 24 hour urinary glucose excretion was reduced from (mean +/- SEM) 47 +/- 14 to 25 +/- 9 g/day. There was no change in either fasting or postprandial insulin concentration, but the postprandial GIP response was also significantly reduced (P less than 0.001). In addition, there were significant reductions in postprandial plasma free fatty acid (P less than 0.05) and triglyceride (P less than 0.001) concentrations, associated with a modest fall in fasting plasma triglyceride (P less than 0.05) and cholesterol (P less than 0.07) concentrations when measured after one week of treatment with enprostil. These results raise the possibility that enprostil may be of some benefit in the treatment of patients with non-insulin-dependent diabetes.     

A randomized, placebo-controlled, double-blind clinical trial of curcuminoids in oral lichen planus.

We studied the efficacy of curcuminoids in the treatment of oral lichen planus (OLP), a chronic, mucocutaneous, immunological disease. Curcuminoids are components of turmeric (Curcuma longa) that have anti-inflammatory activity. Turmeric has been used in Ayurveda (Indian traditional medicine) for centuries. A randomized, double-blind, placebo-controlled trial was conducted. In all, 100 consecutive, eligible patients with OLP presenting to the oral medicine clinic at the University of California, San Francisco, were to be selected. Two interim analyses were to be conducted during the trial. The trial was conducted between February 2003 and September 2004. The first interim analysis was conducted in October 2004 using data from the first 33 subjects. Study subjects were randomized to receive either placebo or curcuminoids at 2000 mg/day for 7 weeks. In addition, all subjects received prednisone at 60 mg/day for the first 1 week. The primary outcome was a change in symptoms from baseline. Secondary outcomes were changes in clinical signs and occurrence of side effects. The first interim analysis did not show a significant difference between the placebo and curcuminoids groups. Conditional power calculations suggested a less than 2% chance that the curcuminoids group would have a significantly better outcome as compared with the placebo group if the trial were continued to completion. Therefore, the study was ended early for futility. Reaching a conclusion regarding the efficacy of curcuminoids based on the results of this study is not possible as it was ended early for futility. Curcuminoids at this dose were well tolerated and the results suggest that for future studies a larger sample size, a higher dose and/or longer duration of curcuminoids administration should be considered; however, for the next step, an RCT of a shorter duration, using a higher dose of curcuminoids, and without an initial course of prednisone, should be considered.     

A controlled study of fluoxetine and cognitive-behavioural counselling in the treatment of postnatal depression.

OBJECTIVE: To study the effectiveness of fluoxetine and cognitive-behavioural counselling in depressive illness in postnatal women: to compare fluoxetine and placebo, six sessions and one session of counselling, and combinations of drugs and counselling. DESIGN: Randomised, controlled treatment trial, double blind in relation to drug treatment, with four treatment cells: fluoxetine or placebo plus one or six sessions of counselling. SUBJECTS: 87 women satisfying criteria for depressive illness 6-8 weeks after childbirth, 61 (70%) of whom completed 12 weeks of treatment. SETTING: Community based study in south Manchester. MAIN OUTCOME MEASURES: Psychiatric morbidity after 1, 4, and 12 weeks, measured as mean scores and 95% confidence limits on the revised clinical interview schedule, the Edinburgh postnatal depression scale and the Hamilton depression scale. RESULTS: Highly significant improvement was seen in all four treatment groups. The improvement in subjects receiving fluoxetine was significantly greater than in those receiving placebo. The improvement after six sessions of counselling was significantly greater than after a single session. Interaction between counselling and fluoxetine was not statistically significant. These differences were evident after one week, and improvement in all groups was complete after four weeks. CONCLUSIONS: Both fluoxetine and cognitive-behavioural counselling given as a course of therapy are effective treatments for non-psychotic depression in postnatal women. After an initial session of counselling, additional benefit results from either fluoxetine or further counselling but there seems to be no advantage in receiving both. The choice of treatment may therefore be made by the women themselves.     

Treatment with a single vaginal suppository containing 15-methyl PGF2 alpha methyl ester at expected time of menstruation.

Termination of early pregnancy, by vaginal administration of prostaglandin analogues, one to three weeks after the first missed menstrual period, has advantages and disadvantages in comparison with vacuum aspiration. Some of these may be reduced if the patient is treated earlier. In the present study the effect and safety of one vaginal administration of 2.5 to 3 mg 15-methyl-PGF2 alpha methyl ester around the expected time of menstruation was evaluated in 16 women exposed to the risk of pregnancy. The overall number of treatment cycles was 35 and pregnancy was confirmed by plasma beta-HCG in eight. The treatment resulted in bleeding in all the pregnant cycles while in the nonpregnant ones it only provoked spotting and bleeding did not begin until the expected time of menstruation. Treatment with 2.5 mg 15-methyl-PGF2 alpha methyl ester resulted in complete abortion in one of three women. If the dose was increased to 3 mg all five treated women aborted. In nonpregnant patients no changes in the levels of estradiol-17 beta or progesterone at any time during the 24-hour observation period were found. Serum cortisol and prolactin but not TSH levels started to increase two hours after the start of treatment and reached a maximum after five hours. The increase coincided with the onset of uterine pain. Ovulatory cycles as judged from basal body temperature occurred in the first menstrual cycle following treatment in all nonpregnant patients. Although possible to use as a "once a month treatment" it seems preferable since the dose is the same, to postpone treatment until menstruation is delayed for a week or more.     

Osteotoxicity after chronic dietary administration of 13-cis-retinoic acid, retinyl palmitate or selenium in mice exposed to tumor initiation and promotion

In view of the clinical trials of retinoids as therapeutic agents for premalignant skin lesions, a radiographic study was undertaken to measure skeletal toxicities after chronic dietary administration of retinoids in mice exposed to tumor initiation and promotion. CD-1 mice were initiated with 0.15 moles of 7,12-dimethylbenz[a]anthracene and promoted twice daily with 8 nmoles of 12-0-tetradecanoylphorbol-13-acetate for 23 weeks. Diets were supplemented with 60 IU, 200 IU, or 700 IU of retinyl palmitate (RP) per g diet. After 5 weeks, the 700 IU of RP /g diet was lowered to 350 IU/g diet. Administration of these diets to mice during the 23 weeks of tumor promotion resulted in a 0-fold, 2-fold, or 10-fold increase in bone fractures, respectively. Osteoporotic bone lesions identified on radiographs rose 0-fold, 0-fold, and 10-fold at the respective doses, whereas metaphyseal flares increased 0-fold, 1.4-fold, and 3.6-fold. Bone deformities were augmented 0-fold, 1.8-fold and 2.9-fold at the respective doses. Addition of selenium (2 ppm in the drinking water) did not alter the bone toxicity of RP. 13-cis-retinoic acid (CRA) was less toxic at 700 IU/g diet than was RP at that dose, as evidenced by the death of 12 of 70 mice by the 6th week of dietary RP and no deaths in the 35 mice fed 700 IU CRA/g diet for 23 weeks. CRA at 700 IU/g diet resulted in 3/4 as many osteoporotic bones, 1/3 as many bone fractures, 4/5 as many metaphyseal flares, and a similar number of bone deformities as mice fed 700/350 IU/g diet. At the dose of 200 IU/g food, osteotoxicities were similar in the mice fed diets supplemented with RP and CRA. Thus, the light dose of CRA (700 IU/g diet) was less toxic than the high dose of, RP but at a lower dose (200 IU/g), CRA was as osteotoxic as was RP. Bone fractures in mice exposed to prolonged dietary administration of retinoids was a more sensitive index of retinoid toxicity than was body weight. We have detected osteotoxicity in mice at a total dose of CRA which was about twice the total dose used clinically.     

Postnatal disappearance of the pregnancy-associated reduced sensitivity of plasma cortisol to feedback inhibition

We recently observed that the characteristic insensitivity of the pituitary-adrenal system in women to feedback inhibition during pregnancy persists for at least four days postnatally. We therefore examined women during the first five weeks after delivery to assess when the sensitivity of plasma cortisol to glucocorticoid inhibition returns to normal. Dexamethasone (DEXA, 1 mg) was ingested at 11 pm by normal healthy women, once between the 3rd and 27th postnatal days, and again on day 35. Blood plasma was collected at 4 pm on the following day for cortisol assay. Plasma cortisol levels (nmol/L, mean +/- sem [n]) after DEXA in the first two weeks (216 +/- 28, [47]) were higher (p less than 0.001) than in nonmedicated nonpregnant women (47.4 +/- 8.9 [12]) and were normal by the 35th day after delivery (41.7 +/- 4.8 [74]). A negative association was found between post-DEXA cortisol and time after delivery in the first 4 post-partum weeks (r = -0.46, p less than 0.001). The study confirms that insensitivity of plasma cortisol to feedback inhibition persists beyond normal pregnancy in a significant proportion of healthy women for two to three weeks, and is absent by the 5th postnatal week.     

Bronchodilator Effect of Oral Salbutamol in Asthmatics Treated with Corticosteroids

In a double-blind trial the effect on ventilatory function of oral salbutamol (in two different doses) and a placebo were studied in 12 patients with chronic asthma receiving regular maintenance treatment with prednisolone. Salbutamol in a dose of 4 mg four times daily, given for a period of four weeks, produced a sustained and statistically significant increase in peak expiratory flow rate over the pretreatment recordings. This effect was not observed with a lower dose of salbutamol (2 mg four times daily) or with a placebo. Salbutamol in the higher dose would seem to be an effective and safe oral bronchodilator that can be recommended for the treatment of mild or moderate asthma. The duration of treatment in this study was, however, limited to four weeks, and it is not known whether effective bronchodilatation would be maintained if the drug were given for longer periods.