Effect of isosorbide dinitrate (sorbonit) on the exercise reaction in patients with coronary disease and in healthy individuals

The study aimed at evaluating an effect of a single dose of isosorbide dinitrate (Sorbonit) on the exercise reaction in the patients with coronary disease of various degree and in healthy individuals. The study involved 20 male patients of mean age 54.0 +/- 4.5 years with history of myocardial infarction and 12 healthy males of mean age 45.6 +/- 5.0 years. Ergometric test has been performed twice: prior to and 15 minutes after sublingual administration of isosorbide dinitrate in the dose of 10-15 mg. The first test has been interrupted when horizontal ST load exceeded 1 mm or contractions rate was 60% of the maximum value. Similar loads have been used after the administration of Sorbonit. The following parameters have been evaluated: heart rate (HR), systolic blood pressure (BPS), HR x BPS, lactate level (LA), and cardiac index. The value of the load has been measured with the aid of oxygen consumption (VO2). Significant depression of ST segment (less than 3 mm) in the exercise ECG has been noted in 8 patients following isosorbide dinitrate. Exercise tolerance has increased in these patients - CI increased during exercise following drug administration (VO2 the same as prior to the drug administration), and VO2/CI has became closer - physiological.     

The accuracy of the electrocardiogram during exercise stress test based on heart size

Background

Multiple studies have shown that the exercise electrocardiogram (ECG) is less accurate for predicting ischemia, especially in women, and there is additional evidence to suggest that heart size may affect its diagnostic accuracy.

Hypothesis

The purpose of this investigation was to assess the diagnostic accuracy of the exercise ECG based on heart size.

Methods

We evaluated 1,011 consecutive patients who were referred for an exercise nuclear stress test. Patients were divided into two groups: small heart size defined as left ventricular end diastolic volume (LVEDV) <65 mL (Group A) and normal heart size defined as LVEDV ≥65 mL (Group B) and associations between ECG outcome (false positive vs. no false positive) and heart size (small vs. normal) were analyzed using the Chi square test for independence, with a Yates continuity correction. LVEDV calculations were performed via a computer-processing algorithm. SPECT myocardial perfusion imaging was used as the gold standard for the presence of coronary artery disease (CAD).

Results

Small heart size was found in 142 patients, 123 female and 19 male patients. There was a significant association between ECG outcome and heart size (χ² = 4.7, p = 0.03), where smaller hearts were associated with a significantly greater number of false positives.

Conclusions

This study suggests a possible explanation for the poor diagnostic accuracy of exercise stress testing, especially in women, as the overwhelming majority of patients with small heart size were women.     

Effect of exercise training on total daily physical activity in elderly humans

This study examined the effect of 12 weeks of exercise training on daily physical activity in elderly humans. Training consisted of a weekly group session and an individual session with cardio- and weight-stack machines. A group of 15 subjects served as the exercise group [EXER mean age 59 (SD 4) years], and 7 subjects as the controls [CONT mean age 57 (SD 3) years]. Physical activity and physical fitness were measured before the start of training (T), at week 6 and week 12 (T0, T6, T12 respectively) in EXER, and at T0 and T12 in CONT. Physical activity over 14 days was measured using a tri-axial accelerometer and physical fitness was measured during an incremental exercise test. At T12, mean maximal power output had significantly increased in EXER compared to CONT 8 (SD 12) vs -5 (SD 9) W; P < 0.02] and mean submaximal heart rate (at 100 W) had reduced [-10 (SD 7) vs -2 (SD 6) beats x min(-1); P < 0.05]. No differences or changes in physical activity were observed between EXER and CONT. At T6, physical activity on training days was significantly higher than on non-training days (P < 0.001). When the accelerometer output of the training session was subtracted from the accelerometer output on training days, at T12 non-training physical activity was significantly lower than on non-training days (P < 0.004). Accelerometer output of the individual training session at T12 had significantly increased compared to T6 (P < 0.05), whereas, accelerometer output of the group training session had remained unchanged. In conclusion, in elderly subjects an exercise training programme of moderate intensity resulted in an improved physical fitness but had no effect on total daily physical activity. Training activity was compensated for by a decrease in non-training physical activity.     

Beta-blockade reduces tidal volume during heavy exercise in trained and untrained men

The effects of beta-blockade on tidal volume (VT), breath cycle timing, and respiratory drive were evaluated in 14 endurance-trained [maximum O2 uptake (VO2max) approximately 65 ml X kg-1 X min-1] and 14 untrained (VO2max approximately 50 ml X kg-1 X min-1) male subjects at 45, 60, and 75% of unblocked VO2max and at VO2max. Propranolol (PROP, 80 mg twice daily), atenolol (ATEN, 100 mg once a day) and placebo (PLAC) were administered in a randomized double-blind design. In both subject groups both drugs attenuated the increases in VT associated with increasing work rate. CO2 production (VCO2) was not changed by either drug during submaximal exercise but was reduced in both subject groups by both drugs during maximal exercise. The relationship between minute ventilation (VE) and VCO2 was unaltered by either drug in both subject groups due to increases in breathing frequency. In trained subjects VT was reduced during maximal exercise from 2.58 l/breath on PLAC to 2.21 l/breath on PROP and to 2.44 l/breath on ATEN. In untrained subjects VT at maximal exercise was reduced from 2.30 l/breath on PLAC to 1.99 on PROP and 2.12 on ATEN. These observations indicate that 1) since VE vs. VCO2 was not altered by beta-adrenergic blockade, the changes in VT and f did not result from a general blunting of the ventilatory response to exercise during beta-adrenergic blockade; and 2) blockade of beta 1- and beta 2-receptors with PROP caused larger reductions in VT compared with blockade of beta 1-receptors only (ATEN), suggesting that beta 2-mediated bronchodilation plays a role in the VT response to heavy exercise.     

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.     

Muscle sarcoplasmic reticulum calcium regulation in humans during consecutive days of exercise and recovery.

The study investigated the hypothesis that three consecutive days of prolonged cycle exercise would result in a sustained reduction in the Ca(2+)-cycling properties of the vastus lateralis in the absence of changes in the sarcoplasmic (endoplasmic) reticulum Ca(2+)-ATPase (SERCA) protein. Tissue samples were obtained at preexercise (Pre) and postexercise (Post) on day 1 (E1) and day 3 (E3) and during recovery day 1 (R1), day 2 (R2), and day 3 (R3) in 12 active but untrained volunteers (age 19.2 +/- 0.27 yr; mean +/- SE) and analyzed for changes (nmol.mg protein(-1).min(-1)) in maximal Ca(2+)-ATPase activity (V(max)), Ca(2+) uptake and Ca(2+) release (phase 1 and phase 2), and SERCA isoform expression (SERCA1a and SERCA2a). At E1, reductions (P < 0.05) from Pre to Post in V(max) (150 +/- 7 vs. 121 +/- 7), Ca(2+) uptake (7.79 +/- 0.28 vs. 5.71 +/- 0.33), and both phases of Ca(2+) release (phase 1, 20.3 +/- 1.3 vs. 15.2 +/- 1.1; phase 2, 7.70 +/- 0.60 vs. 4.99 +/- 0.48) were found. In contrast to V(max), which recovered at Pre E3 and then remained stable at Post E3 and throughout recovery, Ca(2+) uptake remained depressed (P < 0.05) at E3 Pre and Post and at R1 as did phase 2 of Ca(2+) release. Exercise resulted in an increase (P < 0.05) in SERCA1a (14% at R2) but not SERCA2a. It is concluded that rapidly adapting mechanisms protect V(max) following the onset of regular exercise but not Ca(2+) uptake and Ca(2+) release.     

食品级槲皮素粉对机体最大摄氧量和耐力的影响

为了考察食品级槲皮素粉对机体最大摄氧量和耐力的影响,本研究纳入20名健康的大学生志愿者作为本研究的研究对象。将受试者随机分为A组和B组,每组10名,A组饮用剂量为1 mg/mL的槲皮素饮料,B组饮用安慰剂饮料,每天饮用1 000 m L。饮用7 d后,通过自行车分级运动测试最大摄氧量(VO2max),通过骑行疲劳时间测试耐力,同时检测血清丙二醛(MDA)、超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)含量。然后进行交叉实验并测试VO2max、骑行疲劳时间及抗氧化指标。研究显示,与基线VO2max相比,饮用槲皮素饮料后VO2max显著升高13.21%,而饮用安慰剂饮料后的VO2max与基线无显著差异。与基线骑行疲劳时间相比,饮用槲皮素饮料后骑行疲劳时间显著升高25.15%,而饮用安慰剂饮料后的骑行疲劳时间与基线无显著差异。与基线血清MDA相比,饮用安慰剂饮料后受试者血清MDA显著升高27.15%,而饮用槲皮素饮料可抑制血清MDA的升高。与基线血清SOD和GSH-Px相比,饮用安慰剂饮料后受试者血清SOD和GSH-Px分别降低了20.49%和21.08%,而饮用槲皮素饮料可抑制血清SOD和GSH-Px的降低,表明槲皮素可显著提高骑行运动过程中受试者的VO2max和耐力。本研究初步表明,补充槲皮素可通过降低运动过程中MDA水平来减少脂质过氧化损伤。另外,槲皮素通过抑制运动过程中SOD和GSH-Px的降低来提高机体的抗氧化能力,从而延缓疲劳。     

The effects of ovarian hormones on glucose and fatty acid oxidation during exercise in female ovariectomized rats

The effects of ovarian hormones on glucose and fatty acid oxidation during exercise were investigated in adult female ovariectomized rats. Rats subdivided into 3 groups received intraperitoneal injections of hormones or sesame oil for 8 days. Estrogen (E) treated rats received 17-beta estradiol in daily doses of 2 micrograms. Estrogen and progesterone treated rats (EP) received 17-beta estradiol in daily doses of 2 micrograms and 2 mg, respectively. Control rats (S) received sesame oil alone. After an overnight fast, rats ran at the speed of 25 m.min-1 for 60 min. [U-14C]glucose or [1-14C]palmitate was injected into rats at 5 min of exercise and before 10 min of exercise, respectively. Expired 14CO2 was collected using bottomless chamber on a treadmill belt. No significant differences were found in mean blood glucose, lactate and plasma free fatty acid concentrations after the exercise. Until the end of the exercise 34.7 +/- 2.6 (E, n = 5), 40.8 +/- 2.9 (EP, n = 5) and 43.7 +/- 3.5% (S, n = 6) (mean +/- SE) of 14C which was injected as 14C-glucose was recovered as 14CO2. During 60 min of the exercise 27.5 +/- 1.0 (E, n = 7), 19.8 +/- 2.7 (EP, n = 6) and 25.0 +/- 1.9% (S, n = 6) of 14C which was injected as 14C-palmitate was recovered as 14CO2. A significant difference was found in this rate between E and EP (P less than 0.05). It was concluded that estrogen treatment stimulated fatty acid oxidation compared with the estrogen plus progesterone treatment and tended to inhibit glucose oxidation during prolonged exercise.     

Pharmacogenetic-Based Efavirenz Dose Modification: Suggestions for an African Population and the Different CYP2B6 Genotypes

Background

Pharmacogenetics contributes to inter-individual variability in pharmacokinetics (PK) of efavirenz (EFV), leading to variations in both efficacy and toxicity. The purpose of this study was to assess the effect of genetic factors on EFV pharmacokinetics, treatment outcomes and genotype based EFV dose recommendations for adult HIV-1 infected Ugandans.

Methods

In total, 556 steady-state plasma EFV concentrations from 99 HIV infected patients (64 female) treated with EFV/lamivudine/zidovidine were analyzed. Patient genotypes for CYP2B6 (*6 & *11), CYP3A5 (*3,*6 & *7) and ABCB1 c.4046A>G, baseline biochemistries and CD4 and viral load change from baseline were determined. A one-compartment population PK model with first-order absorption (NONMEM) was used to estimate genotype effects on EFV pharmacokinetics. PK simulations were performed based upon population genotype frequencies. Predicted AUCs were compared between the product label and simulations for doses of 300 mg, 450 mg, and 600 mg.

Results

EFV apparent clearance (CL/F) was 2.2 and 1.74 fold higher in CYP2B6*6 (*1/*1) and CYP2B6*6 (*1/*6) compared CYP2B6*6 (*6/*6) carriers, while a 22% increase in F1 was observed for carriers of ABCB1 c.4046A>G variant allele. Higher mean AUC was attained in CYP2B6 *6/*6 genotypes compared to CYP2B6 *1/*1 (p<0.0001). Simulation based AUCs for 600 mg doses were 1.25 and 2.10 times the product label mean AUC for the Ugandan population in general and CYP2B6*6/*6 genotypes respectively. Simulated exposures for EFV daily doses of 300 mg and 450 mg are comparable to the product label. Viral load fell precipitously on treatment, with only six patients having HIV RNA >40 copies/mL after 84 days of treatment. No trend with exposure was noted for these six patients.

Conclusion

Results of this study suggest that daily doses of 450 mg and 300 mg might meet the EFV treatment needs of HIV-1 infected Ugandans in general and individuals homozygous for CYP2B6*6 mutation, respectively.     

The Effect of Phenothiazines on the Electrocardiogram

Thioridazine, chlorpromazine and trifluoperazine were administered to six psychiatric patients. Each was used in four dosage levels (thioridazine and chlorpromazine: 200, 400, 800 and 1200 mg. daily; trifluoperazine: 8, 16, 32, 64 mg. daily); and each increase in dosage was effected after four days of drug administration.Before the trial, twice during each drug period and before commencement of the next dose regimen, an electrocardiogram (ECG) was recorded. The findings indicated that thioridazine modifies the terminal portion (S-T segment, T and U waves) of the human ECG. A similar change occurred in three of six subjects while taking chlorpromazine and in one of six while taking trifluoperazine. Thioridazine induced changes in all six subjects studied, viz., blunting and notching of T waves with or without prolongation of QT interval. In some the notching produced a doublehump appearance in which a T wave of reduced voltage formed the proximal hump and a positive U wave of increased voltage formed the distal hump.Thioridazine-induced alterations in the ECG have been described as resembling those caused by quinidine; they also resemble changes associated with hypokalemia.     

Comparison of the effects of two GnRH antagonists on LH and FSH secretion,follicular growth and ovulation in the mare

The effects of two GnRH antagonists were tested in order to delay and/or synchronise ovulation in mares. Five mares received Antarelix (0.01 mg.kg(-1)), 5 mares received Cetrorelix (the same dose), 5 mares (control mares) received the vehicle intravenously, twice daily, for 8 days from the day the largest follicle reached 22 mm following prostaglandin administration. Ovulation was postponed in all mares injected with Antarelix (19.4 +/- 1.2 days after the beginning of the treatment) and in 2/5 mares injected with Cetrorelix (20 +/- 1 days) vs. 6.2 +/- 0.4 days in control mares. During the treatment, LH concentrations were strongly depressed in Antarelix and in Cetrorelix mares (1.6 +/- 0.1 and 3.8 +/- 0.5 ng.mL(-1) respectively vs. 21 +/- 2.5 ng.mL(-1) in control mares). In the 3 Cetrorelix mares which ovulated during the treatment. 2 initiated their LH surge at this moment. FSH concentrations were not affected in Antarelix or in Cetrorelix mares during the treatment (11.4 +/- 1.3 and 7.9 +/- 0.8 ng.mL(-1) respectively vs. 10.5 +/- 0.8 ng.mL(-1) in control mares). In conclusion, Antarelix seems more efficient than Cetrorelix for postponing ovulation in mares. The role of LH in antral follicular development before the preovulatory stage is confirmed.     

Effects of low-dose tamoxifen on breast cancer biomarkers Ki-67, estrogen and progesterone receptors

Breast carcinoma is the most common malignancy among women and it has a major impact on mortality. Studies of primary chemoprevention with tamoxifen have generated high expectations and considerable success rates. The efficacy of lower doses of tamoxifen is similar to that seen with a standard dose of the drug, and there has been a reduction in healthcare costs and side effects.The immune reaction to monoclonal antibody Ki-67 (MIB-1) and the expression of estrogen receptors (1D5) and progesterone receptors (PgR 636) in breast carcinoma were studied in patients treated with 10 mg of tamoxifen for a period of 14 days.A prospective randomized clinical trial was conducted with 38 patients divided into two groups: Group A: N = 20 (control group-without medication) and Group B: N = 18 (tamoxifen/10 mg/day for 14 days). All patients signed an informed consent term previously approved by both institutions. Patients underwent incisional biopsy before treatment and 14 days later a tumor tissue sample was obtained during surgical treatment. Positivity was quantitatively assessed, counting at least 1.000 cells per slide. For statistical data analysis, a Wilcoxon non-parametric test was used, and α was set at 5%.Both groups (A and B) were considered homogeneous regarding control variables. In Group A (control), there was no statistically significant reduction in Ki-67 (MIB-1) (p = 0.627), estrogen receptor (1D5) (p = 0.296) and progesterone receptor positivity (PgR 636) (p = 0.381).In Group B (tamoxifen 10 mg/day), the mean percentage of nuclei stained by Ki-67 (MIB-1) was 24.69% before and 10.43% after tamoxifen treatment. Mean percentage of nuclei stained by estrogen receptor (1D5) was 59.53% before and 25.99% after tamoxifen treatment. Mean percentage of nuclei stained by progesterone receptor (PgR 636), was 59.34 before and 29.59% after tamoxifen treatment. A statistically significant reduction was found with the three markers (p < 0.001).Tamoxifen significantly reduced monoclonal antibody Ki-67 (MIB-1), estrogen receptor (1D5) and progesterone receptor positivity (PgR 636) in the breast epithelium of carcinoma patients treated with a 10 mg dose of tamoxifen for 14 days.     

Comparison of once daily and twice daily FSH injections for superovulating beef cattle

Twelve cycling Angus-based crossbred cows were used in a crossover experimental design to evaluate two different injection schedules using Follicle Stimulating Hormone (FSH) for superovulating donor cattle. Females randomly assigned to Treatment (A) were given twice daily FSH injections of 5 mg each (12 hours apart) for five consecutive days starting on day 10 of the estrous cycle while those in Treatment (B) received the same daily dose level of FSH, except it was given in a 3.2% protein gelatin carrier vehicle and administered on a once daily injection schedule. Animals in both Treatments (A) and (B) were each given a 30 mg dose of commercially available prostaglandin-F(2alpha) agent 48 hours after the first FSH injection. Cows in estrus were initially handmated to a fertile bull then artificially inseminated 12 hours later with two units of frozen semen. All 12 animals (100%) given twice daily FSH injections and 11 of the females (91.6%) administered once daily FSH injections exhibited standing estrus within 5 days following injection of the luteolytic agent. On day 7 or 8 after the onset of standing estrus a laparotomy was performed to observe ovarian structures. When the superovulation response was evaluated, the mean number of corpora lutea per ovary ranged from 2.9 in the twice daily injection group to 4.1 in the once daily injected group. Unexpectedly, the once daily treated group had significantly more corpora lutea per animal (8.1 vs. 6.4) than those in the twice daily treated group. In addition, mean ovarian size score per animal increased significantly when pre-treatment scores were compared to those recorded following FSH treatment (laparotomy) in both Treatment (A) and (B), however, the post-treatment ovarian size scores were not different between these groups. When evaluating post-treatment follicular development, the once daily injection group had significantly more smaller follicles (<10 mm) and a greater number of ovulatory size follicles (>10 mm) than the twice daily injection group. Furthermore, viable appearing embryos were recovered from both treatment groups and no adverse reactions were observed with the gelatin carrier vehicle in Treatment (B). Since the once daily FSH injection schedule resulted in a superovulatory response equal to or greater than the twice daily FSH injection schedule, this approach to superovulation should not be overlooked by those involved in bovine embryo transplantation.     

Cochleates: New Lipid-Based Drug Delivery System

Abstract

Cochleates are a lipid-based tailored drug delivery system formed by the precipitation of a negatively charged lipid and a cation, for example phosphatidylserine and calcium. Hydrophobic, amphiphilic, negatively or positively charged moieties are suitable candidates to be delivered via cochleates. Various procedures have been developed allowing the control of cochleate particle size, including the trapping and hydrogel methods, which use either a direct addition or a slow diffusion of calcium into the negatively charged liposome/drug suspension. The efficacy of cochleates to encapsulate and deliver drugs was evaluated using amphotericin B as a model. Amphotericin B cochleates (CAMB) were compared to Fungizone® and AmBisome®, two commercially available AmB products. Parenterally, CAMB was given IP to ICR mice infected with Candida albicans. 100% survival was observed with low doses of CAMB (0.5 mg/kg/day, 10 days) compared to 60% for Fungizone, at the same dose. Tissue burden studies were conducted in parallel. Mice were treated daily from day 1 to day 7 post challenge and tissue burden assessed at day 8. In the kidneys, all three formulations were comparable in reducing colony counts. In the spleen, CAMB at 10 mg/kg/day was comparable to AmBisome given IV at the same dose. At 1 mg/kg/day, CAMB was more potent than Fungizone and AmBisome. Oral administration of CAMB in C57BL/6 mice, at 10 mg/kg results in high levels of AmB in target tissues. Multiple daily doses (10) showed accumulation of AmB in key tissues (liver, lungs, spleen, and kidneys) and AmB tissue concentrations are raised to therapeutic levels. Orally administered CAMB are highly effective against fungal infections in mice at very low doses. Balb/C mice were infected with Candida albicans and were given oral CAMB as a daily dose for 15 days. Comparison was done to AmBisome given orally at 10 mg/kg and Fungizone IP. 100% survival was obtained with CAMB at doses as low as 0.5 mg/kg/day (15 days). CAMB eradicate Candida from lungs when given at 2.5 mg/kg/day and was comparable to Fungizone given IP at almost the same dose (2 mg/kg/day). The comparison between CAMB and AmBisome shows that oral CAMB is 10 times more effective than oral AmBisome in reducing colony counts in both kidneys and lungs. Orally administered CAMB were non-toxic even at the highest dose of 50 mg/kg/day (14 days). This was demontrated by 100% survival of the animals and normal histopathology analysis. No lesions in the kidneys, GI tract, lungs, liver and spleen was observed despite the substantial amount of AmB in these organs. AmB cochleate promise to be a safe, broad spectrum, effective and orally available, antifungal formulation.     

Chemopreventive effect of diclofenac on mammary carcinogenesis in Sprague-Dawley rats

Chemopreventive effect of non-steroidal antiinflammatory drugs (NSAIDs) in mammary carcinogenesis was reported in several studies. In this study, the effect of a nonselective cyclooxygenase inhibitor diclofenac (DICLO) in the prevention of N-methyl-N-nitrosourea (NMU)-induced mammary carcinogenesis in Sprague-Dawley female rats was evaluated. NMU was administered to animals intraperitoneally in two doses of 50 mg kg^?1 b.w. within postnatal days 42-48. In experiment A (short-term administration), DICLO was administrated intramuscularly (5 mg kg^?1 b.w.) every other day, starting 3 days before and for subsequent 25 days after first NMU injection. In experiment B (long-term administration), DICLO was administered in tap water (0.01 mg ml^?1) continually, starting 7 days before and for subsequent 22 weeks after first NMU dose. The study was terminated 22 weeks after the first dose of NMU in both experiments. After DICLO treatment, tumor frequency per group was reduced in both variants of drug administration: in experiment A by 38% and in experiment B by 39.5%. Moreover, DICLO decreased tumor incidence by 11.5% and delayed tumor latency by 14 days in experiment B. In our preventive-curative experiments DICLO decreased some parameters of NMU-induced rat mammary carcinogenesis, mainly the tumor frequency.     

Absorption and retinol equivalence of beta-carotene in humans is influenced by dietary vitamin A intake

The effect of vitamin A supplements on metabolic behavior of an oral tracer dose of [14C]beta-carotene was investigated in a longitudinal test-retest design in two adults. For the test, each subject ingested 1 nmol of [14C]beta-carotene (100 nCi) in an emulsified olive oil-banana drink. Total urine and stool were collected for up to 30 days; concentration-time patterns of [14C]beta-carotene, [14C]retinyl esters, and [14C]retinol were determined for 46 days. On Day 53, the subjects were placed on a daily vitamin A supplement (10000 IU/day), and a second dose of [14C]beta-carotene (retest) was given on Day 74. All 14C determinations were made using accelerator mass spectrometry. In both subjects, the vitamin A supplementation was associated with three main effects: 1). increased apparent absorption: test versus retest values rose from 57% to 74% (Subject 1) and from 52% to 75% (Subject 2); 2). an approximately 10-fold reduction in urinary excretion; and 3). a lower ratio of labeled retinyl ester/beta-carotene concentrations in the absorptive phase. The molar vitamin A value of the dose for the test was 0.62 mol (Subject 1) and 0.54 mol (Subject 2) vitamin A to 1 mol beta-carotene. Respective values for the retest were 0.85 and 0.74. These results show that while less cleavage of beta-carotene occurred due to vitamin A supplementation, higher absorption resulted in larger molar vitamin A values.     

Influence of oral dehydroepiandrosterone (DHEA) on urinary steroid metabolites in males and females

Oral dehydroepiandrosterone (DHEA) replacement therapy may have a multitude of potential beneficial effects and exerts its action mainly via peripheral bioconversion to androgens (and estrogens). A daily dose of 50-mg DHEA has been shown by us and others to restore low endogenous serum DHEA concentrations to normal youthful levels followed by an increase in circulating androgens and estrogens. As the hepatic first-pass effect may lead to a non physiological metabolism of DHEA after oral ingestion we studied the influence of two single DHEA doses (50 and 100 mg) on the excretion of steroid metabolites in 14 elderly males [age 58.8+/-5.1 years (mean +/- SEM)] with endogenous DHEAS levels <1500 ng/ml and in 9 healthy females (age 23.3+/-4.1 years) with transient suppression of endogenous DHEA secretion induced by dexamethasone (dex) pretreatment (4x0.5 mg/day/4 days). Urinary steroid profiles in the elderly males were compared to the steroid patterns found in 15 healthy young men (age 28.9+/-5.1 years). In the females the results were compared to their individual baseline excretion without dex pretreatment. Urinary steroid determinations were carried out by semiautomatic capillary gas-liquid chromatography. In both genders DHEA administration induced significant increases in urinary DHEA (females: baseline vs. 50 mg vs. 100 mg: 361+/-131 vs. 510+/-264 vs. 1541+/-587 microg/day; males: placebo vs. 50 mg vs. 100 mg: 434+/-154 vs. 1174+/-309 vs. 4751+/-1059 microg/day) as well as in the major DHEA metabolites androsterone (A) and etiocholanolone (Et). Fifty mg DHEA led to an excretion of DHEA and its metabolites only slightly above baseline levels found in young females and in young men, respectively, whereas 100 mg induced clearly supraphysiological values. After 50 mg DHEA the ratios of urinary DHEA metabolites (A/DHEA, Et/DHEA) were not significantly different between elderly males vs. young male volunteers and young healthy females versus their individual baseline levels. In conclusion, an oral dose of 30 to 50 mg DHEA restores a physiological urinary steroid profile in subjects with DHEA deficiency without evidence for a relevant hepatic first-pass effect on urinary metabolites.     

Comparative study of four antifungal drugs in an experimental model of murine cryptococcosis

A comparative study among amphotericin B, 5-fluorocytosine, itraconazole and fluconazole in the treatment of experimental cryptococcosis in mice, was carried out.Seventy male Balb C mice were inoculated intraperitoneally with 10⁷ cells of Cryptococcus neoformans var. neoformans. They were divided in 7 groups of 10 animals each one: 1) treated with fluconazole by gavage at a daily dose of 16 mg/kg; 2) treated with itraconazole by gavage at a daily dose of 16 mg/kg; 3) treated with 5-fluorocytosine by gavage at a daily dose of 300 mg/kg; 4) treated with amphotericin B intraperitoneally at a dose of 6 mg/kg every other day; 5) control animals receiving polietilenglicol 200 by gavage; 6) control animals receiving distilled water by gavage and 7) control animals receiving sterile distilled water by intraperitoneal route. All the treatments started 5 days after the challenge inoculation and they were given for 2 weeks.The following parameters were taken into account: survival time, macroscopic aspect of the organ after the complete autopsy, microscopic investigation of yeasts in brain, lungs, spleen and liver, histopathology studies of these organs, the colony forming units per gram and massive seeding of brain and lungs.The survival index of the different groups was the most efficient method to measure the antifungal compounds activity. Amphotericin B increased significantly the animals survival and modified the histopathologic response in the studied organs. The colony forming units and the massive seeding in brain and lung showed that this antifungal agent is unable of producing the biological cure of this experimental model.The remaining drugs assayed did not promote important modifications in the histopathologic picture as well as in the tissues cultures. However, the three drugs increased the animals survival. In this aspect, fluconazole proved to be slightly superior.     

Production of [14C]fumonisin B1 by Fusarium moniliforme MRC 826 in corn cultures.

Kinetics of growth and fumonisin production by Fusarium moniliforme MRC 826 in corn "patty" cultures were investigated, and a technique was developed for the production of [14C]fumonisin B1 ([14C]FB1) by using L-[methyl-14C]methionine as the precursor. A significant (P < 0.01) correlation exists between fungal growth and FB1 (r = 0.89) and FB2 (r = 0.87) production in corn patties, beginning after 2 days and reaching the stationary phase after 14 days of incubation. [14C]FB1 was produced by adding L-[methyl-14C]methionine daily to cultures during the logarithmic phase of production. Incorporation of the isotope occurred at C-21 and C-22 of the fumonism molecule and was enhanced in the presence of unlabeled L-methionine. Although the concentration of exogenous unlabeled methionine is critical for incorporation of the 14C label, optimum incorporation was achieved by adding 50 mg of unlabeled L-methionine and 200 mu Ci of L-[methyl-14C]methionine to a corn patty (30 g) over a period of 9 days, yielding [14C]FB1 with a specific activity of 36 mu Ci/mmol.     

Morphological and functional characteristics of the dominant follicle and corpus luteum in cattle and their influence on ovarian function

Predicting the functional activity of a dominant follicle (DF) and corpus luteum (CL) might be important before starting a superovulation regime or a synchronization program. The DF and CL were characterized morphologically by using ultrasonography and were characterized functionally by estimating the estradiol-17beta/progesterone (E2/P4) ratio. Their influence on ovarian function was estimated through their ability to ovulate at different stages of development in response to PGF2alpha-application. A total of 47 Holstein Friesian (35 cows and 12 heifers) were used in two experiments. In Experiment 1, 25 animals were examined by daily transrectal palpation and ultrasonography to follow the morphological development of the DF. The status of the DF was categorized into 3 groups (A1, B1, C1). The A1 group (n=7) contained animals with DF in the growing phase or in early static growth phase for less than 3 days. Group B1 (n=13) included animals with DF in static growth phase for 3 to 4 days, while Group C1 (n=5) comprised animals with DF keeping a plateau for more than 4 days or animals with DF in the regression phase. The DF were aspirated transvaginally and the follicular fluid (FF) was analyzed for E2 and P4. In Experiment 2, 22 animals were included. As in Experiment 1, the animals were classified into three groups (A2, n=10; B2, n=5; C2, n=7). They were treated by a single dose of PGF2alpha (25 mg, i.m.) between Days 8 and 12 of the cycle. Results showed that luteolyses occurred in all animals. The DF, which were in growing or in early static growth phase < 3 days were always E2-dominant (E2 > P4) and ovulated after PGF2alpha-application in 6/8 of cases and persisted in 2 (Group A2). The DF persisting > 4 days or that had been in regression were always P4-dominant. This type of DF regressed after PGF2alpha-application (Group C2). The DF in early static growth phase for 3 to 4 days in 5/13 cases were E2-dominant and in 8/13 cases were P4-dominant. This type of DF ovulated in 3/5 cases and regressed in 2/5 cases after PGF2alpha-application (Group B2). These results suggest that the DF is morphologically and functionally defined as long as the DF is in the growing or early static growth phase (A1, A2) for at least 2 days or if the DF is in regression (C1, C2). However, when the DF is in the static growth phase for 3 or 4 days (B1, B2), their morphological and functional characteristics are different. The CL controlls ovulation in the A and C groups and plays an abettor's roll in the B-group.