Acute effects of d-amphetamine during the follicular and luteal phases of the menstrual cycle in women

Rationale: Little is known about the interactions between ovarian hormones across the menstrual cycle and responses to psychoactive drugs in humans. Preclinical studies suggest that ovarian hormones such as estrogen and progesterone have direct and indirect central nervous system actions, and that these hormones can influence behavioral responses to psychoactive drugs. Objectives: In the present study, we assessed the subjective and behavioral effects of d-amphetamine (AMPH; 15 mg orally) at two hormonally distinct phases of the menstrual cycle in women. Methods: Sixteen healthy women received AMPH or placebo capsules during the follicular and mid-luteal phases of their cycle. During the follicular phase, estrogen levels are low initially and then rise while progesterone levels remain low. During the mid-luteal phase, levels of both estrogen and progesterone are relatively high. Dependent measures included self-report questionnaires, physiological measures and plasma hormone levels. Results: Although there were no baseline differences in mood during the follicular or luteal phase, the effects of AMPH were greater during the follicular phase than the luteal phase. During the follicular phase, subjects reported feeling more “High”, “Energetic and Intellectually Efficient”, and “Euphoric” after AMPH than during the luteal phase, and also reported liking and wanting AMPH more. Further analyses showed that during the follicular phase, but not the luteal phase, responses to AMPH were related to levels of estrogen. Higher levels of estrogen were associated with greater AMPH-induced increases in “Euphoria” and “Energy and Intellectual Efficiency”. During the luteal phase, in the presence of both estrogen and progesterone, estrogen levels were not related to the effects of AMPH. Conclusions: These findings suggest that estrogen may enhance the subjective responses to a stimulant drug in women, but that this effect may be masked in the presence of progesterone. Received: 26 August 1998/Final version: 19 February 1999     

The effect of the menstrual cycle on the pharmacokinetics of caffeine in normal, healthy eumenorrheic females

  Objective: Hormonal fluctuations of estrogen and progesterone in eumenorrheic women may be capable of altering the pharmacokinetics of certain agents. The objective of this study was to determine the effect of the luteal, ovulatory and follicular phases of the menstrual cycle on the pharmacokinetics of caffeine, a low clearance, flow-independent drug. Methods: Subjects were ten healthy, non-smoking, eumenorrheic females who were not pregnant and had not used oral contraceptives for a minimum of 3 months prior to the study. Blood samples were collected during one menstrual cycle for the determination of estradiol and progesterone concentrations during the follicular (days 2–6 post-onset of menses), ovulatory (days 13–16 post-onset of menses) and luteal (days 22–26 post-onset of menses) phases. Caffeine was administered over a single menstrual cycle during the follicular, ovulatory and luteal phases. Each subject was administered a single oral dose of caffeine (300 mg) in 100 ml of lemonade during each phase of the menstrual cycle. A venous catheter was used to collect blood samples at pre-dose and at the following time points: 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 and 24 h. Plasma caffeine concentrations were determined using a validated ultraviolet high-performance liquid chromatography method. Results: There were no significant (P < 0.05) differences in the pharmacokinetic parameters of caffeine across the menstrual cycle phases. The average area under the plasma concentration–time curve (AUC_inf) was 93.01 mg l^−1.h and the absorption rate constant (k _a) was 2.88 h⁻¹ during the ovulatory phase, 83.0 mg l⁻¹ h and 2.06 h⁻¹, respectively, during the luteal phase and 84.7 mg l^−1.h and 1.84 h⁻¹, respectively, during the follicular phase. Conclusions: These findings suggest that the menstrual cycle does not significantly alter the pharmacokinetics of caffeine. Received: 16 November 1998 / Accepted in revised form: 19 April 1999     

Follicular development induced by recombinant luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in anovulatory women with LH and FSH deficiency: evidence of a threshold effect*

ABSTRACT

Objective: To assess the requirement for luteinizing hormone (LH) in women deficient in LH and follicle-stimulating hormone (FSH).

Research design and methods: A prospective, randomized, parallel-group, multicentre study was carried out in tertiary care and academic medical centres. Women with anovulatory amenorrhoea ≥?1 year, serum oestradiol (E₂) <?60?pg/mL (<?220?pmol/L) and low normal serum gonadotrophins were randomized in cycle A to a fixed daily dose of recombinant human (r-h) FSH (150?IU) and r-hLH 0, 25, 75 or 225?IU. Cycles B and C were not randomized.

Main outcome measures: Follicular development, ovulation and luteinization.

Results: In cycle A, follicular development was achieved by 63.6% (7/11), 100% (9/9), 72.7% (8/11) and 66.7% (6/9) of patients who received r-hFSH and r-hLH 0, 25, 75 or 225?IU/day, respectively (?p?=?not significant). Among patients with basal serum LH of <?1.2?IU/L, a dose-response relationship of r-hLH to follicular development was observed (?p?=?0.039). Fourteen of 34 patients (41.2%) wishing to conceive became pregnant. Among patients with hypogonadotrophic hypogonadism (HH) treated with r-hFSH alone, a transition from LH dependence to independence was observed between basal LH values of ≥?1.2?IU/L and ≤?1.6?IU/L. The r-hLH was well tolerated and no serious adverse events occurred during treatment. The most common treatment-related events were related to the reproductive system and the gastrointestinal tract.

Conclusions: Recombinant human LH provides a safe treatment option for women with HH. This small study also provided evidence suggestive of an LH threshold: follicular development was suboptimal when less than 75?IU/day r-hLH was administered.     

Effects of the menstrual cycle on timing and depth of breathing at rest

Volume and timing components of resting ventilation were measured serially in 40 women aged 18 to 36 yr, during menstrual, follicular and luteal phases of menstrual cycle. Resting minute ventilation (VE) was significantly higher (P < 0.001) in luteal phase than in menstrual and follicular phases; in the two latter phases VE was almost equal. This increment in VE during the luteal phase was due to a significant rise (P < 0.001) in tidal volume (VT). Respiratory frequency (f) was unchanged throughout the cycle. Although there was a mean increases in inspiratory time (T1) during the luteal phase compared to the other two phases, the difference did not reach statistical significance. Duty cycle, T1/Ttot, was also unchanged throughout menstrual cycle. However, mean inspiratory flow, VT/T1, was significantly higher (P < 0.05 and P < 0.01) during luteal phase as compared to that during menstrual or follicular phases respectively. Pulmonary mechanics, as measured by forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and forced mid expiratory flow rate (FEF25%, 75%), were within normal limits and remained unaltered during the menstrual cycle. Therefore, in the absence of alteration of pulmonary mechanics, the luteal increase in ventilation and inspiratory flow suggests a possible role for progesterone in stimulating the respiratory drive, either centrally or through the peripheral chemoreceptors or by both.     

Hexachlorobenzene (HCB) suppresses circulating progesterone concentrations during the luteal phase in the cynomolgus monkey.

Hexachlorobenzene (HCB) is a known reproductive toxin. However, the full spectrum of its reproductive toxicity is unknown. Consequently, the effect of HCB on serum oestradiol (E2) and progesterone (P4) concentrations during the follicular (days 1-9), periovulatory (days 10-14) and luteal (days 15 to beginning of next menses) phases was investigated in the spontaneously cycling cynomolgus monkey. Adult female cynomolgus monkeys (n = 16) were randomly assigned to one of four treatment groups and orally doses with gelatin capsules containing HCB (0.0, 0.1, 1.0 and 10.0 mg kg-1 body wt. day-1) mixed with glucose. A 10-week acclimitization phase was followed by 13 weeks of dosing. HCB induced a dose-dependent suppression of serum P4 concentrations during the luteal phase. However, circulating levels of P4 were unaffected during the follicular and periovulatory phases of the menstrual cycle. Serum E2 concentrations, body weight, menstrual cycle length and duration of menses were not affected by HCB treatment. The range of menstrual cycle length and duration range of menses, however, were broader in the highest dose group. We conclude that HCB interfers with mechanisms regulating ovarian steroidogenesis and suppresses P4 levels during the luteal phase in the cynomolgus monkey.     

Luteal-phase accentuation of acoustic startle response in women with premenstrual dysphoric disorder.

Alterations in central nervous system response to menstrual cycle-related fluctuations in neuroactive steroids are thought to underlie the emergence of negative affect in the luteal phase of the menstrual cycle in women with premenstrual dysphoric disorder (PMDD). Such changes in the neuroendocrine milieu may lead to heightened arousal and response to stress in women with PMDD. Using the acoustic startle paradigm, we sought to determine whether women with PMDD have an accentuated physiologic response to a mildly aversive stimulus during the luteal compared to follicular phase. Further, we also examined the impact of visual affective stimuli on acoustic startle response (ASR) magnitude. During the follicular and luteal phases of the menstrual cycle, acoustic stimuli (103 dB) were delivered to 15 women with PMDD and 14 healthy menstruating women of similar age. After obtaining baseline ASR, the procedure was repeated when subjects viewed pleasant, neutral and unpleasant pictures. There was a significant group by menstrual cycle phase interaction for baseline ASR magnitude, which can be attributed to the heightened startle magnitude in women with PMDD compared to healthy women during the luteal relative to the follicular phase. The direction and degree to which picture viewing modulated the startle magnitude did not vary by group or menstrual cycle phase. These data suggest that menstrual cycle phase has a powerful modulatory effect on physiologic reactivity in women with PMDD but not in healthy women. Physiologic response to affective stimuli appears to be intact in women with PMDD across the menstrual cycle.     

Comment on Disin tegra tion/dissolution profiles of copies of Fosamax (alendronate)

ABSTRACT

Objective: A trial was conducted to examine the effects of a timed sequence of hormone supplementation (HS) with oral estradiol (E₂) and vaginal progesterone (P) following clomiphene citrate (CC) therapy to determine if this regimen can increase pregnancy rates in CC cycles.

Methods: This study was a randomized, open-label study. Seventy-one oligo-ovulatory women were randomized into one of two groups; those who received CC plus HS (?n = 34) and those who received no HS (?n = 37). All subjects received 100?mg CC orally from cycle days 3 to 7. Subjects randomized to HS started oral E₂ at a dose of 1.5?mg BID on cycle day 8. All subjects monitored urine luteinizing hormone (LH) levels starting on cycle day 10; additionally, intercourse was encouraged starting on cycle day 10. Subjects receiving HS discontinued E₂ with LH surge and started using vaginal progesterone gel (Prochieve 8%) daily for 2 weeks starting 3 days after LH surge. All subjects had a pregnancy test (Assure) 2 weeks after LH surge. If pregnancy occurred, the subject continued using vaginal progesterone gel daily for an additional 10 weeks.

Results: Sixty-five (65) subjects (31 CC plus HS and 34 no HS) completed the study. Fifty of the 65 subjects (77%) (23 [74%] CC plus HS, 27 [79%] no HS) who completed the study ovulated. The mean (range) progesterone (P) concentration for these 50 subjects was 1662.6 (340 to 5690)?ng/dL, and mean and median P levels were slightly higher, but not statistically significant, in the HS group compared with the no HS group. Pregnancy rates were clinically, but not statistically, different between the treatment groups. Of the 50 responders, 12% became pregnant (17% CC plus HS, 7% no HS).

Conclusion: These findings show a potential supportive effect on pregnancy rates in the CC plus oral estradiol and vaginal progesterone gel group compared to CC alone that needs to be confirmed in a larger study.     

Evidence for a Role of Progesterone in Menstrual Cycle-Related Variability in Prepulse Inhibition in Healthy Young Women

Prepulse inhibition (PPI) of the startle response is sensitive to sex, with healthy young women showing less PPI compared with age-matched men, and varies according to the menstrual cycle phase in women. Relatively less is known regarding sex and hormonal influences in prepulse facilitation (PPF). Menstrual phase-related variability in PPI is suggested to be mediated by fluctuating estrogen level, based on the observations of more PPI in women during the follicular, relative to the luteal, phase. No study has directly assessed the relationship between fluctuating hormones and PPI or PPF levels over the human ovarian cycle. To examine the roles of circulating ovarian hormones in PPI and PPF, 16 non-smoking regularly menstruating healthy women were tested during both the follicular and luteal phases on PPI and PPF and provided saliva samples for measurement of 17β-estradiol (estrogen), progesterone and testosterone. The results showed higher levels of 17β-estradiol and progesterone during the luteal, relative to the follicular, phase; and more PPI during the follicular phase and more PPF during the luteal phase with comparable startle amplitude and habituation during the two phases. A larger increase in progesterone was associated with a smaller decrease in PPI from the follicular to the luteal phase. No significant associations were found between changes in PPI/PPF and estrogen levels. The findings confirm lower PPI during the luteal, compared with the follicular, phase and suggest a role for progesterone, more specifically an antipsychotic-like PPI-restoration action of progesterone, during the luteal phase in PPI of young women.     

Response to alcohol in women: role of the menstrual cycle and a family history of alcoholism

The present study determined whether: (1) the response to alcohol varied as a function of menstrual cycle phase and (2) women with a paternal history of alcoholism (FHP) were less sensitive to the effects of alcohol compared to women without a family history of alcoholism (FHN). The behavioral effects of alcohol (0.00, 0.25, and 0.75 g/kg) were evaluated in 21 FHN and 24 FHP women; each dose was tested during both the midfollicular and late luteal phases of the menstrual cycle. Baseline negative mood was increased during the luteal phase compared to the follicular phase (increased Beck Depression scores and decreased Vigor, Arousal, and Friendly scores). Alcohol increased ratings of Drug Liking and Good Drug Effect more in the luteal phase than the follicular phase. FHP women had greater negative mood during the luteal phase and some of these dysphoric effects were increased by alcohol more in FHP women than FHN women. Alcohol impaired performance, with no group or menstrual cycle differences. However, consistent with previous studies, FHP women were less impaired by alcohol than FHN women on the balance task. These data indicate that (1) the differences in response to alcohol across the menstrual cycle are subtle, although alcohol is liked more during the luteal phase; (2) increases in dysphoric mood during the luteal phase are more pronounced in FHP women compared to FHN women, particularly after alcohol; and (3) the differences observed in response to alcohol between FHP and FHN women are less pronounced than previously shown in men.     

5α-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder

Changes in neurosteroid levels during the luteal phase of the menstrual cycle may precipitate affective symptoms. To test this hypothesis, we stabilized neurosteroid levels by administering the 5α-reductase inhibitor dutasteride to block conversion of progesterone to its neurosteroid metabolite allopregnanolone in women with premenstrual dysphoric disorder (PMDD) and in asymptomatic control women. Sixteen women with prospectively confirmed PMDD and 16 control women participated in one of two separate randomized, double-blind, placebo-controlled, cross-over trials, each lasting three menstrual cycles. After one menstrual cycle of single-blind placebo, participants were randomized to receive, for the next two menstrual cycles, either double-blind placebo or dutasteride (low-dose 0.5 mg/day in the first eight PMDD and eight control women or high-dose 2.5 mg/day in the second group of women). All women completed the daily rating form (DRF) and were evaluated in clinic during the follicular and luteal phases of each menstrual cycle. Main outcome measures were the DRF symptoms of irritability, sadness, and anxiety. Analyses were performed with SAS PROC MIXED. In the low-dose group, no significant effect of dutasteride on PMDD symptoms was observed compared with placebo (ie, symptom cyclicity maintained), and plasma allopregnanolone levels increased in women with PMDD from follicular to the luteal phases, suggesting the absence of effect of the low-dose dutasteride on 5α-reductase. In contrast, the high-dose group experienced a statistically significant reduction in several core PMDD symptoms (ie, irritability, sadness, anxiety, food cravings, and bloating) on dutasteride compared with placebo. Dutasteride had no effect on mood in controls. Stabilization of allopregnanolone levels from the follicular to the luteal phase of the menstrual cycle by blocking the conversion of progesterone to its 5α-reduced neurosteroid metabolite mitigates symptoms in PMDD. These data provide preliminary support for the pathophysiologic relevance of neurosteroids in this condition.     

Hospitalization rates before and after initiation of paliperidone ER in patients with schizophrenia: results from open-label extensions of the US double-blind trials

ABSTRACT

Objective: To assess differences in the number of days hospitalized among schizophrenic patients receiving paliperidone extended-release (paliperidone ER) during the open-label extension (OLE) phases, compared to a similar time period prior to the screening for entry into the double-blind (DB) trials conducted in the United States.

Methods: Mental health-related hospital days during the 52 weeks before entering the DB trials and during the OLE phases were compared. The mean number of hospital days per person per year in the pre- and post-periods was calculated and the statistical significance of pre-post differences was assessed using bootstrap resampling methods. Total person-years were also calculated for the pre- and post-periods to account for different lengths of observation.

Results: Patients' (n = 215) mean (?±?SD) age was 41.2 (?±?11.0) years; most were male (73.0?%?); and black (52.1 vs. 45.1?%?white). The mean (?±?SD) paliperidone ER treatment duration during the OLE phase was 167.0 (?±?145.0) days and the mean (?±?SD) daily dose was 10.5 (?±?2.0) mg. Overall, paliperidone ER patients spent an average (?±?SD) of 13.2 (?±?1.6) and 3.1 (?±?0.7) hospital days per person-year in the pre-and post-periods, respectively (mean?±?SD change 10.0?±?1.8, 95?%?CI 6.5, 13.4, p?<?0.001). Using the 2007 Federal Per Diem Base Rate (i.e., $595.09 per day), this reduction in hospital days would result in an average (?±?SD) cost savings of $5951 (?±?1071) per person per year.

Conclusions: Patients had significantly fewer hospital days in the OLE phase compared to the 1-year period prior to entering the DB trial. Paliperidone ER may play a role in reducing mental health-related hospital days and associated costs. Important study limitations include the lack of a control group, the pre-post design comparing historical data with data collected in the trials which could create a bias due to the mismatch in settings, and patients having more frequent contact with treating physicians and investigators during the trial period, which could favor the outcomes in the OLE phase. Further studies are needed to confirm these findings.     

Comparison of recombinant human luteinising hormone (r-hLH) and human menopausal gonadotropin (hMG) in assisted reproductive technology

SUMMARY

Follicle-stimulating hormone (FSH) and luteinising hormone (LH) act in concert in the stimulation of folliculogenesis and ovulation. However, high levels of LH promote follicular atresia and early miscarriage, and this has led to the concept of a 'therapeutic window' of LH for successful conception in assisted reproductive technology (ART) and ovulation induction. Until now, urinary-derived human menopausal gonadotropin (hMG) has been the only available source of exogenous LH activity. hMG preparations contain highly variable levels of LH, and are often augmented with human chorionic gonadotropin (hCG), which mimics LH activity. Accumulation of hCG bioactivity, however, may have detrimental effects on follicular development and oocyte quality. Recombinant human LH (r-hLH) (Luveris) is the only pure source of LH activity. r-hLH is well characterised and production is tightly controlled, resulting in a highly consistent product. Clinical studies in hypogonadotropic hypogonadal women have demonstrated the efficacy of r-hLH, 75IU/day, together with r-hFSH, 150IU/day, in promoting optimal follicular development, oestrogen secretion and endometrial thickness. r-hLH therefore provides the clinician with the opportunity for precise and consistent dosing within the therapeutic window for patients requiring exogenous LH, without the risk of LH overexposure that is associated with hCG.     

Lack of influence of menstrual cycle and premenstrual syndrome diagnosis on pregnanolone pharmacokinetics

Objective: Pregnanolone is a 3α-hydroxylated-5β-reduced metabolite of the female sex steroid hormone progesterone. The compound is currently being evaluated for anaesthetic purposes. Previous studies have indicated a differential physiological response across the menstrual cycle and a different response in patients with premenstrual syndrome (PMS). This study was undertaken to determine whether hormonal changes during the menstrual cycle influence pregnanolone pharmacokinetics and to compare PMS diagnosis-related differences in pregnanolone pharmacokinetics. Methods: Seven patients with premenstrual syndrome and seven female controls were given three increasing doses of pregnanolone in the follicular and luteal phase of the menstrual cycle. Results: Mean pregnanolone elimination half-life varied between 28.4 min and 31.8 min and clearance between 59.6 ml · min⁻¹ · kg⁻¹ and 64.0 ml · min⁻¹ · kg⁻¹, depending on diagnostic group and cycle phase. No significant differences in pregnanolone pharmacokinetic properties were found between PMS patients and controls in either phase of the menstrual cycle. Furthermore, no differences in pharmacokinetic variables were detected between cycle phases. Conclusion: Pregnanolone pharmacokinetics do not differ between follicular and luteal phase of the menstrual cycle, nor between PMS patients and control subjects. Received: 16 September 1998 / Accepted in revised form: 27 November 1998     

Comparative pharmacokinetics of paracetamol in men and women considering follicular and luteal phases

The pharmacokinetics of paracetamol administered in a single dose were investigated and compared in young male and female subjects, considering follicular and luteal phase of the menstrual cycle. The mean AUC for paracetamol in the blood of female subjects was significantly increased by 39% and 51%, respectively, taking into account the follicular and luteal phase, in comparison with the AUCs of male volunteers. The peak plasma concentration revealed significantly higher values in women in both phases, by 48% and 66%, respectively. The time to reach the peak concentration was shorter by 8% in follicular phase than in males. The difference was statistically insignificant. Elimination constant decreased in follicular phase by 15% and in luteal phase by 21% in comparison with males (the difference--statistically insignificant). The paracetamol half-life was longer (although not significantly) in women than in men: in follicular phase by 29 min, i.e. 15%, and in luteal phase by 65 min, i.e. 33%. The apparent volume of distribution was found to be significantly lower in the female group by 35% and 40% in follicular and luteal phase, respectively. Comparing data obtained in the follicular and luteal phase, it was shown that the AUC was larger, peak plasma concentration was higher and biological half-life was longer in luteal phase. It is likely that the differences in some pharmacokinetic parameters between men and women, as well as in women considering both phases of menstrual cycle, might be of clinical significance.     

Effects of a Fixed Mixture of 25% Insulin Lispro and 75% NPL on Plasma Glucose during and after Moderate Physical Exercise in Patients with Type 2 Diabetes

Summary

Objective: To compare the plasma glucose (PG) response with a fixed mixture of 25% insulin lispro and 75% NPL (Mix25), prior to a meal and 3?h before exercise, to human insulin 30/70 (30/70) in patients with type 2 diabetes.

Research design and methods: Thirty-seven patients were treated in a randomized, open-label, 8-week, two-period crossover study. Mix25 was injected 5?min before breakfast and dinner throughout the study, as was 30/70 on inpatient test days and on outpatient dose titration days. Following the 4-week outpatient phase, patients were hospitalized, and exercised at a heart rate of 120 beats/min on a cycle ergometer two times for 30?min, separated by 30?min rest, starting 3?h after a 339 kcal breakfast.

Results: The 2-h postprandial PG was significantly lower with Mix25 ((mean?±?SEM) 10.5?±?0.4 mmol/lvs 11.6?±?0.4 mmol/l; p?=?0.016). Maximum decrease in PG from onset of exercise to end of exercise was significantly less with Mix25 (-3.6?±?0.29 mmol/l vs -4.7?±?0.31 mmol/l; p?=?0.001). The maximum decrease in PG over 6?h, after exercise onset, was significantly less with Mix25 (-4.3?±?0.4 mmol/l vs -5.9?±?0.4 mmol/l; p?<?0.001). The frequency of hypoglycemia (blood glucose (BG) < 3 mmol/l or symptoms) during the inpatient test was not different between treatments. During the outpatient phase, the frequency of patient-recorded hypoglycemia was significantly lower with Mix25 (0.7?±?0.2 episodes/30d vs 1.2?±?0.3 episodes/30 d; p?=?0.042).

Conclusions: Mix25 resulted in better postprandial PG control without an increase in exercise-induced hypoglycemia. The smaller decrease in PG during the postprandial phase after exercise may suggest a lower risk of exercise-induced hypoglycemia with Mix25 than with human insulin 30/70, especially for patients in tight glycemic control.     

Leonurine hydrochloride induces apoptosis of H292 lung cancer cell by a mitochondria-dependent pathway

Abstract

Context: Leonurine hydrochloride (LH), a major alkaloid compound extracted from Leonurus japonicas Houtt. (Labiatae), is considered to have antitumor roles.

Objective: This study investigated its effects on human non-small cell lung cancer (NSCLC) H292 cells and illustrated the possible mechanism involved.

Materials and methods: After treatment with different concentrations of LH (0, 10, 25, and 50?μmol/L) for 6, 12, 24, 48, and 72?h, the cell viability was assessed by the MTT assay. After exposed to different doses of LH for 24?h, cell-cycle distribution, cell apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) were monitored by flow cytometry. RT-PCR and western blot were used to detect the expression of apoptosis-related genes.

Results: LH significantly inhibited the proliferation of H292 cells in a time- and dose-dependent manner, and induced G0/G1 cell-cycle arrest. Coincidentally, LH treatment at a dose of 10, 25, and 50?μmol/L for 24?h increased apoptotic ratio from 4.9?±?0.43% to 11.5?±?1.12%, 19.3?±?1.16%, and 61.3?±?6.69%, respectively. The inhibition effect of LH on H292 cells was associated with the loss of MMP and the generation of ROS. The phosphorylation level of p38 was increased and Akt phosphorylation was reduced by LH treatment. Furthermore, LH treatment increased the expression levels of caspase-3, caspase-9 and Bax/Bcl-2.

Conclusions: LH inhibits the proliferation and induces the apoptosis of H292 cells in a mitochondria-dependent pathway, and the specific mechanism need to be further explored.     

In vivo hair growth-stimulating effect of medicinal plant extract on BALB/c nude mice

Abstract

Context: Chrysanthemum zawadskii var. latilobum (Asteraceae) (CZ) and Polygonum multiflorum Thunb. (Polygonaceae) (PM) have been used traditionally to treat different systemic diseases and acclaimed for various biological activities including hair growth.

Objective: This study investigates the hair restoration efficacy of selected medicinal plant extracts on nude mice.

Materials and methods: Nude mice genetically predisposed to pattern balding were used in this study. Topical methanol extracts of CZ and PM (10?mg/mouse/d) with standardized vehicle formulation, only vehicle (propylene glycol:ethanol:dimethyl sulfoxide, 67:30:3% v/v) and Minoxidil (2%) were applied daily for 40 consecutive days.

Results: In our study, the maximum hair score (2.5?±?0.29) was obtained in the CZ-treated group. Histological observation revealed a significant increase (p?<?0.001) in the number of hair follicles (HF) in CZ-treated mice (58.66?±?3.72) and Minoxidil-treated mice (40?±?2.71). Subsequently, immunohistochemical analysis also confirmed the follicular keratinocyte proliferation by detection of BrdU-labeling, S-phase cells in Minoxidil and CZ-treated mouse follicular bulb and outer root sheaths.

Conclusion: Our study revealed the underlying mechanism of stimulating hair growth in athymic nude mice by repair the nu/nu follicular keratin differentiation defect. Thus, the topical application of CZ may represent a novel strategy for the management and therapy of certain forms of alopecia.     

The effects of smoked cocaine during the follicular and luteal phases of the menstrual cycle in women

RATIONALE: Few studies have systematically determined whether the response to cocaine in human females is related to hormonal fluctuations at different phases of the menstrual cycle. OBJECTIVES: To investigate the responses to repeated doses of smoked cocaine in women during two phases of the menstrual cycle using a within-subject design. METHODS: Eleven non-treatment seeking female cocaine smokers were administered smoked cocaine during the follicular and mid-luteal phases of the menstrual cycle. The order of menstrual cycle phase was counterbalanced across women and the order of cocaine doses was randomized. During each phase, there were four cocaine administration sessions. During each session, participants could smoke up to six doses of cocaine (either 0, 6, 12, or 25 mg cocaine base, depending on the session) at 14-min intervals. RESULTS: The number of cocaine doses administered did not vary between the follicular and luteal phases. After cocaine administration, heart rate and several ratings - such as "good drug effect", "high", "stimulated", and "drug quality ratings" - were increased more during the follicular phase than the luteal phase, although, for some measures, these effects varied based on the cocaine dose. Further, dysphoric mood during the luteal phase was improved after cocaine administration. CONCLUSIONS: These results indicate that the cardiovascular and subjective effects of repeated doses of smoked cocaine are complex and vary as a function of menstrual cycle phase and cocaine dose.     

Adolescent nicotine exposure sensitizes cue-induced reinstatement of cocaine seeking in rats bred for high and low saccharin intake

Background

Quit attempts may have different outcomes based on menstrual cycle phase on quit day. This is the first preliminary study examining whether smoking cessation outcomes vary by menstrual cycle phase of quit date in women receiving a 6-week open trial of sustained release (SR) bupropion.

Methods

Thirty-three treatment-seeking premenopausal women were studied. Abstinence outcomes were compared for women quitting during the luteal versus follicular phase.

Results

Women receiving bupropion SR whose self-selected quit date occurred in the luteal phase had significantly higher rates of point prevalence abstinence during the final week of a 6-week post-quit treatment period than women quitting in the follicular phase (62.5% versus 29.4%; p < 0.05). A similar, but non-significant, pattern of findings was demonstrated for continuous abstinence during the treatment phase and for point prevalence abstinence at 3-month follow-up.

Conclusions

Women receiving bupropion SR were significantly more likely to be abstinent at treatment completion if quitting occurred during the luteal phase. This is consistent with recent findings of outcome related to cycle phase at quit date in the absence of pharmacotherapy, and differs from findings utilizing nicotine replacement. Results add to emerging data suggesting that smoking cessation interventions with varying mechanisms of action may result in different outcomes for premenopausal women based on gonadal hormones at quit date.     

Sex and menstrual cycle effects on progressive ratio measures of cocaine self-administration in cynomolgus monkeys.

Fluctuations in ovarian steroid hormones across the menstrual/estrous cycle influence the abuse-related effects of acute cocaine administration in women and chronic cocaine self-administration in rodents, but there have been no comparable studies in non-human primates. The interactions among sex, menstrual cycle phase, and cocaine self-administration (0.0032, 0.01, and 0.032 mg/kg/injection (inj)) under a progressive ratio schedule were investigated in four female and two male cynomolgus monkeys. Females were given unrestricted access to cocaine across 54 menstrual cycles, and males were studied over 23 pseudo-cycles of 30 days duration. Ovulatory cycles were defined by luteal phase elevations in progesterone and 44 cycles were ovulatory. During ovulatory menstrual cycles, females reached significantly higher progressive ratio break points than males at all three unit doses of cocaine (P<0.001). During anovulatory cycles, females also reached significantly higher break points than males for 0.032 mg/kg/inj cocaine (P<0.01). Progressive ratio break points for cocaine (0.01 and 0.032 mg/kg/inj) did not vary significantly as a function of ovarian steroid hormone levels during the follicular and the luteal phase of ovulatory menstrual cycles, or during anovulatory cycles. Progressive ratio break points for 0.0032 mg/kg/inj cocaine were significantly higher during the follicular phase than during the late luteal phase (P<0.05-0.001). There were no systematic changes in progressive ratio break points in male pseudo-cycles. Significant cocaine dose-related sex differences were observed, but no consistent changes in cocaine self-administration as a function of menstrual cycle phase, or levels of estradiol and progesterone, were detected in female cynomolgus monkeys.