Female rats are relatively more sensitive to reduced lipid versus reduced carbohydrate availability.

OBJECTIVES: Because females have blunted counterregulatory responses to hypoglycemia relative to males, we hypothesized that females would have greater sensitivity to changes in lipid availability. DESIGN AND SUBJECTS: To assess this, we examined the feeding response to glucoprivation (2-deoxyglucose; 2DG) and lipoprivation (mercaptoacetate; MA) in age-matched male and female Long-Evans rats. RESULTS: Males versus females had significantly greater food intake after 250 mg kg(-1) of 2DG, but there were no sex differences with the 750 mg kg(-1) dose of 2DG. Glucose responses to 250 mg kg(-1) of 2DG were also significantly greater in males versus females. In contrast, females had a significant increase in food intake with all doses of MA versus saline, and had significantly greater food intake compared with males at the lowest and highest doses of MA with a trend towards significance with the intermediate dose. To determine whether estradiol (E2) is the mechanism underlying this sexual dimorphism, ovariectomized females were injected with vehicle or 2 µg of E2 every fourth day to mimic the variations in across the estrous cycle. Ovariectomized females significantly increased feeding and glucose after 250 mg kg(-1) of 2DG over intact females and E2 had no effect on these responses. Although the feeding response to 2DG was not different, the glucose response to 2DG was still significantly greater in males versus ovariectomies females. However, ovariectomized females also did not increase food intake after MA, regardless of E2 treatment. CONCLUSIONS: These data collectively suggest that males are relatively more sensitive to glucose deprivation and females are relatively more sensitive to lipid deprivation. Further, these data rule out a role for cyclic changes in E2 in these sex differences.

Three-dimensional tomographic imaging and characterization of iron compounds within Alzheimer's plaque core material.

Although it has been known for over 50 years that abnormal concentrations of iron are associated with virtually all neurodegenerative diseases, including Alzheimer's disease, its origin, nature and role have remained a mystery. Here, we use high-resolution transmission electron microscopy (HR-TEM), energy dispersive X-ray (EDX) spectroscopy and electron energy-loss spectroscopy (EELS), electron tomography, and electron diffraction to image and characterize iron-rich plaque core material - a hallmark of Alzheimer's disease pathology - in three dimensions. In these cores, we unequivocally identify biogenic magnetite and/or maghemite as the dominant iron compound. Our results provide an indication that abnormal iron biomineralization processes are likely occurring within the plaque or the surrounding diseased tissue and may play a role in aberrant peptide aggregation. The size distribution of the magnetite cores implies formation from a ferritin precursor, implicating a malfunction of the primary iron storage protein in the brain.

Effect of MAO-A inhibition on the pharmacokinetics of almotriptan, an antimigraine agent in humans.

AIMS: To assess the effect of a reversible MAO-A inhibitor, moclobemide, on the single-dose pharmacokinetics of almotriptan and assess the clinical consequences of any interaction. METHODS: Twelve healthy volunteers received the following treatments in a randomized, open-label, two-way crossover design (with a 1 week washout between treatments): (A) one 150 mg moclobemide tablet every 12 h for 8 days and one 12.5 mg almotriptan tablet on the morning of day 8; and (B) one 12.5 mg almotriptan tablet on day 8. Plasma almotriptan was quantified by h.p.l.c.-MS-MS, while urinary concentrations were measured by h.p.l.c.-u.v. Vital signs, ECGs, and adverse events were evaluated after almotriptan administration. Treatment effects on pharmacokinetics and vital signs were assessed by analysis of variance. RESULTS: Mean almotriptan AUC was higher (483 +/- 99.9 vs 352 +/- 75.4 ng ml-1 h, P = 0.0001) and oral clearance was lower (26.6 +/- 4.00 vs 36.6 +/- 5.89 l h-1, P = 0.0001) when almotriptan was administered with moclobemide. Mean half-life was longer (4.22 +/- 0.78 vs 3.41 +/- 0.45 h, P = 0.0002) after coadministration with moclobemide. Renal clearance of almotriptan was unaffected by moclobemide. No serious adverse events occurred and no clinically significant vital sign changes were observed. CONCLUSIONS: Moclobemide increased plasma concentrations of almotriptan on average by 37%, but the combined administration of these two compounds was well tolerated. The degree of interaction was much less than that seen previously for sumatriptan or zolmitriptan given with moclobemide.

Evaluation of the potential pharmacokinetic interaction between almotriptan and fluoxetine in healthy volunteers.

This study was designed to assess the pharmacokinetics of almotriptan, a 5HT1B/1D agonist used to treat migraine attacks, when administered in the presence and absence of fluoxetine. Healthy male (n = 3) and female (n = 11) volunteers received (1) 60 mg fluoxetine daily for 8 days and 12.5 mg almotriptan on Day 8 and (2) 12.5 mg almotriptan on Day 8, according to a two-way crossover design. Plasma and urinary almotriptan concentrations were measured by HPLC methods. Treatment effects on pharmacokinetic parameters were assessed by analysis of variance. Mean almotriptan Cmax was significantly higher following combination treatment with fluoxetine (52.5 +/- 11.9 ng/ml vs. 44.3 +/- 10.9 ng/ml, p = 0.023). Mean AUC0-infinity was not significantly affected by fluoxetine coadministration (353 +/- 55.7 ng.h/ml vs. 333 +/- 33.6 ng.h/ml, p = 0.059). Confidence interval analysis (90%) of log-transformed pharmacokinetic parameters showed that the confidence interval for AUC0-infinity was within the 80% to 125% limit for equivalence, but Cmax was not (90% CI 106%-134% of the reference mean). Adverse events were mild to moderate in intensity, and no clinically significant treatment effects on vital signs or ECGs were observed. The results show that fluoxetine has only a modest effect on almotriptan Cmax. Concomitant administration of the two drugs is well tolerated, and no adjustment of the almotriptan dose is warranted.

Systemic absorption of clindamycin after intravaginal administration of clindamycin phosphate ovule or cream.

The absolute bioavailability of clindamycin phosphate vaginal ovule with comparison to a reference treatment of clindamycin phosphate sterile solution, as well as the relative bioavailability of the ovule compared to clindamycin phosphate vaginal cream, was evaluated in 12 healthy adult female volunteers. Subjects were randomly assigned to receive either the ovule or cream formulation intravaginally for 3 consecutive days during the two-way crossover portion of the study. During a third treatment period, all subjects received 100 mg of clindamycin as a 4-minute intravenous infusion of clindamycin phosphate sterile solution (10 mg/mL). Clindamycin concentrations in serum were assayed by a high-performance liquid chromatography method with detection by mass spectrometry. Pharmacokinetic analyses of the serum data indicated low systemic absorption of clindamycin from the vaginal cream (about 4%), consistent with results of previous bioavailability studies. Following intravaginal administration of the clindamycin phosphate ovule, systemic absorption averaged 30%, which was approximately sevenfold greater than after dosing with the vaginal cream. The higher drug absorption for the ovule may be related to differences in formulation effects on the vaginal membrane. Nevertheless, systemic exposure to clindamycin from the ovule is still considerably lower than from a therapeutic oral dose.

Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension): assessment of return of ovulation after three monthly injections in surgically sterile women.

The pharmacodynamic effects of medroxyprogesterone acetate (MPA) and estradiol cypionate (E2C) (MPA/E2C) (Lunelle Monthly Contraceptive Injection) on ovarian function were assessed through changes in serum progesterone concentrations. The data described here were obtained simultaneously with pharmacokinetic data presented in another article in this issue. Sixteen surgically sterile women with regular menstrual cycles were studied for one control cycle, three consecutive treatment months, and 3-5 months of follow-up. Suppression, followed by resumption of ovulation (the dynamic end point), was assessed by serum progesterone levels. Return of ovulation was presumptive based on progesterone concentrations > or = 4.7 ng/mL, as ultrasound was not used to determine the follicular/ovulatory status of these subjects. Luteal-like serum progesterone peaks were observed in all 16 women before drug administration, confirming the presence of ovulatory cycles. After the third monthly injection of MPA/E2C, progesterone concentrations were measured until demonstration of ovulation. Two women discontinued and three were lost to follow-up before this objective was achieved. Serum progesterone levels and, consequently, ovulation were suppressed beyond the entire dosing interval, indicated by the absence of any luteal-like progesterone peaks (serum progesterone concentrations did not exceed 1 ng/mL). The first normal ovulatory cycle, based on progesterone concentrations > or = 4.7 ng/mL, was observed in 11 women between days 63 and 112 after the third injection. Select medroxyprogesterone acetate parameters (i.e., area under the curve and minimum concentration) were correlated with return of ovulation. The correlation coefficients (r) were 0.757 and 0.492 for area under the curve and minimum concentration, respectively, indicating that return of ovulation is dependent, in part, on area under the curve and on the magnitude of the serum MPA trough level. In general, the higher the minimum concentration levels, the longer the time to return of ovulation. In conclusion, the return of ovulation, as confirmed by serum progesterone concentrations > or = 4.7 ng/mL, was observed as early as 63 days after the third and final monthly intramuscular injection of MPA/E2C, suggesting that consistent suppression of the hypothalamic-pituitary-ovarian axis is reversible after discontinuation of dosing.

PIP: This study assessed the pharmacodynamic effects of medroxyprogesterone acetate (MPA) and estradiol cypionate (E2C) (MPA/E2C) (Lunelle monthly contraceptive injection) through changes in serum progesterone concentrations. A total of 16 surgically sterile women with regular menstrual cycles were studied for one control cycle, three consecutive treatment months, and 3-5 months of follow-up. Serum progesterone levels and, consequently, ovulation were suppressed beyond the entire dosing interval, indicated by the absence of any luteal-like progesterone peaks. The first normal ovulatory cycle, based on progesterone concentrations of 4.7 ng/ml or higher, was noted in 11 women between days 63 and 112 after the third injection. Select MPA parameters were correlated with return of ovulation. The correlation coefficients were 0.757 and 0.492 for area under the curve and minimum concentration, respectively, indicating that return of ovulation is dependent, in part, on area under the curve and on the magnitude of the serum MPA trough level. Generally, the higher the minimum concentration levels, the longer the time to return of ovulation. This study concluded that the return of ovulation, as confirmed by serum progesterone concentrations of 4.7 ng/ml or higher, was observed as early as 63 days after the third and final monthly intramuscular injection of MPA/E2C. This indicates that consistent suppression of the hypothalamic-pituitary-ovarian axis is reversible after discontinuation of dosing.

Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension): steady-state pharmacokinetics of MPA and E2 in surgically sterile women.

The steady-state pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate (MPA) and estradiol (E2, released from E2C by esterase enzymes) were characterized after administration to surgically sterile women. This report describes the pharmacokinetics of this multiple-dose and open-labeled study (pharmacodynamics are reported in a subsequent article in this issue). Women with regular menstrual cycles were studied for one control cycle, 3 consecutive treatment months, and 3-5 months of follow-up. Blood samples were drawn before each monthly dose and at specified time points after the third monthly injection. A total of 16 women were enrolled, 14 of whom completed the study. These 14 women (13 white, one black) ranged in age from 28 to 43.4 years, in body weight from 47.6 to 68.9 kg, and in height from 150 to 175 cm. Mean serum MPA concentrations peaked in the first week after administration of MPA/E2C (Lunelle Monthly Contraceptive Injection). The mean MPA Cmax and AUC0-t(last) were 1.25 ng/mL and 32.13 ng.day/mL, respectively. Serum MPA concentrations declined with a mean terminal half-life of 14.7 days, indicating that absorption from the injection site is prolonged after administration of MPA/E2C. The time for MPA concentrations to fall below the lower limit of quantitation (i.e., < 10 pg/mL) after the third injection ranged from 63 to 84 days. The average MPA trough (Cmin' day 28) concentrations for the three consecutive monthly injections ranged from 0.44 to 0.47 pg/mL, indicating that steady-state conditions were achieved after the first injection. The MPA Cmin values were well above threshold levels required to suppress ovulation throughout the injection interval. Absorption of E2 from the injection site was also prolonged after injection of MPA/E2C. Mean concentrations of E2 peaked at approximately 2 days after the third injection, and the average Cmax was 247 pg/mL. Serum E2 levels declined with a terminal half-life of approximately 8 days; E2 levels returned to baseline (typically, approximately 100 pg/mL) by 14 days after each injection. The average trough (Cmin' day 28) levels for E2 ranged from 40 to 55 pg/mL. The results of this study demonstrate that steady-state conditions are achieved after the first injection of MPA/E2C; no further MPA or E2 accumulation occurs beyond the first injection. Furthermore, the E2 peak observed after injection of MPA/E2C is similar to the nontreated preovulatory E2 range and returns to baseline levels by approximately 14 days after injection.

PIP: This paper characterized the pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate (MPA) and estradiol cypionate (E2C) in 14 healthy, surgically sterile women. These women ranged in age from 28 to 43.4 years, in body weight from 47.6 to 68.9 kg, and in height from 150 to 175 cm. The results of this study demonstrate that steady-state conditions are achieved after the first injection of MPA/E2C; no further MPA or E2C accumulation occurs beyond the first injection. Moreover, the E2 peak observed after injection of MPA/E2C is similar to the nontreated preovulatory E2 range and returns to baseline levels by approximately 14 days after insertion.

Pharmacokinetics of minoxidil in patients with cirrhosis and healthy volunteers.

OBJECTIVES: To determine the effect of reduced hepatic function on the pharmacokinetics of minoxidil. The pharmacokinetics of antipyrine, lorazepam, and indocyanine green were included as indicators of hepatic function. METHODS: Eight mild cirrhotics and eight healthy subjects received antipyrine (po), lorazepam (IV), indocyanine green (IV) and minoxidil 5 mg (po). Blood and urine were sampled for up to 72 h after each drug, and drug concentrations were measured by validated HPLC methods. Blood pressure and heart rate were measured for safety. RESULTS: For unchanged minoxidil, the serum elimination rate constant was significantly smaller and mean residence time was significantly longer in cirrhotic patients. Urinary elimination rate constant for minoxidil glucuronide was significantly smaller and fraction of dose excreted in urine was significantly higher in cirrhotic patients. Antipyrine elimination was significantly slower for cirrhotic patients. No differences were observed in lorazepam pharmacokinetic parameters. CONCLUSION: Pharmacokinetic analysis suggests a longer dosage interval may be appropriate in patients with hepatic impairment. In the absence of multiple-dose minoxidil pharmacodynamic studies in this population, minoxidil should be used as in other populations: begin with a modest dose, and adjust the dose based on clinical response.