Success rates with gamete intrafallopian transfer and in vitro fertilization in women of advanced maternal age.

OBJECTIVE: To evaluate the effect of maternal age on outcomes for IVF and GIFT in women 40 to 45 years of age. DESIGN: Retrospective. SETTING: Boston IVF, a free-standing university-affiliated IVF and GIFT unit. PATIENTS: A total of 2,931 cycles of IVF and 1,826 cycles of GIFT were analyzed in women undergoing assisted reproductive technologies (IVF or GIFT) using autologous eggs. INTERVENTIONS: Medical records of patient outcomes were reviewed. RESULTS: For patients undergoing IVF, the cancellation rate for initiated cycles showed significant differences in women aged 25 to 39 (38.3%), women aged 40 to 43 (49.5%), and women aged 44 to 45 years (69.5%). A significantly lower delivery rate per stimulation and delivery rate per retrieval was found in women aged 40 to 43 years when compared with women aged 25 to 39 years. No deliveries occurred in 59 cycles in women aged 44 to 45 years, thereby representing a significant difference when compared with both women aged 25 to 39 years and women aged 40 to 43 years. For patients undergoing GIFT, the cancellation rate for initiated cycles was significantly higher in women aged 40 to 43 (25.0%) and 44 to 45 years (31.0%) when compared with women aged 25 to 39 years (15.1%). A significantly lower delivery rate per stimulation and delivery rate per retrieval was found in women aged 40 to 43 and 44 to 45 years when compared with women aged 25 to 39 years. CONCLUSIONS: Success rates for IVF and GIFT decline significantly in women > 40 years old. Women aged > or = 44 years are unlikely to benefit from the use of IVF and GIFT.

In vitro plasma protein binding of zileuton and its N-dehydroxylated metabolite.

An ultrafiltration technique or equilibrium dialysis has been used to study the in vitro human plasma protein binding of racemic zileuton, its individual enantiomers, and its pharmacologically inactive metabolite N-dehydroxyzileuton. The plasma protein binding of zileuton and N-dehydroxyzileuton over the concentration range of 0.1 to 100 mg/L averaged 93.1 +/- 0.22 and 92.0 +/- 0.12%, respectively. However, there appeared to be a stereoselective effect, with the R(+) enantiomer of zileuton demonstrating greater binding to plasma proteins than the S(-) enantiomer (96 vs 88%, respectively). Zileuton was bound to both human serum albumin (40 g/L) and alpha 1-acid glycoprotein (1 g/L), although binding affinity to albumin was approximately 3-fold greater. Displacement interactions of zileuton with warfarin, salicylate, theophylline, naproxen, ibuprofen, prednisone, and terfenadine were minimal. The blood to plasma concentration ratio for zileuton and N-dehydroxyzileuton ranged from 0.65 to 0.68, indicating that these compounds were mainly distributed in the plasma. Thus, zileuton is approximately 93% bound to plasma proteins at expected therapeutic concentrations in vitro, and this figure is largely unaffected by several commonly prescribed agents with which the drug may be coadministered.

Stereoselective pharmacokinetics of pazinaclone, a new non-benzodiazepine anxiolytic, and its active metabolite in healthy subjects.

1. Serum and urine concentrations of enantiomers of pazinaclone (DN-2327) and an active metabolite MII, were measured after single and twice daily oral doses of 4 and 8 mg racemic drug to healthy subjects. 2. The kinetics of rac-pazinaclone and rac-MII were dose-independent and no unchanged drug was recovered in urine. 3. The terminal elimination half-lives of the drug isomers were similar (about 10.5 h), but mean steady-state values of AUC were twofold higher for the S-isomer than those of the antipode (e.g., 8 mg dose: 127 vs 69 ng ml(-1) h). However, the corresponding AUC values based upon unbound drug were similar (5.71 vs 5.73 ng ml(-1) h) indicating no stereoselectivity in intrinsic metabolic clearance. 4. The terminal elimination half-lives of S- and R-MII were similar to those of parent compound indicating that the elimination of these metabolites is formation rate-limited. 5. The R:S-ratio for the AUCs of MII was 4:1. Both enantiomers were excreted in the urine mainly as glucuronide conjugates, with stereoselectivity toward S-MII. 6. Since only the S-enantiomers of DN-2327 and MII bind to the benzodiazepine receptor, further measurements of drug effect in patients should be related to combine serum concentrations of the S-enantiomers of both parent drug and MII.

Differences in the stereoselective pharmacokinetics of pazinaclone (DN-2327), a new anxiolytic, and its active metabolite after intravenous and oral single doses to dogs.

The stereoselective pharmacokinetics of the new nonbenzodiazepine anxiolytic compound pazinaclone (DN-2327) were studied in four beagle dogs after oral (2.5 mg/kg) and intravenous (0.5 mg/kg) administration of racemate in a two-way, crossover study design. Racemic pazinaclone was highly cleared after intravenous administration at 2.09 +/- 0.78 l hr-1 kg-1. The total clearance and volumes of distribution (Vc, V beta, and Vss) of (S)-pazinaclone were significantly lower than those of the antipode. The differences in disposition were consistent with stereoselectivity in protein binding, where the unbound fraction of (R)-pazinaclone was almost 5-fold greater than that of the (S)-enantiomer. Lower clearance and distribution for (S)-pazinaclone resulted in comparable elimination half-lives for the two enantiomers. As projected from the intravenous results, the firstpass metabolism of (S)- and (R)-pazinaclone on oral administration of racemic pazinaclone was very extensive and stereoselective, with mean bioavailabilities of 6.0 and 1.2%, respectively, but the rates of absorption of the enantiomers were similar. Simultaneous model-dependent analysis of the intravenous plasma profiles for parent drug and metabolite suggested stereoselectivity of the active metabolite MII with shorter formation half-life for (S)-MII. However, in vitro metabolism by liver slices and our in vivo data indicated exclusive elimination of (S)- and (R)-pazinaclone through complete conversion to the MII metabolite (fm = 1). Thus, the clearances of (S)- and (R)-MII were calculated to be 0.89 and 7.89 l hr-1 kg-1, respectively, indicating pronounced stereoselectivity in the metabolite clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Luteal phase defects.

Luteal phase defects are defined as disorders resulting from abnormal corpus luteum function associated with insufficient progesterone production. The incidence is difficult to estimate accurately, but the disorder may affect 3-4% of infertile couples. Candidates for screening are those with unexplained infertility or recurrent abortion. Blood samples should be obtained seven to nine days after ovulation as determined by the thermogenic shift on basal body temperature monitoring or by a urinary luteinizing hormone surge. A midluteal phase serum progesterone level < 10 ng/mL is suggestive of the diagnosis. Endometrial biopsies are indicated in those couples with unexplained infertility and recurrent abortion, particularly if progesterone levels are > 10 ng/mL. While there have been few comparative studies, the four treatments available are clomiphene citrate, progesterone vaginal suppositories, human menopausal gonadotropins and bromocriptine. Because of its simplicity of use, clomiphene citrate is the recommended first-line treatment.

The significance of bleeding patterns in Norplant implant users.

The purpose of this study was to examine the bleeding patterns of 234 Norplant users during 5 years of use and to identify the bleeding patterns of users who conceived. During the first year of use, 26.6% of users had regular bleeding cycles, 66.3% had irregular cycles, and 7.1% were amenorrheic. By the fifth year of use, 62.5% of users had regular cycles, 37.5% had irregular cycles, and none had amenorrhea. Of the ten users who became pregnant, eight had regular menstrual cycles in the 6 months before the diagnosis of pregnancy, one had an irregular pattern, and one did not keep a bleeding record. None had amenorrhea. The 5-years cumulative pregnancy rate for patients with regular cycles was 17.4%; this was significantly higher (P less than .05) than the 5-year cumulative rates of 4.4% in users with irregular cycles and 0% in users with amenorrhea. This study indicates that during the first year of Norplant use, only 26.6% of users have regular cycles, but after the first year, 50-60% of users develop regular cycles. The bleeding patterns of women using Norplant improve after the first year of use, and those with regular cycles are at greatest risk for method failure.

Contraceptive options for the gestational diabetic woman.

PIP: Of the contraceptive choices open to a post-partum woman with gestational diabetes, this discussion concentrates on low-dose oral contraceptives. Although gestational diabetes usually clears at delivery, 75% of these women will go on to developed impaired glucose tolerance or overt diabetes, especially if they are obese or if their glucose level had been high. Many elect permanent sterilization, but those requiring reversible contraception usually choose the IUD or the pill. IUDs carry a high risk of infection and are less effective in diabetics. The author compared a low-dose combined pill with 400 mcg norethindrone and 35 mcg ethinyl estradiol (Ovcon 35), and a pill containing levonorgestrel (Triphasil), to barrier contraception in 230 women with recent gestational diabetes. After 6-13 months of use 11-17% of each group had impaired glucose tolerance, and 15-20% of each group had diabetes (n.s.). Insulin levels rose from 28.5 mIU/mL to 59.7 in controls, 32.0 to 71.8 in Ovcon 35 users, and from 40.2 to 85.1 in Triphasil users (p0.05). HDL values rose significantly in the group taking Ovcon, and LDL values fell significantly in all 3 groups. These low-dose pills can be used safely in postpartum gestational diabetic women, as long as they do not smoke, are encouraged to lose weight, and have no sign of cardiovascular disease as evidenced by albuminuria and an ophthalmoscopic exam.^ieng

Antiprogestin treatment decreases midluteal luteinizing hormone pulse amplitude and primarily exerts a pituitary inhibition.

Mifepristone (RU 486), a synthetic steroid with antiprogesterone receptor activity, was given with and without naloxone hydrochloride to six women in the midluteal phase to investigate the role of progesterone in the modulation of endogenous opioid activity and the secretion of luteinizing hormone and cortisol. Subjects were evaluated during four sequential monthly admissions during which multiple blood samples were obtained every 15 minutes for 8 hours. Patients were studied during a baseline cycle, after administration of RU 486 alone (100 mg/day), naloxone with RU 486, and naloxone alone. After administration of RU 486 there was a significant decline in total luteinizing hormone secretion (p less than 0.01) and luteinizing hormone pulse amplitude (p less than 0.05), but compared with baseline there was no significant change in luteinizing hormone pulse frequency. After infusion of naloxone there was a significant increase in mean luteinizing hormone values (p less than 0.05) and luteinizing hormone pulse frequency (p less than 0.01) but no change in pulse amplitude. There was no significant difference in mean luteinizing hormone values or luteinizing hormone pulse amplitude and frequency between administration of RU 486 and naloxone plus RU 486. Administration of naloxone alone, RU 486 alone, and RU 486 plus naloxone caused a significant increase in cortisol as compared with baseline cycles (p less than 0.05). These data further support the notion that progesterone is important in the control of luteinizing hormone secretion and suggest that progesterone may primarily influence luteinizing hormone pulse amplitude and pituitary release of luteinizing hormone during the luteal phase.

Water-soluble renin inhibitors: design of a subnanomolar inhibitor with a prolonged duration of action.

Incorporation of nonreactive polar functionalities at the C- and N-termini of renin inhibitors led to the development of a subnanomolar compound (21) with millimolar solubility. This inhibitor demonstrated excellent efficacy and a long duration of action upon intravenous administration to monkeys. While activity was also observed intraduodenally, a comparison of the blood pressure responses indicated low bioavailability. Subsequent experiments in rats showed that, although the compound was absorbed from the gastrointestinal tract, extensive liver extraction severely limited bioavailability.

Metabolism and disposition of clarithromycin in man.

The metabolic fate and pharmacokinetics of clarithromycin following a single 250- or 1200-mg oral dose of 14C-clarithromycin were studied in six healthy adult males. Peak plasma levels of clarithromycin averaged 0.6 microgram/ml after the low dose and 2.7 micrograms/ml after the high dose. The AUC of clarithromycin increased 13-fold, with the 4.8-fold increase in dose, while the plasma half-life increased from 4.4 hr to 11.3 hr. The major metabolite in plasma and urine was the microbiologically active 14-hydroxylated-R epimer of clarithromycin. After 5 days, a mean of 38% of the low dose (18% as clarithromycin) and 46% of the high dose (29% as clarithromycin) was recovered in the urine, with approximately one-third eliminated during the first 24 hr. The nature of the urinary and fecal metabolites revealed the involvement of three metabolic pathways, viz. 1) hydroxylation at the 14-position to form the R and S epimers, 2) N-demethylation, and 3) hydrolysis of the cladinose sugar. Secondary metabolism via these pathways was also evident. The overall recovery of metabolites, but not total radioactivity, decreased 42% after the high dose. The nonlinear pharmacokinetic behavior of clarithromycin and the decrease in metabolite production suggest that clarithromycin metabolism can be saturated at high doses.

Renin inhibitors. Dipeptide analogues of angiotensinogen utilizing a dihydroxyethylene transition-state mimic at the scissile bond to impart greater inhibitory potency.

The synthesis of diol-containing renin inhibitors has revealed that a simple vicinal diol functionality corresponding to the scissile Leu-Val bond in human angiotensinogen is capable of imparting inhibitory activity at a comparable or higher level than either the corresponding aldehyde or hydroxymethyl functionality (compare inhibitors 2a-c or 3a-c). This finding has led to the further optimization of a series of small transition-state analogue inhibitors by the inclusion of a second hydroxyl group in the Leu-Val surrogate to give compounds that inhibited human renin in the 200-700-pM range (e.g. 43, 45, 63, 66). The magnitude of effect of the second hydroxyl group on potency is not only dictated by the absolute stereochemistry of the diol but also by the side chain of the P1 residue. Molecular modeling of the diol-containing inhibitors suggests that one of the hydroxyl groups hydrogen bonds to Asp 32 and Asp 215, while the second hydrogen bonds to Asp 215. These diol inhibitors are extremely selective for human renin over the related enzymes cathepsin D, pepsin, and gastricsin. At high concentrations, compounds containing a leucine or phenylalanine rather than a histidine at the P2 position gave only minor amounts of inhibition of the other enzymes. Inhibitor 43 suppressed plasma renin activity completely and lowered mean blood pressure in monkeys after both intravenous and intraduodenal administration, but the blood pressure drop lasted less than 1 h. Monitoring the blood levels of 43 by enzyme inhibition assay after intraduodenal administration to monkeys or oral administration to rats revealed low absorption and rapid clearance. While intratracheal administration to dogs gave approximately 50% bioavailability, rapid clearance was still a problem. After examination of inhibitor 45 in a sensitive primate model in which monkeys were rendered both hypertensive and hyperreninemic, the effects on lowering systolic but not diastolic pressure were apparent even after 22 h postdosing. Details on the synthesis, in vitro structure-activity relationships, molecular modeling, in vivo activity, and metabolism of these inhibitors are described.

Renin inhibitors. Dipeptide analogues of angiotensinogen utilizing a structurally modified phenylalanine residue to impart proteolytic stability.

A series of renin inhibitors have been prepared and evaluated for their susceptibility to cleavage by the serine protease chymotrypsin. The compounds were designed by consideration of the structural requirements in the active-site region of renin and chymotrypsin. By systematic alteration of the P3 phenylalanine residue, compounds with varying degrees of renin inhibitory potency and chymotrypsin susceptibility were obtained. Selected analogues from this group were examined in vivo for both their hypotensive effects and metabolic patterns.

Optimization and in vivo evaluations of a series of small, potent, and specific renin inhibitors containing a novel Leu-Val replacement.

Further structure-activity relationships (SAR) for a novel dipeptide series inhibitors are reported. These inhibitors retain the Phe8-His9 portion of angiotensinogen and employ a unique Leu10-Val11 replacement [(LVR), ref 2]. SAR at the Leu10 side chain revealed that the LVR derived from cyclohexylalanine provided a nearly 10-fold boost in potency for the final inhibitor. In addition SAR work was carried out to delineate the relationships between binding potency and (1) the size, shape, and charge of the side chain at the His9 position; (2) the size and topology of the side chain at the Phe8 site; and (3) the size of the Phe8 N-protecting group. One of the more potent inhibitors, 12, was shown to provide a substantial antihypertensive effect in a sodium depleted monkey model when administered intravenously. Metabolism work, in Sprague-Dawley rats, provided insights into the susceptibility of 12 to significant hepatic clearance and provided encouraging evidence for intestinal absorption.

Metabolism of 14C-estazolam in dogs and humans.

14C-Estazolam (2 mg) administered orally to dogs and human subjects was rapidly and completely absorbed with peak plasma levels occurring within one hour. In humans, plasma levels peaked at 103 +/- 18 ng/ml and declined monoexponentially with a half-life of 14 h. The mean concn. of estazolam in dog plasma at 0.5 h was 186 ng/ml. Six metabolites were found in dog plasma at 0.5 and 8 h, whereas only two metabolites were detected in human plasma up to 18 h. Metabolites common to both species were 1-oxo-estazolam (I) and 4-hydroxy-estazolam (IV). Major metabolites in dog and human plasma were free and conjugated 4-hydroxy-estazolam; the concn. were higher in dogs. After five days, 79% and 87% of the administered radioactivity was excreted in dog and human urine, respectively. Faecal excretion accounted for 19% of the dose in dog and 4% in man. Eleven metabolites were found in the 0-72 h urine of dogs and humans; less than 4% dose was excreted unchanged. Four metabolites were identified as: 1-oxo-estazolam (I), 4'-hydroxy-estazolam (II), 4-hydroxy-estazolam (IV) and the benzophenone (VII), as free metabolites and glucuronides. The major metabolite in dog urine was 4-hydroxy-estazolam (20% of the dose), while the predominant metabolite in human urine (17%) has not been identified, but is likely to be a metabolite of 4-hydroxy-estazolam. The metabolism of estazolam is similar in dog and man.

Toxicological aspects of cyclamate and cyclohexylamine.

In the late 1960s the artificial sweetener cyclamate was implicated as a bladder carcinogen in rats. This finding and other concerns about its safety ultimately led to a ban on cyclamate in the U.S. and restrictions on its use in many other countries. Since that time, the carcinogenic potential of cyclamate and cyclohexylamine, its principal metabolite, has been reevaluated in a group of well-controlled, well-designed bioassays that have failed to substantiate the earlier findings. This review of the published and unpublished literature on cyclamate attempts to evaluate the carcinogenicity question and other important aspects of the toxicity of cyclamate and cyclohexylamine, including their effects on various organ systems, their genotoxic potential, and their effects on reproduction. In addition, the physiological disposition of cyclamate is reviewed, with particular attention directed toward the site and extent of its conversion to cyclohexylamine.

Metabolism of [14C]Cefmenoxime in normal subjects after intramuscular administration.

The metabolism of cefmenoxime (SCE-1365) was studied in four healthy male volunteers after intramuscular administration of a single 500-mg dose of the 14C-labeled drug. Plasma levels of total radioactivity and cefmenoxime peaked at 0.5 and 1.0 h, corresponding to 16.5 micrograms eq/ml and 15.8 micrograms/ml, respectively. Thereafter, parent drug levels declined rapidly, with a terminal elimination half-life of ca. 1.5 h. No significant differences were noted between total radioactivity and parent drug levels up to 2 h after drug administration. After 3 h, low but persistent levels of radioactivity were significantly greater than parent drug levels, indicating metabolism or degradation of cefmenoxime. The terminal elimination half-life of total radioactivity was estimated to be ca. 40 h. The radioactive plasma metabolite(s) remaining at the end of the 5-day study represented only 1% of the administered dose. Urinary excretion was the major route of elimination of cefmenoxime, accounting for ca. 86% of the dose in 12 h. Analysis of cefmenoxime in urine by total radioactivity, high-pressure liquid chromatography, and a microbiological assay showed that 80 to 92% of the excreted dose was parent drug. Radioactivity was also excreted into the feces via the bile and represented ca. 11% of the dose after 5 days. Although extensive degradation of cefmenoxime was found in fecal samples, it was proposed that this may be due to the metabolic activity of the intestinal flora rather than in vivo biotransformation in the liver. This study supports the concept that cefmenoxime undergoes minimal metabolism in humans and is excreted largely as unchanged drug.

Pharmacokinetics of fostedil, a new calcium antagonist, in beagle dogs following oral and intravenous administration.

Twelve adult beagle dogs received both an oral and intravenous dose (12 mg/kg) of fostedil in a cross-over design. The plasma levels and urinary excretion of intact fostedil were measured, and the pharmacokinetic parameters of the drug were defined. The results indicate that fostedil was at least 68% bioavailable after an oral dose given as a suspension or solution. The terminal half-life was about 7-8 h. The in vitro protein binding, at concentrations of 0.1-100 micrograms/mL, ranged from 95 to 97%. The binding was not concentration dependent, and saturation of the binding sites was not apparent at concentrations up to 100 micrograms/mL. Excretion of unchanged drug from the kidneys accounted for only a small percentage of drug clearance.

Intraocular penetration of topically applied [14C]fosfonet sodium in rabbits.

The intraocular penetration of [14C]fosfonet was studied following topical application of 25 mg of an ointment containing 5% [14C]fosfonet sodium onto the intact and abraded eyes of New Zealand white rabbits. Radioactivity penetrated rapidly through the abraded cornea and entered the anterior chamber. The concentration of fosfonet in the aqueous humor peaked at 7.2 microgram/ml by 90 min. Assuming an aqueous humor volume of 300 microliter, this level would correspond to approximately 0.2% of the applied dose. The highest concentration of fosfonet found in the abraded cornea was 0.3 microgram/mg, or 0.4% of the applied dose. The half-lives for the elimination of fosfonet from the aqueous humor and cornea were about 2.5 and 2.7 hr, respectively. The fosfonet levels in the iris were extremely low throughout the 6-hr period. The penetration of [14C]fosfonet through the intact cornea was considerably less than that found in the abraded eye. The peak concentrations of fosfonet in the aqueous humor and cornea of the intact eye were 0.26 microgram/ml and 0.02 microgram/mg, respectively, and occurred within 10 min of application of ointment.