Pharmacokinetics of metformin gastric-retentive tablets in healthy volunteers.

The single-dose pharmacokinetics of two gastric-retentive, extended-release tablet formulations of metformin hydrochloride in fed, healthy volunteers were compared with those of the currently marketed immediate-release metformin hydrochloride product. The plasma concentration-time profiles demonstrated extended-release characteristics from the gastric-retentive tablets. The mean bioavailability from each gastric-retentive tablet was approximately 115%, relative to the immediate-release (IR) product. Cmax values were lower and tmax values were greater for the gastric-retentive tablets compared with the IR product. In contrast to conventional extended-release metformin tablets reported in the literature, these gastric-retentive tablets showed extended-release plasma concentration profiles of metformin hydrochloride and increased bioavailability compared with the immediate-release tablet.

Comparison of the nicotine pharmacokinetics of Nicoderm (nicotine transdermal system) and half-hourly cigarette smoking.

Nicoderm, a nicotine transdermal system (NTS), provides a continuous, transdermal delivery of nicotine and is used as an aid to smoking cessation. In contrast, cigarette smoking yields nicotine concentrations in plasma that rise and fall with each cigarette. The primary objective of this study was to compare nicotine pharmacokinetics after treatment of subjects with either the NTS or controlled smoking. Fourteen healthy adult male smokers, who smoked at least 30 cigarettes per day, were entered into a randomized crossover design trial that compared the NTS, 21 mg/day applied for 24 hours, with half-hourly smoking during the day. Subjects abstained from smoking for 2 days, and were treated for 5 days with either the NTS (daily) or controlled smoking (30 cigarettes at half-hourly intervals on days 1 and 5; ad libitum smoking on days 2-4). Blood samples were obtained frequently on days 1 and 5 for analysis of nicotine and cotinine. Pharmacokinetic comparisons showed that nicotine Cmax, area under the curve (AUC)inf, and Cavg for the NTS were lower than corresponding values for controlled smoking; Cmax and Cavg values were approximately half those of smoking. Cmax and Cavg values for cotinine were similarly lower for the NTS compared to controlled smoking. For both treatments, plasma nicotine concentrations were higher on day 5 compared to day 1. Thus, the NTS provides concentrations of nicotine that are lower than smoking.

Comparison of the pharmacokinetics of two nicotine transdermal systems: nicoderm and habitrol.

This randomized, crossover study compared the nicotine and cotinine pharmacokinetic parameters and plasma concentration profiles of two different nicotine transdermal products: Nicoderm (Alza, Palo Alto, CA; and Marion Merrell Dow, Kansas City, MO) and Habitrol (Basel Pharmaceuticals, Summit, NJ). The two treatments were randomly assigned to each of 24 male smokers and worn for 24 hours each day for 5 days, with a 6-day washout between treatments. Plasma nicotine and cotinine concentrations were measured on day 1 and day 5 of each treatment. Mean delivered dose differed significantly between products, and the two products were not bioequivalent. The Nicoderm system provided higher mean plasma nicotine concentrations, particularly during the first 8 hours after system application. The mean steady state Cmax, AUC, and degree of fluctuation (DF) values were significantly greater for the Nicoderm system than for Habitrol. The mean nicotine tmax value for the Nicoderm system was significantly shorter (P < .001) than that for Habitrol (2.7 versus 8.6 hours). Steady state cotinine AUC values and plasma concentrations were significantly lower for Habitrol than for the Nicoderm system. The incidence of adverse events was similar for both products.

In vitro and in vivo evaluation of a once-daily controlled-release pseudoephedrine product.

The functionality of a once-daily, osmotic dosage form--gastrointestinal therapeutic system (pseudoephedrine HCl) or GITS (PeHCl)--was studied in vitro and in vivo. The in vitro release profiles were close to identical from pH 1 to 7.5 and between USP apparatus 2 and 7, independent of paddle speeds from 50 to 200 rpm; GITS also released drug at the normal rate in aqueous media after incubation in bile salts or fatty media. Both strengths of GITS (PeHCl)--240 and 120 mg--were then compared with a commercially available pseudoephedrine solution given every 6 hours and a timed-release 12-hour pseudoephedrine capsule given every 12 hours in a randomized 4-way crossover study in 24 healthy men. All four formulations were equivalent in total drug absorbed. Both GITS treatments had AUCinf values equivalent to those of PeHCl solution and capsules, and Cmax values equivalent to PeHCl capsules. Cmax for GITS and capsule treatments were each significantly lower than for solution, but the differences were small (14-17%). A one-to-one correlation was shown between rate of absorption and in vitro release profiles for the GITS products, indicating that drug release from GITS controls absorption. Insensitivity to conditions of in vivo release accounts for the close in vitro/in vivo correlation of release rates. In a second randomized crossover trial (12 men), the effect of a high-fat breakfast on GITS performance was evaluated. Mean pseudoephedrine concentrations in plasma were close to identical with or without the breakfast, and the treatments were bioequivalent.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption and adverse effects following topical and oral administration of three transdermal nicotine products to dogs.

To evaluate potential adverse effects from inadvertent exposure to a nicotine transdermal system or "patch", three marketed products were administered topically and orally to dogs: Nicoderm (nicotine transdermal system), with a drug reservoir and a rate-controlling membrane; Nicotinell, with a nicotine solution dispersed in a cotton gauze pad between layers of adhesive; and Niconil, with a nicotine gel matrix. Nicotine doses during topical administration ranged from 1 to 2 mg/kg/24 h for all three products, with plasma nicotine concentrations as high as 43 ng/mL. Two of the 12 topical exposures (with Nicotinell and Niconil) were associated with clinical signs (excess salivation or emesis). The oral doses from the products ranged from 2.8 mg/kg (one patch) to 13.4 mg/kg (two patches) over 25-57 h, with mean maximal plasma levels of 73 ng/mL for two patches (mean maximal level 36 ng/mL). These doses are 2-9-fold higher than oral doses reported to produce severe toxicity in children and, at the highest dose, within the known lethal range for dogs. Oral dosing of Nicotinell and Niconil (two patches per dog) produced vomiting in 2 of 12 exposures. No clinical signs were observed with either topical or oral dosing of Nicodem. These data suggest that nicotine toxicity in dogs from nicotine transdermal patches may not be as severe as might be anticipated based on nicotine content alone.

Cholesterol changes in smoking cessation using the transdermal nicotine system. Transdermal Nicotine Study Group.

BACKGROUND: Cigarette smoking is a well-known major risk factor in coronary heart disease. Smoking cessation results in a positive change in atherogenic factors. High-density lipoprotein cholesterol has been observed as increasing with smoking cessation. Since the use of nicotine transdermal replacement has become so widespread, this study examined the effect, if any, of the transdermal nicotine system on selected cardiovascular parameters in patients who were abstinent from cigarette smoking, and possible dose effect. METHODS: Eight cardiovascular outcome measures were evaluated at baseline and Week 6 in both abstinent and non-abstinent patients randomized to four treatment groups; transdermal nicotine system 7 mg, 14 mg, and 21 mg per day, and placebos. RESULTS: In abstinent patients, systolic blood pressure and heart rate decreased from baseline (while still smoking, before the start of the study) to the end of transdermal treatment, while weight increased. Similarly, HDL increased while LDL decreased and triglycerides increased. In nonabstinent patients, weight also increased from baseline to Week 6 while heart rate decreased. No other variables showed significant change. In abstinent patients, effect of nicotine dosage was observed with greater weight gain in placebo than 21 mg TTS patients and greater decrease in heart rate in placebo than 21 mg TTS patients. CONCLUSIONS: In summary, the abstinent patients showed a positive effect of smoking cessation on cardiovascular risk factors even while using the transdermal nicotine system. These findings are favorable since the transdermal nicotine system has become a useful method of nicotine replacement in smoking cessation programs.

Bioavailability and absorption kinetics of nicotine following application of a transdermal system.

1. The absolute bioavailability and absorption kinetics of nicotine were investigated in 13 healthy adult male smokers following single and multiple applications of a nicotine transdermal system (NTS), designed to release nicotine at an approximate rate of 1.5 mg h-1 over 24 h. The absorption of nicotine from the single NTS application was calculated with reference to a simultaneous intravenous infusion (i.v.) of deuterium-labelled nicotine. 2. The mean input time (MIT) and mean absorption time (MAT) for nicotine following application of NTS for 24 h were 7.7 and 4.2 h, respectively. 3. Following NTS removal, the mean apparent nicotine elimination half-life was 2.8 h, compared with 2.0 h following i.v. nicotine, reflecting continued absorption of nicotine following NTS removal. 4. The mean amount of nicotine absorbed from the NTS after the 24 h application was 20.9 mg, which represents about 68% of the amount released from the system; the remaining 32% was lost from the system during daily activities. 5. The ratio of AUC values for the metabolite cotinine relative to nicotine was similar whether nicotine was administered transdermally or intravenously. 6. Following i.v. administration, the mean nicotine clearance was 72 l h-1 (coefficient of variation 29%). Since coefficients of variation in AUC values following NTS and i.v. treatments were similar, transdermal administration of nicotine was not associated with increased interindividual variability in plasma nicotine concentrations. 7. No significant changes were seen in the pharmacokinetics of nicotine between single and multiple applications of NTS. 8. As expected from the higher total plasma nicotine concentrations, the incidence of adverse effects was higher following simultaneous intravenous and transdermal administration of nicotine. The most frequently reported systemic side effects were nervousness and headache: mild itching was the most frequent topical effect.

Nicotine pharmacokinetics of Nicoderm (nicotine transdermal system) in women and obese men compared with normal-sized men.

This study examined the effect of gender and body weight on the pharmacokinetic properties of the Nicotine Transdermal System (NTS) (Nicoderm). This NTS was applied for 24 hours to 13 normal-sized men, 13 women, and 13 obese men, all of whom were smokers who had abstained from cigarettes for the previous 24 hours. Pharmacokinetic parameters were determined during a single application of the system. The mean nicotine maximal plasma concentration (Cmax) and area under the curve (AUC) values for women did not differ significantly from those for normal-sized men. Nicotine Cmax and AUC values, however, were significantly lower in obese compared with normal-sized men; nicotine AUC was strongly correlated to body weight and body mass index. Mean apparent nicotine elimination rate constant values were not significantly different between normal-sized and obese men, but the apparent elimination rate constant value was significantly higher in women. The possible clinical significance of the differences in nicotine AUC values with body weight is discussed.

Steady-state pharmacokinetics and dose relationship of nicotine delivered from Nicoderm (Nicotine Transdermal System).

An open-label, randomized, crossover study determined nicotine pharmacokinetics at steady state of a new Nicotine Transdermal System in 24 healthy adult male smokers. Three doses were each administered for 5 days: 7, 14 and 21 mg nicotine per day. Plasma nicotine concentrations reached steady state by the third day and were sustained throughout the 24-hour application periods. Mean steady-state nicotine and cotinine area under the curve (AUC0-24), maximum plasma concentration (Cmax), minimum plasma concentration (Cmin), average plasma concentration (Cavg), and total urinary cotinine were proportional to the dose of nicotine released in vitro from Nicotine Transdermal System. Time to reach peak concentration (tmax), half-life (t1/2), relative degree of fluctuation (DF) in steady-state plasma nicotine and cotinine concentrations, and renal cotinine clearance were similar for all three dosages, indicating linear pharmacokinetics and no change in nicotine metabolism with increasing dose. Findings from a second study also reflect the linear dose relationship for this Nicotine Transdermal System within the 7 to 21 mg/day dosage range. Bioequivalence based on the confidence interval test was demonstrated for a single application of Nicotine Transdermal System 21 mg/day and the same total dosage achieved by combined administration of Nicotine Transdermal System 7 mg/day plus Nicotine Transdermal System 14 mg/day, although there were small statistical differences. This Nicotine Transdermal System has a well-defined pharmacokinetic profile, with sustained plasma nicotine concentrations, and nicotine pharmacokinetics that are independent of the dose of this Nicotine Transdermal System.

Single- and multiple-dose pharmacokinetics of Nicoderm (Nicotine Transdermal System).

The pharmacokinetics and tolerability of single and multiple applications of Nicotine Transdermal Systems (NTS), designed to deliver 14 mg of nicotine per 24 hours, were investigated in 20 healthy adult male smokers. After a single application, mean Cmax and tmax for plasma nicotine were 12.2 ng/mL and 4.4 hours, respectively. Plasma nicotine concentrations rose rapidly and then remained steady between 12 and 24 hours after application. The apparent nicotine half-life (t1/2) after system removal was 3.2 hours. Steady state was attained by the second day of multiple application, and mean steady-state nicotine Cavg was 25% higher on day 5 compared with the first NTS application. Steady-state plasma cotinine was reached by the fourth day of multiple application and, as with nicotine, Cavg and Cmax increased, tmax decreased, and t1/2 did not change compared with single application. The mean ratios of cotinine-to-nicotine area under the curve (AUC) values for single and multiple NTS applications were 14.0 and 15.8, respectively. The pharmacokinetics of nicotine and cotinine were linear between single and multiple NTS applications. The nicotine transdermal systems were generally well tolerated.

Comparison of plasma nicotine concentrations after application of nicoderm (nicotine transdermal system) to different skin sites.

Drug absorption through the skin can vary according to the application site. The nicotine transdermal system, Nicoderm (Alza Corp., Palo Alto, CA) contains a rate-controlling membrane designed to regulate delivery of nicotine to the skin and thus limit variability in nicotine plasma levels. Plasma nicotine concentrations were compared after application of NTS 14 mg/day to three different skin sites (upper back, upper outer arm, upper chest) in a randomized, crossover study involving 12 healthy male smokers. Plasma nicotine profiles from all three sites were similar: nicotine concentrations increased rapidly within 2 to 4 hours, reached broad peaks of approximately 11 to 14 ng/mL, and then remained relatively constant between 8 and 24 hours after application. The mean nicotine maximum peak plasma concentration values for nicotine transdermal system application to the arm, back, and chest were equivalent (13.8, 14.6, and 13.2 ng/mL, respectively). The mean time to reach peak concentration (tmax) (3 to 6 hours), and area under the curve (168, 186, and 183 ng.h/mL) values for the arm, back, and chest, respectively, were not significantly different. Thus, bioequivalent plasma nicotine concentrations were achieved irrespective of the application site on the upper body.

Detection of specific IgG and IgA antibodies to Chlamydia trachomatis in women with salpingitis confirmed by laparoscopy.

The sera from 12 consecutive symptomatic women with laparoscopy-confirmed salpingitis were screened for the presence of specific IgG and IgA antibodies to Chlamydia trachomatis by a single antigen (L-2) immunoperoxidase assay. All women were found to have IgG and IgA antibodies to C trachomatis. Six women had positive endocervical cultures for C trachomatis, and one of these had positive cultures from the conjunctiva and fallopian tubes. Serum chlamydial IgA antibodies may serve as markers for active infection with C trachomatis regardless of whether organisms can be identified by culture or direct fluorescent antibody techniques from endocervical or fallopian tube samples.

Metabolism of aldosterone in the colostomized duck (Anas platyrhynchos): partial characterization of urinary metabolites.

1. Chronically colostomized ducks were injected with [4-14C]-aldosterone to study the metabolism of aldosterone and the pattern of metabolite excretion via the kidney. 2. Nearly half of the injected dose was excreted as radiometabolites during the first 24 hr; the largest amounts being excreted during the first 3 hr after injection. 3. Ion-exchange chromatography showed that monosulfate, disulfate, glucuronide, acidic, and neutral metabolites were excreted during each collection period, and that their relative proportions changed with time after injection of [4-14C]-aldosterone. 4. HPLC analysis of the neutral radiometabolites revealed 15 major peaks with retention times corresponding to both polar and reduced derivatives of aldosterone. 5. Only small quantities of unaltered labelled aldosterone were excreted. 6. Treatment of the birds with SKF 525-A caused a decrease in the total quantity of radiometabolite excreted and a change in the proportions of neutral and acidic metabolites in the cloacal fluid. 7. The decreases that occurred in the absolute amounts of some of the polar metabolites excreted by the birds treated with SKF-525A suggests that they may be hydroxylated and at least part of the aldosterone metabolizing system in the duck is cytochrome P450 dependent.

Prevalence of IgA and IgG antichlamydial antibodies in women in the third trimester of pregnancy.

The prevalence of serum antichlamydial IgA and IgG antibodies was investigated by screening 77 randomly selected patients who were in the third trimester of pregnancy. An indirect immunoperoxidase assay that quantitates IgA and IgG was used for screening. Twenty-five women had both IgA and IgG antibodies; an additional ten women had only IgG antibodies. These findings suggest that greater than 45 percent of pregnant women tested had been exposed to Chlamydia trachomatis, and more than 32 percent had evidence of active infection.

Changes in 5 alpha- and 5 beta-reductase pathways of aldosterone metabolism by dietary sodium.

The effects of dietary Na+ on 5 alpha- and 5 beta-reductase pathways of aldosterone metabolism in the liver were studied in male rats maintained on low, control, and high Na+ diets. A high Na+ diet caused significant increases in the synthesis of 5 beta-reduced metabolites, primarily 3 alpha, 5 beta-tetrahydroaldosterone; whereas a low Na+ diet stimulated the 5 alpha-reductase pathway causing increases in the synthesis of 5 alpha-dihydroaldosterone and 3 beta 5 alpha-tetrahydroaldosterone, as well as certain polar, hydroxylated metabolites of aldosterone. These studies demonstrate that dietary Na+, a known regulator of aldosterone synthesis, may also regulate enzymes involved in aldosterone metabolism in peripheral tissues.

A comparison of culture, direct fluorescent antibody test, and a quantitative indirect immunoperoxidase assay for detection of Chlamydia trachomatis in pregnant women.

An indirect immunoperoxidase assay that quantitates antichlamydial immunoglobulin G (IgG) and IgA antibodies in serum was compared with endocervical culture and direct fluorescent antibody (MicroTrak) for detection of Chlamydia trachomatis in asymptomatic pregnant women. Of the 64 women tested by the three methods, 22 (34%) had antichlamydial IgG and IgA in their serum. The culture was positive in nine patients (14%) and the MicroTrak was positive in eight (12.5%). All positive cultures were immunoperoxidase-positive. One positive MicroTrak was immunoperoxidase- and culture-negative. Thirteen patients had IgG and IgA antichlamydial antibodies with no organisms detected in the endocervix by culture or by direct fluorescent antibody screen.

Effects of adrenalectomy and spironolactone on urinary metabolites of aldosterone in rats.

The quantities and temporal sequences of appearance of aldosterone metabolites in the urine of adrenalectomized rats, and adrenalectomized rats treated with spironolactone, were compared following subcutaneous administration of a physiological dosage (0.05 microgram) of [1,2,-3H]aldosterone. Large amounts of radiometabolites were rapidly excreted during 0-1 and 1-3 h and only small quantities by 3-4 h in urine of both groups of rats. The majority of the urinary radiometabolites (70-85%) were identified by Sephadex DEAP-LH-20 chromatography as neutral metabolites of aldosterone (NMA), together with lesser quantities of acidic, sulfate, and glucuronide conjugates. Further characterization by high pressure liquid chromatography (HPLC) showed that 90% of the NMA excreted by adrenalectomized rats were polar metabolites which could be separated into at least 15 peaks eluting in regions of increasing polarity (designated A, B, C, and D). Only small quantities of unaltered [3H]aldosterone and no ring-A-reduced metabolites were excreted by the adrenalectomized rats. Spironolactone treatment caused large changes in the excretion of acidic and sulfate derivatives of aldosterone, as well as discrete alterations in the HPLC patterns of the polar NMA (particularly those metabolites in regions A and B). Such discrete changes in these metabolic pathways which occur at the same time as the hormonal actions of aldosterone in the kidney may provide further insight into understanding the biological role of aldosterone metabolism.

The effects of 19-nor-aldosterone on blood pressure of adrenalectomized spontaneously hypertensive rats.

The relative hypertensinogenic potencies of recently synthesized 19-nor-aldosterone and its precursor 19-OH-aldosterone were assessed in comparison to that of aldosterone (Aldo) in young (6-week-old) adrenalectomized (ADX) spontaneously hypertensive rats (SHR). Infusion of 19-nor-aldosterone for 2 weeks by Alza mini-osmotic pumps caused significant, dose-dependent increases in the systolic blood pressure (BP) of young ADX SHR; dosages of 0.1 and 0.5 microgram/day raised the BP from 127 +/- 2 mmHg to 164 +/- 9 and 180 +/- 11 mmHg, respectively. During this period, control ADX SHR receiving vehicle only remained normotensive. Similar increases in BP were seen only with infusion of slightly higher dosages of Aldo (0.5 and 1.0 micrograms/day). In contrast, 19-OH-aldosterone infused at higher dosages (10 or 25 micrograms/day) caused little change in BP of ADX SHR. Full suppression of plasma renin activity (PRA) was observed with 0.1 and 0.5 microgram/day 19-nor-aldosterone, whereas Aldo caused similar decreases in PRA only at dosages of 0.5 microgram/day and higher. Interestingly, although infusions of 19-OH-aldosterone did not cause a significant change in BP, these dosages (10 and 25 micrograms/day) significantly suppressed PRA. These studies which show that 19-nor-aldosterone is equipotent to Aldo, and perhaps slightly more active in ADX SHR, indicate that 19-nor-aldosterone is a potentially important hypertensinogenic steroid.

The hypertensinogenic activity of 19-nor-deoxycorticosterone in the adrenalectomized spontaneously hypertensive rat.

Infusions of 10 or 25 micrograms/day 19-nor-DOC for 2 weeks in adrenalectomized spontaneously hypertensive rats led to significant increases in blood pressure, 55 and 70 mmHg respectively. This study provides further evidence that 19-nor-DOC is a potent hypertensinogenic steroid and that the ADX SHR model is a useful, sensitive bioassay system to test for hypertensinogenic activity.

Management of the missing intrauterine contraceptive device: report of a case.

A case of postpartum intrauterine contraceptive device insertion that resulted in a remote complication is described. At the postinsertion follow-up visit the intrauterine contraceptive device was missing and presumed expelled. Four years later it was recovered from a complex mass involving the bladder and the appendix. Management for the missing intrauterine contraceptive device is recommended.

PIP: This paper presents a case of unrecognized uterine perforation in a 27-year-old IUD user. A Cu-7 IUD had been inserted in the patient at her 6-months postpartum examination. At the postinsertion follow up visit, the IUD could not be detected and was presumed to have been expelled. 4 years later, a pelvic mass was found which involved both the bladder and the appendix. Laparotomy revealed that the IUD had perforated the appendix. It was not possible to determine when the IUD became involved with the appendix or how they in turn became involved with the bladder wall. However, early recognition of perforation might have prevented this complication. It is urged that failure to locate the IUD strings in a patient who has not noticed expulsion should be interpreted as indicating perforation until proved otherwise. The search for a missing IUD should include a sonogram and, if inconclusive, an abdominal x-ray.