Percutaneous absorption and pharmacokinetics of eflornithine HCl 13.9% cream in women with unwanted facial hair.

This article reports the results of an open-label, multiple-dose study to determine percutaneous absorption and pharmacokinetics of eflornithine following topical treatment with eflornithine HCl 13.9% cream (Vaniqa). Ten women with excessive facial hair were treated with two 0.5 g single doses of [14C]-labeled eflornithine HCl 13.9% (w/w) cream (periods A and C) separated by twice-daily application of 0.5 g unlabeled eflornithine HCl 13.9% cream for 7 days (period B). Analysis of radioactivity excreted in urine and feces indicated that percutaneous absorption was minimal. Comparison with urinary excretion of eflornithine in period A suggested that most of absorbed eflornithine was excreted in urine without being metabolized. Radioactivity was not detectable in blood or plasma, but eflornithine concentrations were measurable, with peak concentrations of 4.96 ng/ml in period A and 10.44 ng/ml in period C. Eflornithine was eliminated from plasma with a mean terminal half-life of 11 hours (first application) and 8 hours (final application). Trough plasma concentrations reached steady state (4.61-5.50 ng/ml) after 4 days of twice-daily topical treatment, and multiple dosing had no apparent effect on disposition kinetics. The low degree of percutaneous absorption and low systemic exposure to eflornithine offer a favorable clinical safety profile of eflornithine HCl 13.9% cream.

Oral bioavailability and disposition of [14C]omapatrilat in healthy subjects.

The objective of this study was to determine the absolute oral bioavailability and disposition of omapatrilat. This single-dose, randomized, crossover study of 20 mg intravenous and 50 mg oral [14C]omapatrilat was conducted in 12 healthy male subjects to determine the disposition and oral bioavailability of omapatrilat, an orally active vasopeptidase inhibitor. Blood samples were collected up to 120 hours, and the excreta were collected over 168 hours postdose. Plasma concentrations of omapatrilat were determined by a validated LC/MS/MS procedure. Radioactivity in blood, plasma, urine, and feces was determined by liquid scintillation counting. Urinary excretion of radioactivity averaged 80% and 64% of intravenous and oral doses, respectively; < 1% of oral dose was excreted unchanged in urine. The absolute oral bioavailability of omapatrilat averaged 31%. Total body clearance of omapatrilat (80 L/h) exceeded liver plasma flow. Apparent steady-state volume of distribution of omapatrilat (21 L/kg) was extremely high compared with total body water. Omapatrilat undergoes substantial presystemic first-pass metabolism after oral administration. Omapatrilat is eliminated primarily by metabolism, and its metabolites are eliminated primarily in urine. Extrahepatic organs may be involved in the elimination of omapatrilat. Plasma concentrations of omapatrilat exhibit a prolonged terminal elimination phase, which represents elimination from a deep compartment.

Age and gender effects on the pharmacokinetics of gatifloxacin.

STUDY OBJECTIVE: To compare the pharmacokinetics and safety of gatifloxacin in elderly (> or = 65 yrs) and young (18-45 yrs) men and women. DESIGN: Open-label, parallel-group, single-dose study. SETTING: GFI Pharmaceutical Services Inc., Evansville, Indiana, USA. SUBJECTS: Forty-eight healthy subjects in four groups of 12 each. INTERVENTIONS: Subjects received single oral doses of gatifloxacin 400 mg. Serial blood and urine samples were collected for 96 hours after dosing to determine drug concentrations. MEASUREMENTS AND MAIN RESULTS: Age and gender had moderate effects on the pharmacokinetics of gatifloxacin. Elderly women had a 21% higher geometric mean peak plasma concentration (Cmax) and a 32% higher area under the plasma concentration-time curve (AUC0-infinity) than young women. Adjustment for creatinine clearance had only a slight effect on Cmax but reduced the estimated effect of age on AUC0-infinity in women from a 32% increase to a 15% increase. Gender effects on pharmacokinetic values were noted among elderly subjects only. Geometric means for Cmax and AUC0-infinity were 21% and 33% higher, respectively, for elderly women and elderly men. Adjustment for body weight reduced these differences to 11% and 20%, respectively. CONCLUSION: The effects of age on gatifloxacin pharmacokinetic values were largely attributed to declining renal function, whereas those of gender were largely attributed to differences in body weight. These modest age- and gender-related differences do not warrant dosage adjustment.

Feasibility of computer-assisted recognition of different dental hard tissues.

For pattern recognition, fuzzy set theory has been proven to be highly useful. The aim of the present investigation was to combine the fuzzy set with an ultrasonic scaler, to test its suitability for automatic detection of different tooth substances. An experienced operator placed the tip of a piezoceramic ultrasonic scaler on a tooth, thereby inducing oscillations in the contact area around the ultrasonic tip. Each surface showed a characteristic oscillatory behavior in the immediate vicinity of the tip. The oscillations were then re-transmitted to the scaler tip and recorded by the measurement of variations in current and voltage. Because the ultrasonic scaler is driven by piezoceramics, it can be used as both an oscillatory excitation and a sensor system. The data were processed with Fast Fourier transformation and analyzed by means of a fuzzy pattern recognition algorithm. Re-classification of the different measurements was carried out by the experienced operator's assessment. With a combination of six features (frequencies), re-classification was correct for 99% of all surfaces. The diagnostic reliability of the system was tested by the assessment of 50 teeth for which no learning data had previously been recorded. The unknown samples were correctly classified to 100%. The excellent results of these experiments suggest promising possibilities for the implementation of new diagnostic and therapeutic instruments in periodontology practice.

Distribution and prevalence of inducible nitric oxide synthase in atherosclerotic vessels of long-term cholesterol-fed rabbits.

The expression of inducible nitric oxide synthase (iNOS) as well as its functional activity has recently been reported in atherosclerotic lesions. The aim of the present study was to evaluate the expression of iNOS in various arteries of rabbits fed a long-term but low-level cholesterol-enriched diet which promotes different types of atherosclerotic lesions resembling human diseased vessels. No iNOS expression was revealed in arteries from control rabbits and in fatty streaks found in carotid and femoral arteries from hypercholesterolemic rabbits. In transitional lesions from the thoracic and abdominal aortas, the coronary and pulmonary arteries, a punctiform iNOS staining was detected in the intima. When lesions were more advanced, iNOS expression was found more intense and diffuse and localized in the subendothelial layer as well as in the media. Smooth muscle cell accumulation in intimal layers of the arteries is a marker of the degree of evolution of the atherosclerotic lesion; since we found a correlation between the smooth muscle cell infiltration in the intima and the iNOS expression in the intima and the subendothelial layer, our results suggest a link between the severity of the lesion and the iNOS expression.

Increased activity of guanylate cyclase in the atherosclerotic rabbit aorta: role of non-endothelial nitric oxide synthases.

1. Experiments were performed to examine the effects of putative non-endothelial nitric oxide on the soluble guanylate cyclase activity of severe atherosclerotic aortae from hypercholesterolaemic rabbits fed a cholesterol rich diet for 45 weeks. 2. The guanosine 3':5'-cyclic monophosphate (cyclic GMP) content of aortae from rabbits fed either a control diet or a diet containing 0.3% cholesterol for 45 weeks was quantified in saline extracts or in trichloracetic acid/either extracts by use of a competitive immunoenzymatic assay. Rabbit anti-cyclic GMP immunoglobulin G was covalently linked to the solid phase, in order to avoid false positive results due to high rabbit immunoglobulin G concentrations in the atherosclerotic saline extracts. 3. Saline extracts of atherosclerotic aortae which were harvested immediately after death (intact aortae) contained about 6 fold more cyclic GMP than control aortae when expressed in pmol cyclic GMP mg-1 protein. The cyclic GMP concentrations in trichloracetic acid/ether extracts of atherosclerotic and control aortae expressed in pmol mg-1 fresh tissue were not significantly different. 4. Neointimal-medial explants from atherosclerotic and control aortae were placed in a physiological saline solution and incubated at 37 degrees C for six hours in an incubator gassed with 5% CO2. Before the incubation, the cyclic GMP concentrations in saline extracts of atherosclerotic explants (0.74 +/- 0.27 pmol mg-1) were found to be 17 fold higher than those of control explants (0.043 +/- 0.008 pmol mg-1). The cyclic GMP content of control explants decreased significantly after 6 h of incubation, while that of atherosclerotic explants remained elevated. 5. Chronic administration of NG-nitro-L-arginine methyl ester, a non selective inhibitor of nitric oxide synthases, at 12 mg kg-1 day-1 subcutaneously for one month did not reduce the cyclic GMP concentration of intact atherosclerotic aortae, while that of intact aortae from control rabbits decreased by 63.4 +/- 7.6%. 6. These data show that atherosclerotic aortae harvested immediately after death from hypercholesterolaemic rabbits contain higher concentrations of cyclic GMP than control aortae when measured in saline extracts. In vitro, the persistence of the cyclic GMP production in atherosclerotic neointimal medial explants suggests that the guanylate cyclase is activated by an endogenous mediator. This mediator could be NO, synthesized by non endothelial nitric oxide synthases. The results confirm our previous findings on atherosclerotic blood vessel reactivity, but further studies are needed to elucidate why treatment with NG-nitro-L-arginine methyl ester did not decrease the cyclic GMP content of atherosclerotic rabbit aortae.

Single- and multiple-dose pharmacokinetics of nefazodone in patients with hepatic cirrhosis.

OBJECTIVE: To compare the single- and multiple-dose pharmacokinetics of nefazodone and its three pharmacologically active metabolites, hydroxynefazodone, m-chlorophenylpiperazine, and triazoledione, in patients with biopsy-proven cirrhosis and age-, sex-, and weight-matched healthy volunteers. METHODS: Subjects received a single 100 mg dose of nefazodone on day 1 followed by 100 mg nefazodone every 12 hours on days 3 through 10. Serial blood samples were collected on days 1 and 10; blood samples for trough levels were also collected just before the morning doses on days 7, 8, and 9. Plasma samples were assayed for nefazodone and its metabolites by validated chromatographic methods. RESULTS: The blood samples for trough levels indicated that, regardless of hepatic function, steady state for nefazodone and its metabolites was achieved by the fourth day of every-12-hour dosing. Subjects with liver cirrhosis had about a two-fold greater systemic exposure to nefazodone and hydroxynefazodone compared with normal subjects after a single dose of nefazodone, the difference decreasing to approximately 25% at steady state. Exposure to m-chlorophenylpiperazine was twofold to threefold greater and exposure to triazoledione was similar in patients with cirrhosis after a single dose of nefazodone and at steady state. There were no serious or unexpected adverse events observed in this study. CONCLUSIONS: These findings indicate that, although no untoward accumulation is anticipated compared with patients with normal hepatic function, patients with hepatic impairment may be exposed to higher concentrations of nefazodone and its metabolites than would subjects with normal hepatic function. Consequently, a lower daily dose of nefazodone should be considered when treating patients with impairment of hepatic function.

Outpatient sedation for oral surgery: a comparison of butorphanol and fentanyl.

Third molar surgery in the oral and maxillofacial surgery office has been a predictable model for evaluating the efficacy of sedatives and analgesics. In this setting, butorphanol plus diazepam and fentanyl plus diazepam were compared for surgical effectiveness and postoperative recovery. The comparison of butorphanol to a known sedative combination was clinically very satisfactory. It appears from this data that butorphanol has a pharmacologic place in outpatient conscious sedation.

Therapeutic efficacy of cefadroxil and cephalexin for pneumonia in a rat test model.

The therapeutic efficacies of cefadroxil and cephalexin were compared in a Streptococcus pyogenes-induced lung infection in rats. Although MICs, rates of in vitro killing in rat serum, and antibiotic serum levels after oral administration were similar for both drugs, cefadroxil was about eight times more effective than cephalexin in reducing the number of viable streptococci at the site of infection. This excellent in vivo bactericidal activity of cefadroxil in lung tissue and bronchial secretions was reflected in the 50% protective dose (PD50) after single or multiple oral treatments. A single treatment given 24 h after infection resulted in a PD50 of 2.8 mg of cefadroxil per kg, compared with 21 mg of cephalexin per kg. When treatment was administered three times, at 24, 27, and 30 h postinfection, the PD50s of cefadroxil and cephalexin were 0.7 and 8.0 mg/kg, respectively. In infected animals, treated 24 h postinfection, the area under the lung tissue concentration versus time curve for cefadroxil was significantly greater than that of cephalexin. This difference in pharmacokinetic behavior may account, at least in part, for the superior therapeutic results obtained with cefadroxil in this experimental pulmonary infection.

Immunogenicity of wild and attenuated varicella-zoster virus strains in rhesus monkeys.

Thirty susceptible rhesus monkeys were inoculated with cell-free varicella-zoster virus strain OKA or strain KMcC. Both wild and attenuated strains were used. No clinical signs characteristic of human varicella were seen in any of the animals. Virus was not isolated from throat swabs, blood, or cerebrospinal fluid. Antibodies were measured by an enhanced plaque neutralization test. The wild and attenuated OKA strains produced comparable levels of antibodies for 3 months after inoculation. Attenuated KMcC strains produced lower titers than the wild strain. On rechallenge 3 months after primary inoculation animals boostered with the attenuated OKA strain developed significantly higher antibody titers than animals receiving the wild strain. Animals primed and challenged with the attenuated KMcC strains showed significantly lower antibody titers than animals which received the wild strain. The results indicate that the immunogenicity of attenuated OKA and KMcC strains in rhesus monkeys parallels the experience obtained with these strains in humans.