Prospective randomized controlled trial comparing treatment efficacy and tolerance of picosecond alexandrite laser with a diffractive lens array and triple combination cream in female asian patients with melasma.

BACKGROUND: Recent evidence suggests melasma to be a photoaging disorder. Triple combination creams (TCC: fluocinolone acetonide 0.01%, hydroquinone 4% and tretinoin 0.05%) remain the gold standard treatment. Picosecond alexandrite laser treatment using a diffractive lens array (DLA) has been identified to be effective for improving photoaging conditions. OBJECTIVE: We aimed to compare the efficacy and tolerance of the picosecond alexandrite laser with those of DLA and TCC in female Asian patients with melasma. METHODS: Twenty-nine patients were randomly assigned to group A1 (3 laser sessions at 4-week intervals), A2 (5 laser sessions at 4-week intervals) or B (TCC daily for at least 8 weeks and then tapered until the final evaluation). The Melasma Area, Severity Index (MASI) score and VISIA were assessed at baseline, week 12 and week 20. By week 20, the follow-up periods for groups A1 and A2 were 3 months and 1 month, respectively. RESULTS: Nine, 11 and 6 participants in groups A1, A2 and B completed the study, respectively. MASI scores were significantly improved in all 3 groups at weeks 12 and 20. In groups A1, A2 and B, the improvement rates at week 20 were 53%, 38% and 50%, respectively. VISIA® analysis additionally revealed a significant improvement in spots, porphyria, pores and brown spots after 3 laser sessions (P < 0.05). Group A2 showed greater improvements than group A1 in terms of spots, wrinkles and pores; however, only red areas were significantly different (P < 0.001). All side-effects in the 3 groups were transient and gradually subsided after 1-3 months. CONCLUSION: Picosecond alexandrite laser treatment using DLA showed comparable efficacy with TCC for the treatment of melasma. Improvements in texture, spots, wrinkles and pores were observed in the laser groups. Patients with melasma lesions that exhibit telangiectasia may benefit from additional laser treatment sessions.

Effects of celecoxib in human retinoblastoma cell lines and in a transgenic murine model of retinoblastoma.

BACKGROUND/AIM: Celecoxib, a cyclooxygenase-2 inhibitor and antiangiogenic agent, has demonstrated potent anticancer effects in preclinical studies and in human clinical trials. To evaluate the potential utility of this agent in the treatment of retinoblastoma, the authors investigated the effects of celecoxib in retinoblastoma cell lines and in a murine model of this disease. METHODS: Growth inhibitory effects of celecoxib were evaluated in Y79 and Weri-RB1 human retinoblastoma cell lines by WST-1 cell proliferation assay. For animal study, two groups of 24, 8 week old LHbeta-TAg transgenic mice were treated with celecoxib (250 mg/kg, orally once a day) or vehicle control, 5 days/week for 6 weeks. Mice were sacrificed on day 43. Enucleated eyes were serially sectioned and ocular tumour burden was quantified by histopathological analysis. RESULTS: Celecoxib did not inhibit proliferation of Y79 or Weri-RB1 cells, even at concentrations far exceeding clinically achievable levels. No significant difference in ocular tumour burden between celecoxib treated and control mice (p=0.73) was found. CONCLUSION: Celecoxib was ineffective at inhibiting proliferation of retinoblastoma cells in vitro and was ineffective at controlling retinoblastoma tumour growth in a murine model of this disease. On the basis of these findings, oral celecoxib therapy is unlikely to have clinical utility in the treatment of retinoblastoma.

Pharmacokinetics of nitroglycerin and its dinitrate metabolites over a thirtyfold range of oral doses.

The pharmacokinetics of nitroglycerin and the formation of its dinitrate metabolites (1,2-glyceryl dinitrate and 1,3-glyceryl dinitrate) were determined in six healthy volunteers after administration of six oral solution doses ranging from 0.4 mg to 13 mg. ANOVA analysis indicated significant differences between subjects for all Cmax/dose and AUC/dose measurements. No significant difference between doses were noted for these parameters except for AUC/dose for 1,3-glyceryl dinitrate. The ratio of metabolites (1,2-metabolite/1,3-metabolite) for the 0.4 mg dose was significantly different from the ratios for the doses of 1.6 mg or higher. Measurements of the combined residence time parameter suggest nonlinearity in nitroglycerin absorption and metabolism processes of AUMC/AUC between the 0.4 and the 13 mg doses. Consistent results were observed in the AUC ratios of metabolites for 0.4 mg doses of nitroglycerin between oral and sublingual administrations, suggesting that the increased metabolite ratio noted for sublingual nitroglycerin may reflect differences in dose, rather than differences in route of administration.

Oral triamterene disposition.

Earlier studies of triamterene (T) disposition in man have reported hydroxytriamterene (T-OH) and hydroxytriamterene sulfate (T-O-SO3H) conjugate to be the major metabolites. We describe T kinetics through use of an HPLC method and confirm that after hydroxylation, T is rapidly converted to T-O-SO3H. The intermediate T-OH metabolite could not be detected in urine or plasma. Plasma concentrations of T-O-SO3H exceeded those of T by sevenfold to 26-fold, whereas concentrations of that metabolite in the urine were fourfold to thirteenfold higher than those of the parent. Renal clearance of T was 314.5 +/- 121.6 ml/min, exceeding that of the metabolite, which was 206.1 +/- 93.6 ml/min. Coadministration of hydrochlorothiazide increased urine flow and urinary pH, but it did not affect renal clearance of the parent drug or the metabolite. T bioavailability from capsules was poorer and more variable than that from a suspension. Hydrochlorothiazide did not influence the bioavailability of T.

Effect of cimetidine or ranitidine administration on nifedipine pharmacokinetics and pharmacodynamics.

The effect of cimetidine or ranitidine administration on responses to single and multiple doses of nifedipine were studied in 11 subjects who received cimetidine (300 mg q.i.d.) and 12 who received ranitidine (150 mg b.i.d.) in combination with nifedipine. After single doses of nifedipine, cimetidine decreased apparent oral clearance (dose/AUC) from 66 +/- 32 L/hr to 33 +/- 14 L/hr (p less than 0.01); elimination half-life increased from 4.0 +/- 2.2 to 4.9 +/- 2.9 hours (p less than 0.07). Increases in heart rate were greater (26 +/- 13 vs 13 +/- 11 beats/min standing; 19 +/- 11 vs 9 +/- 9 beats/min supine) and lasted longer than after nifedipine alone. Hypotensive effects were similar (10 +/- 7 mm Hg decrease vs 9 +/- 9 mm Hg). During nifedipine multiple-dose administration, cimetidine decreased the apparent oral clearance from 76 +/- 39 to 43 +/- 20 L/hr (p less than 0.01). Blood pressure responses were not altered by cimetidine but heart rate increased more (18 +/- 9 vs 9 +/- 9 beats/min supine; 18 +/- 13 vs 13 +/- 14 beats/min standing). Ranitidine coadministration did not alter nifedipine elimination or dynamic responses. During administration of nifedipine alone, the ratio of oral clearances (multiple to single doses) was 1.1 +/- 0.5. Thus (1) cimetidine but not ranitidine alters responses to nifedipine and (2) nifedipine kinetics do not differ between single- vs multiple-dose conditions.

Cefamandole kinetics in uremic patients undergoing hemodialysis.

A single intravenous 15 mg/kg dose of cefamandole was given to 6 patients in chronic renal failure before hemodialysis, and 3 were examined during an interdialysis period. Mean cefamandole clearance by hemodialysis was 24 +/- 12 ml/min; 35 +/- 15% of the dose was recovered in the dialysate. The cefamandole half-life (1 1/2) on dialysis was 4.0 +/- 0.29 hr; off dialysis it was 13.9 +/- 4.2 hr. High urine concentrations of cefamandole in these patients suggests usefulness in urinary tract infection.

Propranolol disposition in Chinese subjects of different CYP2D6 genotypes.

Propranolol pharmacokinetics among different genotypes of CYP2D6 was compared in this study. The Chinese (Han) population consisted of 44 healthy unrelated individuals living in southern Taiwan. Endonuclease tests based on polymerase chain reaction were used to determine C/T188 genotypes of CYP2D6 in leukocyte deoxyribonucleic acid. Based on codon 188 genotypes, subjects were categorized into three groups: homozygous C/C188 (n = 13), heterozygous C/T188 (n = 14); and homozygous T/T188 (n = 17). Each subject was given a 40 mg propranolol tablet. Blood samples were drawn before and 12 hours after propranolol administration to measure propranolol and 4-hydroxypropranolol. Three genotypes showed distinct time profiles of plasma propranolol and 4-hydroxypropranolol. The area under plasma concentration curve values (mean +/- SEM), were 322.0 +/- 40.8, 481.6 +/- 77.5, and 766.1 +/- 92.8 nmol.hr/L, respectively, for C/C188, C/T188, and T/T188 subjects (p < 0.05). The 48-hour excreted amount of 4-hydroxy-S-propranolol-O-glucuronide, but not 4-hydroxy-R-propranolol-O-glucuronide, was significantly higher for C/C188 than for T/T188 subjects (p < 0.05). This study shows a different propranolol disposition in Chinese subjects of different CYP2D6 genotypes.

Renal excretion of pseudoephedrine.

A patient with renal acidosis developed unanticipated toxicity after ordinary doses of pseudoephedrine, prompting us to study renal determinants of its elimination. We presumed that our patient accumulated the drug because of her persistently alkaline urine, which would favor tubular resorption of this weak base (pKa = 9.4). We studied normal adults and children and one adult and one child with renal tubular acidosis. Increasing urine pH increased the serum elimination half-life from 1.9 to 21 hr. While urinary pH remained alkaline, renal excretion of pseudoephedrine and its metabolite, norpseudoephedrine, was directly correlated with the flow rate of urine in each subject. Both urine pH and flow are important determinants of the elimination of pseudoephedrine in man and could be critical determinants of unanticipated toxicity.

Amdinocillin pharmacokinetics. Simultaneous administration with cephalothin and cerebrospinal fluid penetration.

In the treatment of serious infections, combinations of beta-lactam antibiotics are being utilized in order to avoid aminoglycoside toxicity and to achieve antibacterial synergy. The pharmacokinetic disposition of amdinocillin and cephalothin was determined, when administered alone or in combination to healthy volunteers, as well as the penetration of amdinocillin into human cerebrospinal fluid. Six subjects received, on separate occasions, single intravenous doses of amdinocillin 10 mg/kg, cephalothin 15 mg/kg, or a combination of the two in the same doses. The elimination half-lives of amdinocillin and cephalothin are increased when these drugs are given simultaneously, compared with when they are administered alone. However, no significant differences were observed. When they were given in combination, no significant changes in plasma clearance, renal clearance, or steady-state volume of distribution were found. Eight patients undergoing lumbar puncture for various neurologic disorders without inflamed meninges received a single dose of 10 mg/kg amdinocillin intravenously. One to two hours later, simultaneous plasma and cerebrospinal fluid samples were obtained. The concentration of amdinocillin in the cerebrospinal fluid ranged from approximately 1 to 10 percent of concomitant plasma concentrations. Thus, amdinocillin penetrates in the cerebrospinal fluid in marginal amounts in the absence of meningeal inflammation.

Bioequivalence study of a new tablet formulation of triamterene and hydrochlorothiazide.

A three-treatment, single-dose, crossover bioequivalence study was conducted in healthy volunteers to compare urinary drug recovery following administration of hydrochlorothiazide tablets, the currently marketed capsule formulation of triamterene and hydrochlorothiazide (Dyazide), and a new tablet preparation of these active ingredients (Maxzide). No significant differences were observed in the urinary recovery of hydrochlorothiazide after the administration of hydrochlorothiazide tablets and Maxzide tablets. However, only about one-half as much hydrochlorothiazide was recovered following the administration of Dyazide capsules. Similarly, the urinary recovery of triamterene and the sulfate ester of hydroxy-triamterene after administration of Dyazide capsules was approximately one-half the levels observed after giving the new tablet formulation. The clinical consequences of the limited bioavailability of the active ingredients of Dyazide are discussed.

Stereoselective binding of the glucuronide conjugates of carprofen enantiomers to human serum albumin.

The stereoselective binding of carprofen enantiomers and carprofen glucuronide diastereomers to human serum albumin (HSA) was studied using an ultrafiltration method. Carprofen glucuronides exhibit a considerable and stereoselective affinity to HSA, although less than that seen for the parent enantiomers. The (S)-glucuronide showed a higher binding affinity to HSA than the (R)-glucuronide. The (S)-enantiomer of unmetabolized carprofen was bound to fatty acid free HSA to a much greater extent than the (R)-enantiomer. Warfarin reduced the binding of the glucuronides to a greater extent than did diazepam, but diazepam displaced the unconjugated enantiomers to a greater extent than did warfarin. These results suggest differences in binding region between the carprofen enantiomers and their glucuronides on the albumin molecule.

First-time-in-humans safety and pharmacokinetics of WR 238605, a new antimalarial.

WR 238605 is an 8-aminoquinoline drug currently under development for prophylaxis and treatment of malaria. Preclinical studies have demonstrated that it has greater efficacy and less toxicity compared with primaquine. In this first-time-in-human randomized, double-blind, placebo-controlled study designed to evaluate the safety, tolerance and pharmacokinetics, WR 238605 was administered to 48 men in single oral doses ranging from four to 600 mg (base). It was well tolerated, with gastrointestinal disturbances as possible side effects. Linear kinetics were demonstrated at these doses. WR 238605 has a long absorption phase and is slowly metabolized, with a tmax of 12 hr and an elimination half-life of 14 days. These safety, efficacy and pharmacokinetic properties make this drug an excellent candidate for further testing as a prophylactic, radical curative, and terminal eradication drug.

Kidney function and age are both predictors of pharmacokinetics of metformin.

The effects of renal impairment and age on the pharmacokinetics of metformin were evaluated. The subjects, including 6 young, 12 elderly, and 3 middle-age healthy adults and 15 adults with various degrees of chronic renal impairment (CRI) each were given a single, 850-mg metformin HCl tablet. Multiple whole blood, plasma, and urine samples were collected and analyzed for metformin levels using a high-performance liquid chromatography (HPLC) method. In healthy elderly individuals, the plasma and whole blood clearance/absolute bioavailability values [CL/F and (CL/F)b], and corresponding renal clearance values (CLR and CLR,b) of metformin were 35-40% lower than the respective values in healthy young individuals. These two groups did not differ significantly with respect to volume of distribution (Vd), time to peak concentration (tmax), and parameters related to metformin's appearance in the urine. In the moderate and severe CRI groups, all clearance values were 74-78% lower than in the healthy young/middle-age group, and all other evaluable pharmacokinetic parameters (with the exception of tmax) differed significantly in this group. In the mild CRI group, clearance values of metformin, which were 23-33% lower than in the young/middle-age group, were the only parameters that differed significantly. Based on a regression analysis of the combined data, both creatinine clearance (CL*cr; corrected for body surface area) and age are predictors of metformin clearance, with the following model best fitting the data: CL/F [or (CL/F)b, CLR, CLR,b] = alpha + beta.CL*cr + gamma.CL*cr.age. Metformin should not be used in patients with moderate and severe CRI, or in patients with mild, but not absolutely stable, renal impairment. The initial and maximum doses in elderly patients and patients with stable mild CRI should be lowered to approximately one third that given to the general (i.e., patients without non-insulin-dependent diabetes) population.

Pharmacokinetics and pharmacodynamics of metformin in healthy subjects and patients with noninsulin-dependent diabetes mellitus.

This study was conducted to assess the effect of noninsulin-dependent diabetes mellitus (NIDDM) and gender on the pharmacokinetics of metformin and to investigate whether or not metformin exhibits dose-dependent pharmacokinetics. The pharmacodynamic effects (on plasma glucose and insulin) of metformin in patients with NIDDM and in healthy subjects also were assessed. Nine patients with NIDDM and 9 healthy subjects received 4 single-blind single-dose treatments of metformin HCL (850 mg, 1,700 mg, 2,550 mg, and placebo) and a multiple-dose treatment of 850 mg metformin HCL (3 times daily for 19 doses). After each single-dose treatment and the final dose of the multiple-dose phase, multiple plasma and urine samples were collected for 48 hours and assayed for metformin levels. Plasma samples were also assayed for glucose and insulin levels. There were no significant differences in metformin kinetics in patients with NIDDM compared with healthy subjects, in men compared with women, or during multiple-dose treatment versus single-dose treatment. Plasma concentrations of metformin increase less than proportionally to dose, most likely due to a decrease in percent absorbed. In patients with NIDDM, single doses of 1,700-mg or higher of metformin significantly decrease postprandial, but not preprandial, glucose concentrations and do not influence insulin concentrations. With multiple doses, both preprandial and postprandial glucose concentrations and preprandial insulin concentrations were significantly lower than with placebo. The effect of metformin on glucose level is correlated with the average fasting plasma glucose level without drug. In healthy subjects, single and multiple doses of metformin showed no effect on plasma glucose, but significantly attenuated the rise in immediate postprandial insulin levels.

Hydrochlorothiazide pharmacokinetics and pharmacologic effect: the influence of indomethacin.

It is known that nonsteroidal antiinflammatory drugs such as indomethacin can attenuate the pharmacologic effect of loop diuretics such as furosemide and ethacrynic acid and that indomethacin may also reduce the pharmacologic response to chlorothiazide. To examine further this potential drug-drug interaction, we administered 50- an 100-mg single oral doses of hydrochlorothiazide with and without indomethacin to 10 healthy, normal subjects. We observed no significant influence of indomethacin to 10 healthy, normal subjects. We observed no significant influence of indomethacin either on the pharmacokinetics of hydrochlorothiazide or the pharmacologic response to this diuretic. The adsorption and disposition of hydrochlorothiazide demonstrate that this drug is rapidly absorbed and produces a diuretic and natriuretic response that peaks at approximately 2 hours after dosing and is essentially terminated 12 hours after dosing. There appeared to be no greater pharmacologic response to the 100-mg than to the 50-mg hydrochlorothiazide dose in the ten subjects in this study.

Predictability of the covalent binding of acidic drugs in man.

Although metabolism via glucuronide conjugation has generally been considered a detoxification route for carboxylic acids, the newly discovered chemical reactivity of these conjugates, leading to covalent binding with proteins, is consistent with the toxicity observed for drugs containing the carboxylic acid moiety. Here we report that degradation rates (intramolecular rearrangement and hydrolysis) for 9 drug glucuronide metabolites show an excellent correlation (r2 = 0.995) with the extents of drug covalent binding to albumin in vitro. Furthermore, this binding capacity is predictable based on chemical structure of the acid and depends on the degree of substitution at the carbon alpha to the carboxylic acid. The in vivo covalent binding in humans for these drugs is also predictable (r2 = 0.873) when the extent of adduct formation is corrected for the measured plasma glucuronide concentrations. These results suggest that the structure of a carboxylic acid drug may predict the degree to which the corresponding acyl glucuronides will form covalent adducts that probably/possibly lead to toxicity. This information could be a useful adjunct in drug design.

Liquid chromatographic analysis of triamterene and its major metabolite, hydroxytriamterene sulfate, in blood, plasma, and urine.

The first rapid and highly sensitive high-performance liquid chromatographic (HPLC) assay for triamterene, hydroxytriamterene, and hydroxytriamterene sulfate is reported. Plasma samples were processed by protein precipitation, while urine was used untreated. Three different solvent systems were used to analyze (a) triamterene in plasma (30% acetonitrile, pH 4.0; internal standard: furosemide; sensitivity limit: 1 ng/mL); (b) hydroxytriamterene and hydroxytriamterene sulfate in plasma (12% acetonitrile, pH 5.5; internal standard: cefamandole; sensitivity limits: 20 and 2 ng/mL, respectively) and (c) triamterene, hydroxytriamterene, and hydroxytriamterene sulfate in urine (13% acetonitrile, pH 5.3; internal standard: hydroflumethiazide; sensitivity limits: 0.04 microgram/mL, 0.5 microgram/mL, and 0.1 microgram/mL, respectively). Fluorescence detection of compounds was performed at 365-nm excitation and 440-nm emission wavelengths. Recovery of triamterene and its metabolites from plasma was complete, and calibration curves were linear. Intraday variation was less than 6% except for the lowest plasma concentration. The assay procedure has already been used in several pharmacokinetic studies.

Ofloxacin in human serum, urine, and tear film after topical application.

We evaluated the systemic absorption of ofloxacin eyedrops in humans and their availability in the tear film. Serum, urine, and tear film concentrations of ofloxacin were measured in 30 healthy women topically treated with 0.3% ofloxacin, in both eyes, four times daily for 10 1/2 days. Serum was collected before the first daily dose on days 1 and 11 and at 18 time points before the second dose. Maximum serum ofloxacin concentrations (1.89 +/- 1.13 ng/ml) after 10 1/2 days of topical dosing were more than 1,000 times lower than those reported after standard oral doses of 300 mg ofloxacin. Urine was collected for the 24-h period after the first daily dose on days 1 and 10. Topical ofloxacin was excreted in the urine primarily in unmodified form and recovery rates were significantly higher on day 10 (76.1 +/- 41.5%) than on day 1 (56.6 +/- 31.6%) (p less than 0.05). Both serum and urine data give evidence to accumulations of ofloxacin over a 10 1/2-day period. The low serum concentration at steady state suggests an extremely low potential for producing systemic effects. No systemic side effects attributable to topical ofloxacin were observed. Mild ocular irritation was reported by two patients while under treatment. Tears were collected 4 h after the first treatment on day 11 and at 5, 10, 20, 30, and 40 min after the second treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Preliminary evaluation of furosemide-probenecid interaction in humans.

The pharmacokinetics and pharmacodynamics of intravenous furosemide, 40 mg, were studied in four healthy male subjects in a crossover fashion with and without probenecid pretreatment. In each study, 16 plasma and 10 urine samples were collected over 24 hr. Fluid and electrolyte urinary losses were replaced orally throughout the study. Unchanged furosemide and probenecid were measured using high-pressure liquid chromatography; urinary sodium was measured by flame photometry. Although probenecid caused marked changes in the pharmacokinetic parameters of furosemide (increased area under the curve, decreased plasma and renal clearance, increased half-life, and decreased fraction excreted unchanged in the urine), there was no significant difference in its gross 8-hr natriuretic and diuretic effect. However, analysis of the time course of natriuresis showed a pattern similar to that of the urinary furosemide excretion rate, whereas the plasma concentration was poorly correlated over the entire dose-response curve.

Relative bioavailability of chlorthalidone in humans: adverse influence of polyethylene glycol.

The bioavailability of two commercial preparations of chlorthalidone was studied in healthy male subjects. Reference solutions/suspensions for the two products were chlorthalidone dissolved in a solution of water-polyethylene glycol and a solution/suspension of chlorthalidone. Bioavailability of the chlorthalidone in water-polyethylene glycol solution was significantly reduced in comparison to one of the commercial preparations, and trends in the data suggested that it was less well absorbed than either the chlorthalidone in water solution/suspension or the other commercial preparation of chlorthalidone. These data, together with previous reports indicating that polyethylene glycol may retard the absorption of some drugs in vitro, suggest that this compound should not be used to aid dissolution of drug in a reference standard for bioavailability investigations.