Search

Raspberry ketone (RK)-an aromatic compound found mostly in red raspberries ( Rubus idaeus ) is widely used as an over the counter product for weight loss. The present study was conducted to determine adverse effects associated with RK in obese and health-compromised obese mice. Two sets of experiments were conducted on normal obese and health-compromised obese mice treated with RK for a duration of 10 days. Obese conditions were induced by feeding mice a high fat diet for 10 weeks, while the health compromised obese mouse model was developed by a single intraperitoneal injection of a nontoxic dose of lipopolysaccharide (LPS) (6 mg/kg) to obese mice. Results showed that RK (165, 330, and 500 mg/kg) under obese as well as health-compromised condition retarded the gain in body weights as compared to the control groups. RK at doses 330 and 500 mg/kg resulted in 67.6 and 50% mortality, respectively in normal obese mice and 70% mortality was observed in health-compromised obese mice treated with RK at 500 mg/kg. At higher doses deaths were observed earlier than those given lower doses of RK. Significant elevations in blood alanine transaminase (ALT) were also observed with RK treatment in obese mice. Blood glucose levels were significantly elevated in all groups of mice treated with RK. This study suggests that higher doses of RK may cause adverse effects in health compromised conditions. Under these conditions, prolonged use of RK, especially in high doses, may pose a health hazard.

Raspberry ketone (RK; [4-(4-hydroxyphenyl)-2-butanone]) is used by the food and cosmetic industry as a flavoring agent. RK is also marketed as a dietary supplement for weight maintenance and appetite control. The purpose of the study was to characterize the acute feeding suppression with RK (64-640 mg/kg) by oral gavage in male and female C57BL/6J mice. Cumulative 24 h food intake was reduced at 200 mg/kg (24% feeding suppression) in males and reliably reduced at 640 mg/kg (49-77% feeding suppression). Feeding suppression was not associated with pica behavior over the range of doses or conditioned taste aversion. In a separate experiment, a single oral gavage of RK (640 mg/kg) resulted in approximate 43% mortality rate (6 out 14 male mice) within 2 days. Atrophy of white adipose tissue, splenic abnormalities, and thymus involution were noted after 2-4 days after oral gavage RK. Total white blood cell count, lymphocytes, monocytes, eosinophils were significantly lower, while mean red blood cells, hemoglobin, and hematocrit were significantly higher with RK treatment. Our findings indicated a dose-dependent feeding suppression with acute RK, but doses that reliable suppress food intake are associated with pathological changes., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Raspberry ketone (RK; [4-(4-hydroxyphenyl)-2-butanone]) is a popular nutraceutical used for weight management and appetite control. We sought to determine the physiological benefits of RK on the meal patterns and cardiovascular changes associated with an obesogenic diet. In addition, we explored whether the physiological benefits of RK promoted anxiety-related behaviors. Male and female C57BL/6J mice were administered a daily oral gavage of RK 200 mg/kg, RK 400 mg/kg, or vehicle for 14 days. Commencing with dosing, mice were placed on a high-fat diet (45% fat) or low-fat diet (10% fat). Our results indicated that RK 200 mg/kg had a differential influence on meal patterns in males and females. In contrast, RK 400 mg/kg reduced body weight gain, open-field total distance travelled, hemodynamic measures (i.e., reduced systolic blood pressure (BP), diastolic BP and mean BP), and increased nocturnal satiety ratios in males and females. In addition, RK 400 mg/kg increased neural activation in the nucleus of the solitary tract, compared with vehicle. RK actions were not influenced by diet, nor resulted in an anxiety-like phenotype. Our findings suggest that RK has dose-differential feeding and cardiovascular actions, which needs consideration as it is used as a nutraceutical for weight control for obesity., Competing Interests: The authors declare no conflict of interest.

Background: Nabumetone is biopharmaceutics classification system (BCS) class II drug, widely used in the treatment of osteoarthritis and rheumatoid arthritis. The most frequently reported adverse reactions for the drug involve disturbance in gastrointestinal tract, diarrhea, dyspepsia and abdominal pain. Microemulgel has advantages of microemulsion for improving solubility for hydrophobic drug. Patent literature had shown that the work for drug has been carried on spray chilling, enteric coated tablet, and topical formulation which gave an idea for present research work for the development of transdermal delivery., Objective: The objective of the present research work was to optimize transdermal microemulgel delivery for Nabumetone for the treatment of arthritis., Methods: Oil, surfactant and co-surfactant were selected based on solubility study of the drug. Gelling agents used were Carbopol 934 and HPMC K100M. Optimization was carried out using 32 factorial design. Characterization and evaluation were carried out for microemulsion and microemulsion based gel., Results: Field emission-scanning electron microscopy (FE-SEM) study of the microemulsion revealed globules of 50-200 nm size. Zeta potential -9.50 mV indicated good stability of microemulsion. Globule size measured by dynamic light scattering (zetasizer) was 160nm. Design expert gave optimized batch as F7 which contain 0.2% w/w drug, 4.3% w/w liquid paraffin, 0.71% w/w tween 80, 0.35% w/w propylene glycol, 0.124% w/w Carbopol 934, 0.187% w/w HPMC K100M and 11.68% w/w water. In-vitro diffusion study for F7 batch showed 99.16±2.10 % drug release through egg membrane and 99.15±2.73% drug release in ex-vivo study., Conclusion: Nabumetone microemulgel exhibiting good in-vitro and ex-vivo controlled drug release was optimized., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Methylethylketone (MEK) is widely used in industry, often in combination with other compounds. Although nontoxic, it can make other chemicals harmful. This study investigates the fate of MEK in rat blood, brain and urine as well as its hepatic metabolism following inhalation over 1 month (at 20, 200 or 1400 ppm). MEK did not significantly accumulate in the organism: blood concentrations were similar after six-hour or 1-month inhalation periods, and brain concentrations only increased slightly after 1 month's exposure. Urinary excretion, based on the major metabolites, 2,3-butanediols (± and meso forms), accounted for less than 2.4% of the amount inhaled. 2-Butanol, 3-hydroxy-2-butanone and MEK itself were only detectable in urine in the highest concentration conditions investigated, when metabolic saturation occurred. Although MEK exposure did not alter the total cytochrome P450 concentration, it induced activation of both CYP1A2 and CYP2E1 enzymes. In addition, the liver glutathione concentration (reduced and oxidized forms) decreased, as did glutathione S-transferase (GST) activity (at exposure levels over 200 ppm). These metabolic data could be useful for pharmacokinetic model development and/or verification and suggest the ability of MEK to influence the metabolism (and potentiate the toxicity) of other substances.

This study aimed to determine the antiobesity effects of raspberry ketone (RK), one of the major aromatic compounds contained in raspberry, and its underlying mechanisms. During adipogenesis of 3T3-L1 cells, RK (300 μM) significantly reduced lipid accumulation and downregulated the expression of CCAAT/enhancer-binding protein α (C/EBPα), peroxisome proliferation-activated receptor γ (PPARγ), fatty acid-binding protein 4 (FABP4), and fatty acid synthase (FAS). RK also reduced the expression of light chain 3B (LC3B), autophagy-related protein 12 (Atg12), sirtuin 1 (SIRT1), and phosphorylated-tuberous sclerosis complex 2 (TSC2), whereas it increased the level of p62 and phosphorylated-mammalian target of rapamycin (mTOR). Daily administration of RK decreased the body weight (ovariectomy [Ovx] + RK, 352.6 ± 5 vs Ovx, 386 ± 5.8 g; P < 0.05), fat mass (Ovx + RK, 3.2 ± 0.05 vs Ovx, 5.0 ± 0.4 g; P < 0.05), and fat cell size (Ovx + RK, 6.4 ± 0.6 vs Ovx, 11.1 ± 0.7 × 10 3 μm 2 ; P < 0.05) in Ovx-induced obesity in rats. The expression of PPARγ, C/EBPα, FAS, and FABP4 was significantly reduced in the Ovx + RK group compared with that in the Ovx group. Similar patterns were observed in autophagy-related proteins and endoplasmic reticulum stress proteins. These results suggest that RK inhibited lipid accumulation by regulating autophagy in 3T3-L1 cells and Ovx-induced obese rats.

Queensland fruit fly, Bactrocera tryoni (Froggatt), is the most significant pest of Australia's $9 billion horticulture industry. The sterile insect technique (SIT) and cue-lure (a synthetic analogue of raspberry ketone (RK))-based male annihilation technique (MAT) are two of the most effective management tools against this pest. However, combining these two approaches is considered incompatible as MAT kills sterile and 'wild' males indiscriminately. In the present study we tested the effect of pre-release feeding of B. tryoni on RK on their post-release survival and response to MAT in field cages and in a commercial orchard. In both settings, survival was higher for RK supplemented adults compared to control (i.e. RK denied) adults. A lower number of RK supplemented sterile males were recaptured in MAT baited traps in both the field cages and orchard trials compared to RK denied sterile males. The advantage of this novel "male replacement" approach (relatively selective mortality of wild males at lure-baited traps while simultaneously releasing sterile males) is increasing the ratio of sterile to wild males in the field population, with potential for reducing the number of sterile males to be released.

As the incidence of obesity continues to increase, identifying novel nutritional therapies to enhance weight loss are needed. Raspberry ketone (RK; 4-(4-hydroxyphenyl) butan-2-one) is a bioactive phytochemical that is marketed as a weight loss supplement in the United States, yet there is scant scientific evidence demonstrating that RK promotes weight loss. The aim of the current study was to investigate the effect of RK on accumulation of adipose mass, hepatic lipid storage, and levels of plasma adiponectin in mice fed a high-fat (HF) diet. Mice were individually housed and fed a HF control diet (45% kcal from fat) for two weeks to induce weight gain, then assigned to HF control, high-dose (1.74% wt/wt) raspberry ketone (HRK), low-dose (0.25% wt/wt) raspberry ketone (LRK), or a pair-fed group (PF) fed similar food intake to LRK mice. Following five weeks of feeding, mice fed LRK and HRK diets showed reduced food intake and body weight compared to mice maintained on control diet. When normalized to body weight, mice fed HRK diet exhibited decreased inguinal fat mass and increased liver mass compared to the control group. Hepatic steatosis was lowest in mice fed HRK diet, whereas LRK diet did not have an effect when compared to the PF group. Plasma adiponectin concentration was unaffected by RK and pair-feeding. Our findings demonstrate that RK supplementation has limited benefit to adipose loss beyond reducing energy intake in mice fed a high-fat diet. The present study supports the need for appropriate study design when validating weight-loss supplements.

Background: A correct therapeutic management of acne should include a maintenance therapy to prevent recurrences after discontinuing a successful treatment. The aim of this study is to investigate efficacy and safety of a 12-month maintenance treatment with a product, based on Retinsphere technology that combines retinol encapsulated in glycospheres and hydroxypinacolone retinoate (Biretix gel®), to control acne relapse after a treatment with oral isotretinoin (O.I.)., Methods: The study consisted of 2 phases: active treatment phase (AP) and maintenance phase (MP). In the AP, 40 consecutive patients with moderate facial acne were treated with O.I. until acne remission. Then, the patients entered in the MP and were treated with Biretix gel® once-daily for 12 months. The efficacy parameter was the relapse rate during MP., Results: Thirty-nine patients completed the study. Relapse appeared in 6 patients (15.38%). The new product with Retinsphere technology was well tolerated and none of the subjects complained of adverse events., Conclusions: Our findings seems to provide favorable evidence of the efficacy and the safety of this new product in the maintenance treatment after O.I. in patient with moderate acne. The efficacy is maintain for a period as long as a year after O.I. suspension.

In this open-label, laboratory-blinded, 2-way single dose study in 24 volunteers of both sexes we found that (1) nabumetone reaches mean Cmax ± SD of 0.56 ± 0.20 mg·L at mean tmax of 8.63 ± 7.05 hours, and mean area under the curve (AUC)last of 18.07 ± 7.19 h·mg·L; (2) there are no statistically significant differences between both sexes in pharmacokinetics of nabumetone; (3) 6-methoxy-2-naphthylacetic acid (6-MNA) reaches higher AUClast in men compared with women (mean ± SD, 721.23 ± 185.53 h·mg·L and 545.27 ± 97.69 h·mg·L, respectively; P = 0.013); (4) there is lower 6-MNA clearance in men (0.65 ± 0.22 L·h) in comparison with women (0.88 ± 0.18 L·h, P = 0.019), (5) intersubject variability of nabumetone and 6-MNA is between 35%-45% and 10%-30% for all assessed pharmacokinetics parameters (AUClast, Cmax, partial AUC values); (6) intrasubject variability (ISCV) for AUClast is low, 15.59% and 6.40% for nabumetone and 6-MNA, respectively, (7) ISCV for Cmax is 13.66% and 5.42% for nabumetone and 6-MNA, respectively. Nabumetone thus belongs to compounds with low to moderate ISCV and therefore this product is expected to produce consistent effects in clinical practice.

Dihydroaustrasulfone alcohol is the synthetic precursor of austrasulfone, which is a marine natural product, isolated from the Taiwanese soft coral Cladiella australis. Dihydroaustrasulfone alcohol has anti-inflammatory, neuroprotective, antitumor and anti-atherogenic properties. Although dihydroaustrasulfone alcohol has been shown to inhibit neointima formation, its effect on human vascular smooth muscle cells (VSMCs) has not been elucidated. We examined the effects and the mechanisms of action of dihydroaustrasulfone alcohol on proliferation, migration and phenotypic modulation of human aortic smooth muscle cells (HASMCs). Dihydroaustrasulfone alcohol significantly inhibited proliferation, DNA synthesis and migration of HASMCs, without inducing cell death. Dihydroaustrasulfone alcohol also inhibited platelet-derived growth factor (PDGF)-induced expression of cyclin-dependent kinases (CDK) 2, CDK4, cyclin D1 and cyclin E. In addition, dihydroaustrasulfone alcohol inhibited PDGF-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), whereas it had no effect on the phosphorylation of phosphatidylinositol 3-kinase (PI3K)/(Akt). Moreover, treatment with PD98059, a highly selective ERK inhibitor, blocked PDGF-induced upregulation of cyclin D1 and cyclin E and downregulation of p27kip1. Furthermore, dihydroaustrasulfone alcohol also inhibits VSMC synthetic phenotype formation induced by PDGF. For in vivo studies, dihydroaustrasulfone alcohol decreased smooth muscle cell proliferation in a rat model of restenosis induced by balloon injury. Immunohistochemical staining showed that dihydroaustrasulfone alcohol noticeably decreased the expression of proliferating cell nuclear antigen (PCNA) and altered VSMC phenotype from a synthetic to contractile state. Our findings provide important insights into the mechanisms underlying the vasoprotective actions of dihydroaustrasulfone alcohol and suggest that it may be a useful therapeutic agent for the treatment of vascular occlusive disease.

Aim: A fixed combination of 0.1% hydroxypinacolone retinoate (synthetic esther of 9-cis-retinoic acid), 1% retinol in glycospheres and 2% papain in glycospheres in aqueous gel has been recently introduced into the Italian market in order to reduce the incidence and severity of irritant contact dermatitis caused by topical retinoids, without compromising their efficacy. Primary objectives of this sponsor-free, pilot, open, multicenter study were to evaluate the efficacy and tolerability of this gel in patients with comedonal-papular, mild to moderate acne of the face., Methods: Ninety-eight Caucasian patients (28 males and 70 females), with an age ranging from 15 to 40 years, were treated with the gel once daily for 12 weeks. Acne severity and treatment efficacy were evaluated by means of the Global Acne Grading System (GAGS) and lesions count., Results: Ninety-four patients were considered evaluable. A 41% mean reduction in the GAGS score was observed; a 40.8% mean reduction of total lesions was recorded; 15.3% of patients experienced mild to moderate local side effects (dryness, peeling, erythema, burning). No patients stopped the treatment because of these side effects., Conclusion: This study, based on a high number of evaluable patients, demonstrates that this fixed combination is an effective and safe option for the treatment of comedonal-papular, mild to moderate acne of the face. A controlled clinical study is necessary to confirm these data.

Objective: To investigate the pathological changes of major organs in rats that have inhaled methyl ethyl ketone peroxide (MEKP) aerosol and to provide clues to the oxidative damage mechanism of MEKP., Methods: A total of 100 Sprague-Dawley rats (male-to-female ratio = 1:1) were randomly and equally divided into blank control group, solvent control group, and 50, 500, and 1000 mg/m(3) MEKP exposure groups to inhale clean air, solvent aerosol, or MEKP for 6 h per day, 5 d per week, for 13 weeks. A rat model of subchronic MEKP exposure was established. The clinical manifestations during exposure were recorded. The organ coefficients of the kidney, thymus, and testis were calculated. The histopathological changes of the lung, liver, and testis were observed by HE staining., Results: The male rats in 1000 mg/m(3) MEKP exposure group had significantly lower organ coefficients of the kidney and testis than those in blank control group, solvent control group, and 50 and 500 mg/m(3) MEKP exposure groups (P < 0.05). The rats in 1000 mg/m(3) MEKP exposure group had a significantly lower organ coefficient of the thymus than those in blank control group and solvent control group (P < 0.05). Some rats in 500 and 1000 mg/m3 MEKP exposure groups had significant damage to the lung, liver, and testis, which demonstrated a worsening trend as the dose increased. Pulmonary hyperinflation, hyperemia, bleeding, interstitial pneumonia, and even lung abscess were seen in the damaged lung. Nuclear enrichment, hepatocyte steatosis, and mild cellular edema in the portal area were seen in the damaged liver. Variable degeneration, necrosis, and dysplasia of spermatogenic cells and significant decrease in sperms in spermatogenic cells were seen in the damaged testis. The female rats in blank control group, solvent control group, and 50, 500, and 1000 mg/m(3) MEKP exposure groups showed no pathological changes in the ovary., Conclusion: Inhalation of MEKP aerosol can cause oxidative damage to the liver, lung, kidney, thymus, and testis in rats, particularly to the testis in male rats.

Nabumetone and dipyrone are non-acidic, nonsteroidal anti-inflammatory drugs. Both of them are known to have weak inhibitory effects of cyclooxygenases. Gastric side effects represent the most common adverse drug effects of the widely used nonsteroidal anti-inflammatory drugs. The gastric effects of these drugs may be comparable in experimental ulcer models. In the present study, the gastric ulcerogenic activity of nabumetone and dipyrone were investigated on stress- and diethyldithiocarbamate-induced experimental ulcer models by determining the ulcer index and gastric mucus secretion in rats. It was found that diethyldithiocarbamate increased both ulcer index and mucus secretion. Nabumetone inhibited dose-dependently the increase of diethyldithiocarbamate-induced mucus secretion. Dipyrone inhibited both stress- and diethyldithiocarbamate-induced ulcer index and mucus secretion. Nabumetone inhibited stress-induced ulcer index at 25-mg/kg dose but stimulated dose-dependently mucus secretion. These effects may be attributed to their non-acidic structures and weak inhibitory effects on gastric mucosal cyclooxygenases.

We examined (99m)Tc-exametazime brain blood flow single-photon emission computed tomography (SPECT) images using a spatial covariance analysis (SCA) approach to assess its diagnostic value in distinguishing dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). Voxel SCA was simultaneously applied to a set of preprocessed images (AD, n=40; DLB, n=26), generating a series of eigenimages representing common intercorrelated voxels in AD and DLB. Linear regression derived a spatial covariance pattern (SCP) that discriminated DLB from AD. To investigate the diagnostic value of the model SCP, the SCP was validated by applying it to a second, independent, AD and DLB cohort (AD, n=34; DLB, n=29). Mean SCP expressions differed between AD and DLB (F(1,64)=36.2, P<0.001) with good diagnostic accuracy (receiver operating characteristic (ROC) curve area 0.87, sensitivity 81%, specificity 88%). Forward application of the model SCP to the independent cohort revealed similar differences between groups (F(1,61)=38.4, P<0.001), also with good diagnostic accuracy (ROC 0.86, sensitivity 80%, specificity 80%). Multivariate analysis of blood flow SPECT data appears to be robust and shows good diagnostic accuracy in two independent cohorts for distinguishing DLB from AD.

Diclofenac suppository, a non-steroidal anti-inflammatory drug (NSAID), is used widely in rheumatoid arthritis (RA) patients with severe arthritic pain. As the binding percentage of diclofenac to serum proteins is high, its free (unbound) concentration after rectal administration is low. To increase temporarily the free concentration of diclofenac and to enhance its analgesic effect by inhibiting the protein binding of diclofenac, the analgesic effect of diclofenac was examined before and after the start of an inhibitor administration to RA patients with insufficient control of arthritic pain, and the protein binding capacity of diclofenac was evaluated. Binding experiments were performed by ultrafiltration, and arthritic pain was recorded by the face scale. Free fractions of diazepam and diclofenac were augmented by increasing 6-methoxy-2-naphthylacetic acid (6-MNA; the active metabolite of the NSAID nabumetone) concentrations. The free fraction of diazepam increased after the start of nabumetone administration to RA patients, and arthritic pain relief was observed. These results suggest that 6-MNA has an inhibitory effect on the protein binding of diclofenac and the free fraction of diazepam can be used to evaluate the binding capacity of diclofenac. It is considered that diclofenac suppository-nabumetone combination therapy and the method for protein binding monitoring by diazepam can positively benefit RA patients with insufficient control of arthritic pain., (Copyright © 2013 John Wiley & Sons, Ltd.)

Unlabelled: Methyl trans-styryl ketone is used as a synthetic flavoring agent and a fragrance additive in food and personal care products. Methyl trans-styryl ketone was nominated for study by the National Cancer Institute due to widespread human exposure as a flavoring and fragrance additive, positive results in the Ames/Salmonella assay and the mouse lymphoma L5178Y/tk+/- assay, and as a representative of the α,β-unsaturated ketone chemical class. Male and female F344/N rats and B6C3F1 mice received methyl trans-styryl ketone (98.6% pure) in feed for 3 months and dermally for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. Two-year studies were conducted to provide data for assessment of possible toxicity due to exposure to methyl trans-styryl ketone. The dermal route was chosen since this is the route for highest human exposure and due to studies demonstrating systemic exposure following dermal application to methyl trans-styryl ketone. 3-MONTH FEED STUDY IN RATS Groups of 10 male and 10 female rats were fed diets containing 0%, 0.025%, 0.05%, 0.1%, 0.2%, or 0.4% methyl trans-styryl ketone (equivalent to average daily doses of approximately 18, 36, 72, 145, or 290 mg methyl trans-styryl ketone/kg body weight to males and 19, 38, 77, 150, or 300 mg/kg to females) for 14 weeks. Groups of 10 male and 10 female clinical pathology rats were fed the same concentrations for 24 days. All core study rats survived to the end of the study. Final mean body weights of males and females receiving 0.4% and mean body weight gains of males receiving 0.4% were significantly less than those of the controls. Feed consumption by exposed groups was similar to that by the controls. Clinical findings included diarrhea and hyperactivity in males and females. Results of sperm motility and vaginal cytology evaluations indicated methyl trans-styryl ketone is unlikely to be a reproductive toxicant in male rats; however, it exhibits potential for reproductive toxicity in female rats based upon an increased probability of extended diestrus at the highest exposure concentration. In all exposed groups of males, there were treatment-related increased incidences of goblet cell hyperplasia of the respiratory epithelium of the nose and nephropathy of the kidney. In females, there was an increased incidence of goblet cell hyperplasia of the respiratory epithelium of the nose in the group receiving 0.4%. 3-MONTH FEED STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets containing 0%, 0.025%, 0.05%, 0.1%, 0.2%, or 0.4% methyl trans-styryl ketone (equivalent to average daily doses of approximately 55, 110, 220, 400, or 750 mg/kg to males and 50, 100, 200, 350, or 600 mg/kg to females) for 14 weeks. One male receiving 0.2% and one control female died before the end of the study. Mean body weights of males and females receiving 0.4% were significantly less than those of the controls. Feed consumption by exposed groups was similar to that by the controls. Hyperactivity in both sexes was the only clinical finding. Results of sperm motility and vaginal cytology evaluations indicated methyl trans-styryl ketone is unlikely to be a reproductive toxicant in male mice; however, it exhibits potential for reproductive toxicity in female mice based upon an increased probability of extended diestrus at the lowest and the highest exposure concentrations. There were significantly increased incidences of olfactory epithelial atrophy of the nose in males and females receiving 0.4%. 3-MONTH DERMAL STUDY IN RATS: Groups of 10 male and 10 female rats were dermally administered 0, 22, 44, 87.5, 175, or 350 mg methyl trans-styryl ketone/kg body weight in 95% ethanol, 5 days per week for 14 weeks. Groups of 10 male and 10 female clinical pathology rats were administered the same doses for 23 days. All rats survived to the end of the study. Mean body weights of 175 and 350 mg/kg males were significantly less than that of the vehicle controls. Clinical findings in groups administered 175 or 350 mg/kg included dermal irritation, thickened skin, and ulceration at the site of application. Results of sperm motility and vaginal cytology evaluations indicated methyl trans-styryl ketone is unlikely to be a reproductive toxicant in male or female rats at the doses used in this study. Histologically, there were significantly increased incidences of epidermal hyperplasia, hyperkeratosis, chronic active inflammation, epidermal necrosis, and sebaceous gland hypertrophy in the skin at the site of application in males and/or females. There were significantly increased incidences of goblet cell hyperplasia of the nose in 350 mg/kg males and 22, 175, and 350 mg/kg females. 3-MONTH DERMAL STUDY IN MICE Groups of 10 male and 10 female mice were dermally administered 0, 87.5, 175, 350, 700, or 1,400 mg methyl trans-styryl ketone/kg body weight in 95% ethanol, 5 days per week for 13 weeks. All mice in the 700 and 1,400 mg/kg groups were sacrificed moribund before the end of the study. The final mean body weights of surviving groups of dosed males and females were similar to those of the vehicle controls; however, the mean body weight gains of the 175 mg/kg groups were significantly less than those of the vehicle controls. Clinical findings at the site of application included dermal irritation in 350 mg/kg males and crust formation in all 700 and 1,400 mg/kg mice except one female. Results of sperm motility and vaginal cytology evaluations indicated methyl trans-styryl ketone is unlikely to be a reproductive toxicant in male or female mice at the doses used in this study. There were treatment-related increased incidences of epidermal hyperplasia, hyperkeratosis, chronic active inflammation, epidermal necrosis, sebaceous gland hypertrophy, and hair follicle hyperplasia in the skin at the site of application in males and females. There were increased incidences of olfactory epithelial atrophy of the nose in groups of males and females administered 350 mg/kg or greater. 2-YEAR DERMAL STUDY IN RATS: Groups of 50 male and 50 female rats were dermally administered 0, 10, 30, or 90 mg methyl trans-styryl ketone/kg body weight in 95% ethanol, 5 days per week for 105 weeks. Survival of all dosed groups was similar to that of the vehicle controls. Mean body weights of dosed groups were within 10% of those of the vehicle control groups throughout the study. In the skin at the site of application, there were increased incidences of epidermal hyperplasia and hyperkeratosis in males and females administered 30 or 90 mg/kg. 2-YEAR DERMAL STUDY IN MICE: Groups of 50 male and 50 female mice were dermally administered 0, 10, 30, or 90 mg methyl trans-styryl ketone/kg body weight in 95% ethanol, 5 days per week for 105 weeks. Survival of all dosed groups was similar to that of the vehicle controls. Mean body weights of dosed groups were within 10% of those of the vehicle control groups throughout the study. In the skin at the site of application in males and females, there were treatment-related increased incidences of epidermal hyperplasia, hyperkeratosis, chronic inflammation, and melanocyte hyperplasia., Genetic Toxicology: Methyl trans-styryl ketone was mutagenic in Salmonella typhimurium strain TA100 when testing was conducted in the presence of rat liver microsomes (S9). No mutagenic activity was seen with methyl trans-styryl ketone in strain TA98 with or without S9 or in Escherichia coli strain WP2 uvrA/pKM101 in the absence of S9. With S9, inconsistent responses were seen in the E. coli tester strain. No increases in the frequencies of micronucleated normochromatic erythrocytes were seen in peripheral blood samples from male or female mice administered methyl trans-styryl ketone for 3 months via dosed feed or dermal application., Conclusions: Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity of methyl trans-styryl ketone in male or female F344/N rats or in male or female B6C3F1 mice administered 10, 30, or 90 mg/kg. Administration of methyl trans-styryl ketone resulted in nonneoplastic lesions of the skin at the site of application in male and female rats and mice. Synonyms: Acetocinnamone; benzalacetone; benzylideneacetone; methyl 2-phenylvinyl ketone; methyl styryl ketone; methyl β-styryl ketone; MSK; 4-phenyl-3-butene-2-one; 4-phenylbutenone; 2-phenylvinyl methyl ketone; styryl methyl ketone Systematic name: (3E)-4-Phenylbut-3-en-2-one.

Enhancement of glucose utilization in the brain has been well known during acute seizure in various kinds of animal model of epilepsy. This enhancement of glucose utilization might be related to neural damage in these animal models. Recently, we found that methyl ethyl ketone (MEK) had both anticonvulsive and neuroprotective effects in lithium-pilocapine (Li-pilo) status epilepticus (SE) rat. In this article, we measured the uptake of [(14)C]2-deoxyglucose ([(14)C]DG) in the Li-pilo SE and Li-pilo SE with MEK rat brain in order to assess whether the glucose utilization was a useful biomarker for the detection of efficacy of anticonvulsive compounds. Significant increase of [(14)C]DG uptake (45 min after the injection) in the cerebral cortex, hippocampus, amygdala and thalamus during acute seizure induced by Li-pilo were observed. On the other hand, the initial uptake of [(14)C]DG (1 min after the injection) in the Li-pilo SE rats was not different from the control rats. Therefore, the enhancement of glucose metabolism during acute seizure was due to the facilitation of the rate of phosphorylation process of [(14)C]DG in the brain. Pretreatment with MEK (8 mmol/kg) completely abolished the enhancement of glucose utilization in the Li-pilo SE rats. The present results indicated that glucose utilization in the brain during acute seizure might be a useful biomarker for the evaluation of efficacy of anticonvulsive compounds.

Background: Nabumetone is a non-steroidal anti-inflammatory drug (NSAID) used mainly in treating pain associated with arthritis. The usual oral dose for osteoarthritis is 1000 mg daily, and higher doses are not advised in older patients. There are no known systematic reviews of its analgesic efficacy in acute postoperative pain. This review sought to evaluate the efficacy and safety of oral nabumetone in acute postoperative pain, using clinical studies of patients with established pain, and with outcomes measured primarily over 6 hours using standard methods. This type of study has been used for many decades to establish whether drugs have analgesic properties., Objectives: To assess the efficacy of single dose oral nabumetone in acute postoperative pain, and any associated adverse events., Search Strategy: We searched The Cochrane Library (Issue 2, 2009), MEDLINE (May 2009); EMBASE via Ovid (May 2009); and the Oxford Pain Relief Database., Selection Criteria: Randomised, double-blind, placebo-controlled clinical trials of oral nabumetone for relief of acute postoperative pain in adults., Data Collection and Analysis: Two review authors independently assessed trial quality and extracted data. The area under the "pain relief versus time" curve was used to derive the proportion of participants with nabumetone and placebo experiencing at least 50% pain relief over 4 to 6 hours, using validated equations. The number needed to treat to benefit (NNT) was calculated using 95% confidence intervals (CI). The proportion of participants using rescue analgesia over a specified time period, and time to use of rescue analgesia, were sought as additional measures of efficacy. Information on adverse events and withdrawals was also collected., Main Results: No studies were identified by the searches that examined oral nabumetone in participants with established postoperative pain., Authors' Conclusions: In the absence of evidence of efficacy, at present, for oral nabumetone in acute postoperative pain, its use in this indication is not justified. Because trials clearly demonstrating analgesic efficacy in the most basic of acute pain studies is lacking, use in other indications should be evaluated carefully. Given the large number of available drugs of this and similar classes, there is no urgent research agenda.

Introduction: Aceclofenac, a NSAID is widely used in the treatment of pain and inflammation associated with osteoarthritis. Nabumetone, a recently developed preferential cyclo-oxygenase 2 inhibitor has also proved to be equally effective. The present study was undertaken to evaluate the 'real better' drug, amongst these with better efficacy and gastro-intestinal tolerability as well., Methods: Four hundred and twenty-three patients of either sex, aged 40-64 years with uncomplicated osteoarthritis of knee joint were randomly allocated into three equal groups receiving aceclofenac, nabumetone or placebo. A baseline pain measurement was done with Visual Analogue Scale (VAS: 0-10 scale) and Investigator Global Assessment of Disease status (IGADS: 0-4 point scale). Code was broken at the end of two weeks or earlier to eliminate any real fatal outcome. Final evaluation of efficacy was done at the end of four weeks. The significance of difference between the treatment outcomes was analyzed using one way ANOVA test., Results: During the active comparator controlled period, the most common reason for discontinuation was unacceptable adverse events. While 108 (76.6%) participants could take the full course of treatment with aceclofenac, 118 (83.7%) of the nabumetone group completed the study. Drop outs were highest in the placebo group (33.9%) followed by the aceclofenac group (12.1%) and nabumetone group (8.5%). Discontinuation due to G.I. intolerance was least in the placebo group (2.1%) followed by the nabumetone group (5%) and aceclofenac group (7.8%)., Conclusions: The preferential inhibition of cyclo-oxygenase 2 by nabumetone was postulated to afford better clinical efficacy and gastrointestinal tolerability in osteoarthritis as compared to aceclofenac.

Sensory neurons release calcitonin gene-related peptide (CGRP) on activation. We recently reported that topical application of capsaicin increases facial skin elasticity and promotes hair growth by increasing dermal insulin-like growth factor-I (IGF-I) production through activation of sensory neurons in mice and humans. Raspberry ketone (RK), a major aromatic compound contained in red raspberries (Rubus idaeus), has a structure similar to that of capsaicin. Thus, it is possible that RK activates sensory neurons, thereby increasing skin elasticity and promoting hair growth by increasing dermal IGF-I production. In the present study, we examined this possibility in mice and humans. RK, at concentrations higher than 1 microM, significantly increased CGRP release from dorsal root ganglion neurons (DRG) isolated from wild-type (WT) mice and this increase was completely reversed by capsazepine, an inhibitor of vanilloid receptor-1 activation. Topical application of 0.01% RK increased dermal IGF-I levels at 30 min after application in WT mice, but not in CGRP-knockout mice. Topical application of 0.01% RK increased immunohistochemical expression of IGF-I at dermal papillae in hair follicles and promoted hair re-growth in WT mice at 4 weeks after the application. When applied topically to the scalp and facial skin, 0.01% RK promoted hair growth in 50.0% of humans with alopecia (n=10) at 5 months after application and increased cheek skin elasticity at 2 weeks after application in 5 females (p<0.04). These observations strongly suggest that RK might increase dermal IGF-I production through sensory neuron activation, thereby promoting hair growth and increasing skin elasticity.

Background: Rofecoxib and nabumetone were developed to provide gastrointestinal benefits over traditional nonsteroidal antiinflammatory drugs (NSAIDs). However, there is limited comparative information relating to these 2 drugs., Objective: The objective of this study was to compare rofecoxib and nabumetone, at their lower, recommended doses, in patients with osteoarthritis (OA)., Methods: Nine hundred seventy-eight patients with knee OA and a positive history of NSAID response were randomized to 12.5 mg rofecoxib per day (N=390), nabumetone 500 mg twice a day (N=392), or placebo (N=196) for 6 weeks. The primary efficacy end point was percent of patients with a "good" or "excellent" Patient Global Assessment of Response to Therapy (PGART) at week 6; PGART was also evaluated over days 1 to 6. Additional end points included investigator assessment of response, pain walking over 6 days and 6 weeks, joint tenderness, discontinuation as a result of lack of efficacy, and quality of life. Adverse experiences (AEs) were collected., Results: Significantly more rofecoxib (50.4%) than nabumetone (43.3%, P=0.043) or placebo (29.5%, P<0.001) patients had a good or excellent PGART at week 6. Median time to a good or excellent PGART was significantly shorter with rofecoxib (52 hours) than nabumetone (100 hours, P=0.001) or placebo (>124 hours, P<0.001). Results for rofecoxib and nabumetone were similar in all additional end points except pain in walking over 6 days and 6 weeks, in both of which the rofecoxib treatment group demonstrated better results. There were significantly (P<0.050) more overall and serious AEs and discontinuations resulting from AEs with rofecoxib than nabumetone. Five rofecoxib and one nabumetone patients had confirmed thrombotic cardiovascular events (P=0.123). Information on thrombotic cardiovascular events from this study was included in a published, prespecified pooled analysis and is included here for completeness., Conclusions: At their recommended starting doses for OA, both agents were more effective than placebo. Rofecoxib at a dosage of 12.5 mg demonstrated significantly better efficacy in PGART than 1000 mg nabumetone in these patients known to be NSAID responders. Significantly more AEs occurred with rofecoxib than nabumetone. Considering these data and other recent safety information regarding cyclooxygenase-2 selective and nonselective NSAIDS, physicians must make risk/benefit assessments for each individual patient when considering the use of these agents, as recommended by the U.S. Food and Drug Administration.

Prodrugs of non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for clinical purposes because they are not harmful to the gastrointestinal mucosa. We recently showed that NSAIDs have direct cytotoxicity in NSAID-induced gastric lesions. We show here that under conditions where the NSAIDs indomethacin and celecoxib clearly induce cell death, an NSAID prodrug, nabumetone, and its active metabolite 6-methoxy-2-naphthylacetic acid (6MNA), did not have such effects. Moreover, nabumetone and 6MNA exhibited much lower membrane permeabilizing activities than did indomethacin and celecoxib. We recently reported that when an orally administered NSAID was used in combination with a low dose of intravenously administered indomethacin, the severity of gastric lesions produced in rats depended on the cytotoxicity of the orally administered NSAID. Using a similar protocol, we show here that gastric lesions were produced when the orally administered NSAID was celecoxib, but not when nabumetone was used. We thus propose that the low direct cytotoxicity of nabumetone observed in vitro is maintained in vivo, and that the use of nabumetone does not harm the gastric mucosa.

Unlabelled: We compared onset of efficacy (during days 1 to 6) of 2 coxibs (rofecoxib, celecoxib) with acetaminophen and nabumetone by using a prespecified approach to data from 4 similarly designed 6-week randomized osteoarthritis trials. In 2 trials, rofecoxib (12.5 mg and 25 mg once daily) was compared with celecoxib (200 mg once daily) and acetaminophen (4000 mg daily). In the other 2 trials, rofecoxib (12.5 mg) was compared with nabumetone (1000 mg once daily) and placebo. Efficacy end points included Patient Global Response to Therapy and Western Ontario and McMaster Osteoarthritis Index scores. Rofecoxib (12.5- and 25-mg doses) consistently demonstrated a faster onset of osteoarthritis (OA) efficacy than the comparator drugs during the first 6 days of therapy of OA patients experiencing "flare." Acetaminophen resulted in the slowest onset of efficacy. There was a strong correlation (0.7) between efficacy response during days 1 to 6 and that averaged over 6 weeks. Rates of discontinuation as a result of lack of efficacy were significantly lower (P < .02) for each of the coxib-treated groups compared with acetaminophen and for rofecoxib 12.5 mg (P = .01) compared with nabumetone. Rofecoxib treatment, with its faster onset of OA efficacy and lower rates of related discontinuations, might provide efficacy advantages in the treatment of OA pain., Perspective: The efficacy of rofecoxib, celecoxib, nabumetone, and acetaminophen is established for the majority of OA patients within the first 6 days of therapy, and this predicts efficacy during the longer term. Rofecoxib provides significantly faster time to onset of efficacy and better improvement on multiple measures versus the comparators.

Objectives: To evaluate the use of starting doses of rofecoxib and nabumetone in patients with osteoarthritis (OA) of the knee., Design: A 6-week, randomized, parallel-group, double-blind, placebo-controlled study., Setting: One hundred thirteen outpatient sites in the United States., Participants: A total of 1,042 male and female patients aged 40 and older with OA of the knee (>6 months)., Interventions: Rofecoxib 12.5 mg once a day (n=424), nabumetone 1,000 mg once a day (n=410), or placebo (n=208) for 6 weeks., Measurements: The primary efficacy endpoint was patient global assessment of response to therapy (PGART) over 6 weeks, which was also specifically evaluated over the first 6 days. The main safety measure was adverse events during the 6 weeks of treatment., Results: The percentage of patients with a good or excellent response to therapy as assessed using PGART at Week 6 was significantly higher with rofecoxib (55.4%) than nabumetone (47.5%; P=.018) or placebo (26.7%; P<.001 vs rofecoxib or nabumetone). Median time to first report of a good or excellent PGART response was significantly shorter in patients treated with rofecoxib (2 days) than with nabumetone (4 days, P=.002) and placebo (>5 days, P<.001) (nabumetone vs placebo; P=.007). The safety profiles of rofecoxib and nabumetone were generally similar, including gastrointestinal, hypertensive, and renal adverse events., Conclusion: Rofecoxib 12.5 mg daily demonstrated better efficacy over 6 weeks of treatment and quicker onset of OA efficacy over the first 6 days than nabumetone 1,000 mg daily. Both therapies were generally well tolerated.

The synthesis and introduction of interleukin-1 receptor antagonists established a promising strategy in the treatment of inflammatory diseases. This kind of therapy is claimed now to be available for osteoarthritis and other orthopedic disorders also. In the case of "orthokin", the interleukin-1 receptor antagonist is produced by stimulation of own blood-cells. It is not possible, to evaluate the practicability of this therapeutic approach because there are no published experimental data. We also found no results of clinical studies, which would allow an estimation of the effectiveness and the risks of this method. Therefore treatment with "orthokin" cannot be recommended at present.

The developmental toxicity of methyl ethyl ketoxime (MEKO), an industrial antioxidant used primarily as an antiskinning agent in alkyd paint, was investigated in rats and rabbits. Following preliminary dose range finding studies, groups of 25 pregnant rats or 18 pregnant rabbits were dosed by gavage with aqueous solutions of MEKO at 0, 60, 200, or 600 mg/kg (rats) or 0, 8, 14, 24, or 40 mg/kg (rabbits) on gestation days 6-15 or 6-18, respectively. In rats, dose-dependent clinical signs of maternal toxicity including reduced body weight gains were noted at 200 and 600 mg/kg. At 60 mg/kg and above enlarged spleens were observed at necropsy. The preliminary study found methemoglobin formation and reticulocytosis indicative of anemia at these dose levels. No treatment-related gestational effects, malformations or developmental variations were observed in the rats. In rabbits, 3 females aborted and 8 females were found dead at 40 mg/kg between gestation days 11 and 24. Clinical signs of maternal toxicity were present in surviving doses at this dose level. Body weight gains were reduced at 24 and 40 mg/kg. The preliminary study indicated maternal hematological effects in the rabbits similar to the rats at dose levels as low as 10 mg/kg. MEKO was not considered to have produced any treatment-related gestational effects, malformations or developmental variations in the rabbit at dose levels at or below 24 mg/kg. Because of excessive maternal mortality and abortions at the 40 mg/kg dose level, only 6 rabbits produced litters. The severe maternal toxicity and limited number of litters precluded a full assessment of developmental toxicity at 40 mg/kg. Nonetheless, MEKO did not appear to be teratogenic to the rabbit at this dose level.

Aspirin and all nonsteroidal anti-inflammatory drugs (NSAIDs) are a chemically heterogeneous group of compounds that share the ability to inhibit the enzyme cyclooxygenase (COX). This inhibitory effect, especially of COX-1, is suggested as the mechanism underlying NSAID-induced hypersensitivity reactions. In this study, we evaluated the safety and convenience of a single full-dose challenge with nabumetone, a selective COX-2 inhibitor, in patients with hypersensitivity to nonselective NSAIDs (ns-NSAIDs). Twenty-four subjects with a history of hypersensitivity reactions to at least two different ns-NSAIDs on two different occasions were enrolled in the study. The patients were otherwise healthy and did not suffer from NSAID- or aspirin-induced asthma or urticaria. All subjects were orally challenged by a single full dose (1000 mg) of nabumetone, monitored closely in the hospital for the next 4 hours and contacted by telephone the next morning and 3-12 months afterward. Twenty-two patients tolerated nabumetone without any reaction during and after the challenge. One patient had a single urticarial lesion and one patient reported mild pruritus without objective signs, both of which resolved spontaneously. Thirteen patients, including the patient who responded with pruritus to the challenge, used nabumetone on several occasions during the follow-up period without any adverse reaction. Our study shows that in patients with a history of aspirin- and ns-NSAID-induced hypersensitivity reaction, a rapid one-step challenge with nabumetone was well tolerated. These initial data support the possibility that a single full dose of nabumetone can be tried as a safe alternative in most patients with a hypersensitivity reaction to ns-NSAIDs.

A simple and sensitive high performance liquid chromatography method for the determination of nabumetone in human plasma is described. The procedure involves liquid-liquid extraction with ethyl acetate and reversed-phase chromatography with fluorimetric detection (excitation 230 nm, emission 356 nm). The chromatographic conditions and the extraction procedure gave a clean chromatogram for the compound. The limit of quantitation was established as 0.313 ng/ml and the calibration curve was linear up to 20 ng/ml. The within-day and between-day relative standard deviations were less than 10% and the accuracy of the assay was in the range of 99-104%. The suitability of the method is shown for pharmacokinetic studies.

Objective: Once-a-day dosing with nabumetone has been shown to be effective in adults with rheumatoid arthritis. We establish dosing recommendations for nabumetone in children and adolescents with juvenile rheumatoid arthritis (JRA)., Methods: An open label, multicenter study was conducted in children with JRA aged 2-16 years, weighing > 14 kg, and requiring nonsteroidal antiinflammatory drugs (NSAID) for control of symptoms. NSAID were discontinued one day prior to study initiation to minimize disease flare. Patients received nabumetone 30 mg/kg once daily (as a tablet or a slurry) for 12 weeks. Efficacy assessment evaluations were performed at Weeks 1, 3, 6, and 12, based on the mean change from baseline at the study endpoint for 6 standard rheumatology variables. An overall assessment of efficacy was determined based on the percentage of patients who did not experience a flare, using the 6 rheumatology variables. Since this was an open label study, only descriptive statistics were obtained for efficacy variables. Routine safety assessments were completed for all patients., Results: In total, 99 patients with JRA were enrolled and 89 completed the study; mean age was 9.2 years. The proportion of nabumetone treated patients with no flare in disease activity during the nabumetone treatment period was 92/99 (93%). Improvement was noted in each efficacy assessment, although statistical evaluations were not performed. The adverse event profile was similar to that reported for nabumetone in adults with RA., Conclusion: Nabumetone 30 mg/kg/day (up to 2000 mg/day) demonstrated a safe profile with no loss of efficacy compared to previous treatment in children with JRA. The dose can be administered by suspending tablets in warm water to create a slurry.

Objectives: Animal studies demonstrate that the formation of the neurotoxic metabolite, 2,5-hexanedione (HD) decreases during co-exposure to methyl ethyl ketone (MEK). The aim of the present study was to describe the influence of co-exposure to MEK on n-hexane toxicokinetics in humans., Methods: Four healthy male volunteers were exposed, on different occasions, to three different combinations of vapor of these solvents, namely: 50 ppm n-hexane alone, and in combination with 100 and 200 ppm MEK, for 2 h during light physical exercise (50 W). Arterialized capillary blood, venous blood, and urine were sampled at scheduled intervals before, during, and up to 24 h after the onset of the exposure. HD in venous blood and urine was analyzed by gas chromatography with electron capture detector after derivatization with O-(pentafluorobenzyl) hydroxylamine., Results: Serum HD decreased with increasing exposure to MEK at 2 h after the onset of the exposure, from an average concentration of 2.2 micromol/l in the n-hexane-alone condition to 1.2 and 0.44 micromol/l in the 100 and 200-ppm MEK conditions, respectively. The area under the concentration-time curve of HD in venous blood and the concentration of HD at 2 and 4 h after the end of exposure decreased with increasing MEK. These results suggest that combined exposure to MEK and n-hexane at occupationally realistic levels depresses the metabolism of n-hexane in a dose-dependent fashion., Conclusion: The internal exposure to the toxic metabolite of n-hexane decreased with co-exposure to MEK in a dose-dependent fashion. Estimation of external exposure by HD in serum or urine could be confounded by the co-exposure to MEK.

Nasal function has not yet been investigated under controlled exposures in individuals with self-reported Multiple Chemical Sensitivity (sMCS). Therefore, anterior rhinomanometry and acoustic rhinometry were applied in 12 individuals with sMCS, and 12 age-matched controls. The sMCS individuals and controls were selected on the basis of a standardized questionnaire. Controlled 4-hr exposures to ethylbenzene and 2-butanone were performed during 4 sessions. Exposures were close to the current German threshold limit values, and they approximated odor thresholds. Subjects with sMCS had a significant decrease in the flow value in anterior rhinomanometry, independent of substance and doses, compared with controls. This result suggests somatic reactions to the exposure. The result must be confirmed in additional studies, and pathophysiological examinations must be performed. For these investigations, anterior rhinomanometry was usable, but acoustic rhinometry can be recommended only after sufficient standardization has occurred. Furthermore, biochemical parameters of nasal mucosa must be considered.

Objective: To comparre the safety and efficacy of naproxen CR (1,000 mg once daily) with that of nabumetone (1,000 mg once daily) in the treatment of patients with symptomatic knee osteoarthritis(OA)., Methods: A total of 159 Korean patients (80 in the naproxen CR group and 79 in the nabumetone group) were enrolled in this 4-week, single-blind, controlled, randomized, parallel study and an intention-to-treat model was used for data analysis. Six efficacy parameters were measured: Lequesne index, visual analogue pain scale at rest and atactivity, patient's and physician's global assessment, and time to walk 50 feet., Results: Significant improvement in all efficacy parameters except time to walk 50 feet occurred at Week 2 and Week 4 in both groups. Themean improvement from baseline at Week 2 and Week 4 for the efficacy variables was not different between naproxen CR and nabumetone group. Twenty-four patients (30%) in the naproxen CR group and 18 patients (22.8%) in the nabumetone group withdrew from the study. Among them, only 1patient in the naproxen CR group terminated the study prematurely due to an adverse event of dyspepsia. No statistically significant difference in the frequency of adverse events, including gastrointestinal symptoms, was observed between these 2 groups during the treatment period. Significant laboratory abnormalities also did not occur during the study period in both groups., Conclusions: Naproxen CR is an effective and tolerable drug in the treatment of knee OA. Efficacy and safety profiles are comparable to those of nabumetone.

The objective of this work was to synthesize two bioreversible diacyl derivatives of t-butalone (chemical delivery systems), determine their chemical and in vitro stability, and investigate their potential use as topical antiglaucoma agents. The stability of these compounds was determined in isotonic phosphate buffers (pH range 5-8) and in selected biological media, including human whole blood, rabbit and rat blood, and the anterior segment tissues of rabbit. The ocular hypotensive activity of these compounds in unrestrained, normotensive albino rabbits was determined with a pneumatonometer. The two compounds were stable at lower pH. The stability decreased as the pH increased, suggesting their lability to base-catalyzed hydrolysis. These compounds exhibited significant differences in the hydrolytic rates in the whole blood among species examined (rat > rabbit > human). The observed rates of disappearance in different ocular tissues were indicative of relative enzyme activity in these media (iris-ciliary body > cornea > aqueous humor). The two compounds exhibited a significant ocular hypotensive activity (P < 0.01) at 2% dose level. The peak activity was found between 2 and 4 h, and the activity was maintained for 4.5 to 7 h. The dipivalyl derivative of t-butalone exhibited more pronounced decrease in intraocular pressure than that of diisovaleryl derivative. The present study suggests the possible use of diacyl derivatives of t-butalone as ocular hypotensive agents., (Copyright 2001 Wiley-Liss, Inc.)

The National Toxicology Program is conducting a chemical class study to investigate the structure-activity relationships for the toxicity of alpha,beta-unsaturated ketones. Methylvinyl ketone (MVK) was selected for study because it is a representative straight-chain aliphatic alpha,beta-unsaturated ketone and because of its extensive use and widespread exposure. Short-term inhalation studies of MVK were conducted to provide toxicity data for comparison with other alpha,beta-unsaturated ketones and for use in designing chronic toxicity and carcinogenicity studies. In 2-week studies, rats and mice were exposed to 0, 0.25, 0.5, 1, 2, 4, or 8 ppm MVK 6 h/day, 5 days/week for 12 exposures. Morbidity and early deaths occurred in all male and female rats after 1 exposure and in 2 male mice after 10 exposures to 8 ppm. Rats exhibited nasal cavity toxicity and lung necrosis at 4 ppm. No toxicity was observed in animals exposed to less than 2 ppm. Based on these results a 13-week study was conducted at 0, 0.5, 1, and 2 ppm MVK. As observed in the 2-week study, the nasal cavity was the main target organ and rats were more sensitive than mice. Respiratory and olfactory epithelial necrosis were prominent by day 21 in the rat. At study termination these lesions were still evident but not as severe as noted earlier. Additionally, changes such as olfactory epithelial regeneration and metaplasia (respiratory) as well as respiratory epithelial hyperplasia and metaplasia (squamous) were clearly evident. Nasal lesions in mice were limited to a subtle squamous metaplasia of transitional and/or respiratory epithelium covering predominantly the tips of naso- and maxilloturbinates in Levels I and II. A transient, leukopenia was observed in rats exposed to 2 ppm, however, this effect was not present after 13 weeks of exposure. In mice, leukocyte counts were significantly decreased at all exposure concentrations after 13 weeks of exposure. Absolute testicular and epididymal weights and sperm counts were decreased at the high dose only. MVK can be characterized as a reactive, direct-acting gaseous irritant. MVK exposure causes the same nasal cavity lesions as the cyclic alpha,beta-unsaturated ketone, 2-cyclohexen-1-one, although at lower exposure concentrations.

Objective: The purpose of this study was to compare the tolerability and efficacy of nabumetone and naproxen in the treatment of patients with rheumatoid arthritis (RA). The occurrence of gastrointestinal (GI) adverse events was compared., Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) have similar efficacy at equipotent doses, but the therapeutic response to various NSAIDs often differs in individual patients., Methods: This was a 3-month, randomized, double-blind, multicenter, parallel-group study conducted in adult patients with RA. The study had 2 phases: a 3- to 14-day washout period and a 12-week treatment period. During the treatment phase, the tolerability and efficacy of nabumetone 2000 mg/d were compared with those of naproxen 1000 mg/d. The change from baseline in efficacy variables, including global assessments, number of tender or swollen joints, and pain, was evaluated. The study was sized to provide an 80% power to detect a 15% difference in the percentage improvement on the physician's global assessment (alpha = 0.05). GI safety was assessed by monitoring the occurrence of clinically important adverse GI events., Results: A total of 346 RA patients at 31 US rheumatology centers were randomly assigned to treatment (173 patients per group). The study population was predominantly white (87.0%) and female (70.5%), with a mean age of 54 years. Both treatments improved the signs and symptoms of RA, with no statistically significant differences between groups for any efficacy variables. No serious GI adverse events occurred with either NSAID. The most frequent treatment-related adverse events in both groups were predominantly GI in origin, as were those that resulted in withdrawal from the study. Diarrhea with lower abdominal pain was the most common adverse event in the nabumetone group; upper abdominal pain was the most common adverse event in the naproxen group. The only significant difference between the 2 groups was a higher incidence of diarrhea (P < 0.01) in patients receiving nabumetone., Conclusions: Nabumetone 2000 mg/d was as effective as naproxen 1000 mg/d in relieving the signs and symptoms of RA. In this study, no serious GI adverse events were observed with either NSAID, but nabumetone was associated with a higher incidence of diarrhea.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for the treatment of signs and symptoms of osteoarthritis (OA). Nabumetone and oxaprozin are 2 of the newer NSAIDs and have been shown to have similar safety and efficacy profiles. Nabumetone 1000 mg to 1500 mg once a day (QD) and oxaprozin 1200 mg QD are commonly recommended doses. This study compared the health-related quality of life (HRQOL) of patients receiving oxaprozin 1200 mg QD with that of patients receiving nabumetone 1000 mg QD or nabumetone 1500 mg QD for the treatment of signs and symptoms of OA of the knee. Two similarly designed, independent, randomized, double-masked, placebo-controlled clinical trials were conducted. In trial 1, patients were randomized to receive oxaprozin 1200 mg QD (n = 109), nabumetone 1000 mg QD (n = 110), or placebo (n = 109); in trial 2, patients received oxaprozin 1200 mg QD (n = 116), nabumetone 1500 mg QD (n = 115), or placebo (n = 116). HRQOL was measured by the Medical Outcomes Study Short-Form-36 Health Survey (1-week recall period) at baseline and weeks 2 and 6. Data from the 2 trials were combined to assess differences across the 4 groups in 8 domains and 2 summary scores at baseline, and changes in HRQOL scores at weeks 2 and 6. At week 2, the oxaprozin group showed significantly greater improvement than the placebo group in role physical, vitality, and mental component summary (MCS) scores (P < 0.05), and in physical functioning, bodily pain, social functioning, and physical component summary (PCS) scores (P < 0.01). The nabumetone 1500-mg group showed significantly greater improvement than the placebo group in bodily pain and social functioning (P < 0.05), and in vitality and MCS score (P < 0.01). No significant differences were observed between the nabumetone 1000-mg and placebo groups. At week 2, the oxaprozin group showed a greater change than the nabumetone 1000-mg group in PCS score (P < 0.05). At week 6, oxaprozin treatment resulted in significantly greater improvement than placebo in physical functioning, role physical, and bodily pain (P < 0.05); social functioning, role emotional, and mental health (P < 0.01); and vitality and MCS score (P < 0.001). The nabumetone 1500-mg group showed significantly greater responses than the placebo group in vitality (P < 0.05), mental health (P < 0.01), and MCS score (P < 0.001). The oxaprozin group had significantly better scores than the nabumetone 1500-mg group in the PCS (P < 0.05), and it showed significantly greater improvement than the nabumetone 1000 mg group in role physical and PCS score (P < 0.01) and in role emotional (P < 0.05). No statistically significant differences were found between placebo and nabumetone 1000 mg at week 6. Results of this study suggest that oxaprozin 1200 mg QD has a significant positive impact on the HRQOL of patients with OA of the knee compared with nabumetone 1000 mg QD and placebo.

1. The disposition of 14C-methyl ethyl ketoxime (MEKO) was determined in the male F344 rat following oral, intravenous (i.v.) and dermal administration. 2. Oral doses of 2.7, 27 and 270 mg/kg were primarily excreted as CO2 (71-49%) in decreasing percentage as the dose increased. Excretion in urine (13-26%) and as volatiles (5-18%) increased as the dose increased. Five to 6% of the dose remained in the major tissues after 72 h. 3. An i.v. dose of 2.7 mg/kg was also principally excreted as CO2 (48.8%) with excretion in urine and as expired volatiles accounting for 21.4 and 11.4%, respectively. About 7% of the administered radioactivity remained in the tissues after 72 h. 4. Following dermal administration, 13 and 26% of a 2.7 and 270 mg/kg dose, respectively, were absorbed. Volatilization from the dose site prior to placement in the metabolism cage may account for the low absorption. 5. MEKO was biotransformed to at least five polar metabolites that could only be partially resolved by anion exchange chromatography. Incubation with glucuronidase, but not sulphatase, changed the urinary metabolic profile. Methyl ethyl ketone was a major component in the volatiles.

To ascertain the relationship among 2,5-hexanedione (2,5-HD) concentrations in nerve, serum and urine, rats were injected subcutaneously with 2.6 mmol/kg 2,5-HD alone, or together with 2.6 or 13.0 mmol/kg of methyl ethyl ketone, acetone and toluene. 2,5-HD concentrations in sciatic nerve (NC), serum (SC) and urine (UC) were determined, and the linear regression between each two of NC, SC, and UC were calculated. There was good correlation between NC and SC, SC and UC in the 2,5-HD alone group, and good correlation between NC and SC in the co-treated groups. Co-treatment solvent had little effect on the relationship between SC and NC. 13.0 mmol/kg co-treated solvent tended to decrease the regression coefficients compared with 2.6 mmol/kg co-treated solvent. These results show that SC can be used in estimating NC in the 2,5-HD alone or co-treated groups, and UC can be used in estimating SC in the 2,5-HD alone group.

Several dietary compounds have been demonstrated to reduce gastrointestinal cancer rates in both humans and animals. We showed that high human gastrointestinal tissue levels of glutathione S-transferase (GST), a family of detoxification enzymes consisting of class Alpha, Mu, Pi and Theta isoforms, were inversely correlated with cancer risk. We now investigated whether the sulforaphane analog compound 30, indole-3-carbinol, D-limonene or relafen, supplemented in the diet for two weeks at 1450, 250, 10,000, and 200 ppm, respectively, influenced (i) GST activity, (ii) GST isoenzyme levels, (iii) GSH levels, or (iv) glutathione peroxidase (GPx) activity in the gastrointestinal tract of male Wistar rats. Sulforaphane analog compound 30 enhanced GST activity in all organs studied (1.2-2.4 x). It induced GST Alpha levels in small intestine and liver, GST Mu levels in stomach and small intestine, GST Pi levels in stomach and small and large intestine, and GSH levels in stomach and proximal and middle small intestine. Indole-3-carbinol induced gastric GST Mu and hepatic GST Alpha levels. D-limonene induced hepatic GST Alpha, colonic GST Pi levels and proximal small intestinal GST enzyme activity and GST Pi levels. Relafen induced hepatic GST Alpha levels, distal small intestinal and gastric GST Pi levels, and oesophageal and proximal small intestinal GSH levels. GPx activity was enhanced by relafen in oesophagus, and in distal small intestine by sulforaphane analog compound 30. Enhancement of GSTs and to a lesser extent GPx and GSH, resulting in a more efficient detoxification, may explain at least in part the anticarcinogenic properties of sulforaphane analog compound 30, and to a much lesser extent of indole-3-carbinol and D-limonene.

In order to study the effects of methyl ethyl ketone (MEK) on the toxicokinetics of n-hexane and, in particular, the formation of 2,5-hexanedione from n-hexane in humans, volunteers were exposed to n-hexane (approx. 60 ppm, 2.4 microM in the inhaled air) with or without simultaneous inhalatory coexposure to MEK for 15.5 min. The concentration-time course of n-hexane (in exhaled alveolar air) and its neurotoxic metabolite, 2,5-hexanedione (in serum), were studied. The concentration-time courses obtained after exposure to n-hexane alone were compared with those obtained after coexposure to 200 or 300 ppm MEK in the same volunteer on the same day. No effect of MEK was observed on the concentration-time course of exhaled n-hexane. The concentration-time course of the metabolite, 2,5-hexanedione, revealed a decrease in the rate of formation of 2,5-hexanedione (about three-fold) after coexposure to MEK. Furthermore, the time to reach the peak concentration was increased from 18 to 30 min after the start of exposure. These changes in the concentration-time course of 2,5-hexanedione caused by MEK are most likely the result of inhibition of the biotransformation of one of the intermediate steps in the conversion of n-hexane to 2,5-hexanedione. These results indicate that the interaction of n-hexane and MEK leads to a decreased concentration of the neurotoxic metabolite 2,5-hexanedione (after short-term, acute exposure).

trans-Methyl styryl ketone (MSK; trans-4-phenyl-3-buten-2-one) is a beta-unsaturated ketone that has a wide range of uses in industry and is present in numerous consumer products. Although MSK has been shown to be positive in several in vitro mutagenic assays, it does not seem to be overtly toxic in animal models. This lack of toxicity may relate to its poor absorption and/or rapid elimination. However, little is known about the fate of MSK in the body. Studies were conducted to characterize the absorption, and disposition kinetics of MSK after intravenous, oral, and topical administration to male Fischer 344 rats. After intravenous administration of [14C]MSK (20 mg/kg, 120 microCi/kg), blood concentration-time data could be characterized with a biexponential equation and apparent first-order elimination kinetics. The following pharmacokinetic parameter values were obtained (mean +/- SD): terminal disposition half-life, 17.7 +/- 0.08 min; apparent steady-state volume of distribution, 0.89 +/- 0.14 liters/kg; systemic body clearance, 68.9 +/- 10.0 ml/kg *min; and mean residence time, 13.1 +/- 2.2 min. Within 48 hr, 95.5% of the dose was excreted in the urine and 2.7% in the feces. The major blood metabolite after intravenous administration was identified by GC/MS as the 4-phenyl-3-buten-2-ol (methyl styryl carbinol). After oral administration of [14C]MSK (200 mg/kg, 100 microCI/kg), approximately 96.6% of the dosed radioactivity was recovered in the urine and 4.8% in the faces within 48 hr. Major urinary metabolites identified by LC-MS/MS and quantified by HPLC radioassay were N-phenylacetyl-L-glycine (64.9% of dose) and N-benzyl-L-glycine (9.9% of dose). Parent compound could not be detected in the blood after oral administration, and 14C-equivalents in the blood never exceeded 1.3% of the dose. Results suggest near-total presystemic elimination of the oral dose. After topical application of [14C]MSK (250 mg/kg, 50 microCi/kg), > 60% of the dose was absorbed, and the majority of the dose was excreted into the urine (55% of dose) in the form of metabolites. Urinary metabolites were similar to those described after oral administration. 14C-equivalents were not detected in the blood at any time after topical administration. These results indicate that MSK is almost totally metabolized before systemic distribution after oral or topical administration. The systemic exposure dose of MSK seems to be exceedingly low at the doses studied herein.

The motility of lymphatic vessels is regulated by arachidonate metabolites and, therefore, can be altered by cyclo-oxygenase blockers such as non-steroidal anti-inflammatory drugs (NSAIDs). In order to investigate the lymphotropic properties of different NSAIDs, pharmacokinetics in plasma and lymph following intragastric administration of three model compounds, namely racemic ibuprofen, tenoxicam and nabumetone, were investigated in rats. Microsurgical cannulation of the thoracic duct allowed cumulative sampling of lymph fluid up to 48 hrs (n = 16). Pharmacokinetic parameters in plasma were determined in a control group (n = 12). Concentrations of R-, S-ibuprofen, tenoxicam, nabumetone and the metabolites OH-ibuprofen, COOH-ibuprofen and 6-methoxy-2-naphthyl-acetic acid (6MNA, metabolite of nabumetone) were monitored in lymph and plasma by HPLC. To quantify the lymphotropic properties of the investigated compounds, a "lymphatic clearance" was defined by dividing the amount recovered in lymph fluid by the corresponding area under the plasma concentration-time curve (AUCP). The "lymphatic clearance" substantially differed between the investigated compounds (mean +/- SD: R-ibuprofen 6.71 +/- 3.15 microliters/min, S-ibuprofen 3.24 +/- 1.20 microliters/min, tenoxicam 8.74 +/- 8.11 microliters/min, nabumetone 46.05 +/- 26.08 microliters/min and 6MNA 6.32 +/- 2.96 microliters/min). The overall recovery of the investigated compounds in lymph did not exceed 5% of the doses given. The known fact that lymphatic drainage is regulated by arachidonate metabolites might suggest that NSAIDs differing in their lymphotropic properties could result in different responses of lymphatic vessels to an inflammatory fluid load.

Objective: To examine, in horses, the disposition and excretion of the active metabolite 6-methoxy-2-naphthylacetic acid (6MNA) of the nonsteroidal anti-inflammatory prodrug nabumetone., Design: Pharmacokinetic analysis of 6MNA after oral administration of nabumetone and IV administration of 6MNA., Procedure: Using a crossover design, 5 horses were orally administered 3.7 mg of nabumetone/kg of body weight. After a 3-week washout period, 4 horses were administered 2.5 mg of 6MNA/kg, IV., Results: Absorption of nabumetone from the gastrointestinal tract and its metabolism to 6MNA had a median appearance half-life of 0.88 hour. The elimination half-life was 11 hours. Area under the plasma concentration time curve for 6MNA after oral administration of nabumetone was 120.6 mg/h/L. A dose of 2.5 mg/kg of 6MNA administered IV resulted in plasma concentration nearly equivalent to that induced by the orally administered dose. Disposition of 6MNA was modeled as a one-compartment, first-order elimination. The area under the plasma concentration time curve for IV administration of 6MNA was 117.0 mg/h/L, and the specific volume of distribution was 0.247 L/kg. The distribution half-life and the elimination half-life were 0.56 and 7.90 hours, respectively. Percentage of total dose recovered in urine for the 36-hour collection period after the oral and IV administrations was 7.4 and 5.3%, respectively., Conclusions: Metabolism of nabumetone to 6MNA, as reported in other species, also occurs in horses. There were a number of additional metabolites of nabumetone in urine that could not be fully identified and characterized.

Carbon tetrachloride (CCl4) induced hepatotoxicity and chloroform (CHCl3) induced nephrotoxicity were evaluated in male Sprague-Dawley rats pretreated with acetone (A), methyl ethyl ketone (MEK), and methyl isobutyl ketone (MiBK). Dose-response relationships for A, MEK, and MiBK potentiation of CCl4-induced hepatotoxicity and CHCl3-induced nephrotoxicity were compared. A, MEK, and MiBK pretreatment at a dosage of 6.8 mmol/kg, given daily for 3 d, markedly potentiated CCl4-induced liver toxicity as indicated by a decrease in the CCl4 ED50 to 3.4, 4.6, and 1.8 mmol/kg, respectively, compared to vehicle-pretreated rats (17.1 mmol/kg). Similarly, pretreatment with these ketones (13.6 mmol/kg) potentiated CHCl3 kidney toxicity but to a lesser degree; CHCl3 ED50 values for vehicle-, A-, MEK-, and MiBK-pretreated rats were 3.4, 1.6, 2.1, and 2.2 mmol/kg, respectively. Our results indicate a potency ranking profile for the potentiation of CCl4 hepatotoxicity of MiBK > A > MEK and of A > MEK > or = MiBK for CHCl3 nephrotoxicity. These dissimilar ranking profiles could be due to differences in mechanisms of action for the two target sites.

This 4-week, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicenter study was designed to compare the efficacy and safety of etodolac and nabumetone in the treatment of patients with active osteoarthritis (OA) of the knee. Ninety-one patients received etodolac 400 mg twice daily, 89 received nabumetone 1500 mg once daily, and 90 received placebo. Both active treatments significantly improved the patients' condition relative to baseline (P < or = 0.001) at all evaluations during treatment and relative to placebo (P < or = 0.05) by visit 4. Improvement relative to placebo in investigator's global assessments was earlier in the etodolac group (ie, by visit 3) than in the nabumetone group. At visit 4, improvement in investigator's and patient's global assessment scores, and in the distribution of investigator's assessment scores, was significantly (P < or = 0.05) greater in the etodolac group than in the nabumetone group. Other than hypokalemia, which occurred only in three patients in the nabumetone group (P = 0.035), there were no significant differences among the groups in the frequency of study events or premature discontinuation from the study as a result of study events. Study events considered at least possibly treatment related were reported for 26 patients in the etodolac group (28.6%), 20 in the nabumetone group (22.5%), and 23 in the placebo group (25.6%). The most frequently reported symptoms for all groups were dyspepsia, nausea, and headache. Four patients treated with nabumetone (4.5%) had elevations in aspartate aminotransferase or alanine aminotransferase during treatment. The results of this study show that etodolac 400 mg twice daily is at least as effective as nabumetone 1500 mg once daily and is equally well tolerated in the treatment of patients with active OA of the knee; etodolac may have an earlier onset of action and/or a relatively greater efficacy in patient and investigator global assessments than nabumetone.