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Ten asthmatic patients were enrolled in our study of the effects of dry powder formoterol fumarate. The onset was 2-5 minutes and a long duration of action (over 12 hours) appeared. The mean baseline FEV1 was 1.67 liters (49-74%). Mean reversibility was 17 per cent (range 15-19%). There was no adverse effect in this study.
Fumaric acid monoethylester (FAME) inhibits the incorporation of 14C-Thymidin, 14C-Uridin, 14C-Alanin and 14C-Leucin into acid-insoluble biopolymers of cultivated PHA-stimulated human lymphocytes. At high concentrations of FAME (500 mug/ml culture medium) the inhibition of nucleic acid synthesis is 6 times higher on the average than the inhibition of protein synthesis. However, the application of the cis-isomer, maleic acid monoethylester (MAME), results in an increase of the incorporation rate of the labelled precursors into the RNA and DNA. This is 3.5--9.3 times higher than after application of FAME. The results demonstrate the specific inhibition by FAME. The rate of labelling of nucleic acids is decreased above 10 mug FAME/ml culture medium and in the case of MAME above 50 mug/ml medium. As an explanation of the specific action of FAME its influence on the enzymes of the nucleic acid synthesis, the citric acid cycle or a faulty synthesis of enzymes are discussed.
Among atypical antipsychotics, quetiapine is characterized by a lower incidence of aggravation of parkinsonism due to its lower affinity to D 2. In this study, the effect of quetiapine fumarate (quetiapine) on antiparkinsonian-drug-induced psychosis (e.g. hallucination and delusion) in patients with Parkinson's disease was examined. Ten patients with antiparkinsonian-drugs-induced psychosis were enrolled in this study. The average age of the patients was 69 years and the mean duration of illness was 7 years and 5 months. Psychosis and parkinsonism in these patients were assessed by the Japanese version of PANSS (Positive and Negative Symptom Scale) and UPDRS (Unified Parkinson's Disease Rating Scale) before and during administration of quetiapine, respectively. During the assessment of the effect of quetiapine, the antiparkinsonian drugs that the patients were taking were unchanged. In nine out of the 10 patients, psychotic symptoms disappeared following administration of a relative small dose of quetiapine. No remarkable aggravation of parkinsonism was observed. The present results indicate that quetiapine is an useful drug for treating antiparkinsonian-drug-induced psychosis in the patient with Parkinson's disease.
Human alpha-methylacyl-CoA racemase (AMACR) was overexpressed in prostate cancer compared with nonmalignant tissues. The Gene Logic Inc. BioExpress database containing Affymetrix U133 GeneChip expression profiles of 4400 human normal, benign, diseased, and tumor samples from >60 tissue types was examined to determine the specificity of AMACR mRNA expression. One particular AMACR probeset was derived from an alternatively spliced exon with 88% identity to a 521-bp sequence that spans four exons of the fumarate hydratase. The predicted protein sequence revealed a novel GLGELIL peptide shared by both proteins. Whether the mitochondrial and peroxisomal AMACR described previously are distinct products from alternatively spliced transcripts remains to be determined. The determination of the cellular location and function of the altered AMACR will be critical in the elucidation of the role of AMACR in prostate cancer diagnosis and pathogenesis.
The regularities for changes were established in activity of hexokinase, glucokinase, glucosephosphate-isomerase, phosphofructokinase and glucose-6-phosphate dehydrogenaseduring the early development of loach (Misgurnus fossilis). It was found that a 30-minute incubation of fertilized loach eggs in the lactate or fumarate solutions decreases the glucokinase activity in the embryos of 3, 6, 9, 12, 15, 18 and 24 hours of their development, while the inhibitory effect of glucose on the enzyme activity is pronounced only after 18 and 24 hours of the development. A significant increase in the hexokinase and glucose-6-phosphate dehydrogenase activities under the above-mentioned conditions is observed only under the effect of glucose 9 and 6 and 9 hours, respectively, after fertilization. The glucose phosphate isomerase and phosphofructokinase activites under the effect of used compounds undergo no changes during the primary stages of embryogenesis.
We report on two cases of adverse reactions to topical treatment with monoethyl fumarate. One patient suffering from atopic dermatitis reacted with contact dermatitis; the other, suffering from psoriasis, developed a generalized, partly pustulous exanthema as well as signs of systemic involvement, such as tachycardia and dyspnea. As the causative mechanism we suggest non-immunological contact urticaria syndrome.
We describe four female patients with psoriasis treated with fumaric acid esters. In two patients acute renal failure developed during this therapy. Histological investigation of renal biopsy in one patient was compatible with the diagnosis of acute tubular necrosis; her renal function was reversible after cessation of the medication. The histological diagnosis of the other patient was tubulo-interstitial nephritis, possibly as a reaction to acute tubular necrosis. The recovery of her renal function was incomplete after 9 months.
An inhibitory effect of fumaric acid (FA) on hepatocarcinogenesis was examined in rats fed thioacetamide (TAA). A group of male DONRYU rats were fed TAA at a level of 0.035% in the diet for 40 weeks and then fed a basal diet for 40 weeks. Hepatic carcinomas developed in 9 of 41 animals of this group fed TAA alone. The effect of FA on the carcinogenesis was examined in 2 groups fed both TAA and FA; one group of rats were fed FA at 1% in a basal diet after ingestion of TAA, and another group of rats were fed TAA plus a supplement of 1% FA in the diet. The inhibitory effect of FA on TAA carcinogenesis was so marked that no hepatic carcinomas were found in both groups fed FA in combination with TAA.
E. coli 85 cells with a high aspartate-ammonia-lyase activity were immobilized through polyacrylamide gel incorporation. Proper conditions to assay aspartase activity of E. coli cells were developed. Kinetic patterns of aspartate-ammonia-lyase reaction catalyzed by free and immobilized E. coli 85 cells were studied. The synthesis of L-aspartic acid from ammonium fumarate had the following characteristics: specific activity of (4--6) . 10(-5) mmole/mg.sec for free cells and (6--8) . 10(-5) mmole/mg.sec for immobilized cells with their content in polyacrylamide gel of 5--10 mg protein per g wet gelm pH 8.3--10.0.
Bencyclane hydrogen fumarate (Fludilat) was tested on the stickiness of tumor cells in vivo and in vitro. It was intended to determine whether Fludilat reduced the cancer cell stickiness in vitro, and if the survival time of cancer cell carrying animals can be increased with Fludilat in vivo, or in combination with a cytostatic. For the in vitro trials, concentrations from 0.001 mg/ml to 1 mg/ml medium were chosen. The survival trial on NMRI-mice with Nemeth-Kellner lymphosarcoma was performed in three groups, each with 4-5 sub-groups: Control group--Fludilat 5 mg, 10 mg, 20 mg/kg bodyweight, Bleomycin--50 mg/kg bodyweight, 100 mg/kg bodyweight, 250 mg/kg bodyweight, Bleomycin 50 mg/kg bodyweight + Fludilat 5 mg/kg bodyweight, Bleomycin 100 mg/kg + Fludilat 10 mg/kg bodyweight, Bleomycin 250 mg/kg + Fludilat 20 mg/kg bodyweight. The sequence of deaths was determined, and the 50% survival time was taken as criterium for the effect of the treatment. The in vitro trials showed a complete removal of the monolayer of the tumor cells from the bottom of the culture flask, in doses of 0.01-1 mg/ml medium. In the in vivo trial an increase in the 50% survival time could be achieved in all groups. The results of combined therapy of Fludilat and Bleomycin were striking. In comparison to the control animals, the treated animals showed that the occurrence of solid abdominal metastases from the Nemeth-Kellner lymphosarcoma could be almost completely prevented, especially at high doses. The Ca++-antagonistic effect, in changing the surface of the cells, is discussed as a mechanism of action.
Fumaric acid (FA) was examined for its effect on hepatocarcinogenesis in rats fed 3-methyl-4'-(dimethylamino)azobenzene (3-Me-DAB). Male DONRYU rats were given approximately 0.5 g 3-Me-DAB by being fed a diet containing 0.06% 3-Me-DAB for 50 days; they were then given a diet containing 1% FA and drinking water containing 0.025% FA for 51 weeks. The administration of FA effectively suppressed the development of hepatocellular carcinoma, hyperplastic nodules, and hyperplastic areas in the livers of rats fed 3-Me-DAB.
The inhibitory effect of fumaric acid (FA) on carcinogenesis by potassium 1-methyl-7-[2-(5-nitro-2-furyl)vinyl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (trans, NFN) was examined histologically with male ICR/JCL mice. NFN was fed to mice at a dose level of 0.012% in the diet for 14 weeks. These mice were then divided into 2 groups. One group was given a basal diet, and the other group was given a diet containing 1% FA in the subsequent 39 weeks. In the group of 30 mice fed NFN alone, squamous cell carcinomas were found in the stomachs of 7 mice, multiple papillomas in the stomachs of 13 mice, and multiple and large papillary adenocarcinomas in the lungs of 27 animals. The administration of FA suppressed the NFN-induced stomach and lung carcinogenesis. In the group of 32 mice fed NFN and FA, no stomach tumors developed except 1 early-stage of squamous cell carcinoma. In the lungs, only a small focus of mild atypical hyperplasia and a few early-stage adenocarcinomas were noted in 7 and 11 animals, respectively.
A histological-immunohistological study was conducted to investigate the effect of systemically administered fumaric acid esters (FAEs) on epidermal thickness and composition of the inflammatory infiltrate in psoriatic plaques. The very first effect of systemic therapy with FAEs is the disappearance of CD 15-positive cells in the beneath the epidermis, accompanied by a significant reduction in T-helper cells beneath the epidermis, pointing to an immunosuppressive effect. This is followed after some delay by a reduction in acanthosis and hyperkeratosis. The reduction in infiltrating T-lymphocytes corresponds to that seen after systemic or intralesional therapy with cyclosporin. However, the normalization of the psoriatic plaques takes longer under the influence of FAEs than under cyclosporin.
Echinococcus granulosus cyst wall exhibited activities of fumarate hydratase (FH), pyruvate kinase (PK), and phosphoenolpyruvate carboxykinase (PEPCK) with 911-1433, 151-215, and 54-98U, respectively. The ratio of PK/PEPCK was 2.2-2.7, indicating that glycolysis is the main pathway of carbohydrate metabolism in the cyst wall. When infected mice were treated ig with mebendazole, albendazole or praziquantel at the respective daily dose of 25-50, 300, and 500 mg.kg-1 for 7-14 d, no apparent change of FH activity in the cyst wall was found, while PK and PEPCK activities in the cyst wall were markedly inhibited by mebendazole and albendazole. The inhibition rates of PK and PEPCK activities in mebendazole group were 85-88% and 90-92%, respectively, while in albendazole group were 55.3 and 71.6%, respectively. The results suggest that PK or PEPCK in the cyst wall may the important site attacked by effective anti-hydatid drugs.
BACKGROUND: Ketotifen fumarate blocks histamine1 (H1) receptors, stabilizes mast cells, and acts as an eosinophil inhibitor (decreases chemotaxis and activation of eosinophils). OBJECTIVE: To assess the efficacy of ketotifen 0.025% ophthalmic solution in the prevention of symptoms of allergic conjunctivitis, using the conjunctival allergen challenge model. METHODS: This was a single-center, double-masked, randomized, placebo-controlled, contralateral-eye comparison, allergen challenge trial conducted in the United States. Subjects were randomized to receive ketotifen 0.025% in one eye and placebo in the other. At visits 1 and 2, allergen challenges were performed to determine the allergen concentration eliciting a qualifying reaction for each subject. At the 3 subsequent visits, subjects received 1 drop of ketotifen 0.025% ophthalmic solution in one eye and vehicle solution as placebo in the other eye 15 minutes (visit 3), 6 hours (visit 4), and 8 hours (visit 5) before allergen challenge. The primary efficacy measure was the subject's rating of itching at 3, 7, and 10 minutes after challenge. RESULTS: Of the 89 subjects randomly assigned to masked trial medication at visit 3, 72 completed the study. At visits 3, 4, and 5, mean itching scores were significantly better for ketotifen-treated eyes at all postchallenge time points, compared with placebo (P<.001). Also at visits 3, 4, and 5, ketotifen was statistically superior to placebo in reducing ocular hyperemia at all postchallenge time points (P<.05). CONCLUSIONS: Ketotifen was safe and statistically effective in reducing ocular itching and hyperemia associated with allergic conjunctivitis. Ketotifen's rapid onset of action (within 15 minutes) and extended duration of action (at least 8 hours) make it a valuable treatment for allergic conjunctivitis.
In two Segment II Teratology studies, timed-pregnant Crl:CD[BR] (Sprague-Dawley) rats were treated orally (gastric intubation) on days 6-15 of gestation with ibutilide fumarate (ibutilide), a class III antiarrhythmic that has been shown to increase the refractory period and action potential duration of myocardial cells. In the first study, ibutilide does of 20, 40, and 80 mg/kg/ day were tested. Although maternal toxicity was equivocal in the 80 mg/kg/day group, all 23 rats that conceived had entirely resorbed liters when the animals were killed on day 20 of gestation. Similarly, 12 of 24 litters were completely resorbed in the 40 mg/kg/day group, with an 87.7% postimplantational loss. Of the surviving fetuses in this group, 48.6% had at least one malformation. The incidences of malformed pharynx and malformed palate, along with adactyly, were statistically significantly higher in this group than in the control group. In addition, a significant (P < 0.05) increase in total malformations (5.7% of the fetuses), relative to the controls (0.8%), was found for the 20 mg/kg/day group. Since a no observed adverse effect level (NOAEL) was not found, a second teratology study was performed. In this study, the ibutilide doses were 5, 10, and 20 mg/kg/day. The 20 mg/kg/day dose was again teratogenic with 9.2% of the fetuses malformed, as compared to a control value of 1.0%. Also, the incidences of scoliosis and interventricular septal defect were statistically significantly higher in this group. Although statistically significant differences were not detected, scoliosis was also found in the 10 mg/kg/day group (3 fetuses in 2 litters), along with a significant dose-response trend for this malformation. As the result, the NOAEL for ibutilide teratogenicity in rats was set at 5 mg/kg/day. This dose is 4 times the proposed maximum clinical dose (two 1 mg doses, each infused over 10 minutes, or 0.033 mg/kg for a 60 kg person), when corrected for 2.6% oral bioavailability in the rat at a dose of 10 mg/kg, as determined in separate studies.
The degradation of poly(propylene fumarate-co-ethylene glycol) hydrogels was examined in vitro in phosphate-buffered saline at pH 7.4 and in vivo in a subcutaneous rat model. These hydrogels have potential application as biodegradable, injectable cardiovascular stents, and, as such, their mass loss, dimensional changes, mechanical properties, morphology, and biocompatibility over a 12-week time course were evaluated. Three formulations were fabricated: one base formulation consisting of 25% (w/w) PEG, molecular weight 4,600; one high weight percent PEG formulation with 50% (w/w) PEG; and one high molecular weight PEG formulation, molecular weight 10,500. All three formulations showed significant weight loss (between 40 and 60%) on the first day due to leaching of the uncrosslinked fraction. Further weight loss was observed only for the low weight percent PEG copolymers in the in vivo case, and a slight increase in volume was observed due to degradative swelling. The mechanical properties of the P(PF-co-EG) hydrogels decreased significantly in the first 3 weeks, showing the biphasic pattern typical of bulk degradation. In vitro, the hydrogels showed at least a 20% retention of their initial ultimate tensile stress after 3 weeks. The dynamic mechanical properties showed similar retention, with the in vivo mechanical properties differing from the in vitro properties only after 6 weeks of degradation. Differences in PEG molecular weight appeared to have little effect, but increasing the weight percent PEG decreased the rate of degradation both in vitro and in vivo. The morphology of the copolymer films, based on scanning electron microscopy observation, was not significantly different either among the three formulations or over the time course of the study, suggesting there were no macroscopic structural changes during this time period. The P(PF-co-EG) hydrogels demonstrated good initial biocompatibility, showing responses characteristic of biomaterial implants.
The in vitro cytotoxicity and in vivo biocompatibility of poly(propylene fumarate-co-ethylene glycol) [P(PF-co-EG)] hydrogels were assessed in order to investigate the influence of poly(ethylene glycol) molecular weight and copolymer composition. These materials have application as injectable cardiovascular implants; cytotoxicity due to leachable products, as well as inflammation caused by the biomaterial itself, may ultimately affect the biocompatibility of the implant. We utilized a 7-day in vitro cytotoxicity assay to quantify cell density and cellular proliferation in the presence of copolymer films. The copolymer films exhibited slight to moderate cytotoxicity toward cultured endothelial cells, showing 20-86% viability relative to controls. Cell viability increased with an increasing weight percent of PEG or, to a lesser extent, the molecular weight of PEG. In vivo biocompatibility was assessed using a cage implantation model over a 21-day time period. This system was used to characterize the local cellular and humoral inflammatory response in the surrounding exudate, as well as the size and density of macrophages adherent to the material itself. All copolymer formulations exhibited excellent biocompatibility relative to controls with no significant differences in total leukocyte count among the different formulations. The in vivo inflammatory reaction displayed normal wound healing over 21 days as shown by a progressive decrease in both leukocyte concentration and enzymatic activity. The surface coverage of the copolymer films remained relatively constant from 7 to 21 days. There were no cells larger than 0.003 mm2, which was previously shown to be the threshold value for foreign-body giant cells. These data suggest that P(PF-co-EG) hydrogels have potential for use as injectable biomaterials.