New drugs--reports of new drugs recently approved by the FDA. Alendronate.
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Alendronate↗
Biomedical subjects
Y Ohta
Publications and source records attributed to Y Ohta.
New drugs--reports of new drugs recently approved by the FDA. Dirithromycin.
Dirithromycin is a semisynthetic derivative of erythromycin, a 14-membered ring macrolide antibiotic. The drug is converted during absorption and distribution, to an active metabolite 9-(S)-erythromycylamine, which is the predominant compound found in plasma and extravascular tissues. High tissue concentration of erythromycylamine is achieved after oral doses of dirithromycin, with slow release back into the circulation. The mechanism of action of dirithromycin is like that of erythromycin and other macrolides. These compounds inhibit RNA-dependent protein synthesis. It has recently been suggested that all macrolides stimulate dissociation of peptidyl-tRNA from ribosomes during the elongation phase, leading to inhibited protein synthesis. The antimicrobial spectrum of dirithromycin is similar to that of erythromycin, although the drug offers no significant advantage with regard to MIC values. In vitro against Gram-positive isolates, dirithromycin exhibits similar potency to that of clarithromycin, erythromycin, roxithromycin, and clindamycin. In vivo, dirithromycin is active against penicillin-susceptible Staphylococcus aureus, beta-hemolytic streptococci, and Streptococcus pneumoniae. Dirithromycin is as effective as penicillin VK against streptococcal pharyngitis and tonsilitis, and as effective as erythromycin against acute superimposed chronic bronchitis and skin and soft-tissue infections. In comparison with other newer macrolides, dirithromycin has shown similar or lesser in vitro activity. In particular, Haemophilus influenzae, Bacteroides spp., Peptococcus-Peptostreprococcus spp., Clostridium perfringens, Legionella spp., Neisseria gonorrhoeae, and Chlamydia trachomatis were all less sensitive to dirithromycin than azithromycin or clarithromycin. Once-daily oral administration of dirithromycin (500 mg) has been demonstrated to be similar in efficacy to erythromycin (250 mg, 4 times daily), each for approximately 7 days, in the treatment of acute bronchitis or acute-exacerbations of chronic bronchitis in controlled studies. Proven or presumed pathogen eradication rates were 83 and 86% for acute bronchitis patients treated with dirithromycin and erythromycin, respectively. Corresponding bacteriological response rates in acute exacerbations of chronic bronchitis were 75 to 84% with dirithromycin and 75 to 82% with erythromycin. Both agents achieved clinical cure or improvement in over 85% of the patients with either condition. The main advantage of dirithromycin over erythromycin appears to be once-daily administration. Lilly launched dirithromycin in September 1993, in Spain, received approval from FDA in August 1995, and launched it during October 1995.
Anti-Bacterial Agents↗
The hypolipidemic action of the ACAT inhibitor HL-004 in hamsters fed normal chow.
1. A novel ACAT (acyl-CoA: cholesterol acyltransferase) inhibitor, HL-004, exhibited a strong inhibitory effect on the hepatic and intestinal ACAT, but was less effective on the adrenal ACAT in vitro. 2. HL-004 selectively decreased serum VLDL cholesterol, and inhibited hepatic ACAT activity in hamsters fed normal chow. 3. These results suggest that the cholesterol-lowering effect of HL-004 can be attributed to a decrease in hepatic VLDL secretion via inhibition of ACAT.
Acetanilides↗
Surgical management of the plunging ranula: a review of seven cases.
We have treated seven patients with a plunging ranula during the past 10 years. All patients underwent surgery via a cervical approach. In two, the ranula reached the anterior neck by passing through a dehiscence in the mylohyoid muscle, while in the other five the plunging ranula passed posteriorly to the mylohyoid muscle. A pseudocyst was extirpated in each patient. Although total sublingual gland excision was not performed in two patients, no recurrence was observed in any patient. Incision of the pseudocyst facilitated subsequent procedures and decreased the incidence of transient facial paralysis. In the presence of a cervical mass without swelling of the oral floor, a cervical approach may still be the method of choice either for the first operation or for salvage surgery after recurrence subsequent to intraoral procedures. It is based on the fact that there may be ectopic sublingual glands residing on the inferior surface of the mylohyoid muscle.
Adolescent↗
Serum levels of hepatitis C virus core protein in patients with chronic hepatitis C treated with interferon alfa.
The quantitation of hepatitis C virus (HCV) viremia can be helpful in the diagnosis, therapy, and monitoring of patients with chronic hepatitis C. A sensitive and quantitative fluorescence enzyme immunoassay (FEIA) has recently been developed for assaying HCV core protein in serum. To assess the utility of measurements of serum HCV core protein during the course of treatment of chronic hepatitis C, we studied 27 patients who were treated with a single schedule of interferon alfa (IFN-alpha) (9 million units per dose for 24 weeks; total dose, 720 million units). Eleven of the 27 patients responded with clearance of HCV RNA and fall of aminotransferase to normal; 16 patients did not respond to treatment. Before therapy, HCV core antigen was detectable in 25 of the 27 patients (93%). The initial serum concentration of HCV core protein was significantly (P < .01) higher in the nonresponders versus the responders. Two weeks after initiating IFN-alpha therapy, HCV core protein was not detectable in any of the 11 responders, but was detected in 8 of 16 nonresponders (P < .01). All responders, but none of the nonresponders, remained negative for core protein after IFN-alpha therapy. The measurement of HCV core protein by FEIA may be useful for predicting the response to IFN-alpha and for monitoring its therapeutic efficacy.
Adult↗
Crystallization and preliminary X-ray diffraction studies of N-acyl-D-glucosamine 2-epimerase from porcine kidney.
N-Acyl-D-glucosamine 2-epimerase from porcine kidney, which was cloned and expressed in Escherichia coli, was crystallized by the vapor-diffusion method, using polyethylene glycol and ammonium acetate as precipitants. The crystals were resistant to X-ray radiation damage and diffracted to more than 2.0 A resolution. The diffraction pattern indicated that the crystals belong to the orthorhombic system, space group P2(1)2(1)2(1), with unit-cell dimensions of a = 78.1, b = 97.2, and c = 100.7 A. It is supposed that the asymmetric unit consists of two N-acyl-D-glucosamine 2-epimerase molecules. Collection of data on the native crystals indicated that they are suitable for X-ray structural analysis.
Animals↗
Increased uptake of I-123 IMP in peritoneal metastases of hepatocellular carcinoma.
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Amphetamines↗
Suppression of the malignant phenotype of melanoma cells by anti-oncogene ribozymes.
The activation of signal transduction pathways by mutation or overexpression of cellular oncogenes has been associated with neoplastic transformation. In this study, we addressed the therapeutic potential of ribozymes targeted against the activated H-ras oncogene as well as against the nuclear proto-oncogenes c-fos and c-myc in the FEM human melanoma cell line containing a H-ras mutation. FEM cells transfected with the anti-ras ribozyme were shown to have the longest doubling time, the least DNA synthesis, and the fewest colonies in soft agar when compared with transfectants with ribozymes against c-fos or c-myc mRNA. Furthermore, anti-ras ribozyme clones showed a dendritic appearance in monolayer culture that was associated with enhanced melanin synthesis. These results suggest that the anti-ras ribozyme could affect not only the proliferation but also the differentiation process of human melanoma cells in vitro. They also reinforce the role of anti-oncogene ribozymes as suppressors of the neoplastic phenotype of melanoma cells.
Antibodies↗
Quantification of serum hepatitis C virus core protein level in patients chronically infected with different hepatitis C virus genotypes.
BACKGROUND/AIM: A novel fluorescent enzyme immunoassay (FEIA) for the detection and quantification of serum hepatitis C virus (HCV) core protein was developed. The aim of this study was to evaluate the relation among serum HCV core protein level, HCV RNA level, and HCV genotype in patients with chronic HCV infection. PATIENTS AND METHODS: Serum HCV core protein, HCV RNA, HCV genotype were determined in 175 patients using the FEIA, branched DNA assay (Quantiplex HCV RNA ver 1.0), and serologically defined genotyping assay, respectively. For the specificity, all 13 patients seronegative for anti-HCV were negative for serum core antigen and HCV RNA by FEIA and bDNA, respectively. RESULTS: FEIA assay seems to be more sensitive than bDNA for patients with HCV type 2 infection (detection: 83.4% v 63.4%, p < 0.01). There was a good overall correlation between the FEIA and bDNA results. However, when the patients were stratified into their HCV types, a correlation was observed in HCV type 1 but not in type 2 infection. Patients with HCV type 2 infection had a lower serum HCV core protein level (median 56 RFI) compared with type 1 infection (median 149 RFI, p < 0.01). Thirty seven patients subsequently received interferon alpha therapy, patients who showed a complete and sustained response had a lower pretreatment serum HCV core protein level compared with patients who had a relapse and nonresponders (36 v 338 RFI, p < 0.01). CONCLUSIONS: This study showed that FEIA (1) is a good assay for the detection and quantification of serum HCV core protein level, (2) is also very sensitive in detecting HCV core protein in patients with HCV type 2 infection, and (3) may have a role as a predictor of subsequent response to interferon therapy.
Female↗
Sleep apnea syndrome: comparison of MR imaging of the oropharynx with physiologic indexes.
PURPOSE: To compare magnetic resonance (MR) imaging of the oropharynx in patients with sleep apnea syndrome with fiberoptic nasopharyngoscopy, and oropharyngeal pressure and apnea index values. MATERIALS AND METHODS: After sleep induction, 24 patients with sleep apnea syndrome and nine patients with non-sleep-apnea snoring underwent MR imaging and fiberoptic nasopharyngoscopy combined with subsequent measurement of oropharyngeal pressure. Patients were previously classified with apnea index values obtained at polysomnography. MR imaging and fiberoptic nasopharyngoscopic findings of severity and location of oropharyngeal abnormalities were compared. Oropharyngeal pressure and apnea index values were also compared with MR findings. RESULTS: A statistically significant correlation was observed between MR and fiberoptic nasopharyngoscopic findings (r = .931; P < .0001). The degree of decompression in oropharyngeal pressure and apnea index values in the multiple-site abnormality group were statistically significantly higher than those in the single-site abnormality group. CONCLUSION: MR imaging is useful for localization of sites of oropharyngeal abnormalities and for evaluation of the severity of apnea.
Adult↗
Morphological and histochemical study of nonhemiplegic muscle in acute stroke patients manifesting respiratory failure.
There is little information on skeletal muscle changes in patients with acute stroke. We performed morphological and histochemical examinations of nonhemiplegic sternothyroid muscles biopsied at the time of tracheostomy from 13 patients with acute stroke manifesting acute respiratory failure. Degenerating and regenerating fibers were observed in all 13 specimens. Following characteristic myopathic changes suggestive of mitochondrial abnormalities were also demonstrated in a majority of patients. Namely, ragged-red fibers, focal increase in NADH-TR activity in subsarcolemmal areas and increases in acid phosphate activity were found. The changes were similar but extremely slight in control patients with acute respiratory failure due to causes other than stroke and were absent in the other control patients with adenomatous thyroid tumor. The severity and extent of the histopathological changes in the muscle fibers in patients with acute stroke were closely correlated with the duration of hypoxemia but not with such items as type of stroke, site of cerebral lesion, consciousness level, days of biopsy after the stroke, clinical outcome, levels of serum creatine kinase, myoglobin and PaO2. This acute nonhemiplegic muscle involvement was considered to be a very common complication in severe stroke patients.
Acute Disease↗
Hypolipidemic effect of taurine in stroke-prone spontaneously hypertensive rats.
The hypolipidemic and antiatherosclerotic effects of taurine were investigated in genetically hypertensive rats: strokeprone spontaneously hypertensive rats (SHRSP). SHRSP were fed a hypercholesterolemic (HC) diet supplemented with 3% taurine for 50 days, and serum cholesterol was monitored. Cholesterol content and enzymatic activity responsible for cholesterol synthesis and metabolism were also determined in the liver, aorta, and intestine. Taurine prevented increases in the cholesterol level of the serum, liver, and aorta induced by a HC diet. Severe fat deposits of the mesenteric arteries induced by a HC diet were improved by the taurine treatment, showing the hypolipidemic and antiatherosclerotic effects of taurine. Taurine enhanced the activity of cholesterol 7 alpha-hydroxylase, a rate-limiting enzyme of bile acid synthesis, and stimulated bile acid production. These results suggest that taurine stimulates bile acid synthesis, which is closely related to the enhancement of cholesterol 7 alpha-hydroxylase activity, and thereby reduces serum cholesterol. In addition, a decrease in the intestinal acyl CoA:cholesterol acyltransferase activity by taurine suggests that the inhibition of cholesterol absorption may also be related to the hypolipidemic effect of taurine, in part.
Animals↗
Apoptosis in adult mouse testis induced by experimental cryptorchidism.
Induction of cryptorchidism in the mouse causes infertility due to disruption of spermatogenesis including reduction of germ cells; however, the cellular mechanism responsible for the degenerative changes in cryptorchid testis is still unclear. In surgically induced bilateral cryptorchidism of 3-month-old C57BL/Tw mice, cellular changes in the cryptorchid testis were studied 1, 2, 3, 7, 14 and 21 days after the operation by electron microscopy, DNA fragmentation, in situ 3'-end labeling, serum and testicular testosterone measurements and gene expression. Although the testis showed DNA fragmentation even in intact mice, the cryptorchidism increased the degree of the fragmentation at 1 postcryptorchidism (p.c.) day. Apoptosis was encountered mainly in spermatids and spermatocytes. The number of apoptotic cells in the cryptorchid testis showed a 7-fold increase at 1 p.c day as compared to the intact testis, then it gradually decreased. Serum testosterone levels showed a significant decrease at 2 p.c. days and remained low thereafter. Expression of transforming growth factor-beta 2 (TGF-beta 2), TGF-beta 3, tumor necrosis factor-alpha receptor and Fas mRNAs increased in the cryptorchid testis within 24 h after the operation. In lpr(cg) and lpr mice lacking functional Fas, gld mice lacking functional Fas ligand and lpr(cg)-gld mice lacking both functional Fas and Fas ligand, the experimental cryptorchidism also induced apoptosis in germ cells at 1 p.c. day. The present results indicate that cryptorchidism induces apoptotic dell death in germ cells, and that testosterone reduction and the Fas system may not be significantly involved in the apoptosis of male germ cells.
Animals↗
Role of catalase in retinal antioxidant defence system: its comparative study among rabbits, guinea pigs, and rats.
The role of catalase in the retinal antioxidant defence system was examined in rabbits, guinea pigs, and rats with and without prolonged administration of a diet containing 0.4% 3-aminotriazole (3-AT), a catalase inhibitor. When weanling rabbits, guinea pigs, and rats we administered 3-AT for 8, 7, and 10 weeks, respectively, retinal catalase activity was reduced by approximately 50% in all these animals. In the retina of rabbits with 3-AT administration, a decrease in superoxide dismutase (SOD) activity and an increase in lipid peroxide (LPO) concentration occurred. while glutathione peroxidase (GSH-px) activity did not change. In the retina of guinea pigs with 3-AT administration, an increase in LPO concentration occurred, while SOD and GSH-px activities did not change. In the retina of rats with 3-AT administration, a decrease in GSH-px activity and an increase in LPO concentration occurred, while SOD activity did not change. An increase in serum LPO concentration was found in rats with 3-AT administration, while the concentration did not change in rabbits and guinea pigs. These results indicate that catalase plays an important role in the retinal antioxidant defence system, but that the way catalase contributes to the maintenance of the retinal antioxidant defence system is different among these animals. The present results suggest that under the prolonged inhibition of catalase, the retina of rats, but not of rabbits and guinea pigs, may suffer from the influence of systemic oxidative stress.
Amitrole↗
Anticataract action of vitamin E: its estimation using an in vitro steroid cataract model.
The aim of this study was to estimate the anticataract action of vitamin E using an in vitro methylprednisolone (MP)-induced cataract model. The same severity of early cortical cataract was induced in lenses isolated from male Wistar rats aged 6 weeks by incubation with MP (1.5 mg/ml) in TC-199 medium. The cataractous lenses showed slight increases in lipid peroxide (LPO) content and Na+/K+ ratio and slight decreases in reduced glutathione (GSH) content and glyceraldehyde-3-phosphate dehydrogenase (GAP-DH), a sensitive index of oxidative stress, and Na+,K(+)-ATPase activities. When the cataractous lenses were further incubated in TC-199 medium with and without vitamin E (250 micrograms/ml) for 48 h, the progression of cataract was prevented in the vitamin E-treated lenses, but not in the vitamin E-untreated lenses. The vitamin E-untreated lenses showed a decrease in vitamin E content and an increase in water content in addition to further increases in LPO content and Na+/K+ ratio and further decreases in GSH content and GAP-DH and Na+,K(+)-ATPase activities. In contrast, the changes of these components and enzymes except for GSH were attenuated in the vitamin E-treated lenses. From these results, it can be estimated that vitamin E prevents in vitro cataractogenesis in rat lenses treated with MP by protecting the lenses against oxidative damage and loss of membrane function.
Animals↗
Suppression of atherosclerotic changes in cholesterol-fed rabbits treated with an oral inhibitor of neutral endopeptidase 24.11 (EC 3.4.24.11).
Neutral endopeptidase 24.11 (NEP), widely distributed in the body, hydrolyzes and inactivates a number of endogenous vasoactive peptides, some of which could alter various functions of cells present in the arterial wall. Recently NEP has been found to exist in the vascular endothelium. The aim of this study was to assess the influence of chronic NEP inhibition by daily administration of UK79300 (candoxatril), an orally active NEP inhibitor (NEPI), on the development of atherosclerotic changes in high-cholesterol-fed rabbits. Male New Zealand White rabbits were fed for 8 weeks as follows: normal rabbit diet (Normal, n = 15), 1.5% cholesterol diet (Cholesterol, n = 15), or 1.5% cholesterol diet containing NEPI (20 mg.kg-1.d-1) (Cholesterol+NEPI, n = 15). At the end of the dietary period, NEPI treatment was found to suppress the surface area of the aorta covered by plaques (% surface area: Cholesterol, 59 +/- 6 versus Cholesterol+NEPI, 36 +/- 7, P < .01) and decreased contents of cholesterol and cholesterol esters in the aortas. NEPI also reduced plasma total cholesterol by 27% of Cholesterol rabbits (1781 +/- 130 mg/dL). The endothelial function, estimated by the endothelium-dependent relaxation of the isolated aortas in response to acetylcholine, was preserved in Cholesterol+NEPI rabbits compared with that in Cholesterol rabbits. NEP enzymatic activities in plasma and the particulate fraction of the homogenates from the aortas in Cholesterol rabbits were both increased, 3.1- and 3.9-fold, respectively, above those in Normal rabbits, but the activities in Cholesterol+NEPI rabbits were significantly lower than those in Cholesterol rabbits. UK73967, an active form of UK79300, or phosphoramidon partly reversed the atherosclerotic impairment of relaxation of the isolated thoracic aortic rings from Cholesterol rabbits in response to exogenous additions of C-type natriuretic peptide (CNP) and substance P, which are NEP substrates known to exist endogenously in the vascular endothelium. The results suggest that the increased NEP activity plays a significant role in atherogenesis, and NEPIs might be therapeutically useful in the prevention of atherosclerosis. Reduction of plasma cholesterol and suppression of degradations in the arteries of endogenously released CNP, substance P, or possibly other kinins known to have anti-atherosclerotic actions may at least partially contribute to the inhibitory effects of NEPIs on atherosclerotic changes.
Administration, Oral↗
Rush immunotherapy with house dust extract in patients with mild extrinsic asthma.
Rush immunotherapy (RIT) with house dust extract was given to 15 patients with mild extrinsic or mixed asthma. Every patient was strongly positive for IgE on the radioimmunosorbent test and sensitive to house dust extract on the scratch skin test. Nine patients were positive on the bronchial provocation test to house dust extract and 6 could not be examined. All patients did not drop out and got to house dust extract solution 10(-1) within 1 week. The symptom-medication scores decreased significantly after RIT. During RIT 1 patient developed a mild asthmatic attack and 3 patients developed generalized skin reaction. Eight weeks later, the threshold for house dust-provoked bronchoconstriction increased in 9 patients, but did not in 3 patients. The blood eosinophil count and blood histamine level significantly decreased. We conclude that RIT is able to raise antigen concentrations for a short periods and effective but not risky for mild asthma.
Adolescent↗
Effect of estrogen on ontogenic expression of progesterone and estrogen receptors in rat uterus.
The ontogenic expression of progesterone and estrogen receptors (PR and ER) and effect of estrogen on these receptors were investigated immunohistochemically in rat uterus from the day of birth ( = 0 day) to 30 days of age. Uterine epithelial and stromal cells showed a negative PR immunoreaction at 0 day. The PR in the epithelial cell nuclei appeared by 5 days, while the stromal cells showed a negative PR reaction until 12 days. The staining of the stromal cells appeared from 12 to 15 days. In both the epithelial and stromal cells, the initiation of the PR appearance was not affected by ovariectomy performed at 0 day or 5 days prior to the appearance of PR in the epithelial and stromal cells. Estrogen injections from 0 day failed to initiate the appearance of PR in the epithelial cells, regardless of doses of estradiol-17 beta (0.1, 1 and 10 micrograms daily), but induced PR in the stromal cells. The staining of ER appeared at 5 days in the epithelial cells and at 1 day in the stromal cells, respectively. ER appeared after 2-3 daily injections of estrogen from 0 day depending upon the doses. These results suggest that steroid hormones secreted from neonatal ovary do not play any important role in ontogenic expression of PR during the postnatal uterine maturation.
Animals↗