Efficacy of 12 or 18 weeks of elbasvir plus grazoprevir with ribavirin in treatment-naïve, noncirrhotic HCV genotype 3-infected patients.

Elbasvir (EBR; HCV NS5A inhibitor) and grazoprevir (GZR; HCV NS3/4A protease inhibitor) are approved as a fixed-dose combination to treat patients chronically infected with HCV genotypes 1 and 4. During the development programme and supported by in vitro potency, the efficacy of EBR+GZR was assessed in HCV GT3-infected patients. This study's aim was to determine the efficacy and tolerability of 12 or 18 weeks of EBR+GZR with ribavirin (RBV) in treatment-naïve, noncirrhotic HCV GT3-infected patients. Randomized patients received open-label EBR (50 mg once daily) + GZR (100 mg once daily) + RBV. The primary efficacy objective was to evaluate the sustained virologic response rates 12 weeks after the end of all study therapy (SVR12). SVR12 rates (95% confidence interval) were 45.0% (23.1, 68.5) and 57.1% (34.0, 78.2) after treatment with EBR+GZR+RBV for 12 weeks or 18 weeks, respectively. On-treatment virologic failure was observed in 41% (17 of 41) of patients. At virologic failure, resistance-associated substitutions (RASs) with a >five-fold shift in potency occurred in the NS3 region in six (35%) patients and in the NS5A region in 16 (94%) patients. The most common RAS at virologic failure was Y93H in NS5A which was identified in 13 of 17 (76%) patients. The efficacy of EBR+GZR+RBV was suboptimal in HCV GT3-infected patients due to a high rate of on-treatment virologic failure and treatment-emergent RASs which demonstrates an inadequate barrier to the development of GT3 resistance. However, rapid viral clearance demonstrated the antiviral activity of EBR+GZR+RBV in GT3-infected patients.clinicaltrials.gov: NCT01717326.

Disruption of p53 in human cancer cells alters the responses to therapeutic agents.

We have examined the effects of commonly used chemotherapeutic agents on human colon cancer cell lines in which the p53 pathway has been specifically disrupted by targeted homologous recombination. We found that p53 had profound effects on drug responses, and these effects varied dramatically depending on the drug. The p53-deficient cells were sensitized to the effects of DNA-damaging agents as a result of the failure to induce expression of the cyclin-dependent kinase inhibitor p21. In contrast, p53 disruption rendered cells strikingly resistant to the effects of the antimetabolite 5-fluorouracil (5-FU), the mainstay of adjuvant therapy for colorectal cancer. The effects on 5-FU sensitivity were observed both in vitro and in vivo, were independent of p21, and appeared to be the result of perturbations in RNA, rather than DNA, metabolism. These results have significant implications for future efforts to maximize therapeutic efficacy in patients with defined genetic alterations.

Efficacy of pentosan polysulfate in the treatment of interstitial cystitis: a meta-analysis.

OBJECTIVES: To determine the efficacy of pentosan polysulfate (Elmiron) compared to placebo in the treatment of interstitial cystitis. METHODS: The data sources used were MEDLINE, Excerpta Medica, and International Pharmaceutical Abstracts databases, and the manufacturer. Bibliographies of articles obtained were reviewed. The keywords used were pentosanpolysulfate, pentosanpolysulfate sodium, and pentosan. Inclusion criteria were blinded selection of English language, prospective, randomized, placebo-controlled comparative trials; > or = 8 weeks' duration; > or = 300 mg daily; adult humans with > or = 1 symptoms including pain, urgency, frequency, and nocturia; symptoms for > or = 12 months; normal urinalysis; negative findings for urine culture and cytology. Exclusion criteria were hemorrhagic cystitis; drug-, microbial-, or radiation-induced cystitis; carcinoma in situ; other influencing diseases. The outcome of success was defined as a > or = 50% decrease in pain, urgency, frequency, and nocturia. The number of successes was extracted by blinded investigators, treating withdrawals as failures. The percentage difference in success rates of pentosan polysulfate and placebo, and the number needed to treat (NNT) were determined for each variable; P values and 95% confidence intervals (CIs) were determined for combined data. Homogeneity of effect was determined by calculating Q (chi-squared). Article quality was assessed using the Chalmers scale to determine if quality affected outcome. Effective inter-rater reliability was determined using Rosenthal's method. Significance was set at P < 0.05. RESULTS: Four studies were included. Data were extracted from all four studies for pain (n = 398), three for urgency (n = 306), two for frequency (n = 160), and one study for nocturia (n = 106). The differences (95% confidence limits) were pain: 16.6% (95% CI 8%, 25%), NNT = 7; urgency: 13.0% (1.0%, 25%), NNT = 7.5; frequency: 16.7% (2.3%, 31.1%), NNT = 6; nocturia: -1% (-19.8%, 21.8%). P values from homogeneity tests were not significant. Mean quality scores were 63.8%, 48.1%, 50.4%, and 65.6%, respectively, in the four studies; the effective inter-rater reliability was 0.96. Results did not differ when weighted by quality score. CONCLUSIONS: Pentosan polysulfate is more efficacious than placebo in the treatment of pain, urgency, and frequency associated with interstitial cystitis. Pentosan polysulfate is not significantly different from placebo in treating nocturia associated with interstitial cystitis.

Interactions of clobazam with conventional antiepileptics in children.

Clobazam is a 1,5-benzodiazepine effective in antiepileptic therapy of children and adults. Presently it is mainly used as adjuvant therapy for intractable seizures. Our objective was to evaluate the effect of clobazam on the apparent clearance of other antiepileptic drugs at steady state, and to determine the factors that determine the plasma levels of clobazam and its active metabolite N-desmethylclobazam. Patients were 74 children with intractable seizures who received treatment with clobazam at our institution as part of the Canadian Cooperative Clobazam Study Group during the years 1987 to 1991. Serum concentrations of clobazam, N-desmethylclobazam, and of concomitant antiepileptic drugs were monitored and prospectively collected. The effect of clobazam treatment on the apparent clearance steady state of the other antiepileptic drugs was determined by statistical comparison of the clearances of each drug before and after initiation of clobazam treatment using Wilcoxon's signed rank test. The effects of dosage, age, and concomitant antiepileptic therapy on the levels of clobazam and N-desmethylclobazam was assessed by multivariate analysis. Response to treatment and incidence of adverse effects were evaluated for each conventional antiepileptic drug to possibly identify favorable or unfavorable combinations with clobazam. Whereas the clearances of most conventional antiepileptics are not affected by cotherapy with clobazam, the apparent clearances of valproic acid and primidone are significantly reduced in the presence of clobazam. Serum concentrations of clobazam increased with dosage and age, and decreased with phenobarbital cotherapy. Serum concentrations of N-desmethylclobazam significantly correlated with clobazam serum levels, age, or clobazam dosage and were significantly increased by cotherapy with phenytoin or carbamazepine. None of the concomitantly used drugs were associated with increased or decreased rate of seizure control. Twelve patients experienced mild adverse drug effects that were not associated with particular cotherapy, clobazam dose, or plasma concentrations. When clobazam is added to a therapy regimen that includes valproic acid, the patient should be closely followed for possible adverse drug reactions caused by elevated valproic acid serum concentrations, and monitoring of valproate serum levels should be considered. When clobazam doses are gradually increased to achieve an optimal clinical effect, the interactions with phenobarbital, carbamazepine, and phenytoin do not necessitate therapeutic drug monitoring of clobazam or N-desmethylclobazam, because there is a large therapeutic window and a poor correlation between plasma concentrations and therapeutic efficacy.

Interaction of mistletoe toxic lectin-I with sialoglycoproteins.

The binding properties of mistletoe toxic lectin-I (ML-I) with sialo-N- and O-glycans were investigated by quantitative precipitin and precipitin inhibition assays. Human alpha 1-acid glycoprotein reacted strongly with ML-I, precipitating over 82% of the lectin nitrogen tested, while the precipitability of its asialo product decreased by 30%. Native fetuin precipitated 50% of the ML-I added, and its reactivity was reduced by 20% after desialylation. On the contrary, the poor reactivity of rat sublingual sialoglycoprotein with ML-I increased substantially after removal of sialic acid and completely precipitated the lectin added. The glycoprotein-lectin interactions were inhibited by NeuAc alpha 2-->3/alpha 2-->6Gal beta 1-->4Glc and/or Gal beta 1-->4Glc (NAc) residues. From the above results, it is concluded that ML-I is specific for sialic acid. However, sialic acid of some O-glycans also acts as masking molecule as the precipitability of rat sublingual and bovine submandibular glycoproteins with ML-I increased after desialylation.

Characterization of the okra mucilage by interaction with Gal, GalNAc and GlcNAc specific lectins.

A bio-active polysaccharide, which was the major component of the extract of the common okra, Hibiscus esculentus, was isolated from the extract by precipitation with ethanol between 28.5 to 45%. According to a previous report (Whistler, R.L. and Conrad, H.E. (1954) J. Am. Chem. Soc. 76, 1673-1674), this polysaccharide contains the Gal alpha 1-->4Gal sequence, which is the ligand for the uropathogenic Escherichia coli and toxic lectins. Analysis of the binding property of the okra polysaccharide by precipitin assay with Gal, GalNAc and GlcNAc specific lectins showed that this okra mucilage reacted best with Mistletoe toxic lectin-I (ML-I) and precipitated over 80% of the ML-I nitrogen (5.1 micrograms N) added. It also precipitated well with Abrus precatorius (APA), Momordica charantia (MCA) and Ricinus communis (RCA1) agglutinins, but poorly with other lectins. The results obtained suggest that this polysaccharide is a valuable reagent to differentiate Gal specific lectins from the GalNAc and/or GlcNAc specific series.

The anticonvulsant effects of vitamin E: a further evaluation.

Vitamin E (d-alpha-tocopherol) has proven to be a useful adjunct to anticonvulsant drugs in clinical studies. Improvement has occurred even in patients with complex partial seizures, which are often resistant to drug therapy. In animals, vitamin E is effective against ferrous chloride seizures, hyperbaric oxygen seizures and penicillin-induced seizures. It has failed, however, to show anticonvulsant effects in the standard animal models used for drug screening--the maximal electroshock and threshold pentylenetetrazol tests. The present experiments were designed to further explore the anti-epileptic actions of vitamin E in animals. Three models related to complex partial epilepsy were used: 1) the development of amygdala-kindled seizures; 2) the development of electrically-induced status in kindled animals; and 3) the development of kainic-acid seizures. Vitamin E failed to produce significant effects in any of the models.

Gelastic seizures treated by resection of a hypothalamic hamartoma.

A 7-year-old girl presented for evaluation of a peculiar kind of epilepsy. Her seizures began before 1 year of age and consisted of episodes of brief, uncontrolled and unprovoked laughter than with time progressed to include cursive, complex partial and generalized tonic-clonic seizures. Progressive impairment of cognitive functions was noted as well as precocious puberty. Neuroimaging examination disclosed a hypothalamic hamartoma. It was excised by a pterional approach, and no further seizures were noted. The authors propose direct surgery for the hypothalamic hamartoma as a treatment for this progressive syndrome.

Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase.

Nitric oxide is a messenger molecule, mediating the effect of endothelium-derived relaxing factor in blood vessels and the cytotoxic actions of macrophages, and playing a part in neuronal communication in the brain. Cloning of a complementary DNA for brain nitric oxide synthase reveals recognition sites for NADPH, FAD, flavin mononucleotide and calmodulin as well as phosphorylation sites, indicating that the synthase is regulated by many different factors. The only known mammalian enzyme with close homology is cytochrome P-450 reductase.