Safety, tolerability, and pharmacokinetics of ribavirin in hepatitis C virus-infected patients with various degrees of renal impairment.

Ribavirin (RBV) is an integral part of standard-of-care hepatitis C virus (HCV) treatments and many future regimens under investigation. The pharmacokinetics (PK), safety, and tolerability of RBV in chronically HCV-infected patients with renal impairment are not well defined and were the focus of an open-label PK study in HCV-infected patients receiving RBV plus pegylated interferon. Serial RBV plasma samples were collected over 12 h on day 1 of weeks 1 and 12 from patients with moderate renal impairment (creatinine clearance [CLCR], 30 to 50 ml/min; RBV, 600 mg daily), severe renal impairment (CLCR, <30 ml/min; RBV, 400 mg daily), end-stage renal disease (ESRD) (RBV, 200 mg daily), or normal renal function (CLCR, >80 ml/min; RBV, 800 to 1,200 mg daily). Of the 44 patients, 9 had moderately impaired renal function, 10 had severely impaired renal function, 13 had ESRD, and 12 had normal renal function. The RBV dose was reduced because of adverse events (AEs) in 71% and 53% of severe and moderate renal impairment groups, respectively. Despite this modification, patients with moderate and severe impairment had 12-hour (area under the concentration-time curve from 0 to 12 h [AUC0-12]) values 36% (38,452 ng · h/ml) and 25% (35,101 ng · h/ml) higher, respectively, than those with normal renal function (28,192 ng · h/ml). Patients with ESRD tolerated a 200-mg daily dose, and AUC0-12 was 20% lower (22,629 ng · h/ml) than in patients with normal renal function. PK modeling and simulation (M&S) indicated that doses of 200 mg or 400 mg alternating daily for patients with moderate renal impairment and 200 mg daily for patients with severe renal impairment were the most appropriate dose regimens in these patients.

Shorter durations and lower doses of peginterferon alfa-2a are associated with inferior hepatitis B e antigen seroconversion rates in hepatitis B virus genotypes B or C.

UNLABELLED: As there is currently a lack of consensus on the most appropriate dose and duration of peginterferon alfa-2a (PEG-IFNα-2a) therapy in hepatitis B e antigen (HBeAg)-positive patients, the efficacy and safety of either 24 or 48 weeks' duration and 90 µg/week or 180 µg/week doses were compared. HBeAg-positive patients (n = 544; 34% genotype B, 51% genotype C) were randomized to receive PEG-IFNα-2a (2 × 2 factorial design) for 24 or 48 weeks and at 90 µg/week or 180 µg/week and included in the per-protocol population. The primary efficacy endpoint of the noninferiority study was HBeAg seroconversion 6 months posttreatment. The prespecified odds ratio (OR) noninferiority margin was 1.88 with a one-sided significance level of 0.025. The highest rates of HBeAg seroconversion 6 months posttreatment were in the 180/48 arm (36.2% versus 14.1%-25.8% in the other arms). When the dose and duration arms were pooled, the OR for noninferiority of 24 weeks versus 48 weeks was 2.17 (95% confidence interval [CI] 1.43, 3.31; P = 0.749) and for 90 µg versus 180 µg was 1.79 (95% CI 1.18, 2.72; P = 0.410). As the upper limit of the 95% CI of the ORs were >1.88, 24 weeks were inferior to 48 weeks and 90 µg/week was inferior to 180 µg/week. The highest rates of response in the 180/48 arm were achieved by patients with HBsAg <1,500 IU/mL at Week 12 (58%) or Week 24 (57%), whereas patients with HBsAg >20,000 IU/mL did not respond. Adverse events were typical of those associated with PEG-IFNα-2a. CONCLUSION: Compared with lower doses and shorter durations, the licensed PEG-IFNα-2a treatment regimen (180 µg/48 weeks) was the most efficacious and beneficial for HBeAg-positive patients predominantly infected with hepatitis B virus genotypes B or C.

Placing the tip of the endotracheal tube at the carina and passing the endobronchial blocker through the Murphy eye may reduce the risk of blocker retrograde dislodgement during one-lung anaesthesia in small children.

We present nine cases of one-lung anaesthesia in small children and infants in which a novel technique was used to reduce the risk of endobronchial blocker retrograde dislodgement. The technique involved threading the stem of the blocker through the Murphy eye of the endotracheal tube (ETT) and deliberately passing the tip of the ETT all the way to the carina. The tip of the ETT blocked any retrograde movement of the blocker.

Responses are durable for up to 5 years after completion of peginterferon alfa-2a treatment in hepatitis B e antigen-positive patients.

BACKGROUND: In the large randomised NEPTUNE study, peginterferon alfa-2a 180 µg/wk for 48 weeks produced higher hepatitis B e antigen (HBeAg) seroconversion rates 24 weeks post-treatment (36%) than a lower dose (90 µg/wk) and/or shorter duration (24 weeks) (range 14%-26%). AIM: To determine seroconversion rates 5 years after completion of treatment in NEPTUNE. METHODS: HBeAg-positive patients who completed 24 weeks' follow-up in NEPTUNE (with peginterferon alfa-2a 90 µg/wk × 24 weeks [group 1]; 180 µg/wk × 24 weeks [2]; 90 µg/wk × 48 weeks [3] or 180 µg/wk × 48 weeks [4]) were followed up. RESULTS: Three hundred and eighty three of the 544 patients in the original study were enrolled in the long-term follow-up study. Many patients (196 overall; more in groups 1-3 than 4) received nucleos(t)ide analogues or immunomodulators during follow-up, and more patients had missing data at year 5 in groups 2 and 4 (48 weeks, 50/112) than in groups 1 and 3 (24 weeks, 23/103), which confounds the planned per-protocol analysis. HBeAg seroconversion rates in groups 1, 2, 3 and 4 at year 5 were 47.5%, 50.7%, 52.2% and 67.1%, respectively, (odds ratio for group 4 versus 1-3: 2.02; 95% CI 1.21, 3.38), using multiple imputation methods for missing measurements. CONCLUSION: Seroconversion rates are durable for up to 5 years after completion of peginterferon alfa-2a therapy and, consistent with NEPTUNE, the results suggest that the licensed regimen (180 µg × 48 weeks) is more efficacious for HBeAg-positive patients than a lower dose and/or shorter treatment duration.

Ability of specific monoclonal antibodies and conventional antisera conjugated to hematoporphyrin to label and kill selected cell lines subsequent to light activation.

A variety of cell lines have been prepared by fusion of the murine WEH1 3B cell line with peripheral blood leukocytes from a patient with chronic granulocytic leukemia. Fusion products were selected for their ability to produce a leukemia-associated antigen (CAMAL) previously described. One such line which originally produced CAMAL subsequently lost this ability and was used as a negative control. A number of antibodies were conjugated to hematoporphyrin (HP) and tested for their ability to bind to cell lines as detected by either fluorescence or by their ability to kill cells after light activation. The antibodies used were: rabbit anti-Hu (a conventional rabbit antiserum raised to membrane preparations from normal human peripheral blood leukocytes which served as a positive control); CAMAL-1 (a monoclonal gamma 1 antibody with specificity for the CAMAL antigen); and L1210 (an irrelevant monoclonal gamma 1 antibody). HP was conjugated to the antibodies by a carbodiimide procedure. When labeled cells were examined by fluorescence microscopy, it was apparent that both the rabbit antibody and CAMAL-1:HP showed positive labeling. The ability of the antibody:HP conjugates to kill labeled cells following light activation was tested. It was shown that rabbit anti-Hu:HP and CAMAL-1:HP conjugates were capable of killing significant numbers of cells when HP concentrations were as low as 1.2 ng/10(6) cells, whereas similarly treated cells exposed to either L1210:HP or HP alone did not exhibit significant killing until concentrations reached 240 and 120 ng/10(6) cells, respectively. Further experiments in which other cell lines were tested, all at HP concentrations of 12 ng/10(6) cells, demonstrated that those lines producing CAMAL were killed, whereas negative lines were not.

Phototoxic and antibiotic activities of plants of the Asteraceae used in folk medicine.

Ethanolic extracts of forty-four commercial herbal drugs and two fresh plants used in folk medicine, all species of the Asteraceae, were examined for their phototoxic and antibiotic activities against Escherichia coli, Saccharomyces cerevisiae and Candida albicans. Twenty samples were found to be active as either phototoxic and/or antibiotic agents and their phototoxic effects correlate with the presence of polyacetylenes and thiophenes.

Hypotensive effect of dehydroevodiamine from Evodiae Fructus.

Dehydroevodiamine isolated from Evodiae Fructus lowered blood pressure with bradycardia in anesthetised rats. At a cumulative dose of 22.5mg/kg/30min, there was a very significant decrease in blood pressure and heart rate. There was a more important decrease in diastolic pressure than systolic pressure, implying a vasodilatory effect. The hypotensive effect of dehydroevodiamine can be abolished partly by indomethacin and more completely, polyphoretin phosphate. It is suggested that the hypotensive effect of dehydroevodiamine may be mediated through prostaglandin synthesis. A similar action mechanism in dehydroevodiamine-stimulated rat uterus contraction is also discussed.

Examination of naturally occurring polyacetylenes and alpha-terthienyl for their ability to induce cytogenetic damage.

alpha-Terthienyl and 5 polyacetylenes were examined for chromosome damaging activity using Syrian hamster cells. None of these naturally occurring compounds induced sister chromatid exchanges and neither alpha-terthienyl nor phenylheptatriyne induced chromosome aberrations.

Photoimmunotherapy: treatment of animal tumors with tumor-specific monoclonal antibody-hematoporphyrin conjugates.

The term "photoimmunotherapy" describes an anti-cancer treatment that combines the phototoxic effects of chemical such as hematoporphyrin and the target-seeking ability of antibodies. Hematoporphyrin was chemically coupled to monoclonal antibodies directed to the DBA/2J myosarcoma M-1. Administration of anti-M-1-hematoporphyrin conjugates i.v. to M-1 tumor-bearing animals followed by exposure to incandescent light resulted in suppression of M-1 growth. The time interval between injection and light exposure was an important parameter in terms of tumor suppression. Tumor-bearing animals maintained in the dark for 96 to 196 hr after hematoporphyrin-antibody injection followed by 4-hr light exposure demonstrated significantly lower tumor incidence and longer latency periods, in comparison to conjugate-treated animals instantly exposed to light. The growth inhibiting properties of the conjugate appeared to be M-1-specific; it had no effect on the growth of a C57BL/6J lymphoma EL4. In addition, conjugates made with a nonspecific monoclonal antibody did not have any specific anti-tumor effect on M-1 growth. Treatment with equivalent doses of hematoporphyrin or antibody had no significant inhibiting effect on tumor growth. Clearly, the homing ability of the specific monoclonal antibody-hematoporphyrin conjugate was essential for effective drug delivery and inhibition of tumor growth.

Ultraviolet-mediated cytotoxic activity of phenylheptatriyne from Bidens pilosa L.

The tropical weed Bidens pilosa L. (Asteraceae) contains a number of polyacetylenes which are phototoxic to bacteria, fungi, and human fibroblast cells in the presence of sunlight, artificial sources of long-wave ultraviolet light, or cool-white fluorescent light. The principle photoactive compound in the leaf, phenylheptatriyne, is present in the cuticle as well as in the underlying cells. Experiments with calf thymus DNA indicate that, unlike photoactive furanocoumarins, phenylheptatriyne does not form interstrand cross linkages with DNA in ultraviolet light.

Phototoxic polyacetylenes and their thiophene derivatives. (Effects on human skin).

Polyacetylenes and their thiophene derivatives were tested for their effects on human skin. Topically applied alpha-terthienyl evoked bi-phasic phototoxic dermatitis and the appearance of 'sunburn' cells in human epidermis. None of 11 polyacetylenes had the same effect although they mimicked alpha-terthienyl in their phototoxic effects on Candida albicans and certain pathogenic microorganisms. The UV-mediated antibiotic activity of the compounds and their apparent lack of phototoxicity towards the skin suggest a potential topical therapeutic role for them in yeast, fungal and bacterial infections and light-responsive dermatoses. Their topical sensitizing capacity, however, has not yet been studied.

Early administration of oral oseltamivir increases the benefits of influenza treatment.

Our objective was to evaluate the benefit of early treatment of influenza illness using oral oseltamivir. This open-label, multicentre international study investigated the relationship between the interval from illness onset to first dose (time-to-treatment) and illness duration in the intent-to-treat infected population using accelerated failure time (AFT) modelling. A total of 1426 patients (12-70 years) presenting within 48 h of the onset of influenza symptoms were treated with oseltamivir 75 mg twice a day for 5 days during the 1999-2000 influenza season; 958 (67%) had laboratory-confirmed influenza virus infection. Earlier intervention was associated with shorter illness duration (P < 0.0001). Initiation of therapy within the first 12 h after fever onset reduced the total median illness duration by 74.6 h (3.1 days; 41%) more than intervention at 48 h. Intermediate interventions reduced the illness proportionately compared with 48 h. In addition, the earlier administration of oseltamivir further reduced the duration of fever, severity of symptoms and the times to return to baseline activity and health scores. Oseltamivir was well tolerated. The most common adverse events were nausea and vomiting, which were transient and generally occurred only with first dosing. When oseltamivir was taken with food, the tolerability was enhanced. The overall discontinuation rate was low (1.8%). In conclusion, the IMPACT study demonstrated that earlier initiation of oral oseltamivir therapy increased its therapeutic effects, which were seen at every time point of intervention and were progressive. Thus, early presentation, diagnosis and treatment of patients with influenza maximized the benefits of oseltamivir therapy.

Ultraviolet-mediated antibiotic activity of species of Compositae caused by polyacetylenic compounds.

A survey of North, Central, and South American composites, and of certain polyacetylenic compounds occurring in them, confirmed that the ultraviolet-mediated antibiotic activity against Candida albicans can be ascribed to the presence of particular polyacetylenes and their thiophene derivatives. Leaves, stems, roots, and achenes were assayed separately. An attempt was made to relate the phototoxic activity of specific compounds to their chemical structures. Most composites tested were not phototoxic against Candida, but many were antibiotic. The antibiotic activity also appears to be caused by polyacetylenes. Of 65 sequiterpene lactones assayed, only a few were found to be antibiotic, and only one, glaucolide G, was phototoxic.