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Biomedical subjects

G Farrell

Publications and source records attributed to G Farrell.

At least 19 recordsLinked to original sources
PubMed2006

Role of individualization of hepatitis C virus (HCV) therapy duration in HIV/HCV-coinfected individuals.

OBJECTIVE: The aim of this study was to assess the efficacy, safety and tolerability of pegylated interferon and ribavirin in HIV/hepatitis C virus (HCV)-coinfected patients, prescribed for the same duration and at the same dosage as that used in HCV monoinfection studies. DESIGN: It was an open-label, single-centre, prospective study. METHODS: Forty-five patients coinfected with HIV and HCV with CD4 counts >200 cells/microL were treated with pegylated interferon-alpha2b 1.5 microg/kg/week and ribavirin 1000-1200 mg/day for 24-48 weeks depending on HCV genotype. Safety and tolerability were assessed weekly for the first month and monthly thereafter. Virological response was assessed at weeks 4, 12 and 24 and at the end of treatment and 12 and 24 weeks post completion of treatment. The primary endpoint was defined as undetectable HCV RNA at 24 weeks post completion of treatment [sustained virological response (SVR)]. RESULTS: The majority of patients were male and had been injecting drug users. Sixty per cent were on antiretroviral therapy. In an intention-to-treat analysis, 53% had an SVR (genotype 1, 19% and genotype 2/3, 75%). All patients who had undetectable HCV RNA at week 4 of HCV treatment [very early virological response (VEVR)] had a SVR. On multivariate analysis only HCV genotype predicted SVR. Adverse events occurred frequently. CONCLUSIONS: These results indicate that 24 weeks of HCV treatment may be adequate for HIV-infected individuals coinfected with HCV genotype 2 or 3. VEVR can predict SVR in this group and may be used to guide the subgroup of genotype 2/3 individuals who will respond to 24 weeks of treatment.

Adult↗
PubMed2004

Racial differences in responses to interferon-beta-1a in chronic hepatitis C unresponsive to interferon-alpha: a better response in Chinese patients.

Re-treatment with interferon-alpha alone for chronic hepatitis C nonresponders to interferon-alpha monotherapy is almost ineffective. This multicentre, randomized, parallel-group, dose-finding study evaluated the efficacy of interferon-beta-1a in the treatment of chronic hepatitis C patients unresponsive to interferon-alpha. A total of 267 patients were randomized to one of four groups: subcutaneous interferon-beta-1a 12 MIU (44 microg) or 24 MIU (88 microg) administered three times weekly or daily. Patients were treated for 48 weeks and then followed up for an additional 24 weeks. There was a trend towards a dose-response relationship regarding virological [loss of detectable serum hepatitis C virus (HCV) RNA] and biochemical response (normalization of serum alanine aminotransferase). Overall, 22 patients (8.3%) had a virological response at the end of treatment; nine patients (3.4%) had a sustained virological response (SVR). Strikingly, 21.7% (5/23) of Chinese patients achieved SVR. Univariate analysis revealed that race was the only variable related to SVR [odds ratio (OR) 16.6; 95% CI 4.1-67.3; P < 0.0001]. Multiple logistic regression analysis also confirmed that more Chinese patients achieved SVR than non-Chinese patients (OR 12.3; 95% CI 2.6-59.3; P = 0.0017). In addition, complete clearance of HCV-RNA occurred earlier in Chinese than in non-Chinese responders (median 2 vs 30 weeks; P = 0.020). Thirty-six patients were withdrawn from treatment because of adverse events. Most adverse events were mild or moderate in severity. In conclusion, interferon-beta-1a provided considerable clinical benefit in Chinese patients with chronic hepatitis C unresponsive to interferon-alpha. The evaluation of interferon-beta-1a in this setting is progressing.

Adolescent↗
PubMed2003

Cystic fibrosis mutation frequencies in an Irish population.

The incidence of cystic fibrosis (CF) at birth in Ireland is 1/1461. Neonate CF genetic testing is not routinely performed in Ireland. Currently, screening is only carried out where there is clinical evidence or a family history to suggest disease. Here we report the frequencies of common CF mutations occurring in an Irish population composed of samples collected from western, mid-western and southern regions of Ireland. Rarer CF mutations were also identified in a selected number of CF patients. In addition, a number of polymorphisms were identified, some of which are reported to be functionally and phenotypically important.

Cystic Fibrosis↗
PubMed2000

Hepatitis B e antigen seroconversion: effects of lamivudine alone or in combination with interferon alpha.

Seroconversion of hepatitis B e antigen (HBeAg) is an important marker for resolution of active hepatitis B virus (HBV) infection and for a long-term positive response to treatment. Lamivudine, a nucleoside analogue, is the first effective oral treatment for chronic hepatitis B in patients with evidence of viral replication and liver disease. When appropriate patient groups are compared, treatment with lamivudine for 1 year leads to HBeAg seroconversion in a similar proportion of patients as a standard course of interferon (IFN) alpha therapy. Seroconversion increases during prolonged therapy (up to 3 years), and is sustained post-treatment in more than three-quarters of patients. Response rates are related to the pretreatment level of serum alanine aminotransferase (ALT) and reach 65% in those patients with serum ALT > 5 x upper limit of normal (ULN) after one year. For patients with pretreatment ALT > 2 x ULN, response was seen in 38% after one year, rising to 65% after 3 years. To date, combination with IFN and lamivudine has not been shown to confer additional benefit compared with lamivudine monotherapy. Lamivudine is effective and appropriate for use in a greater proportion of HBV infected patients than IFN alpha, particularly those infected at birth or in early childhood. Furthermore, because seroconversion after lamivudine is not normally associated with a severe flare of liver disease, as seen with IFN, it is more suitable for use in patients with active liver disease and cirrhosis. In conclusion, lamivudine is more suitable than IFN for a broad range of patients, including those with severe liver disease, recurrent flares, pre-core mutant HBV and those who have failed previously IFN treatment or are immunosuppressed. Lamivudine is also better tolerated than IFN.

Antiviral Agents↗
PubMed2000

Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial.

UNLABELLED: BACKGROUND, AIM, AND METHODS: Alpha interferon is the generally approved therapy for HBe antigen positive patients with chronic hepatitis B, but its efficacy is limited. Lamivudine is a new oral nucleoside analogue which potently inhibits hepatitis B virus (HBV) DNA replication. To investigate the possibility of an additive effect of interferon-lamivudine combination therapy compared with interferon or lamivudine monotherapy, we conducted a randomised controlled trial in 230 predominantly Caucasian patients with hepatitis B e antigen (HBeAg) and HBV DNA positive chronic hepatitis B. Previously untreated patients were randomised to receive: combination therapy of lamivudine 100 mg daily with alpha interferon 10 million units three times weekly for 16 weeks after pretreatment with lamivudine for eight weeks (n=75); alpha interferon 10 million units three times weekly for 16 weeks (n=69); or lamivudine 100 mg daily for 52 weeks (n=82). The primary efficacy end point was the HBeAg seroconversion rate at week 52 (loss of HBeAg, development of antibodies to HBeAg and undetectable HBV DNA). RESULTS: The HBeAg seroconversion rate at week 52 was 29% for the combination therapy, 19% for interferon monotherapy, and 18% for lamivudine monotherapy (p=0.12 and p=0.10, respectively, for comparison of the combination therapy with interferon or lamivudine monotherapy). The HBeAg seroconversion rates at week 52 for the combination therapy and lamivudine monotherapy were significantly different in the per protocol analysis (36% (20/56) v 19% (13/70), respectively; p=0.02). The effect of combining lamivudine and interferon appeared to be most useful in patients with moderately elevated alanine aminotransferase levels at baseline. Adverse events with the combination therapy were similar to interferon monotherapy; patients receiving lamivudine monotherapy had significantly fewer adverse events. CONCLUSIONS: HBeAg seroconversion rates at one year were similar for lamivudine monotherapy (52 weeks) and standard alpha interferon therapy (16 weeks). The combination of lamivudine and interferon appeared to increase the HBeAg seroconversion rate, particularly in patients with moderately elevated baseline aminotransferase levels. The potential benefit of combining lamivudine and interferon should be investigated further in studies with different regimens of combination therapy.

Adolescent↗
PubMed1998

Prolonged treatment with interferon in patients with histologically mild chronic hepatitis C: a decision analysis.

Short courses (6 months) of interferon (IFN) are highly cost-effective in patients with histologically mild chronic hepatitis C. However, IFN treatment lasting 12-24 months is now the standard of care. We utilized a previously published and validated model of the natural history of chronic hepatitis C and the treatment outcomes from two large multicentre treatment trials of IFN-alpha 2b, given for 6 months or 18-24 months, to estimate the incremental cost-effectiveness of prolonged IFN treatment in patients with histologically mild chronic hepatitis C (formerly chronic persistent or mild chronic active hepatitis). In the two treatment trials, pooled analysis of the patients with mild hepatitis showed that 36.4% of them normalized serum alanine aminotransferase and remained virus negative (sustained response) after completing an 18-24 month course of IFN vs 15.3% for a 6-month course and no response in the absence of treatment. The model then estimated that for patients aged 20-50 years, the discounted marginal cost per year of life gained by long-term IFN treatment ranged from US $735 to US $8856, and the gain in life expectancy ranged from 4.35 years to 0.75 years, respectively, compared with an untreated age-matched cohort. Compared with treatment for only 6 months, the incremental marginal cost per life year gained by longer treatment at age 20-50 years ranged from $938 to $9957. The treatment and healthcare costs, sustained response rates and the rate of progression during early disease were identified as significant variables in sensitivity analyses. However, longer treatment always showed a survival benefit compared with 6 months of IFN or no treatment, and the cost of longer treatment is reasonable compared with that for a 6-month course.

Adult↗
PubMed1998

Factors affecting epirubicin pharmacokinetics and toxicity: evidence against using body-surface area for dose calculation.

PURPOSE: An exploratory study to test whether body-surface area (BSA) should be used for the calculation of epirubicin dose. PATIENTS AND METHODS: The relationship between pretreatment characteristics and the effects of epirubicin were investigated in 20 chemotherapy-naive patients. Measurements of body size, renal and hepatic function, and other factors were correlated with epirubicin pharmacokinetics (PK) and epirubicin-induced neutropenia. All patients received 150 mg of epirubicin infused continuously over 120 hours, regardless of body size. Factors were analyzed by univariate and multivariate linear regression. RESULTS: There were no correlations between BSA or weight with any PK parameter or with the degree of neutropenia. In multivariate analysis, indicators of liver function were the only factors that correlated with neutropenia and epirubicin PK. Thus, correlations for neutropenia were seen with antipyrine clearance (P = .003), activated partial thromboplastin time (APTT) (P = .005) and serum transferrin (P = .01). Further, the area under the concentration-time curve (AUC) for epirubicin correlated with prothrombin index (P < .01), antipyrine clearance (P < .01), and serum bile salt concentration (P = .03), and there were similar correlations for epirubicin steady-state concentration (CpSS). Epirubicin clearance correlated with antipyrine clearance (P = .02). PK parameters for dihydroepirubicin correlated with prothombin index, serum transferrin, and bile salt concentrations (P < .001 for all correlations). Because of the number of statistical examinations performed, some of these correlations may be spurious. However, some are likely to be real, since the same variables repeatedly correlated with different epirubicin-associated outcomes. There were no correlations between epirubicin PK indices or neutropenia and serum aminotransferase levels or other biochemical liver function tests, creatinine, or any of the clinical factors examined. CONCLUSION: These results led us to question the use of BSA for epirubicin dose calculation. In contrast, quantitative liver function tests may give a better indication of drug handling and toxicity and may be useful to determine more accurate methods for dose calculation of epirubicin.

Adult↗
PubMed1997

Efficacy and tolerance of a 6-month treatment course of daily interferon-alpha 2a for chronic hepatitis C with cirrhosis. The Australian Hepatitis C Study Group.

Response to interferon-alpha (IFN-alpha) treatment in hepatitis C is poorer when cirrhosis is present. In the third Australian multicentre hepatitis C trial, Aushep-3, we examined the efficacy and tolerability of an intensive 24-week course of interferon-alpha 2a in Child-Pugh grade A patients with chronic hepatitis C and cirrhosis. This was an open uncontrolled trial of 4.5 million units (MU) of IFN-alpha 2a daily for 24 weeks; follow-up was 48 weeks. Chronic hepatitis C and cirrhosis were confirmed histologically. HCV RNA was determined in serum by reverse transcriptase polymerase chain reaction (PCR), and viral genotyping was by line-probe assay. Treatment response was defined as a reduction of alanine aminotransferase (ALT) to less than 1.5 times the upper limit of normal (and by at least 50% of pretreatment values) at weeks 20 and 24. Sustained response was defined as normal serum ALT after treatment from trial week 28 until week 48. Among the 56 patients, a treatment response occurred in 18 (32% by intention-to-treat; 42% of those who completed treatment) and eight (14%) had a sustained response. At 24 weeks, HCV RNA was not detectable in 12 of 17 treatment responders, and remained negative at 48 weeks in six of eight sustained responders. Treatment response by genotype occurred in 75% of patients with HCV type 2, in 38% with HCV type 3a and in 12% with HCV genotype 1. Sustained response occurred in only one (4%) patient with HCV genotype 1 but in five (20%) with genotypes 2 or 3a. Among 13 patients withdrawn, nine were for adverse effects, most often haematological; 10 others underwent dose reduction for adverse effects. It is concluded that a sustained biochemical and viral response to treatment with IFN-alpha 2a can be obtained in some patients with hepatitis C and cirrhosis, particularly those with genotypes 2 or 3a. Therefore, patients with cirrhosis should be considered for interferon treatment on an individual basis. Genotyping may improve case selection, but vigilance is required for haematological complications.

Adult↗
PubMed1997

Diterpenoids from germander, an herbal medicine, induce apoptosis in isolated rat hepatocytes.

BACKGROUND & AIMS: Germander was withdrawn from the market after its use for weight control caused an epidemic of hepatitis. Its toxicity was shown to be caused by diterpenoids and their cytochrome P4503A-mediated metabolic activation into electrophilic metabolites that deplete cellular thiols. The aim of the present study was to determine the mechanisms of cell death. METHODS: Isolated rat hepatocytes were incubated for 2 hours with germander diterpenoids (100 micrograms/mL). RESULTS: Diterpenoids decreased cell glutathione, increased cytosolic [Ca2+], activated Ca(2+)-dependent tissue transglutaminase forming a cross-linked protein scaffold, and caused internucleosomal DNA fragmentation and the ultrastructural features of apoptosis. Cell death was prevented by decreasing metabolic activation (with troleandomycin), preventing depletion of glutathione (with cystine), blocking activation of Ca(2+)-modulated enzymes (with calmidazolium), or inhibiting internucleosomal DNA fragmentation (with aurintricarboxylic acid). Apoptosis was increased and diterpenoids caused overexpression of p53 and interleukin 1 beta-converting enzyme in rats treated with dexamethasone (cytochrome P4503A inducer). Apoptosis was also increased by a diet deficient in sulfur amino acids. CONCLUSIONS: The germander furano diterpenoids cause apoptosis within 2 hours in isolated rat hepatocytes. Electrophilic metabolites may stimulate apoptosis by decreasing thiols, increasing [Ca2+], and activating Ca(2+)-dependent transglutaminase and endonucleases.

Amino Acids, Sulfur↗
PubMed1996

Telephoning a nursing department: callers' experiences.

This preliminary, exploratory study examined the level of satisfaction of patients and relatives with the telephone communication skills of nurses. Results indicate that callers experienced several difficulties, particularly with regards to knowing who they were speaking to, being treated as an individual rather than just another caller, having their calls dealt with efficiently, or redirected correctly. It is suggested that nurse educators include training in telephone use in courses on communication skills.

Communication↗
PubMed1994

Comparative study of three doses of interferon-alpha 2a in chronic active hepatitis B. The International Hepatitis Trial Group.

To determine the efficacy of interferon-alpha 2a in chronic active hepatitis B, 238 patients were randomly divided, into four groups: three groups received either 2.5 MIU m-2, 5.0 MIU m-2 or 10.0 MIU m-2, three times weekly by intramuscular injection for 12-24 weeks; and a control group received no treatment. Patients were followed for up to 12 months after treatment was discontinued. There was a statistically significant difference in response [clearance of hepatitis B e antigen (HBeAg) and hepatitis B viral DNA (HBV-DNA)] between treated and untreated patients (37 vs 13%) but no statistically significant difference was seen between treatment groups (33%, 34% and 43% for the 2.5, 5.0 and 10.0 MIU m-2 groups, respectively). A transient rise in transaminases (seroconversion hepatitis) was seen in responders, but levels returned to within the normal range after response to treatment. In patients responding to interferon therapy there was a significant reduction in the severity of the hepatitis. Interferon-alpha 2a was generally well tolerated with respect to vital signs and laboratory parameters.

Adolescent↗
PubMed1992

Liver function tests in persons receiving anticonvulsant medications.

Liver function tests were carried out in 206 adults and children taking anticonvulsants to ascertain the prevalence of biochemical abnormalities in asymptomatic patients. It was observed that serum gamma-glutamyl transpeptidase was elevated in 74.6% of patients, alkaline phosphatase in 29.7% and alanine aminotransferase in 25.2% of cases. These figures are similar to those previously reported in the literature and probably reflect hepatic enzyme induction by the anticonvulsants. It is suggested that there is no value in the routine performance of liver function tests in patients with epilepsy. However, such patients should be informed of the symptoms of hepatic dysfunction and asked to report for liver function tests should they have such symptoms.

Adolescent↗
PubMed1992

The effect of posture on three objective audiological measures.

This study examines the effect of posture on click evoked otoacoustic emissions, tympanic membrane displacement, and travelling wave velocity obtained using the auditory brainstem response. Statistically significant changes with posture were observed for each technique. The changes in evoked emission and tympanic membrane displacement measurements were comparable with those reported by previous experiments. Travelling wave velocity measurements were shown to be sensitive to inferred posturally-induced changes in labyrinthine fluid pressure of around 150 mm saline. There was no statistically significant correlation between posturally-induced changes measured by the three techniques. It is suggested that different mechanisms are responsible for the posturally-induced changes observed for the three techniques.

Adult↗
PubMed1991

A non-invasive, objective test of endolymphatic hydrops.

Our previous work has shown that auditory brainstem responses (ABRs) can be used to measure the basilar membrane travelling wave velocity (TWV). Based upon the hypothesis that increased pressure in the scala media will increase the stiffness of the basilar membrane and, hence, increase the speed of the travelling wave. ABRs have been used to provide a means of objectively testing for endolymphatic hydrops. Ten normally hearing subjects and 20 Meniere's patients were tested. The data for the Meniere's group show that the TWV was within normal limits at all frequencies tested, except 5.7 kHz. At this frequency, the TWV greatly exceeded that of the normal group. A short duration (15-30 min) clinical test has been developed which involves the recording of two masked brainstem responses and the measurement of the difference in wave V latencies. Clinical verification that the technique is valid was obtained by monitoring patients undergoing glycerol dehydration. The additional hardware to enable this test to be carried out with a standard evoked response system has been constructed and three, parallel, clinical trials are in hand. Currently, this technique is being applied to longitudinal studies of Meniere's patients and to evaluating the action and efficacy of various drugs. A double-blind trial using a placebo and two different drugs is underway and preliminary results are presented here.

Adolescent↗
PubMed1991

Apparent travelling wave velocity changes in cases of endolymphatic hydrops.

This study attempted to develop a test which would be specific for endolymphatic hydrops. It is based upon the hypothesis that increased pressure in the scala media will alter the stiffness of the basilar membrane and hence increase the speed of the travelling wave. Auditory brainstem-derived responses were used to measure the basilar membrane travelling wave velocity in normals and to take the equivalent measures in Meniere's patients. Ten normally hearing subjects and 20 Meniere's patients were tested. The data for the Meniere's group showed that the travelling wave velocities were within normal limits at all frequencies tested, except 5.7 kHz where the travelling wave velocity greatly exceeded that of the normal group. A theoretical possibility that these findings may be the result of damaged and broadened VIIIth nerve tuning curves is discussed but travelling wave measures and psychophysical tuning curve measurements on the Meniere's group, normals and noise-induced hearing loss (NIHL) cases showed that this was not a significant factor. The data indicate that this technique can detect endolymphatic hydrops and a short duration clinical procedure has been devised.

Adolescent↗