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HCV viraemia and liver injury in symptom-free blood donors
In this case psychotic symptoms were related to zolpidem. In previous amnesic psychotic reactions reported with and triazolam, our patient retained full memory of zolpidem the event. Macropsia occurred with zolpidem, a specific benzodiazepine type 1 receptor (BZ1) agonist with rapid absorption (cmax in 1 ’8 h) and short halflife (2-2 h), and not with quazepam, also a BZ1 1 agonist2 but with slow absorption (cmax 2-5h) and long halflife (> 27 h). Ansseau et all suggested that psychotic reactions with hypnotics depend more on the pharmacokinetics of the drug than on receptor specificity. The other two cases of psychotic reactions with zolpidem and our case are women. The toxicity of zolpidem in women could in part be explained by plasma zolpidem concentration being 40% higher in women.3 In anorexia nervosa, hypoalbuminaemia is common and in this situation free drug concentration is higher, which could also be related to zolpidem toxicity in our case. We suggest that zolpidem be contrast to
given cautiously to low-weight women.
inflammation (range 0-3, median 1), lobular inflammation (range 0-4, median 1), and piecemeal necrosis (range 0-5, median 0) correlated with HCV viraemia levels (r=0’64, and f=049, r=0-60, p<001; r=048, p<005; p<001;
portal
p < 005;
respectively).
Chronic hepatitis seems to be frequently caused by HCV infection irrespective of biochemical evidence of liver injury. We conclude that high level HCV replication is a contributory cause of liver injury in symptom-free blood donor populations.
Yuki, Norio Hayashi, Takenobu Kamada Department of Medicine, Osaka University Medical School, Suita 565, Japan
Nobukazu First
1
2
Hagiwara H, Hayashi N, Mita E, et al. Quantitative analysis of hepatitis C virus RNA in serum during interferon alfa therapy. Gastroenterology 1993; 104: 877-83. Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981; 1: 431-35.
Luis M Iruela, Vicente lbañez-Rojo, Enrique Baca Department of Psychiatry, Universidad Autonoma de Madrid, Clinica Puerta de Hierro, Madrid 28035, Spain
1 2 3
Ansseau M, Pitchot W, Hansenne M, Gonzalez-Moreno A. Psychotic reactions to zolpidem. Lancet 1992; 339: 809. Kales A. Quazepam: hypnotic efficacy and side effects. Pharmacotherapy 1990; 10: 1-12. Bianchetti G, Dubruc C, Thiercelin JF, et al. Clinical pharmacokinetics of zolpidem in various physiological and pathological conditions. In: Sauvanet JP, Langer SZ, Morselli PL, eds. Imidazopyridines in sleep disorders. New York: Raven Press, 1988: 155-63.
HCV viraemia and liver blood donors
injury in symptom-free
SIR-Lau and colleagues (June 12, p 1501) draw attention to the potential relation between serum hepatitis C virus (HCV) RNA concentrations and degree of liver inflammation in patients with chronic HCV infection. They applied a new quantitative branched DNA (bDNA) assay for detecting serum HCV RNA. We have evaluated this assay by comparing the results with those of the competitive reverse transcription polymerase chain reaction (RT-PCR), and have further examined the correlation between HCV viraemia and histological indices in blood donors with chronic HCV infection. We tested by bDNA (Chiron) 39 serum samples that had HCV RNA of 104-109copies/mL (median 10’) by competitive RT-PCR.1 HCV RNA of 105 6-10’equivalents/mL (median 1065) was detected in 37 (95 %) samples, whereas 2 samples with low concentrations of HCV RNA (104 and 1045 copies/mL, respectively) tested negative. A significant correlation was observed between values by competitive RT-PCR and those by bDNA (r = 072, p < 0-01), indicating that the bDNA assay is a powerful approach in analysis of HCV infection. Since January, 1992, 21 symptom-free blood donors who were positive by HCV RNA PCR were monitored monthly for at least one year by liver function tests, and underwent liver biopsy. Liver histological analysis showed chronic persistent hepatitis in 18 (86%) patients and chronic active hepatitis in 2. Only 1 of the 7 patients with persistently normal aminotransferase concentrations throughout follow-up had histologically normal livers; the other 6 had chronic persistent hepatitis. Liver biopsy specimens were semiquantitatively evaluated by the histological activity index (HAI) scoring system described by Knodell et aI,2 and the results were correlated with HCV viraemia levels. Serum samples obtained on the day of liver biopsy were tested by bDNA assay and HCV RNA concentrations were 105’-10’equivalents/mL (median 10*’ ). The total HAI score (range 0-15, median 2) and scores of
444
Tamoxifen trial in healthy women at risk of breast cancer SIR-In your July 17 news section you report the start of the breast cancer prevention trial with tamoxifen in the UK, but do not mention that Italy is among the group of countries in which such trials have started. A tamoxifen study in healthy women was begun in our country in October, 1992, and by July 26, 1993, 1169 women have been randomised. The study design foresees the accrual of only women who have had hysterectomy until the issue of endometrial carcinogenesis with tamoxifen is clarified. More than 30 Italian centres are participating in the study, which is mainly funded by the Milanese League against Cancer and other local charities. Alberto Costa Centro Operativo, Ambulatorio 20146 Milan, Italy
Lega Italiana per la
Lotta Contro
i Tumon,
SIR-In your news item, you say that "for the 85 women who have become pregnant while on tamoxifen no fetal abnormalities have been reported". How is it that if tamoxifen is contraindicated in pregnancy, so many have become pregnant? Can we be sure that no women included in the prevention trials will become pregnant, despite warnings? Furthermore, how can we be sure that there are no long-term effects on the fetus that are so far undiscovered? The role of stilboestrol (once prescribed to prevent miscarriage, and still used to treat breast cancer) in the aetiology of vaginal cancers and testicular problems in the offspring of mothers who took the drug in pregnancy is a case in point. It may be twenty years before such
problems
come to
light.
Heather Goodare 1 Heron
Way, Horsham, West Sussex RH13 6DF, UK
Tamoxifen and liver cancer SiR-Your
April 24 note (p 1086) draws attention to the hepatocarcinogenicity of tamoxifen in female rats reported by usl and raises concernabout the use of this drug as a prophylactic agent in women at high risk of breast cancer (see July 17, p 168). The projected risk in man may have been underestimated by supporters of the use of tamoxifen in chemopreventionon the basis of the belief that the doses producing liver cancer in rats are much larger than those for women. We have just completed a second 12-month daily gavage study in female Sprague-
given cautiously to low-weight women.
inflammation (range 0-3, median 1), lobular inflammation (range 0-4, median 1), and piecemeal necrosis (range 0-5, median 0) correlated with HCV viraemia levels (r=0’64, and f=049, r=0-60, p<001; r=048, p<005; p<001;
portal
p < 005;
respectively).
Chronic hepatitis seems to be frequently caused by HCV infection irrespective of biochemical evidence of liver injury. We conclude that high level HCV replication is a contributory cause of liver injury in symptom-free blood donor populations.
Yuki, Norio Hayashi, Takenobu Kamada Department of Medicine, Osaka University Medical School, Suita 565, Japan
Nobukazu First
1
2
Hagiwara H, Hayashi N, Mita E, et al. Quantitative analysis of hepatitis C virus RNA in serum during interferon alfa therapy. Gastroenterology 1993; 104: 877-83. Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981; 1: 431-35.
Luis M Iruela, Vicente lbañez-Rojo, Enrique Baca Department of Psychiatry, Universidad Autonoma de Madrid, Clinica Puerta de Hierro, Madrid 28035, Spain
1 2 3
Ansseau M, Pitchot W, Hansenne M, Gonzalez-Moreno A. Psychotic reactions to zolpidem. Lancet 1992; 339: 809. Kales A. Quazepam: hypnotic efficacy and side effects. Pharmacotherapy 1990; 10: 1-12. Bianchetti G, Dubruc C, Thiercelin JF, et al. Clinical pharmacokinetics of zolpidem in various physiological and pathological conditions. In: Sauvanet JP, Langer SZ, Morselli PL, eds. Imidazopyridines in sleep disorders. New York: Raven Press, 1988: 155-63.
HCV viraemia and liver blood donors
injury in symptom-free
SIR-Lau and colleagues (June 12, p 1501) draw attention to the potential relation between serum hepatitis C virus (HCV) RNA concentrations and degree of liver inflammation in patients with chronic HCV infection. They applied a new quantitative branched DNA (bDNA) assay for detecting serum HCV RNA. We have evaluated this assay by comparing the results with those of the competitive reverse transcription polymerase chain reaction (RT-PCR), and have further examined the correlation between HCV viraemia and histological indices in blood donors with chronic HCV infection. We tested by bDNA (Chiron) 39 serum samples that had HCV RNA of 104-109copies/mL (median 10’) by competitive RT-PCR.1 HCV RNA of 105 6-10’equivalents/mL (median 1065) was detected in 37 (95 %) samples, whereas 2 samples with low concentrations of HCV RNA (104 and 1045 copies/mL, respectively) tested negative. A significant correlation was observed between values by competitive RT-PCR and those by bDNA (r = 072, p < 0-01), indicating that the bDNA assay is a powerful approach in analysis of HCV infection. Since January, 1992, 21 symptom-free blood donors who were positive by HCV RNA PCR were monitored monthly for at least one year by liver function tests, and underwent liver biopsy. Liver histological analysis showed chronic persistent hepatitis in 18 (86%) patients and chronic active hepatitis in 2. Only 1 of the 7 patients with persistently normal aminotransferase concentrations throughout follow-up had histologically normal livers; the other 6 had chronic persistent hepatitis. Liver biopsy specimens were semiquantitatively evaluated by the histological activity index (HAI) scoring system described by Knodell et aI,2 and the results were correlated with HCV viraemia levels. Serum samples obtained on the day of liver biopsy were tested by bDNA assay and HCV RNA concentrations were 105’-10’equivalents/mL (median 10*’ ). The total HAI score (range 0-15, median 2) and scores of
444
Tamoxifen trial in healthy women at risk of breast cancer SIR-In your July 17 news section you report the start of the breast cancer prevention trial with tamoxifen in the UK, but do not mention that Italy is among the group of countries in which such trials have started. A tamoxifen study in healthy women was begun in our country in October, 1992, and by July 26, 1993, 1169 women have been randomised. The study design foresees the accrual of only women who have had hysterectomy until the issue of endometrial carcinogenesis with tamoxifen is clarified. More than 30 Italian centres are participating in the study, which is mainly funded by the Milanese League against Cancer and other local charities. Alberto Costa Centro Operativo, Ambulatorio 20146 Milan, Italy
Lega Italiana per la
Lotta Contro
i Tumon,
SIR-In your news item, you say that "for the 85 women who have become pregnant while on tamoxifen no fetal abnormalities have been reported". How is it that if tamoxifen is contraindicated in pregnancy, so many have become pregnant? Can we be sure that no women included in the prevention trials will become pregnant, despite warnings? Furthermore, how can we be sure that there are no long-term effects on the fetus that are so far undiscovered? The role of stilboestrol (once prescribed to prevent miscarriage, and still used to treat breast cancer) in the aetiology of vaginal cancers and testicular problems in the offspring of mothers who took the drug in pregnancy is a case in point. It may be twenty years before such
problems
come to
light.
Heather Goodare 1 Heron
Way, Horsham, West Sussex RH13 6DF, UK
Tamoxifen and liver cancer SiR-Your
April 24 note (p 1086) draws attention to the hepatocarcinogenicity of tamoxifen in female rats reported by usl and raises concernabout the use of this drug as a prophylactic agent in women at high risk of breast cancer (see July 17, p 168). The projected risk in man may have been underestimated by supporters of the use of tamoxifen in chemopreventionon the basis of the belief that the doses producing liver cancer in rats are much larger than those for women. We have just completed a second 12-month daily gavage study in female Sprague-