864
in lymphocytes cultured as described for 4 weeks from a new blood sample taken 8 months after the first. The significance of these retrovirus-like particles for this patient’s MS is uncertain.
WethankDrHansGelderblom,RobertKochInstitute,Berlin,forexamining Supported by the Danish MS Society and
and discussing our EM pictures. Warwara-Larsen Foundation. Institute of Medical Microbiology, University of Aarhus, DK-8000 Aarhus C, Denmark, and Department of Neurology, Aarhus Kommunehospital
SVEN HAAHR METTE SOMMERLUND ANNÉ MØLLER-LARSEN RUTH NIELSEN HANS JAKOB HANSEN
1. Poser CM. Viruses, multiple sclerosis and HTLV-I. In: Roman GC, Vemant J-C, Osame M, eds. Neurol Neurobiol 1989; 51: 373-84. 2. Koprowski H, DeFreitas E, Harper M, et al. Multiple sclerosis and human T-cell lymphotropic retroviruses. Nature 1985; 318:154-60. 3. Bangham C, Nightingale S, Cruickshank JK, et al. PCR analysis of DNA from multiple sclerosis patients for the presence of HTLV-I. Science 1989; 246: 821. 4. Hollsberg P, Møller-Larsen A, SkouPedersen F, et al. Search for a retrovirus in long-term cultured cerebrospinal fluid cells from patients with multiple sclerosis. Acta Neurol Scand 1989; 80: 603-09. 5. Terzakis JA. Uranyl acetate, a stain and a fixative. J Ultrastruc Res 1968; 22: 168-84.
Simvastatin and
proteinuria
SjR,—Two recent letters in The Lancet have presented conflicting views on the effects of simvastatin on proteinuria. Rabelink et all found that simvastatin produced substantial reductions in proteinuria in seven patients with the nephrotic syndrome. Deslypere et alz reported preliminary data on ten patients who had proteinuria during simvastatin treatment. We summarise here data from long-term clinical trials of simvastatin conducted by Merck Sharp & Dohme Research Laboratories (MSDRL) and worldwide experience with this simvastatin and provide previously unpublished data on the patients reported by Deslypere et al. In MSDRL sponsored clinical trials, over 2400 patients were treated with simvastatin for a mean of 1-4 years, including the patients reported by Deslypere et al. As in the report by Deslypere et al, urine proteins were not based on 24 h collections but were reported as concentrations or qualitative assessments. 7% of patients before and 6% of patients at the end of simvastatin treatment had detectable protein or urinalysis, values usually being 30 mgfdl (1 +) or less. Quantitative 24 h urinary excretion of albumin, transferrin, al-microglobulin, and immunoglobulin G is now being measured in a placebo-controlled simvastatin study before and after 24 weeks of treatment. Of 99 patients who have completed treatment, 3 of 74 receiving simvastatin 10 or 20 mg daily and 1 of 25 on placebo had abnormal urinary albumin excretion (ie, microalbuminuria, over 20 g/min or about 30 mg in 24 h) after 24 weeks of therapy. The highest value (51 g/min) was in the patient on placebo. Transferrin, oti-microglobulin, and immunoglobulin G were undetectable or very low. There was no significant difference between the placebo and simvastatin treatment groups for any urinary measurement. Simvastatin does not seem to be associated with either glomerular or tubular abnormalities of protein excretion. Additional data on the ten patients reported by Deslypere et al do not support the suggestion of a nephrotoxic effect with simvastatin. Concentrations of albumin above the upper limit of normal (0-2 g/1) in spot urine specimens were first noted in these ten patients between 1 and 11 months after they had started taking simvastatin. Albuminuria above 0-2 g/l was no longer present in eight of the ten patients during therapy continuing from 12 to 43 months, including one patient initially reported to have had a positive rechallenge. Of the remaining two patients, one had a positive value (06 g/1) after 9 months of therapy and discontinued for unrelated reasons; the other was reported to have a positive rechallenge but was lost to follow-up, with a value of 0-7 g/l after 11 months of therapy. No patient who received 24 months of simvastatin therapy continued to have albuminuria. Outside the long-term MSDRL clinical trial experience with simvastatin, more than eight hundred thousand patients have been
treated worldwide over the past 3 years and more than eighteen thousand patients have been treated in open-label studies. Reports of proteinuria have been remarkably infrequent. Only nine cases have been reported to Merck and Co Inc, only one being thought by the reporting physician to be related to therapy. There is no definitive evidence that simvastatin is associated with the development of proteinuria. Quantitative 24 h urine protein measurements in a placebo-controlled study confirm the lack of association of simvastatin with proteinuria. Indeed, data from Rabelink et al suggest that simvastatin may improve proteinuria in the nephrotic syndrome. Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486, USA 1. Rabelink
PATRICE LA BELLE GERALDINE MANTEL
AJ, Hene RJ, Erkelens DW, Joles JA, Koomans HA. Partial remission of in patient on long-term simvastatin. Lancet 1990; 335:
nephrotic syndrome 1045-46. 2.
Deslypere JP, Delanghe J, Vermeulen A. Proteinuria as complication of simvastatin treatments. Lancet 1990; 336: 1453.
Dietary germanium supplements SIR,-In our report on a patient who had ingested germanium lactate/citrate capsules daily from early, 1986, to November, 1988, the cumulative dose was estimated at 10-8 g over two years. The patient showed us 33 mg capsules of which, she said, she took two every day. However, we later learned from the community pharmacy that she had mostly ingested 250 mg capsules and that at least 32g germanium had been taken between July, 1987, and November, 1988. We apologise for this error, but the higher cumulative dose endorses our conclusions, especially now that similar cases have been published.2 Netherlands Centre for Monitoring of Adverse Reactions to Drugs, 2280 HK Rijswijk, Netherlands 1. 2.
B. H. CH. STRICKER
der Spoel JI, Stricker BHC, Esseveld MR, Schipper MEI. Dangers of dietary germanium supplements. Lancet 1990; 336: 117. Krapf R. Warnung vor schwerwiegender Germanium-Toxizität. Schweiz Apoth Ztg 1991; 129: 10.
van
Creutzfeldt-Jakob disease in children treated with growth hormone SiR,—Creutzfeldt-Jakob disease (CJD) has been reported in six young adults who had been treated with pituitary growth hormones (GH) and in a 16-year-old on GH treatment without clinical manifestations but with neuropathological lesions. We describe here two children meeting clinical criteria for CJD.I Case 1 (M, 11). He had been on GH since 1979 for total GH deficiency. From 1988 pituitary GH had been replaced by recombinant GH. In August, 1989, he complained of diplopia and progressive cerebellar ataxia, soon followed by pyramidal
syndrome, extrapyramidal rigidity, and mental deterioration. CSF, CT scan, and cerebral magnetic resonance imaging were normal. Electroretinograms were abnormal. 5 months after onset, myoclonic jerks, ophthalmoplegia, and blindness occurred and electroencephalographic complexes characteristic of CJD were a
recorded. Case 2 (F, 10). She had been receiving GH since 1982 for a panhypopituitarism complete GH deficiency. From 1989 pituitary GH was replaced by recombinant GH. In April, 1990, headache and diplopia were followed by cerebellar ataxia, pyramidal syndrome, and extrapyramidal rigidity. The electroretinogram was abnormal. 6 months later she had myoclonic jerks, ophthalmoplegia, and mental deterioration. CSF examination, a CT scan, and cerebral magnetic resonance scans were normal. Periodic characteristic EEG complexes were found. In both cases metabolic and degenerative disease were excluded. Blood and CSF have been inoculated into animals but, after 15 and 10 months, there is no clear-cut result. Both children present elements of the definite clinical diagnosis of CJD2-mental deterioration, myoclonus, and slow periodic complexes. The first symptoms were diplopia and cerebellar ataxia.
in lymphocytes cultured as described for 4 weeks from a new blood sample taken 8 months after the first. The significance of these retrovirus-like particles for this patient’s MS is uncertain.
WethankDrHansGelderblom,RobertKochInstitute,Berlin,forexamining Supported by the Danish MS Society and
and discussing our EM pictures. Warwara-Larsen Foundation. Institute of Medical Microbiology, University of Aarhus, DK-8000 Aarhus C, Denmark, and Department of Neurology, Aarhus Kommunehospital
SVEN HAAHR METTE SOMMERLUND ANNÉ MØLLER-LARSEN RUTH NIELSEN HANS JAKOB HANSEN
1. Poser CM. Viruses, multiple sclerosis and HTLV-I. In: Roman GC, Vemant J-C, Osame M, eds. Neurol Neurobiol 1989; 51: 373-84. 2. Koprowski H, DeFreitas E, Harper M, et al. Multiple sclerosis and human T-cell lymphotropic retroviruses. Nature 1985; 318:154-60. 3. Bangham C, Nightingale S, Cruickshank JK, et al. PCR analysis of DNA from multiple sclerosis patients for the presence of HTLV-I. Science 1989; 246: 821. 4. Hollsberg P, Møller-Larsen A, SkouPedersen F, et al. Search for a retrovirus in long-term cultured cerebrospinal fluid cells from patients with multiple sclerosis. Acta Neurol Scand 1989; 80: 603-09. 5. Terzakis JA. Uranyl acetate, a stain and a fixative. J Ultrastruc Res 1968; 22: 168-84.
Simvastatin and
proteinuria
SjR,—Two recent letters in The Lancet have presented conflicting views on the effects of simvastatin on proteinuria. Rabelink et all found that simvastatin produced substantial reductions in proteinuria in seven patients with the nephrotic syndrome. Deslypere et alz reported preliminary data on ten patients who had proteinuria during simvastatin treatment. We summarise here data from long-term clinical trials of simvastatin conducted by Merck Sharp & Dohme Research Laboratories (MSDRL) and worldwide experience with this simvastatin and provide previously unpublished data on the patients reported by Deslypere et al. In MSDRL sponsored clinical trials, over 2400 patients were treated with simvastatin for a mean of 1-4 years, including the patients reported by Deslypere et al. As in the report by Deslypere et al, urine proteins were not based on 24 h collections but were reported as concentrations or qualitative assessments. 7% of patients before and 6% of patients at the end of simvastatin treatment had detectable protein or urinalysis, values usually being 30 mgfdl (1 +) or less. Quantitative 24 h urinary excretion of albumin, transferrin, al-microglobulin, and immunoglobulin G is now being measured in a placebo-controlled simvastatin study before and after 24 weeks of treatment. Of 99 patients who have completed treatment, 3 of 74 receiving simvastatin 10 or 20 mg daily and 1 of 25 on placebo had abnormal urinary albumin excretion (ie, microalbuminuria, over 20 g/min or about 30 mg in 24 h) after 24 weeks of therapy. The highest value (51 g/min) was in the patient on placebo. Transferrin, oti-microglobulin, and immunoglobulin G were undetectable or very low. There was no significant difference between the placebo and simvastatin treatment groups for any urinary measurement. Simvastatin does not seem to be associated with either glomerular or tubular abnormalities of protein excretion. Additional data on the ten patients reported by Deslypere et al do not support the suggestion of a nephrotoxic effect with simvastatin. Concentrations of albumin above the upper limit of normal (0-2 g/1) in spot urine specimens were first noted in these ten patients between 1 and 11 months after they had started taking simvastatin. Albuminuria above 0-2 g/l was no longer present in eight of the ten patients during therapy continuing from 12 to 43 months, including one patient initially reported to have had a positive rechallenge. Of the remaining two patients, one had a positive value (06 g/1) after 9 months of therapy and discontinued for unrelated reasons; the other was reported to have a positive rechallenge but was lost to follow-up, with a value of 0-7 g/l after 11 months of therapy. No patient who received 24 months of simvastatin therapy continued to have albuminuria. Outside the long-term MSDRL clinical trial experience with simvastatin, more than eight hundred thousand patients have been
treated worldwide over the past 3 years and more than eighteen thousand patients have been treated in open-label studies. Reports of proteinuria have been remarkably infrequent. Only nine cases have been reported to Merck and Co Inc, only one being thought by the reporting physician to be related to therapy. There is no definitive evidence that simvastatin is associated with the development of proteinuria. Quantitative 24 h urine protein measurements in a placebo-controlled study confirm the lack of association of simvastatin with proteinuria. Indeed, data from Rabelink et al suggest that simvastatin may improve proteinuria in the nephrotic syndrome. Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486, USA 1. Rabelink
PATRICE LA BELLE GERALDINE MANTEL
AJ, Hene RJ, Erkelens DW, Joles JA, Koomans HA. Partial remission of in patient on long-term simvastatin. Lancet 1990; 335:
nephrotic syndrome 1045-46. 2.
Deslypere JP, Delanghe J, Vermeulen A. Proteinuria as complication of simvastatin treatments. Lancet 1990; 336: 1453.
Dietary germanium supplements SIR,-In our report on a patient who had ingested germanium lactate/citrate capsules daily from early, 1986, to November, 1988, the cumulative dose was estimated at 10-8 g over two years. The patient showed us 33 mg capsules of which, she said, she took two every day. However, we later learned from the community pharmacy that she had mostly ingested 250 mg capsules and that at least 32g germanium had been taken between July, 1987, and November, 1988. We apologise for this error, but the higher cumulative dose endorses our conclusions, especially now that similar cases have been published.2 Netherlands Centre for Monitoring of Adverse Reactions to Drugs, 2280 HK Rijswijk, Netherlands 1. 2.
B. H. CH. STRICKER
der Spoel JI, Stricker BHC, Esseveld MR, Schipper MEI. Dangers of dietary germanium supplements. Lancet 1990; 336: 117. Krapf R. Warnung vor schwerwiegender Germanium-Toxizität. Schweiz Apoth Ztg 1991; 129: 10.
van
Creutzfeldt-Jakob disease in children treated with growth hormone SiR,—Creutzfeldt-Jakob disease (CJD) has been reported in six young adults who had been treated with pituitary growth hormones (GH) and in a 16-year-old on GH treatment without clinical manifestations but with neuropathological lesions. We describe here two children meeting clinical criteria for CJD.I Case 1 (M, 11). He had been on GH since 1979 for total GH deficiency. From 1988 pituitary GH had been replaced by recombinant GH. In August, 1989, he complained of diplopia and progressive cerebellar ataxia, soon followed by pyramidal
syndrome, extrapyramidal rigidity, and mental deterioration. CSF, CT scan, and cerebral magnetic resonance imaging were normal. Electroretinograms were abnormal. 5 months after onset, myoclonic jerks, ophthalmoplegia, and blindness occurred and electroencephalographic complexes characteristic of CJD were a
recorded. Case 2 (F, 10). She had been receiving GH since 1982 for a panhypopituitarism complete GH deficiency. From 1989 pituitary GH was replaced by recombinant GH. In April, 1990, headache and diplopia were followed by cerebellar ataxia, pyramidal syndrome, and extrapyramidal rigidity. The electroretinogram was abnormal. 6 months later she had myoclonic jerks, ophthalmoplegia, and mental deterioration. CSF examination, a CT scan, and cerebral magnetic resonance scans were normal. Periodic characteristic EEG complexes were found. In both cases metabolic and degenerative disease were excluded. Blood and CSF have been inoculated into animals but, after 15 and 10 months, there is no clear-cut result. Both children present elements of the definite clinical diagnosis of CJD2-mental deterioration, myoclonus, and slow periodic complexes. The first symptoms were diplopia and cerebellar ataxia.
