- Email: [email protected]
GIANT MITOCHONDRIA IN RENAL TUBULAR CELLS AND CYCLOSPORIN A
1162 observed with ketanserin in animals with serotonin-induced hypertension.3 Serotonin is a potent vasoconstricting and platelet aggregating agent by itself and it is a potent amplifier of vasoconstriction such as noradrenaand platelet aggregation induced by other line, angiotensin, and prostaglandins (and unpublished). Ketanserin antagonises the direct and the amplification effects of serotonin in blood vessels and platelets.3(and unpublished). The platelet release reaction increases and platelet survival shortens with age in man.4An increased serotonin release from platelets in atherosclerotic patients, and an increased sensitivity of blood vessels to serotonin during ageing,5might be causally related to hypertension in elderly people. The striking activity of ketanserin in essential hypertension of the elderly can probably be explained by its antagonism of the direct vasopressor effect of serotonin-but also in part by the abolition of the amplification
aents
’
effect of serotonin on the adrenergic system. It seems worthwhile to investigate the effects of ketanserin in hypertensive emergencies and in patients with essential hypertension, particularly in elderly hypertensives where such 6 treatment might reduce the incidence of cardiovascular disease. Clinical Research Unit, St Bartholomeus,
Jan Palfijn Ziekenhuis, B-2060 Merksem, Belgium
Department of
GGT activity and body weight apparently unrelated to age. Our findings confirm those by Schiele et allo Perhaps substances in the food may induce GGT production in the liver.
serum
Department of Clinical Chemistry, Central Hospital, S29185 Kristianstad, Sweden
B. BERG N.TRYDING
GIANT MITOCHONDRIA IN RENAL TUBULAR CELLS AND CYCLOSPORIN A
SIR,—We studied five renal biopsy specimens using electron (EM) and light (LM) microscopy,1 from three patients who had been treated with cyclosporin A (CyA).2 One patient had three biopsies done from a transplanted kidney with poor function, but no clinical signs of rejection. The other patients had both received bone-marrow transplants, and had no previous evidence of renal dysfunction, though one of them was receiving potentially nephrotoxic drugs, other than CyA. Daily dosage of CyA varied between 10 and 20 mg/kg body weight. LM showed eosinophilic inclusion bodies and some unspecific changes. EM showed giant mitochondria with disoriented cristae and paracrystalline inclusions (see figure). There were many
J. DE CREE H. VERHAEGEN
Clinical Research,
Janssen Pharmaceutica, B-2340 Beerse, Belgium
J. SYMOENS
FALSE POSITIVE SERUM GGT TESTS
SIR,-Mrs Penn and her colleagues (April 18, p. 894) discuss the non-alcoholic "unidentified" factors which provoke increases in serum y-glutamyltransferase (GGT), the most important of which is probably intake of drugs. For example, almost all patients taking antiepileptics have increased serum GGT values. The International Federation of Clinical Chemistry has an expert panel on drug effects in clinical chemistry since 1978, the object being to coordinate and rationalise efforts to avoid the problems caused by drugs in clinical
chemistry. A new data file on well documented drug effects on laboratory investigations has lately been added to the computerised Swedish drug information system.7 This includes ten drugs sold in Sweden which, in therapeutic doses, have been shown to alter serum GGT levels significantly. Another possible explanation for high GGT values may be heredity. A few years ago we found that serum diamine oxidase can be higher than usual in some families without known disease.Also other serum enzymes have been reported to be high for genetic reasons. We have seen one family with constantly raised serum GGT values, although the members totally abstained from alcohol and drugs. Furthermore, in a local population study the reference intervals for the teetotallers did not differ significantly from the age and sex specific reference intervals for the population as a whole, after exclusion of individuals with high intake of alcohol or drugs. Men generally had higher values than women and reference limits increased markedly with.age. There was also a correlation between 3.
van Nueten JM, Janssen PAJ, Van Beek J, Xhonneux R, Verbeuren TJ, Vanhoutte PM. Vascular effects of R 41468, a novel antagonist
of 5-HT2 serotonergic receptors.J Pharmacol Exp Ther (in press). 4. Zahavi J, Jones NAG, Leyton J, Dubiel M, Kakkar VV Enhanced in vivo platelet "release reaction" in old healthy individuals. Thromb Res 1980; 17: 329-36. 5. Henry PD, Yokoyama M. Supersensitivity of atherosclerotic rabbit aorta to ergonovine. Mediation by a serotonergic mechanism. J Clin Invest 1980; 66: 306-13. 6 Koch-Weser J, O’Malley K, O’Brien E Management of hypertension in the elderly. N Engl J Med 1980; 302: 1397-1401. 7. Tryding N, Johansson SG, Manell P Data banks and other documents on drug effects in clinical chemistry. In. Siest G, ed Drug effects on laboratory test results. The Hague: Martinus Nijhoff Publishers, 1980. 8. Tryding N, Elmfors B, Gennser G, Söderberg Hanna. Families with high serum enzyme level. JAMA 1974; 229: 23-24. 9. Berg B, Gerhardt W, Nilsson JE, Theodorsen L, Tryding N, Waldenström J. Collection of reference values for serum &ggr;-glutamyltransferase and creatine kinase. Scand J Clin Lab Invest 1980; 39: 37.
Giant mitochondrium in a renal tubular cell with paracrystalline inclusion bodies. Note several mitochondria of normal size (EM x 21 000).
lysosomes
which contained dense
granules and mitrochondrial
remnants.
Giant mitochondria
syndrome, but
are
sometimes
are not seen
in
seen
in
cases
of the nephrotic or acute renal
transplant rejection
F, Guilmin A-M, Detienne H, Siest G Gamma-glutamyltransferase activity in plasma: Statistical distributions, individual variations and reference intervals Clin
10 Schiele
Chem 1977; 23: 1023-28. 1.
Zollinger HU, Mihatsch MJ Kidney morphology in biopsy
1978: 8-20. 2. Editorial Cyclosporin A. Lancet 1979;
ii.
779-80
Berlin
Springer-Verlag.
1163
failure.3 We
assume
that
CyA
or
its metabolites interfere with
6[ochondrial metabolism and produce the changes described. This interference may be the cause of tubular cell necrosis and cause renal failure from CyA treatment.
of Pathology, University of Basel, CH-4056 Basel, Switzerland; and Departments of Medicine and Surgery, Kantonsspital, University of Basel Institute
PLASMA FPZ LEVELS
(ng/ml) IN NINE SCHIZOPHRENIC PATIENTS
AFTER STOPPING CHRONIC TREATMENT WITH FPZ DECANOATE
25 mg EVERY 3 WEEKS -
M. J. MIHATSCH W. OLIVIERI U. MARBET G. THIEL F. HARDER H. U. ZOLLINGER
SLOW DECLINE OF PLASMA DRUG AND PROLACTIN LEVELS AFTER DISCONTINUATION OF CHRONIC TREATMENT WITH DEPOT NEUROLEPTICS
SIR,-Depot injections of fluphenazine (FPZ) and flupenthixol decanoates are widely used for long-term treatment of chronic schizophrenia. Sometimes this treatment is discontinued because of side-effects, poor response, remission of symptoms, or the patient’s refusal. How long do the effects of these preparations last after injections cease? In patients receiving chronic treatment, half-times of disappearance (T1f2) of 9 days for FPZ decanoate4and 17 days for flupenthixol decanoate5 have been reported. We suspected a much longer duration of drug action when, in a female patient, we noted that the plasma prolactin fell progressively for about one year after flupenthixol decanoate injections stopped. Prolactin levels were high during weekly doses of 300 mg and remained above the upper limit of normal (600 mIU/1) until eleven months after the last dose (see figure, patient A). In two of three patients whose treatment with FPZ decanoate was discontinued, prolactin also declined slowly, entering the normal range after 4-6 months (see figure, patients B and C). Plasma FPZ levels were monitored by radioimmunoassay. Concentrations of approximately 1 ng/ml were found at 7 and 5 3 Suzuki T, Furusato M, Takasaki S, Ishikawa E. Giant mitochondria in the epithelial cells of the proximal convoluted tubules of diseased human kidneys. Lab Invest 1975; 33: 578-90.
*Patient
relapsed, drug re-started before next time point.
months, respectively, after stopping treatment in patients C and D. Regular maintenance doses of 12.55 mg every 1-2 weeks produce similar FPZ levels. Approximate TVz’s in these subjects ranged between 31f2 and 14 weeks. A more systematic study of depot neuroleptic withdrawal (to be presented at this year’s World Congress of Psychiatry, in Stockholm) confirms these findings. FPZ decanoate, 25 mg every 3 weeks, was discontinued in nine schizophrenics. FPZ levels (table) of between 0’ 3 and 1 ng/ml persisted for 12 weeks in five of seven patients observed and FPZ was still measurable at 24 weeks in three of five patients. The range of approximate T1f2’s was 2112-16 weeks. These preliminary observations, to our knowledge the first concerning the rate of drug disappearance after stopping chronic depot neuroleptic treatment, suggest that, in some patients at least, plasma drug concentrations remain within the usual therapeutic range for several months and continue to exert their antidopa-
minergic effect on prolactin. The mechanism of this unexpectedly slow drug decline is likely to be related to slow drug absorption from multiple depot sites, but this question can only be answered by more detailed study of the pharmacokinetics of the depot neuroleptics. Department of Psychiatry, Huddinge University Hospital, S-141 86 Huddinge, Sweden
B. WISTEDT
5 Jorgensen A, Fredricson-Overø K. Clopenthixol and flupenthixol depot preparations in outpatient schizophrenics. III. Serum levels. Acta Psychiat Scand 1980; 61: suppl
M.R.C. Unit of Clinical Pharmacology, Radcliffe Infirmary, Oxford
D. WILES
279, 41-54. 6 Wiles DH, Franklin M. Radioimmunoassay for Clin Pharmacol 1978; 5: 265-68.
Department of Psychiatry, Littlemore Hospital Research Unit
T. KOLAKOWSKA
4
Curry SH, Whelpton R, de Schepper PJ, Vrankx S, Schiff AA. Kinetics of fluphenazine after fluphenazine dihydrochloride enanthate and decanoate administration to man. Br Clin J Pharmacol 1979; 7: 325-31.
fluphenazine in human plasma. Br J
COLLECTION OF HUMAN OÖCYTES FOR IN VITRO FERTILISATION BY ULTRASONICALLY GUIDED FOLLICULAR PUNCTURE
SIR,-Human oocytes fertilised and cultivated in vitro have in a few cases been used successfully in the treatment of infertility due to tubal occlusion. 1,2 The oocytes were collected by laparoscopy, but to the ovaries was in many patients the laparoscopic
approach I
prevented by severe pelvic adhesions. By means of ultrasonography the growth of developing graafian follicles can be followed, and ultrasonography offers a method for an
Plasma prolactin
levels in four schizophrenic patients during and after withdrawal of chronic treatment with flupenthixol or
fluphenazine. P,uent A. flupenthixol 300 mg/wk (0-0). ?anent B: FPZ 150 mg/wk (A-A). PsMnts C and D: FPZ 25mg/2 wk (8-8 and 0 - 0).
atraumatic percutaneous abdominal puncture even in the presence of abdominal scarring or pelvic adhesions. The following is a preliminary report of the results of collecting preovulatory oocytes for in vitro fertilisation (IVF) by ultrasonically guided percutaneous puncture of the ovarian follicles. Five patients (age 26-36 years), who were admitted because of infertility, were studied. The patients and their husbands participated in our IVF study. They were aware of the experimental nature of the procedure and gave their informed consent. 1. Edwards
RG, Steptoe PC, Purdy JM. Establishing full-term pregnancies using cleaving embryos grown in vitro. Br J Obstet Gynaecol 1980; 87: 737-56. 2. Lopata A, Johnston IWH, Hoult IJ, Speirs AI. Pregnancy following intrauterine implantation of an embryo obtained by in vitro fertilization of a preovulatory egg Fertil Steril 1980; 33: 117-20.
aents
’
effect of serotonin on the adrenergic system. It seems worthwhile to investigate the effects of ketanserin in hypertensive emergencies and in patients with essential hypertension, particularly in elderly hypertensives where such 6 treatment might reduce the incidence of cardiovascular disease. Clinical Research Unit, St Bartholomeus,
Jan Palfijn Ziekenhuis, B-2060 Merksem, Belgium
Department of
GGT activity and body weight apparently unrelated to age. Our findings confirm those by Schiele et allo Perhaps substances in the food may induce GGT production in the liver.
serum
Department of Clinical Chemistry, Central Hospital, S29185 Kristianstad, Sweden
B. BERG N.TRYDING
GIANT MITOCHONDRIA IN RENAL TUBULAR CELLS AND CYCLOSPORIN A
SIR,—We studied five renal biopsy specimens using electron (EM) and light (LM) microscopy,1 from three patients who had been treated with cyclosporin A (CyA).2 One patient had three biopsies done from a transplanted kidney with poor function, but no clinical signs of rejection. The other patients had both received bone-marrow transplants, and had no previous evidence of renal dysfunction, though one of them was receiving potentially nephrotoxic drugs, other than CyA. Daily dosage of CyA varied between 10 and 20 mg/kg body weight. LM showed eosinophilic inclusion bodies and some unspecific changes. EM showed giant mitochondria with disoriented cristae and paracrystalline inclusions (see figure). There were many
J. DE CREE H. VERHAEGEN
Clinical Research,
Janssen Pharmaceutica, B-2340 Beerse, Belgium
J. SYMOENS
FALSE POSITIVE SERUM GGT TESTS
SIR,-Mrs Penn and her colleagues (April 18, p. 894) discuss the non-alcoholic "unidentified" factors which provoke increases in serum y-glutamyltransferase (GGT), the most important of which is probably intake of drugs. For example, almost all patients taking antiepileptics have increased serum GGT values. The International Federation of Clinical Chemistry has an expert panel on drug effects in clinical chemistry since 1978, the object being to coordinate and rationalise efforts to avoid the problems caused by drugs in clinical
chemistry. A new data file on well documented drug effects on laboratory investigations has lately been added to the computerised Swedish drug information system.7 This includes ten drugs sold in Sweden which, in therapeutic doses, have been shown to alter serum GGT levels significantly. Another possible explanation for high GGT values may be heredity. A few years ago we found that serum diamine oxidase can be higher than usual in some families without known disease.Also other serum enzymes have been reported to be high for genetic reasons. We have seen one family with constantly raised serum GGT values, although the members totally abstained from alcohol and drugs. Furthermore, in a local population study the reference intervals for the teetotallers did not differ significantly from the age and sex specific reference intervals for the population as a whole, after exclusion of individuals with high intake of alcohol or drugs. Men generally had higher values than women and reference limits increased markedly with.age. There was also a correlation between 3.
van Nueten JM, Janssen PAJ, Van Beek J, Xhonneux R, Verbeuren TJ, Vanhoutte PM. Vascular effects of R 41468, a novel antagonist
of 5-HT2 serotonergic receptors.J Pharmacol Exp Ther (in press). 4. Zahavi J, Jones NAG, Leyton J, Dubiel M, Kakkar VV Enhanced in vivo platelet "release reaction" in old healthy individuals. Thromb Res 1980; 17: 329-36. 5. Henry PD, Yokoyama M. Supersensitivity of atherosclerotic rabbit aorta to ergonovine. Mediation by a serotonergic mechanism. J Clin Invest 1980; 66: 306-13. 6 Koch-Weser J, O’Malley K, O’Brien E Management of hypertension in the elderly. N Engl J Med 1980; 302: 1397-1401. 7. Tryding N, Johansson SG, Manell P Data banks and other documents on drug effects in clinical chemistry. In. Siest G, ed Drug effects on laboratory test results. The Hague: Martinus Nijhoff Publishers, 1980. 8. Tryding N, Elmfors B, Gennser G, Söderberg Hanna. Families with high serum enzyme level. JAMA 1974; 229: 23-24. 9. Berg B, Gerhardt W, Nilsson JE, Theodorsen L, Tryding N, Waldenström J. Collection of reference values for serum &ggr;-glutamyltransferase and creatine kinase. Scand J Clin Lab Invest 1980; 39: 37.
Giant mitochondrium in a renal tubular cell with paracrystalline inclusion bodies. Note several mitochondria of normal size (EM x 21 000).
lysosomes
which contained dense
granules and mitrochondrial
remnants.
Giant mitochondria
syndrome, but
are
sometimes
are not seen
in
seen
in
cases
of the nephrotic or acute renal
transplant rejection
F, Guilmin A-M, Detienne H, Siest G Gamma-glutamyltransferase activity in plasma: Statistical distributions, individual variations and reference intervals Clin
10 Schiele
Chem 1977; 23: 1023-28. 1.
Zollinger HU, Mihatsch MJ Kidney morphology in biopsy
1978: 8-20. 2. Editorial Cyclosporin A. Lancet 1979;
ii.
779-80
Berlin
Springer-Verlag.
1163
failure.3 We
assume
that
CyA
or
its metabolites interfere with
6[ochondrial metabolism and produce the changes described. This interference may be the cause of tubular cell necrosis and cause renal failure from CyA treatment.
of Pathology, University of Basel, CH-4056 Basel, Switzerland; and Departments of Medicine and Surgery, Kantonsspital, University of Basel Institute
PLASMA FPZ LEVELS
(ng/ml) IN NINE SCHIZOPHRENIC PATIENTS
AFTER STOPPING CHRONIC TREATMENT WITH FPZ DECANOATE
25 mg EVERY 3 WEEKS -
M. J. MIHATSCH W. OLIVIERI U. MARBET G. THIEL F. HARDER H. U. ZOLLINGER
SLOW DECLINE OF PLASMA DRUG AND PROLACTIN LEVELS AFTER DISCONTINUATION OF CHRONIC TREATMENT WITH DEPOT NEUROLEPTICS
SIR,-Depot injections of fluphenazine (FPZ) and flupenthixol decanoates are widely used for long-term treatment of chronic schizophrenia. Sometimes this treatment is discontinued because of side-effects, poor response, remission of symptoms, or the patient’s refusal. How long do the effects of these preparations last after injections cease? In patients receiving chronic treatment, half-times of disappearance (T1f2) of 9 days for FPZ decanoate4and 17 days for flupenthixol decanoate5 have been reported. We suspected a much longer duration of drug action when, in a female patient, we noted that the plasma prolactin fell progressively for about one year after flupenthixol decanoate injections stopped. Prolactin levels were high during weekly doses of 300 mg and remained above the upper limit of normal (600 mIU/1) until eleven months after the last dose (see figure, patient A). In two of three patients whose treatment with FPZ decanoate was discontinued, prolactin also declined slowly, entering the normal range after 4-6 months (see figure, patients B and C). Plasma FPZ levels were monitored by radioimmunoassay. Concentrations of approximately 1 ng/ml were found at 7 and 5 3 Suzuki T, Furusato M, Takasaki S, Ishikawa E. Giant mitochondria in the epithelial cells of the proximal convoluted tubules of diseased human kidneys. Lab Invest 1975; 33: 578-90.
*Patient
relapsed, drug re-started before next time point.
months, respectively, after stopping treatment in patients C and D. Regular maintenance doses of 12.55 mg every 1-2 weeks produce similar FPZ levels. Approximate TVz’s in these subjects ranged between 31f2 and 14 weeks. A more systematic study of depot neuroleptic withdrawal (to be presented at this year’s World Congress of Psychiatry, in Stockholm) confirms these findings. FPZ decanoate, 25 mg every 3 weeks, was discontinued in nine schizophrenics. FPZ levels (table) of between 0’ 3 and 1 ng/ml persisted for 12 weeks in five of seven patients observed and FPZ was still measurable at 24 weeks in three of five patients. The range of approximate T1f2’s was 2112-16 weeks. These preliminary observations, to our knowledge the first concerning the rate of drug disappearance after stopping chronic depot neuroleptic treatment, suggest that, in some patients at least, plasma drug concentrations remain within the usual therapeutic range for several months and continue to exert their antidopa-
minergic effect on prolactin. The mechanism of this unexpectedly slow drug decline is likely to be related to slow drug absorption from multiple depot sites, but this question can only be answered by more detailed study of the pharmacokinetics of the depot neuroleptics. Department of Psychiatry, Huddinge University Hospital, S-141 86 Huddinge, Sweden
B. WISTEDT
5 Jorgensen A, Fredricson-Overø K. Clopenthixol and flupenthixol depot preparations in outpatient schizophrenics. III. Serum levels. Acta Psychiat Scand 1980; 61: suppl
M.R.C. Unit of Clinical Pharmacology, Radcliffe Infirmary, Oxford
D. WILES
279, 41-54. 6 Wiles DH, Franklin M. Radioimmunoassay for Clin Pharmacol 1978; 5: 265-68.
Department of Psychiatry, Littlemore Hospital Research Unit
T. KOLAKOWSKA
4
Curry SH, Whelpton R, de Schepper PJ, Vrankx S, Schiff AA. Kinetics of fluphenazine after fluphenazine dihydrochloride enanthate and decanoate administration to man. Br Clin J Pharmacol 1979; 7: 325-31.
fluphenazine in human plasma. Br J
COLLECTION OF HUMAN OÖCYTES FOR IN VITRO FERTILISATION BY ULTRASONICALLY GUIDED FOLLICULAR PUNCTURE
SIR,-Human oocytes fertilised and cultivated in vitro have in a few cases been used successfully in the treatment of infertility due to tubal occlusion. 1,2 The oocytes were collected by laparoscopy, but to the ovaries was in many patients the laparoscopic
approach I
prevented by severe pelvic adhesions. By means of ultrasonography the growth of developing graafian follicles can be followed, and ultrasonography offers a method for an
Plasma prolactin
levels in four schizophrenic patients during and after withdrawal of chronic treatment with flupenthixol or
fluphenazine. P,uent A. flupenthixol 300 mg/wk (0-0). ?anent B: FPZ 150 mg/wk (A-A). PsMnts C and D: FPZ 25mg/2 wk (8-8 and 0 - 0).
atraumatic percutaneous abdominal puncture even in the presence of abdominal scarring or pelvic adhesions. The following is a preliminary report of the results of collecting preovulatory oocytes for in vitro fertilisation (IVF) by ultrasonically guided percutaneous puncture of the ovarian follicles. Five patients (age 26-36 years), who were admitted because of infertility, were studied. The patients and their husbands participated in our IVF study. They were aware of the experimental nature of the procedure and gave their informed consent. 1. Edwards
RG, Steptoe PC, Purdy JM. Establishing full-term pregnancies using cleaving embryos grown in vitro. Br J Obstet Gynaecol 1980; 87: 737-56. 2. Lopata A, Johnston IWH, Hoult IJ, Speirs AI. Pregnancy following intrauterine implantation of an embryo obtained by in vitro fertilization of a preovulatory egg Fertil Steril 1980; 33: 117-20.