- Email: [email protected]
INHALED SALBUTAMOL: A NEW FORM OF DRUG ABUSE?
1030 In day 1 cow colostrum neutralising antibody titres to human rotavirus ranged from 400 to 6400 while the IgA and IgG content was 23-170 mg/dl and 1500-4200 mg/dl, respectively. Both titres and Ig concentrations were lower in colostrum from days 2 and 3. Market milk contained little IgA or IgG and few neutralising antibodies. Because the human jejunum contains 200 Ilg/ml trypsin we treated colostrum samples with trypsin (100-800 fg/ml) for 1 h at 37 °C: rotavirus neutralising titres were not affected. In the therapeutic trial rota colostrum had no effect on duration of diarrhoea, bowel movements, or virus shedding in stool. However, there were no side-effects of rota colostrum-in particular, no milk
allergy. 6 orphans were given 20 ml rota colostrum (titre 400-1280) every morning. Of the 9 controls, given 20 ml of market milk, 2, who had had diarrhoea in 1981, were already seropositive for rotavirus and were excluded from the statistical analysis. In Tsuruoka city, sporadic cases of acute gastroenteritis were reported in midDecember, 1982, so rota colostrum (or milk) prophylaxis was started in the orphanage on Dec 14. On Jan 26 there was an outbreak of rotavirus diarrhoea at the orphanage, affecting 6 of the 7 controls but only 1 of the 6 infants given rota colostrum (p<0 05). All 13 infants had fever but influenza A virus was prevalent in the orphanage at the time. 5 infants given rota colostrum had paired complement fixation tests for rotavirus antibody before and after the epidemic of diarrhoea. Sera were negative (titre <4) in all 5 before the epidemic. 2 infants who escaped diarrhoea showed rises in antibody titre after the epidemic, suggesting that rota colostrum causes natural inapparent rotavirus infection but prevents the onset of diarrhoea. Rota colostrum
seems to
be
an
effective and safe
measure
for
preventing diarrhoea caused by rotavirus infection.
Dr
We thank Dr Natsume Yazaki, Michiyo Sakamoto, Dr Yoshio Okuyama, and Dr Kayoko Hori (Yamagata City Hospital, Saiseikan) and the nurses at Tsuruoka Orphanage. This work was supported in part by a grant from the Sendai Institute of Microbiology.
Department of Bacteriology and Paediatrics, Tohoku University School of Medicine,
Sandai 980, Japan; Yamagata Prefectural
Institute
of Public Health, and
Yamagata City Hospital, Saiseikan
T. EBINA A. SATO K. UMEZU N. ISHIDA S. OHYAMA A. OHIZUMI K. AIKAWA S. KATAGIRI N. KATSUSHIMA A. IMAI S. KITAOKA H. SUZUKI T. KONNO
Multilobulated lymphocytes. Left:
SIR,-Few cases of adult T-cell lymphoma-leukaemia (ATL) have reported from the United States. We describe here a case with
antibodies to human T-cell lymphoma virus (HTLV) in which there was spontaneous remission without evidence of residual leukaemia at
necropsy. A 73-year-old White
man from Michigan was admitted to the University of Michigan Hospital because of altered mental status. He had enlarged inguinal lymph nodes, a serum calcium of 17’ 1 mg/dl, and a white blood cell (WCC) count of 20 400x 109/1 with 44% lymphocytes. With hydration and steroid therapy, the serum calcium fell to normal. over 4 days and the inguinal lymphadenopathy disappeared. The WCC rose to 32 800x 109/1 with 68% lymphocytes, 75% of which had multilobulated nuclei (figure). Less than 10% abnormal lymphocytes were detected in a bone marrow smear. Skin lesions were absent. ATL was suspected. The WCC fell to 20 400 x 109/1 with 80% lymphocytes, and during the following weeks returned to normal with only occasional lobulated lymphocytes. Cell surface antigen phenotyping (’EPICS V’ flow cytometer; Coulter Electronics) revealed that more than 80% of peripheral blood lymphocytes had the phenotype T11+, T3+, T4, T 10 +. Aneuploidy was not detected. 70% of these cells were T4+ (helper/inducer) and 26% were T8+ (suppressor/cytotoxic). The T4 + and T8 + subpopulations were tested for human interleukin-2
1. Bunn
et al. Clinical courses of retrovirus-associated adult the United States. N Engl J Med 1983; 309: 257-64.
PA, Schecter GP, Jaffe E,
T-cell
lymphoma
in
blood.
Right:
sorted
Tac-positive
cell
(Wright’s stain,
_______________
receptor with the anti-Tac monoclonal antibody.2,3 This receptor is present on circulating lymphocytes or monocytes, but is present on circulating cells from Japanese patients with ATL.4 In our patient 33% of lymphocytes were Tac + and all of these cells bore not
the T4 antigen. None of the T8 + cells were Tac +. Both the T4+ Tac + and the T8 + Tac - populations were sorted and examined morphologically (figure). The Tac+ cells had diffuse granular acid phosphatase activity and multilobulated nuclei; the T8+ cells appeared normal. Examination of cytocentrifuge preparations of several pleural and abdominal fluids also revealed the presence of multilobulated lymphocytes. No definite evidence of lymphoma was detected at necropsy, although on careful examination of lymph nodes, scattered lymphocytes with lobulated nuclei were seen. Scalloping of trabecular bone with increased osteoclasts was evident. The cause of death (6 weeks .after onset of illness) was
cytomegalovirus pneumonia. Although the hypercalcaemia, absolute lymphocytosis with T4++ Tac + multilobulated lymphocytes in the blood, lymphadenopathy, and antibodies to HTLV suggested that the patient had ATL, no evidence of neoplasm was present post mortem despite the fact that no chemotherapy had been given. Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA
ADULT T-CELL LEUKAEMIA WITH SPONTANEOUS REMISSION been
peripheral
x 600).
BERTRAM SCHNITZER EDMUND J. LOVETT, III LARRY E. KAHN
INHALED SALBUTAMOL: A NEW FORM OF DRUG ABUSE?
SIR,-While looking after asthmatic children at Sheffield Children’s Hospital, I have noticed several adolescents who, given a salbutamol inhaler, abuse it and take bigger and bigger doses more and more often. Often they admit to taking the inhaler not only when they are wheezy but also when they "feel the need" and are tense and anxious. In at least five cases they or their parents have expressed great concern at this "addiction". Even more disturbing are other reports I have had. One from a patient was of salbutamol inhalers being freely available for f1each in a flat frequented by young people not known to be asthmatic, but who do indulge in glue-sniffing. Another was from a medical student who saw some teenagers passing an inhaler round the group at a local disco. Also a school nurse reported that a non-asthmatic boy had been caught using salbutamol ’Rotacaps’ because he said it made him feel "good". Hyperactivity and a manic mood are well recognised side-effects of oral salbutamol in young children, and an antidepressant effect of 2.
Uchiyama T, Broder S, Waldman TA. A monoclonal antibody (anti-Tac) reactive with activated and functionally mature human T cells I: Production of anti-Tac
monoclonal antibody and distribution of Tac (+) cells. J Immunol 1981; 126: 1393-97. 3. Leonard WJ, Depper JM, Uchiyama T, et al. A monoclonal antibody that appears to recognize the receptor for human T cell growth factor: Partial characterization of the receptor Nature 1982; 300: 267-69. 4. Uchiyama T, Nelson DL, Fleisher TA, Waldmann TA. A monoclonal antibody (antiTac) reactive with activated and functionally mature human T cells II: Expression of Tac antigen on activated cytotoxic killer cells, suppressor cells, and on one of two types of helper cells. J Immunol 1981; 126: 1398-1403
1031 infused salbutamol has been reported in adults.’ It seems that adolescents, asthmatic and otherwise, have also discovered these effects and are using salbutamol as a new form of drug abuse. Children’s Hospital, Sheffield S10 2 TH
P. O. BRENNAN
RAPID METABOLISM OF CYCLOSPORIN AND PREDNISONE IN KIDNEY TRANSPLANT PATIENT RECEIVING TUBERCULOSTATIC TREATMENT
SIR,-In renal transplantation cyclosporin is usually administered together with low-dose prednisone. Tuberculostatic therapy is occasionally given at the same time for prophylactic or therapeutic reasons, and isoniazid and rifampicin increase prednisolone clearance, probably by hepatic microsomal enzyme induction.2 We report ’here a case of altered cyclosporin kinetics during tuberculostatic therapy. A 25-year-old man was given cyclosporin 2 mg/kg intravenously 4 h before cadaveric kidney transplantation, postoperative doses being adjusted according to whole blood concentrations (figure). The dose of prednisone, 2 mg/kg daily during the first 3 postoperative weeks, was tapered off to 0-55 mg/kg over the next 3 weeks. Prophylactic rifampicin 450 mg/daily and isoniazid 300 mg daily were given postoperatively because of recent pulmonary tuberculosis. During the first week after transplantation there was renographic uptake in the graft but no significant diuresis. A biopsyconfirmed rejection episode occurred in the second week and highdose prednisone was given. Simultaneously biochemical signs of parenchymal liver involvement were noted. Whole blood concentrations of cyclosporin fell and became undetectable, despite massive doses (figure), and then rose to toxic levels 2 weeks after cessation of rifampicin therapy even though the cyclosporin dose was much reduced. Whole body prednisolone clearance was measured during rifampicin treatment and 8 weeks after stopping this therapy by the area under the plasma concentration/time curve after 10 mg oral prednisone, assuming an absorption fraction of 0 - 85. The bars in the figure demonstrate a seven-fold difference in prednisolone clearance on the two occasions. The prednisolone half-life increased from 13to 4Ih, while Cmax and tmax did not change.
azathioprine treatment was started instead. However, renal function gradually declined and the grafted kidney was removed 13 weeks after transplantation. Graft biopsy at this time showed severe chronic rejection without signs of nephrotoxicity. The extraordinarily rapid clearance of prednisolone (about seven times normal2), the normal clearance after cessation of rifampicin, and the whole blood concentrations of cyclosporin suggest that cyclosporin, like prednisolone, was metabolised very rapidly during the period of tuberculostatic treatment. Low blood levels of cyclosporin, despite increasing doses, were accompanied by biochemical signs of parenchymal liver disease. Since isoniazid and, even more so, rifampicin seem responsible for the markedly altered kinetic behaviour of cyclosporin, administration of these tuberculostatic drugs may be a potential hazard in renal transplantation. We thank Miss H. F. Flachs for
help
Tissue-typing Laboratory and Department of Nephrology, State University Hospital (Rigshospitalet), DK-2100 Copenhagen N, Denmark
with
prednisolone
assays.
E. LANGHOFF S. MADSEN
ALLERGIC CONTACT DERMATITIS WITH TRANSDERMAL CLONIDINE
SIR,-The antihypertensive efficacy and tolerance of a clonidine transdermal therapeutic system (clonidine-TTS) was studied in 21 patients with mild to moderate hypertension (WHO grade 1-11). Clonidine-TTS, put on the outer upper arm, delivers clonidine through the skin into the bloodstream continuously over 7 days. Patients with adequate blood pressure control on a diuretic and oral clonidine 0-15-0-45 mg daily participated in the study. Oral clonidine was replaced by one, two, or three units of clonidine-TTS, applied once weekly. Blood pressure, pulse rate, tolerance, and clonidine plasma levels were evaluated during 2 weeks of stable dose oral clonidine, during clonidine-TTS titration, and during 4 weeks of titrated stable dose clonidine-TTS treatment. 10 patients responded to one unit, 5 to two, and 6 to three units of clonidine-TTS. 16 patients completed the study strictly according to the protocol and their blood pressure data were used for the analysis of efficacy. Mean sitting blood pressure was 155/89 mm Hg during stable dose oral clonidine therapy and 156/91 mm Hg after 4 weeks of stable dose clonidine-TTS. Steady-state clonidine plasma concentrations during transdermal therapy remained stable, and were in general lower than clonidine levels during stable dose oral I clonidine. Systemic side-effects reported by the 21 patients during oral clonidine therapy were dry mouth (10), sedation (3), and headache (3). During 4 weeks of stable dose clonidine-TTS treatment the incidence and severity of side-effects was lowered. 2 patients reported dry mouth and 1 patient felt nervous. Local side-effects during transdetmal clonidine (up to 10 weeks’ treatment) were transient and not predictive of the later development of allergic contact dermatitis. These early skin reactions were itching (3 patients) and erythema (5). After 4 weeks on stable dose clonidineTTS all 21 patients preferred to continue transdermal therapy. Efficacy and tolerance were monitored regularly. 2 patients terminated transdermal clonidine treatment after 17 and 28 weeks. The patient who stopped after 17 weeks had a localised skin reaction (erythema, infiltration, itching). The second patient had a localised skin reaction after 24 weeks and continued transdermal therapy, but discontinued treatment after 28 weeks when a generalised reaction appeared. A third patient had a localised skin reaction after 23 weeks, but treatment was continued at the special request of the patient because of the much improved systemic tolerance of clonidine-TTS treatment over oral clonidine. All 3 patients had positive reactions to clonidine-containing patch-test materials. However, this does not mean that only the clonidine molecule itself is responsible for sensitisation. Another -
weeks
Prednisolone clearance and whole blood cyclosporin concentrations in relation to cyclosporin dose and to tuberculostatic therapy.
Graft function gradually improved after treatment of the rejection peak, in terms of creatinine clearance (25 ml/min), 5 transplantation, but then slowly deteriorated. Cyclosporin immunosuppression was withdrawn after 7 weeks and and reached a weeks after
1 Wildlocher D, Lecrubier Y, Jouvent R, Puech AJ, Simon P. Antidepressant effect of salbutamol. Lancet 1977; ii: 767. 2 McAllister WAC, Thompson PJ, Al-Habet SM, Rogers HJ. Rifampicin reduces effectiveness and bioavailability of prednisolone. Br Med J 1983; 286: 923-25.
3.
Gambertoglio JG, Amend WJC, Benet LZ. Pharmacokinetics and bioavailability of prednisone and prednisolone in healthy volunteers and patients a review. J Pharmacokinet Biopharm 1980, 8: 1-52.
allergy. 6 orphans were given 20 ml rota colostrum (titre 400-1280) every morning. Of the 9 controls, given 20 ml of market milk, 2, who had had diarrhoea in 1981, were already seropositive for rotavirus and were excluded from the statistical analysis. In Tsuruoka city, sporadic cases of acute gastroenteritis were reported in midDecember, 1982, so rota colostrum (or milk) prophylaxis was started in the orphanage on Dec 14. On Jan 26 there was an outbreak of rotavirus diarrhoea at the orphanage, affecting 6 of the 7 controls but only 1 of the 6 infants given rota colostrum (p<0 05). All 13 infants had fever but influenza A virus was prevalent in the orphanage at the time. 5 infants given rota colostrum had paired complement fixation tests for rotavirus antibody before and after the epidemic of diarrhoea. Sera were negative (titre <4) in all 5 before the epidemic. 2 infants who escaped diarrhoea showed rises in antibody titre after the epidemic, suggesting that rota colostrum causes natural inapparent rotavirus infection but prevents the onset of diarrhoea. Rota colostrum
seems to
be
an
effective and safe
measure
for
preventing diarrhoea caused by rotavirus infection.
Dr
We thank Dr Natsume Yazaki, Michiyo Sakamoto, Dr Yoshio Okuyama, and Dr Kayoko Hori (Yamagata City Hospital, Saiseikan) and the nurses at Tsuruoka Orphanage. This work was supported in part by a grant from the Sendai Institute of Microbiology.
Department of Bacteriology and Paediatrics, Tohoku University School of Medicine,
Sandai 980, Japan; Yamagata Prefectural
Institute
of Public Health, and
Yamagata City Hospital, Saiseikan
T. EBINA A. SATO K. UMEZU N. ISHIDA S. OHYAMA A. OHIZUMI K. AIKAWA S. KATAGIRI N. KATSUSHIMA A. IMAI S. KITAOKA H. SUZUKI T. KONNO
Multilobulated lymphocytes. Left:
SIR,-Few cases of adult T-cell lymphoma-leukaemia (ATL) have reported from the United States. We describe here a case with
antibodies to human T-cell lymphoma virus (HTLV) in which there was spontaneous remission without evidence of residual leukaemia at
necropsy. A 73-year-old White
man from Michigan was admitted to the University of Michigan Hospital because of altered mental status. He had enlarged inguinal lymph nodes, a serum calcium of 17’ 1 mg/dl, and a white blood cell (WCC) count of 20 400x 109/1 with 44% lymphocytes. With hydration and steroid therapy, the serum calcium fell to normal. over 4 days and the inguinal lymphadenopathy disappeared. The WCC rose to 32 800x 109/1 with 68% lymphocytes, 75% of which had multilobulated nuclei (figure). Less than 10% abnormal lymphocytes were detected in a bone marrow smear. Skin lesions were absent. ATL was suspected. The WCC fell to 20 400 x 109/1 with 80% lymphocytes, and during the following weeks returned to normal with only occasional lobulated lymphocytes. Cell surface antigen phenotyping (’EPICS V’ flow cytometer; Coulter Electronics) revealed that more than 80% of peripheral blood lymphocytes had the phenotype T11+, T3+, T4, T 10 +. Aneuploidy was not detected. 70% of these cells were T4+ (helper/inducer) and 26% were T8+ (suppressor/cytotoxic). The T4 + and T8 + subpopulations were tested for human interleukin-2
1. Bunn
et al. Clinical courses of retrovirus-associated adult the United States. N Engl J Med 1983; 309: 257-64.
PA, Schecter GP, Jaffe E,
T-cell
lymphoma
in
blood.
Right:
sorted
Tac-positive
cell
(Wright’s stain,
_______________
receptor with the anti-Tac monoclonal antibody.2,3 This receptor is present on circulating lymphocytes or monocytes, but is present on circulating cells from Japanese patients with ATL.4 In our patient 33% of lymphocytes were Tac + and all of these cells bore not
the T4 antigen. None of the T8 + cells were Tac +. Both the T4+ Tac + and the T8 + Tac - populations were sorted and examined morphologically (figure). The Tac+ cells had diffuse granular acid phosphatase activity and multilobulated nuclei; the T8+ cells appeared normal. Examination of cytocentrifuge preparations of several pleural and abdominal fluids also revealed the presence of multilobulated lymphocytes. No definite evidence of lymphoma was detected at necropsy, although on careful examination of lymph nodes, scattered lymphocytes with lobulated nuclei were seen. Scalloping of trabecular bone with increased osteoclasts was evident. The cause of death (6 weeks .after onset of illness) was
cytomegalovirus pneumonia. Although the hypercalcaemia, absolute lymphocytosis with T4++ Tac + multilobulated lymphocytes in the blood, lymphadenopathy, and antibodies to HTLV suggested that the patient had ATL, no evidence of neoplasm was present post mortem despite the fact that no chemotherapy had been given. Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA
ADULT T-CELL LEUKAEMIA WITH SPONTANEOUS REMISSION been
peripheral
x 600).
BERTRAM SCHNITZER EDMUND J. LOVETT, III LARRY E. KAHN
INHALED SALBUTAMOL: A NEW FORM OF DRUG ABUSE?
SIR,-While looking after asthmatic children at Sheffield Children’s Hospital, I have noticed several adolescents who, given a salbutamol inhaler, abuse it and take bigger and bigger doses more and more often. Often they admit to taking the inhaler not only when they are wheezy but also when they "feel the need" and are tense and anxious. In at least five cases they or their parents have expressed great concern at this "addiction". Even more disturbing are other reports I have had. One from a patient was of salbutamol inhalers being freely available for f1each in a flat frequented by young people not known to be asthmatic, but who do indulge in glue-sniffing. Another was from a medical student who saw some teenagers passing an inhaler round the group at a local disco. Also a school nurse reported that a non-asthmatic boy had been caught using salbutamol ’Rotacaps’ because he said it made him feel "good". Hyperactivity and a manic mood are well recognised side-effects of oral salbutamol in young children, and an antidepressant effect of 2.
Uchiyama T, Broder S, Waldman TA. A monoclonal antibody (anti-Tac) reactive with activated and functionally mature human T cells I: Production of anti-Tac
monoclonal antibody and distribution of Tac (+) cells. J Immunol 1981; 126: 1393-97. 3. Leonard WJ, Depper JM, Uchiyama T, et al. A monoclonal antibody that appears to recognize the receptor for human T cell growth factor: Partial characterization of the receptor Nature 1982; 300: 267-69. 4. Uchiyama T, Nelson DL, Fleisher TA, Waldmann TA. A monoclonal antibody (antiTac) reactive with activated and functionally mature human T cells II: Expression of Tac antigen on activated cytotoxic killer cells, suppressor cells, and on one of two types of helper cells. J Immunol 1981; 126: 1398-1403
1031 infused salbutamol has been reported in adults.’ It seems that adolescents, asthmatic and otherwise, have also discovered these effects and are using salbutamol as a new form of drug abuse. Children’s Hospital, Sheffield S10 2 TH
P. O. BRENNAN
RAPID METABOLISM OF CYCLOSPORIN AND PREDNISONE IN KIDNEY TRANSPLANT PATIENT RECEIVING TUBERCULOSTATIC TREATMENT
SIR,-In renal transplantation cyclosporin is usually administered together with low-dose prednisone. Tuberculostatic therapy is occasionally given at the same time for prophylactic or therapeutic reasons, and isoniazid and rifampicin increase prednisolone clearance, probably by hepatic microsomal enzyme induction.2 We report ’here a case of altered cyclosporin kinetics during tuberculostatic therapy. A 25-year-old man was given cyclosporin 2 mg/kg intravenously 4 h before cadaveric kidney transplantation, postoperative doses being adjusted according to whole blood concentrations (figure). The dose of prednisone, 2 mg/kg daily during the first 3 postoperative weeks, was tapered off to 0-55 mg/kg over the next 3 weeks. Prophylactic rifampicin 450 mg/daily and isoniazid 300 mg daily were given postoperatively because of recent pulmonary tuberculosis. During the first week after transplantation there was renographic uptake in the graft but no significant diuresis. A biopsyconfirmed rejection episode occurred in the second week and highdose prednisone was given. Simultaneously biochemical signs of parenchymal liver involvement were noted. Whole blood concentrations of cyclosporin fell and became undetectable, despite massive doses (figure), and then rose to toxic levels 2 weeks after cessation of rifampicin therapy even though the cyclosporin dose was much reduced. Whole body prednisolone clearance was measured during rifampicin treatment and 8 weeks after stopping this therapy by the area under the plasma concentration/time curve after 10 mg oral prednisone, assuming an absorption fraction of 0 - 85. The bars in the figure demonstrate a seven-fold difference in prednisolone clearance on the two occasions. The prednisolone half-life increased from 13to 4Ih, while Cmax and tmax did not change.
azathioprine treatment was started instead. However, renal function gradually declined and the grafted kidney was removed 13 weeks after transplantation. Graft biopsy at this time showed severe chronic rejection without signs of nephrotoxicity. The extraordinarily rapid clearance of prednisolone (about seven times normal2), the normal clearance after cessation of rifampicin, and the whole blood concentrations of cyclosporin suggest that cyclosporin, like prednisolone, was metabolised very rapidly during the period of tuberculostatic treatment. Low blood levels of cyclosporin, despite increasing doses, were accompanied by biochemical signs of parenchymal liver disease. Since isoniazid and, even more so, rifampicin seem responsible for the markedly altered kinetic behaviour of cyclosporin, administration of these tuberculostatic drugs may be a potential hazard in renal transplantation. We thank Miss H. F. Flachs for
help
Tissue-typing Laboratory and Department of Nephrology, State University Hospital (Rigshospitalet), DK-2100 Copenhagen N, Denmark
with
prednisolone
assays.
E. LANGHOFF S. MADSEN
ALLERGIC CONTACT DERMATITIS WITH TRANSDERMAL CLONIDINE
SIR,-The antihypertensive efficacy and tolerance of a clonidine transdermal therapeutic system (clonidine-TTS) was studied in 21 patients with mild to moderate hypertension (WHO grade 1-11). Clonidine-TTS, put on the outer upper arm, delivers clonidine through the skin into the bloodstream continuously over 7 days. Patients with adequate blood pressure control on a diuretic and oral clonidine 0-15-0-45 mg daily participated in the study. Oral clonidine was replaced by one, two, or three units of clonidine-TTS, applied once weekly. Blood pressure, pulse rate, tolerance, and clonidine plasma levels were evaluated during 2 weeks of stable dose oral clonidine, during clonidine-TTS titration, and during 4 weeks of titrated stable dose clonidine-TTS treatment. 10 patients responded to one unit, 5 to two, and 6 to three units of clonidine-TTS. 16 patients completed the study strictly according to the protocol and their blood pressure data were used for the analysis of efficacy. Mean sitting blood pressure was 155/89 mm Hg during stable dose oral clonidine therapy and 156/91 mm Hg after 4 weeks of stable dose clonidine-TTS. Steady-state clonidine plasma concentrations during transdermal therapy remained stable, and were in general lower than clonidine levels during stable dose oral I clonidine. Systemic side-effects reported by the 21 patients during oral clonidine therapy were dry mouth (10), sedation (3), and headache (3). During 4 weeks of stable dose clonidine-TTS treatment the incidence and severity of side-effects was lowered. 2 patients reported dry mouth and 1 patient felt nervous. Local side-effects during transdetmal clonidine (up to 10 weeks’ treatment) were transient and not predictive of the later development of allergic contact dermatitis. These early skin reactions were itching (3 patients) and erythema (5). After 4 weeks on stable dose clonidineTTS all 21 patients preferred to continue transdermal therapy. Efficacy and tolerance were monitored regularly. 2 patients terminated transdermal clonidine treatment after 17 and 28 weeks. The patient who stopped after 17 weeks had a localised skin reaction (erythema, infiltration, itching). The second patient had a localised skin reaction after 24 weeks and continued transdermal therapy, but discontinued treatment after 28 weeks when a generalised reaction appeared. A third patient had a localised skin reaction after 23 weeks, but treatment was continued at the special request of the patient because of the much improved systemic tolerance of clonidine-TTS treatment over oral clonidine. All 3 patients had positive reactions to clonidine-containing patch-test materials. However, this does not mean that only the clonidine molecule itself is responsible for sensitisation. Another -
weeks
Prednisolone clearance and whole blood cyclosporin concentrations in relation to cyclosporin dose and to tuberculostatic therapy.
Graft function gradually improved after treatment of the rejection peak, in terms of creatinine clearance (25 ml/min), 5 transplantation, but then slowly deteriorated. Cyclosporin immunosuppression was withdrawn after 7 weeks and and reached a weeks after
1 Wildlocher D, Lecrubier Y, Jouvent R, Puech AJ, Simon P. Antidepressant effect of salbutamol. Lancet 1977; ii: 767. 2 McAllister WAC, Thompson PJ, Al-Habet SM, Rogers HJ. Rifampicin reduces effectiveness and bioavailability of prednisolone. Br Med J 1983; 286: 923-25.
3.
Gambertoglio JG, Amend WJC, Benet LZ. Pharmacokinetics and bioavailability of prednisone and prednisolone in healthy volunteers and patients a review. J Pharmacokinet Biopharm 1980, 8: 1-52.