1065
the treatment of postmenopausal osteoporosis vary from stabilisation of bone mass7 to significant dose-dependent increase of bone-mineral density at both the vertebral and the femoral levels.88 The nasal administration of 200 IU per day of salmon calcitonin modified bone metabolism in osteoporotic women with a decrease in the biochemical indices that measured bone resorption and bone formation, resulting in prevention of further bone loss both at trabecular (spine) and cortical (radius) sites.9 Recently, a retrospective study showed that calcitonin induced a striking reduction in postmenopausal osteoporotic vertebral fracture.10 Finally, calcitonin had pronounced analgesic effects. Although no consensus has been reached about the mechanism behind the hormone’s analgesic effects, it is clear that they are quite distinct from effects on bone tissue. Intranasal salmon calcitonin given to osteoporotic women decreases bone pain at rest and at motion and allows a significant reduction in analgesic requirements compared with placebo-treated patients. Bone Metabolism Unit, University of Liège, 4020 Liège, Belgium,
and Georgetown
University
Washington DC, USA
provocative letter should have a stimulating effect on all companies in calcitonin development. The search for scientific evidence of an antifracture efficacy of calcitonin in established osteoporosis should be renewed, but its ability to reduce postmenopausal bone loss has already been convincingly established. INSERM Unit 234, Pavilion P, Edouard Herriot Hospital, 69437 Lyon, France
Denis D, Albert A, et al. 1-year controlled randomised trial of prevention of early postmenopausal bone loss by intranasal calcitonin. Lancet 1987; ii: 1481-83 2. Overgaard K, Riis BJ, Christiansen C, Hansen MA. Effect of salcatonin given intranasally on early postmenopausal bone loss. Br MedJ 1989; 299: 477-79. 3. Meunier PJ, Delmas PD, Chaumet-Riffaud PD, et al. Intransal salmon calcitonin for prevention of postmenopausal bone loss: a placebo-controlled study in 109 women. In: Chnstiansen C, Overgaard, K, eds. Osteoporosis, 1990. Copenhagen: Osteopress, 1990: 1861-67. 4. Overgaard K, Rus BJ, Christiansen C, et al Nasal calcitonin for treatment of established osteoporosis. Clin Endocrinol 1989; 30: 435-42.
1. Reginster JY,
Insulin Medical Center,
J. Y. REGINSTER
1. Nicholson GC, Moseley JM, Sexton PM, Mendelsohn FAO, Martin TJ. Abundant calcitonin receptors in isolated rat osteoclasts. biochemical and autoradiographic characterization. J Clin Invest 1986; 78: 355-60. 2. Reginster JY, Denis D, Albert A, et al. 1-year controlled randomised trial of prevention of early postmenopausal bone loss by intranasal calcitonin. Lancet 1987;
ii: 1481-83.
3. Overgaard K, Riis BJ, Christiansen C, Hansen MA. Effect of salcatonin given intranasally on early postmenopausal bone loss Br Med J 1989; 299: 477-79 4 Meunier PJ, Delmas PD, Chaumet-Riffaud PD, et al. Intranasal salmon calcitonin for prevention of postmenopausal bone loss a placebo controlled study in 109 women. In: Christiansen C, Overgaard K, eds Osteoporosis 1990, Copenhagen: Osteopress, 1990; 1861-67. 5. MacIntyre I, Stevenson JC, Whitehead MI, Wimalawansa SJ, Banks LM, Healy MJR. Calcitonin for prevention of postmenopausal bone loss. Lancet 1988; i: 900-02. 6. Reginster JY Effects of calcitonin on bone mass and fracture rates. Am J Med 1991, 91: 19-22. 7. Gruber HE, Ivey JL, Baylink DJ, et al Long-term calcitonin therapy in postmenopausal Osteoporosis. Metabolism 1984; 33: 295-303 8 Mazzuoli GF, Passen M, German C, et al. Effects of salmon calcitonin in postmenopausal osteoporosis a controlled double-blind study Calcif Tissue Int 1986; 38: 3-8. 9. Overgaard K, Hansen MA, Hers Nielsen VA, Christiansen C. Discontinuous calcitonin treatment of established osteoporosis: effect of withdrawal of treatment. Am J Med 1990; 89: 1-6. 10. Rico H, Hernandez ER, Revilla M, Gomez-Castresana F. Salmon calcitonin reduces vertebral fracture rate in postmenopausal crush fracture syndrome. Bone Miner 1992, 16: 131-38.
SIR,-Dr Magrini and colleagues’ data comparing oestrogens and calcitonin prescriptions in the Italian female population are very impressive. Their findings may induce an unjustified negative opinion about calcitonins, but should also lead to a positive reappraisal by pharmaceutical companies of the urgent need for rigorous controlled studies evaluating the actual effects of calcitonin on fracture rate in established osteoporosis. It is true that 30 years after the discovery of calcitonin, no prospective controlled study has clearly proven that the administration of this hormone, given parenterally or intranasally, could substantially reduce the risk of new vertebral fractures in osteoporotic patients. By contrast, several controlled studies in Denmark, Belgium, and France have shown convincingly that intranasal salmon calcitonin, most often combined with a calcium supplement, reduces the rate of postmenopausal bone loss-ie, it represents a valid alternative to oestrogens for the prevention of postmenopausal osteopenia.1-3 Because of the much too low percentage of women accepting oestrogen replacement therapy in many countries (about 9% in France, less than 5% in Italy), these well-established effects of calcitonin on axial skeleton bone mass should not be forgotten in considerations of the excessive sales in Italy. In addition, another Danish study4 has shown that intranasal calcitonin given in old women with wrist fracture (200 IU per day) prevented bone loss in spine and forearm. Furthermore, its proven usefulness in the treatment of hypercalcaemia or Paget’s disease of bone should not be overlooked. Clearly the strategy of research and development departments of major pharmaceutical companies should not be driven only by marketing considerations. Magrini and colleagues’
PIERRE J. MEUNIER
sensitivity after phototherapy for seasonal affective disorder
SiR,—Patients with seasonal affective disorder (SAD) are highly sensitive to suppression of melatonin secretion by light in winter and have reduced sensitivity in summer.1 Phototherapy might return winter supersensitivity towards normal, while improving depression. Healthy adults have seasonal variations in glucose and insulin concentrations,2 with raised values in winter. In diabetes, poor blood glucose control has been statistically related to anxiety, stress, and mood disturbancesWe report the effect of phototherapy in a patient with both SAD and insulin-dependent diabetes mellitus (IDDM). A 46-year-old single man presented with a history of winter depression for 3 consecutive years. During winter he had hypersomnia, poor concentration, anxiety, and sadness, and could not undertake any physical activity. In the two summers he had clear episodes of hypomania, both lasting for 6 weeks. During these episodes he became overactive, worked long hours, and was irritable. Diabetes mellitus was diagnosed in the first winter and he became insulin dependent (26 IU/day) in the second. During the third winter his insulin requirement rose to 60 IU/day; in summer this fell to 30 IU/day. A younger brother has non-seasonal affective disorder. The patient had an episode of depression 19 years earlier. At the time of the investigation he had no psychiatric illness other than SAD. The patient was admitted for 2 nights during which his sensitivity to light (melatonin suppression) was measured. On the intervening day insulin sensitivity and awareness of hypoglycaemic symptoms were assessed.* Growth hormone and cortisol were also measured. He started morning phototherapy at home and was readmitted after 5 days for post-treatment light, insulin, and symptom sensitivity tests. 1 week of phototherapy did not alter his mental state. After 2 further weeks of this treatment the typical symptoms of SAD had improved and his insulin requirement had decreased. A phase advance of 2-4 h in melatonin profile was seen at the end of the first week of phototherapy. Melatonin was also measured on control and exposure nights before and after phototherapy. Results were expressed as percentages of the melatonin value at 0030 h on each night.1 After the first exposure the difference at 0130 h was 80-4% and after a week of phototherapy the difference had decreased to 58-2%, indicating a reduction in the suppression of melatonin by light. Growth hormone and cortisol responses to hypoglycaemia did not differ significantly before and after phototherapy (table i), but symptoms and awareness of hypoglycaemia were more pronounced after phototherapy (table n). Insulin sensitivity (average glucose infusion rate to maintain normal blood glucose) rose from 5-12 to 6.28 mg/kg per min. 1 week of phototherapy is associated with both phase advance of melatonin and a decrease in light sensitivity. The improvement in affective state takes longer than this, which is not unusual. (Rosenthal NE, personal communication). Improvement in mood and self-image by psychological means might be associated with improvements in diabetic control, although this is controversial.4 In our patient, SAD symptoms in *Further details of method available from The Lancet.
1066
TABLE I-CORTISOL AND GROWTH HORMONE BEFORE AND AFTER 1 WEEK OF PHOTOTHERAPY
achieve effective drug concentrations in newly formed lunula and ventral nail with a few doses or even a single dose. We have done a pilot study to test this hypothesis in 11 patients (6 men, 5 women; age 31-62) with fmgemail and/or toenail
onychomycosis due to Trichophyton rubrum or T interdigitale which had not responded to conventional therapy with oral griseofulvin. Terbinafme is usually given in a daily dose of 250 mg for several months; instead we used a single dose of 1000 mg given once (5 patients) or twice (2) or three times (4) with two weeks between doses. 1 patient complained of mild dyspepsia after one of two doses sampled dunng insulin sensitivity testing at time 0, after 120 mms of clamped normoglycaemia, after 30 mln dunng which the blood glucose was lowered to 2 5 mmoljl, and after 30 mm of clamped hypoglycaemia. Blood
was
TABLE II-RESPONSES TO VISUAL ANALOGUE SCALE FOR HYPOGLYCAEMIC SYMPTOMS
but there were no other adverse events. The response was measured’ by the outward movement of the affected segment in a nail designated for study at the start of treatment. None of the patients given a single dose, but 1 of 2 given two doses and 3 of 4 given three doses, showed a clear response. In 1 of the patients given three doses, improvement began before the third dose, and seven of eight affected naits became normal within six months.
*mm from left-hand end of a 100 mm line, respresentmg "absent" (0) to "severe" (100) Patients are assessed during final 30 min of Insulin sensitivity testing when blood glucose is clamped at 25 mmol/I.
probably increased his insulin requirements. The improvement in insulin sensitivity and intensity of hypoglycaemic warning symptoms after phototherapy were not accounted for by alterations in diet, physical activity, alcohol,s or glycaemic control, since there was only 1 week between each clamp study. Furthermore, the patient had no pronounced episodes of hypoglycaemia between investigations that could affect warning symptoms and hormonal counter-regulatory responses to hypoglycaemia.6 The failure of cortisol to increase when blood glucose was low may have resulted from the suppressive effect of peripheral hyperinsulinaemia.7 A circadian rhythm of insulin clearance might have been advanced by phototherapy. winter
Department of Psychiatry, University of Southampton, Royal South Hants Hospital, Southampton SO9 4PE, UK and Department of Clinical Biochemistry, Southampton General Hospital 1.
N. H. P. ALLEN D. KERR P. J. SMYTHE N. MARTIN K. OSOLA C. THOMPSON
Thompson C, Stinson D, Smith A. Seasonal affective disorder is associated with seasonally dependent abnormalities of melatonin suppression by light. Lancet 1990
336: 703-06. 2. Suarez L, Barrett-Connor E. Seasonal variation in fasting glucose levels in man. Diabetologia 1982; 22: 250-53 3. Mazze RS, Lucido D, Shamoon H. Psychological and social correlates of glycaemic control. Diabetes Care 1984; 7: 360-66. 4. Williams G, Pickup J, Keen H. Psychological factors and metabolic control: time for reappraisal? Diabet Med 1988; 5: 211-15. 5. Kerr D, Macdonald IA, Heller SR, Tattersall RB. Alcohol causes hypoglycaemic unawareness in healthy volunteers and patients with type 1 (insulin-dependent) diabetes. Diabetologia 1990; 33: 216-21. 6. Heller S, Cryer PE. Reduced neuroendocrine and symptomatic responses to subsequent hypoglycaemia after one episode of hypoglycaemia in non-diabetic humans. Diabetes 1991; 40: 223-26. 7. Kerr D, Reza M, Smith N, Leatherdale BP. Importance of insulin in the subjective, cognitive and hormonal responses to hypoglycaemia in patients with IDDM. Diabetes 1991; 40: 1057-62.
Single dose treatment of fungal nail disease SIR,-Our finding of a rapid therapeutic effect of terbinafme on distal onychomycosis1,2 refuted the conventional view that drugs reach the nail only by the outward growth of drug-containing new nail from the lunula. The rapid shunting of antifungal drugs into the distal nail3,4 occurs through the ventral nail bed,l,2 now known to form nail continuously along its length. 5,6 We therefore argued that instead of the traditional approach of giving antifungal drugs continuously until a normal nail is grown, it should be possible to
Effect of one, two, or three doses of terbinafine on proximal nail free of clinical fungal invasion.
- =fingernails;
...
= toenails.
Arrows
length of
indicate
drug
administration.
Prolonged therapy for onychomycosis owes more to tradition than to pharmacokinetics. This study supports our suggestion that since drugs have adequate access to the site of fungal nail disease through both the lunula and ventral nail, outcome of therapy is determined by adequacy of dosage rather than by duration of treatment. Use of a single or few-dose regimen is a real possibility for onychomycosis, and should be considered for other fungal diseases. A trial of higher doses of terbinafme and other antifungal drugs is now desirable, toxicity permitting, although the amount of drug given as a single dose would still be very much less than that accumulating with conventional regimens over months or years. It may also be necessary to develop new drugs for this purpose by selecting for low toxicity with a few high doses rather than with chronic low dosage. Although there is no reason why existing antifungal drugs should not be studied for such an effect, the advantages of taking a few high doses may be greater for the patients who use the drugs than for the industry that produces them. University Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK
SAM SHUSTER COLIN S. MUNRO
1. Munro CS, Rees JL, Shuster S. Short duration terbinafine therapy penetrates diseased distal nail via the ventral nailbed and is effective in onychomycosis. Br J Dermatol 1990; 123: 825. 2. Munro CS, Rees JL, Shuster S. The unexpectedly rapid response of fungal nail infection to short duration therapy. Acta Dermatovenereol 1992; 72: 128-30. 3. Dykes PJ, Thomas RA, Finlay AY. Determination of terbinafine in nail samples J during systemic treatment for onychomycosis. Br Dermatol 1990, 123: 481-86. 4. Matthieu L, De Donker P, Cauwenbergh G, et al. Itroconazole penetrates the nail via the nail matrix and nail bed: an investigation in onychomycosis. Clin Exp Dermatol
1991, 16: 374-76.
Johnson M, Shuster S. Ventral nail contribution to the nail plate is continuous along the length of the nail bed. BrJ Dermatol 1990; 123: 825 6. Johnson M, Comaish JS, Shuster S. Nail is produced by the normal nail bed. a controversy resolved. Br J Dermatol 1991; 125: 27-29. 5.
the treatment of postmenopausal osteoporosis vary from stabilisation of bone mass7 to significant dose-dependent increase of bone-mineral density at both the vertebral and the femoral levels.88 The nasal administration of 200 IU per day of salmon calcitonin modified bone metabolism in osteoporotic women with a decrease in the biochemical indices that measured bone resorption and bone formation, resulting in prevention of further bone loss both at trabecular (spine) and cortical (radius) sites.9 Recently, a retrospective study showed that calcitonin induced a striking reduction in postmenopausal osteoporotic vertebral fracture.10 Finally, calcitonin had pronounced analgesic effects. Although no consensus has been reached about the mechanism behind the hormone’s analgesic effects, it is clear that they are quite distinct from effects on bone tissue. Intranasal salmon calcitonin given to osteoporotic women decreases bone pain at rest and at motion and allows a significant reduction in analgesic requirements compared with placebo-treated patients. Bone Metabolism Unit, University of Liège, 4020 Liège, Belgium,
and Georgetown
University
Washington DC, USA
provocative letter should have a stimulating effect on all companies in calcitonin development. The search for scientific evidence of an antifracture efficacy of calcitonin in established osteoporosis should be renewed, but its ability to reduce postmenopausal bone loss has already been convincingly established. INSERM Unit 234, Pavilion P, Edouard Herriot Hospital, 69437 Lyon, France
Denis D, Albert A, et al. 1-year controlled randomised trial of prevention of early postmenopausal bone loss by intranasal calcitonin. Lancet 1987; ii: 1481-83 2. Overgaard K, Riis BJ, Christiansen C, Hansen MA. Effect of salcatonin given intranasally on early postmenopausal bone loss. Br MedJ 1989; 299: 477-79. 3. Meunier PJ, Delmas PD, Chaumet-Riffaud PD, et al. Intransal salmon calcitonin for prevention of postmenopausal bone loss: a placebo-controlled study in 109 women. In: Chnstiansen C, Overgaard, K, eds. Osteoporosis, 1990. Copenhagen: Osteopress, 1990: 1861-67. 4. Overgaard K, Rus BJ, Christiansen C, et al Nasal calcitonin for treatment of established osteoporosis. Clin Endocrinol 1989; 30: 435-42.
1. Reginster JY,
Insulin Medical Center,
J. Y. REGINSTER
1. Nicholson GC, Moseley JM, Sexton PM, Mendelsohn FAO, Martin TJ. Abundant calcitonin receptors in isolated rat osteoclasts. biochemical and autoradiographic characterization. J Clin Invest 1986; 78: 355-60. 2. Reginster JY, Denis D, Albert A, et al. 1-year controlled randomised trial of prevention of early postmenopausal bone loss by intranasal calcitonin. Lancet 1987;
ii: 1481-83.
3. Overgaard K, Riis BJ, Christiansen C, Hansen MA. Effect of salcatonin given intranasally on early postmenopausal bone loss Br Med J 1989; 299: 477-79 4 Meunier PJ, Delmas PD, Chaumet-Riffaud PD, et al. Intranasal salmon calcitonin for prevention of postmenopausal bone loss a placebo controlled study in 109 women. In: Christiansen C, Overgaard K, eds Osteoporosis 1990, Copenhagen: Osteopress, 1990; 1861-67. 5. MacIntyre I, Stevenson JC, Whitehead MI, Wimalawansa SJ, Banks LM, Healy MJR. Calcitonin for prevention of postmenopausal bone loss. Lancet 1988; i: 900-02. 6. Reginster JY Effects of calcitonin on bone mass and fracture rates. Am J Med 1991, 91: 19-22. 7. Gruber HE, Ivey JL, Baylink DJ, et al Long-term calcitonin therapy in postmenopausal Osteoporosis. Metabolism 1984; 33: 295-303 8 Mazzuoli GF, Passen M, German C, et al. Effects of salmon calcitonin in postmenopausal osteoporosis a controlled double-blind study Calcif Tissue Int 1986; 38: 3-8. 9. Overgaard K, Hansen MA, Hers Nielsen VA, Christiansen C. Discontinuous calcitonin treatment of established osteoporosis: effect of withdrawal of treatment. Am J Med 1990; 89: 1-6. 10. Rico H, Hernandez ER, Revilla M, Gomez-Castresana F. Salmon calcitonin reduces vertebral fracture rate in postmenopausal crush fracture syndrome. Bone Miner 1992, 16: 131-38.
SIR,-Dr Magrini and colleagues’ data comparing oestrogens and calcitonin prescriptions in the Italian female population are very impressive. Their findings may induce an unjustified negative opinion about calcitonins, but should also lead to a positive reappraisal by pharmaceutical companies of the urgent need for rigorous controlled studies evaluating the actual effects of calcitonin on fracture rate in established osteoporosis. It is true that 30 years after the discovery of calcitonin, no prospective controlled study has clearly proven that the administration of this hormone, given parenterally or intranasally, could substantially reduce the risk of new vertebral fractures in osteoporotic patients. By contrast, several controlled studies in Denmark, Belgium, and France have shown convincingly that intranasal salmon calcitonin, most often combined with a calcium supplement, reduces the rate of postmenopausal bone loss-ie, it represents a valid alternative to oestrogens for the prevention of postmenopausal osteopenia.1-3 Because of the much too low percentage of women accepting oestrogen replacement therapy in many countries (about 9% in France, less than 5% in Italy), these well-established effects of calcitonin on axial skeleton bone mass should not be forgotten in considerations of the excessive sales in Italy. In addition, another Danish study4 has shown that intranasal calcitonin given in old women with wrist fracture (200 IU per day) prevented bone loss in spine and forearm. Furthermore, its proven usefulness in the treatment of hypercalcaemia or Paget’s disease of bone should not be overlooked. Clearly the strategy of research and development departments of major pharmaceutical companies should not be driven only by marketing considerations. Magrini and colleagues’
PIERRE J. MEUNIER
sensitivity after phototherapy for seasonal affective disorder
SiR,—Patients with seasonal affective disorder (SAD) are highly sensitive to suppression of melatonin secretion by light in winter and have reduced sensitivity in summer.1 Phototherapy might return winter supersensitivity towards normal, while improving depression. Healthy adults have seasonal variations in glucose and insulin concentrations,2 with raised values in winter. In diabetes, poor blood glucose control has been statistically related to anxiety, stress, and mood disturbancesWe report the effect of phototherapy in a patient with both SAD and insulin-dependent diabetes mellitus (IDDM). A 46-year-old single man presented with a history of winter depression for 3 consecutive years. During winter he had hypersomnia, poor concentration, anxiety, and sadness, and could not undertake any physical activity. In the two summers he had clear episodes of hypomania, both lasting for 6 weeks. During these episodes he became overactive, worked long hours, and was irritable. Diabetes mellitus was diagnosed in the first winter and he became insulin dependent (26 IU/day) in the second. During the third winter his insulin requirement rose to 60 IU/day; in summer this fell to 30 IU/day. A younger brother has non-seasonal affective disorder. The patient had an episode of depression 19 years earlier. At the time of the investigation he had no psychiatric illness other than SAD. The patient was admitted for 2 nights during which his sensitivity to light (melatonin suppression) was measured. On the intervening day insulin sensitivity and awareness of hypoglycaemic symptoms were assessed.* Growth hormone and cortisol were also measured. He started morning phototherapy at home and was readmitted after 5 days for post-treatment light, insulin, and symptom sensitivity tests. 1 week of phototherapy did not alter his mental state. After 2 further weeks of this treatment the typical symptoms of SAD had improved and his insulin requirement had decreased. A phase advance of 2-4 h in melatonin profile was seen at the end of the first week of phototherapy. Melatonin was also measured on control and exposure nights before and after phototherapy. Results were expressed as percentages of the melatonin value at 0030 h on each night.1 After the first exposure the difference at 0130 h was 80-4% and after a week of phototherapy the difference had decreased to 58-2%, indicating a reduction in the suppression of melatonin by light. Growth hormone and cortisol responses to hypoglycaemia did not differ significantly before and after phototherapy (table i), but symptoms and awareness of hypoglycaemia were more pronounced after phototherapy (table n). Insulin sensitivity (average glucose infusion rate to maintain normal blood glucose) rose from 5-12 to 6.28 mg/kg per min. 1 week of phototherapy is associated with both phase advance of melatonin and a decrease in light sensitivity. The improvement in affective state takes longer than this, which is not unusual. (Rosenthal NE, personal communication). Improvement in mood and self-image by psychological means might be associated with improvements in diabetic control, although this is controversial.4 In our patient, SAD symptoms in *Further details of method available from The Lancet.
1066
TABLE I-CORTISOL AND GROWTH HORMONE BEFORE AND AFTER 1 WEEK OF PHOTOTHERAPY
achieve effective drug concentrations in newly formed lunula and ventral nail with a few doses or even a single dose. We have done a pilot study to test this hypothesis in 11 patients (6 men, 5 women; age 31-62) with fmgemail and/or toenail
onychomycosis due to Trichophyton rubrum or T interdigitale which had not responded to conventional therapy with oral griseofulvin. Terbinafme is usually given in a daily dose of 250 mg for several months; instead we used a single dose of 1000 mg given once (5 patients) or twice (2) or three times (4) with two weeks between doses. 1 patient complained of mild dyspepsia after one of two doses sampled dunng insulin sensitivity testing at time 0, after 120 mms of clamped normoglycaemia, after 30 mln dunng which the blood glucose was lowered to 2 5 mmoljl, and after 30 mm of clamped hypoglycaemia. Blood
was
TABLE II-RESPONSES TO VISUAL ANALOGUE SCALE FOR HYPOGLYCAEMIC SYMPTOMS
but there were no other adverse events. The response was measured’ by the outward movement of the affected segment in a nail designated for study at the start of treatment. None of the patients given a single dose, but 1 of 2 given two doses and 3 of 4 given three doses, showed a clear response. In 1 of the patients given three doses, improvement began before the third dose, and seven of eight affected naits became normal within six months.
*mm from left-hand end of a 100 mm line, respresentmg "absent" (0) to "severe" (100) Patients are assessed during final 30 min of Insulin sensitivity testing when blood glucose is clamped at 25 mmol/I.
probably increased his insulin requirements. The improvement in insulin sensitivity and intensity of hypoglycaemic warning symptoms after phototherapy were not accounted for by alterations in diet, physical activity, alcohol,s or glycaemic control, since there was only 1 week between each clamp study. Furthermore, the patient had no pronounced episodes of hypoglycaemia between investigations that could affect warning symptoms and hormonal counter-regulatory responses to hypoglycaemia.6 The failure of cortisol to increase when blood glucose was low may have resulted from the suppressive effect of peripheral hyperinsulinaemia.7 A circadian rhythm of insulin clearance might have been advanced by phototherapy. winter
Department of Psychiatry, University of Southampton, Royal South Hants Hospital, Southampton SO9 4PE, UK and Department of Clinical Biochemistry, Southampton General Hospital 1.
N. H. P. ALLEN D. KERR P. J. SMYTHE N. MARTIN K. OSOLA C. THOMPSON
Thompson C, Stinson D, Smith A. Seasonal affective disorder is associated with seasonally dependent abnormalities of melatonin suppression by light. Lancet 1990
336: 703-06. 2. Suarez L, Barrett-Connor E. Seasonal variation in fasting glucose levels in man. Diabetologia 1982; 22: 250-53 3. Mazze RS, Lucido D, Shamoon H. Psychological and social correlates of glycaemic control. Diabetes Care 1984; 7: 360-66. 4. Williams G, Pickup J, Keen H. Psychological factors and metabolic control: time for reappraisal? Diabet Med 1988; 5: 211-15. 5. Kerr D, Macdonald IA, Heller SR, Tattersall RB. Alcohol causes hypoglycaemic unawareness in healthy volunteers and patients with type 1 (insulin-dependent) diabetes. Diabetologia 1990; 33: 216-21. 6. Heller S, Cryer PE. Reduced neuroendocrine and symptomatic responses to subsequent hypoglycaemia after one episode of hypoglycaemia in non-diabetic humans. Diabetes 1991; 40: 223-26. 7. Kerr D, Reza M, Smith N, Leatherdale BP. Importance of insulin in the subjective, cognitive and hormonal responses to hypoglycaemia in patients with IDDM. Diabetes 1991; 40: 1057-62.
Single dose treatment of fungal nail disease SIR,-Our finding of a rapid therapeutic effect of terbinafme on distal onychomycosis1,2 refuted the conventional view that drugs reach the nail only by the outward growth of drug-containing new nail from the lunula. The rapid shunting of antifungal drugs into the distal nail3,4 occurs through the ventral nail bed,l,2 now known to form nail continuously along its length. 5,6 We therefore argued that instead of the traditional approach of giving antifungal drugs continuously until a normal nail is grown, it should be possible to
Effect of one, two, or three doses of terbinafine on proximal nail free of clinical fungal invasion.
- =fingernails;
...
= toenails.
Arrows
length of
indicate
drug
administration.
Prolonged therapy for onychomycosis owes more to tradition than to pharmacokinetics. This study supports our suggestion that since drugs have adequate access to the site of fungal nail disease through both the lunula and ventral nail, outcome of therapy is determined by adequacy of dosage rather than by duration of treatment. Use of a single or few-dose regimen is a real possibility for onychomycosis, and should be considered for other fungal diseases. A trial of higher doses of terbinafme and other antifungal drugs is now desirable, toxicity permitting, although the amount of drug given as a single dose would still be very much less than that accumulating with conventional regimens over months or years. It may also be necessary to develop new drugs for this purpose by selecting for low toxicity with a few high doses rather than with chronic low dosage. Although there is no reason why existing antifungal drugs should not be studied for such an effect, the advantages of taking a few high doses may be greater for the patients who use the drugs than for the industry that produces them. University Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK
SAM SHUSTER COLIN S. MUNRO
1. Munro CS, Rees JL, Shuster S. Short duration terbinafine therapy penetrates diseased distal nail via the ventral nailbed and is effective in onychomycosis. Br J Dermatol 1990; 123: 825. 2. Munro CS, Rees JL, Shuster S. The unexpectedly rapid response of fungal nail infection to short duration therapy. Acta Dermatovenereol 1992; 72: 128-30. 3. Dykes PJ, Thomas RA, Finlay AY. Determination of terbinafine in nail samples J during systemic treatment for onychomycosis. Br Dermatol 1990, 123: 481-86. 4. Matthieu L, De Donker P, Cauwenbergh G, et al. Itroconazole penetrates the nail via the nail matrix and nail bed: an investigation in onychomycosis. Clin Exp Dermatol
1991, 16: 374-76.
Johnson M, Shuster S. Ventral nail contribution to the nail plate is continuous along the length of the nail bed. BrJ Dermatol 1990; 123: 825 6. Johnson M, Comaish JS, Shuster S. Nail is produced by the normal nail bed. a controversy resolved. Br J Dermatol 1991; 125: 27-29. 5.
