- Email: [email protected]
Antifungal agents
A.V. Astahova
Antifungal agents
28 Amphotericin B
{SED-I O, 51 7;
SEDA-8, 263) A review article by Drutz (1 r) discusses problems in the treatment o f coccidioidomycosis. Amphotericin B has clearly demonstrated its value in the management o f this disease, but in certain forms o f coccidioidomycosis such high doses are required that its renal toxicity becomes a major obstacle. As is well known, it involves both glomerular and tubular function, and is manifested by azotemia and renal tubular acidosis, with potassium wasting. Although amphotericin B undoubtedly produces permanent renal structural damage in every patient treated, laboratory evidence o f permanent renal dysfunction is seldom demonstrable with total doses o f less than 3 - 4 g. Since most mycoses can be effectively treated with amphotericin B doses in this general range, permanent renal dysfunction is seldom an important clinical problem. The situation, however, differs with certain forms o f coccidioidomycosis, and particularly where there is widely disseminated chronic disease, in the presence o f an elevated complement-fixing antibody titer and non-reactivity to coccidioides immitis skin tests. Some patients in this category have req uired more than 12-15 g o f drug over a period o f years merely to suppress the infection. Under these circumstances, renal damage o f a significant degree may occur, occasionally sufficient to require renal transplanation. In patients with the host status described above, these authors have often provided interval courses o f 1 - 3 amphotericin B sufficient to bring the patient's infection under control and have then maintained the remissions by interval outpatient infusions o f amphotericin B. Side Effects of Drugs Annual 9 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1985 ISBN 0 444 90394 1 $0.85 per article per page {transactional system) $0.20 per article per page (licensing system)
Encouraging experience dealing with 5 patients in whom impaired renal function developed early during amphotericin B therapy was reported by Heidemann et al (2Cr). All patients had evidence of impaired renal function, as indicated by increases in plasma concentrations of blood urea nitrogen and creatinine early during the course of amphotericin B therapy for systemic fungal infections. These patients were for a variety of reasons likely to have been somewhat sodium-depleted before or during amphotericin B treatment. The patients were either receiving low-sodium diets, anorectic on treatment with diuretics, or vomiting due to the amphotericin B itself. Because of the rapid onset of the amphotericin-B induced nephrotoxicity, and the possibility that the apparent sodium depletion of the patients may have exacerbated the drug's effects on the kidney, it was decided to increase the sodium intake of the patients and then to continue with the amphotericin B therapy. In addition to increasing salt intake, the authors withdrew any concomitant diuretic therapy and in 1 patient concurrently administered intravenous albumin. These maneuvers were associated with progressive decreases in serum concentrations of blood urea nitrogen and creatinine despite continued treatment with amphotericin B. In all 5 patients the full course of therapy was administered, with clinical resolution of the fungal infection and without further deterioration of kidney function. These observations suggest a critical role for sodium balance during amphotericin B therapy and are consistent with the hypothesis that tubuloglomerular feedback is involved in mediating imparied renal function. Whether they provide a means of dealing more broadly witl~ the renal toxicity of this drug will have to be determined by future clinical work. As pointed out in SED-10, the use of sodium bicarbonate, mannitol and cortisone have all proved disappointing - or at most sporadically successful - in the past.
248 Ketoconazole (SED-1 O, 520; SEDA-8, 264) New publications in the literature on the evaluation of ketoconazole efficacy and safety (3 r, 4 r) continue to merit attention so long as the efficacy/safety balance of this drug has not been definitively delineated. The hepatotoxicity of ketoconazole, extensively discussed in previous volumes in this series (SEDA-8, 265), is still a subject of debate, since not all the reported cases were clearly due to the drug (SED-10, 520). Further cases of hepatic damage to ketoconazole treatment continue, however, to be reported in the literature (5 C, 6c); Svedhem described a reaction (5c), which points to the possibility of a late onset. A 61-year-old woman was suffering from chronic candidiasis of the finger nails. Treatment with 200 mg ketoconazole daily was initiated because of the onychomycosis and a suspected allergy to Candida. Before the start of ketoconazole treatment, and then monthly afterwards, checks were made of the serum concentrations of aspartate aminotransferase (ASAT), alanine aminotmnsferuse (ALAT), alkaline phosphatase (ALP), bilirubin and of ketoconazole. Except for slight nausea a couple of hours after intake occurring only during the first 2 weeks of treatment, the patient seemed to tolerate the ketoconazole, and there were no marked side effects. Serum concentrations of ketoconazole, obtained about 2 hours after intake, varied between 2.6 and 4.0 ug/ml. At the scheduled 4-month check, a moderate rise in serum ASAT and ALAT levels was noted and, as the patient also reported recurrent nausea and fatigue during the preceding 2 days, the treatment was discontinued. The serum bilirubin level began to rise alarmingly a week later, reaching a maximum 1 month after ketoconazole had been withdrawn. Convalescence took 3 months, during which only symptomatic treatment was given, and a rich carbohydrate diet prescribed because of hepatic insufficiency. No liver biopsy was taken. Neither hepatitis B surface antigen and antibodies nor hepatitis A IgM antibodies could be detected, but tests for hepatitis IgG antibodies remained consistently positive. Hollmen et al (6 c) noted an increase in serum ASAT and/or A L A T levels in 4 of 24 patients with onychomycosis during ketoconazole treatment. These data confirm the wisdom of warning patients to stop treatment and have a liver function test performed as soon as they experience any nausea or other discomfort. Some authors have reported the results o f treatment o f vaginal candidosis with
Chapter 28 A. K Astahova oral ketoconazole (7 c , 8t:). Van der Pus et al (7 c ) have evaluated several dose regimens. The 5-day regimens (200 a'ng b.i.d, or 400 mg once daily) seem to be the most appropriate in this infection. Side effects were in their experience minor, 5% o f patients variously developing nausea, headache, epigastric pain, somnolence or weakness. In another report (8) there were 5 patients (out of 56) with side effects. Two women who had received ketoconazole complained of nausea, and one each of dyspepsia, constipation and increased
frequency o f micturition. Further concern was expressed as to the possible hepatic complications of ketoconazole treatment. A statement issued by Britain's Committee on Safety of Medicines to physicians drew attention to the fact that there had up to then been at least 5 deaths and 77 other cases of liver damage, the actual figures perhaps being higher, and stressed the need for intensive monitoring of patients receiving the medicine (9). Miconazole (SED-IO, 521; SEDA-8, 270) Stevens ( 10 cr) has summed up the literature data and his own experience on the efficacy and safety of miconazole in the treatment of coccidioidomycosis. In 4 large series of patients with skin and soft tissue, chronic pulmonary, meningeal and skeletal coccidioidomycosis, response rates of 3 1 - 7 2 % were achieved. C o m m o n side effects of the intravenous miconazole doses needed to attain this result included phlebitis, pruritus,
anemia, thrombocytosis, hyponatremia, nausea, hyperlipidemia, vomiting, central nervous system effects, and rashes. On the basis of comparative evaluation of safety of miconazole, amphotericin B and ketoconazole in the treatment of coccidioidomycosis the author concludes that miconazole is a less toxic drug than amphotericin B, but more toxic than ketoconazole. Enilconazole A 43-year-old woman developed a scaly red patch on the dorsal aspect of the right hand. Her employer considered the lesion as a dermatophyte infection of the skin and gave her the veterinary antimycotic Imaverol, which is a 10% solution o f enilconazole. Two weeks later, she consulted her doctor for an acute eczematous contact der-
Antifungal agents Chapter 28 matitis of the right hand and forearm. After discontinuing Imaverol, the dermatitis healed quickly with wet dressings and topical steroids. Patch tests showed allergy to the imidazole derivatives econazole, enilconazole, isoconazole and miconazole The tests with Imaverol were strongly positive (I 1c). In a previous paper, cross-sensitivity of the imidazole derivatives was described. This new report shows that clinicians can extend the cross-sensitivity patterns of econazole and miconazole to enilconazole and isoconazole. This might have been anticipated since they are ~substituted 1-phenethyl imidazoles. Nifuratel (SEDA-8, 156) Bedello et al (12 C) in a paper incidentally mentioned in the dermatological chapter of the previous Annual have described 1 case of contact dermatitis from nifuratel; such a case has been reported previously. Their 43-year-old patient developed marked edema of the penis and scrotum with early phimosis, beginning approximately 5 hours after application of the ointment. He also had periorbital edema and erythema with mild scaling. Epicutaneous tests were carried out with the standard European series of the ICDRG and with Macmiror ointment (Macmiror being the Italian trade name for preparations containing nifuratel) and a positive result was obtained only to Macmiror ointment. Of the various components of Macmixor o i n t m e n t only nifuratel gave a positive reaction. The first sensitizing contact with allergen had occurred during intercourse with his wife who was being treated with a Macmiror vaginal suppository. The subsequent single application of the ointment to the penis apparently represented the eliciting exposure which produced the severe allergic reaction. INTERACTIONS Smith (13 C) has reported a case in which treatment with ketoconazole potentiated the anticoagulant effect of warfarin. This is the first such published report to date. In the light of this case, when ketoconazole is prescribed for patients being treated with wax-
249 farin, the precautions currently advised for patients being treated with broad-spectrum antibiotics should be taken, namely more frequent monitoring of anticoagulant control and reduction of the warfarin dosage by one third. The combination of amphotericin B and flucytosine (fluorocytosine) is widely used for the treatment of severe fungal infections, in order to secure potentiation of the antifungal effects. Cherfan et al (14 C) observed a case of aplasia of the bone marrow due to amphotericin B and flucytosine therapy in low doses. A 62-year-old woman recovering from a surgical operation was admitted to the reanimation department because of septic shock and renal insufficiency. Torulopsis glabrata was cultured from urine and blood. Treatment with 20 mg/kg/d (total dose 18 g) flucytosine and 30 mg/48 h (total dose 400 mg) amphotericin B was started on the basis of these findings. After 20 days of treatment leukopenia (2100/ mm 3) and thrombocytopenia (165,000/mm 3) developed. After discontinuing the drugs the clinical situation worsened, leukopenia and thrombocytopenia progressing to 500]mm ~ and 46,000]mm 3 respectively. The patient died from septicemia, and autopsy confirmed the bone marrow hypoplasia. Although it is known that amphotericin B can cause anemia, leukopenia and thrombocytopenia are only rarely observed. Flucytosine alone may induce neutropenia and thrombocytopenia. The combination of the 2 drugs apparently increases their toxic effects. In the above case, 2 drugs were applied with great caution; doses were adapted to ereatinine clearance, concentrations of drug in serum were measured and hemodialysis was performed. In view of the complication which nevertheless occurred, the authors recommend avoiding concomitant application of amphotericin B and flucytosine in patients with renal insufficiency. Current scientific literature on the side effects of antifungal drugs relates mostly to old and well-known compounds; most of the topics discussed in these papers are by now familiar and have been reviewed in previous editions of Meyler's Side Effects o f Drugs and in SEDA. The present overview is limited strictly t o a number of subjects on which recent reports have thrown some additional light.
REFERENCES 1. Drutz DJ (1983) Amphotericin B in the treatment of coccidioidomycosis. Drugs, 26, 337. 2 Heidemann HTh, Gerkens JF, Spickard WA et al (1983) Amphotericin B nephrotoxicity
in humans decreased by salt repletion. Am. J.
Med., 75,476. 3. Henry JC (1984) Ketoconazole. Clin., 2, 121.
Dermatol.
Chapter 28
250 4. Galgiani JN (1983) Ketoconazole in the treatment of coccidioidomycosis. Drugs, 26, 355. 5. Svedhem A (1984) Toxic hepatitis following ketoconazole treatment. Scand. J. Infect. Dis., 16, 123. 6. HoUmen A, Lakkakorpi A, V~i/~tainenN (1983) Ketokonatsoli kynsisienen hoidossa. Duodecim, 99, 1046. 7. Van der Pas H, Peeters F, Janssens D et al (1983) Treatment of vaginal candidosis with oral ketoconazole. Eur. J. Obstet. Gynaecol. Reprod. Biol., 14, 399. 8. Scudamore J, Tooley P (1983) The treatment of recurrent vaginal candidiasis in general practice with the orally active antifungal agent ketoconazole. Curr. Ther. Res., 33, 917. 9. Anonymous (1985) Doctors warned of liver risk
A. E Astahova
after five skin drug patients die. The Times, Jan.
5th, London. 10. Stevens DA (1983) Miconazole in the treatment of coccidioidomycosis. Drugs, 26, 347. 11. Hecke E, Vos L (1983) Contact sensitivity to enilconazole. Contact Dermatitis, 9, 144. 12. Bedello PG, Goitre M, Cane D et al (1983) Contact dermatitis from nifuratel. Contact Dermatitis, 9, 166. 13. Smith AG (1984) Potentiation of oral anticoagulants by ketoconazole. Br. Med. J., 288, 188. 14. Cherfan J, Maurier F, Koenig F (1983) Aplasie m6dullaire au cours d'une association amphot6ricine B-fluorocytosine. J. Mkd. Strasbourg, 14, 468.
Antifungal agents
28 Amphotericin B
{SED-I O, 51 7;
SEDA-8, 263) A review article by Drutz (1 r) discusses problems in the treatment o f coccidioidomycosis. Amphotericin B has clearly demonstrated its value in the management o f this disease, but in certain forms o f coccidioidomycosis such high doses are required that its renal toxicity becomes a major obstacle. As is well known, it involves both glomerular and tubular function, and is manifested by azotemia and renal tubular acidosis, with potassium wasting. Although amphotericin B undoubtedly produces permanent renal structural damage in every patient treated, laboratory evidence o f permanent renal dysfunction is seldom demonstrable with total doses o f less than 3 - 4 g. Since most mycoses can be effectively treated with amphotericin B doses in this general range, permanent renal dysfunction is seldom an important clinical problem. The situation, however, differs with certain forms o f coccidioidomycosis, and particularly where there is widely disseminated chronic disease, in the presence o f an elevated complement-fixing antibody titer and non-reactivity to coccidioides immitis skin tests. Some patients in this category have req uired more than 12-15 g o f drug over a period o f years merely to suppress the infection. Under these circumstances, renal damage o f a significant degree may occur, occasionally sufficient to require renal transplanation. In patients with the host status described above, these authors have often provided interval courses o f 1 - 3 amphotericin B sufficient to bring the patient's infection under control and have then maintained the remissions by interval outpatient infusions o f amphotericin B. Side Effects of Drugs Annual 9 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1985 ISBN 0 444 90394 1 $0.85 per article per page {transactional system) $0.20 per article per page (licensing system)
Encouraging experience dealing with 5 patients in whom impaired renal function developed early during amphotericin B therapy was reported by Heidemann et al (2Cr). All patients had evidence of impaired renal function, as indicated by increases in plasma concentrations of blood urea nitrogen and creatinine early during the course of amphotericin B therapy for systemic fungal infections. These patients were for a variety of reasons likely to have been somewhat sodium-depleted before or during amphotericin B treatment. The patients were either receiving low-sodium diets, anorectic on treatment with diuretics, or vomiting due to the amphotericin B itself. Because of the rapid onset of the amphotericin-B induced nephrotoxicity, and the possibility that the apparent sodium depletion of the patients may have exacerbated the drug's effects on the kidney, it was decided to increase the sodium intake of the patients and then to continue with the amphotericin B therapy. In addition to increasing salt intake, the authors withdrew any concomitant diuretic therapy and in 1 patient concurrently administered intravenous albumin. These maneuvers were associated with progressive decreases in serum concentrations of blood urea nitrogen and creatinine despite continued treatment with amphotericin B. In all 5 patients the full course of therapy was administered, with clinical resolution of the fungal infection and without further deterioration of kidney function. These observations suggest a critical role for sodium balance during amphotericin B therapy and are consistent with the hypothesis that tubuloglomerular feedback is involved in mediating imparied renal function. Whether they provide a means of dealing more broadly witl~ the renal toxicity of this drug will have to be determined by future clinical work. As pointed out in SED-10, the use of sodium bicarbonate, mannitol and cortisone have all proved disappointing - or at most sporadically successful - in the past.
248 Ketoconazole (SED-1 O, 520; SEDA-8, 264) New publications in the literature on the evaluation of ketoconazole efficacy and safety (3 r, 4 r) continue to merit attention so long as the efficacy/safety balance of this drug has not been definitively delineated. The hepatotoxicity of ketoconazole, extensively discussed in previous volumes in this series (SEDA-8, 265), is still a subject of debate, since not all the reported cases were clearly due to the drug (SED-10, 520). Further cases of hepatic damage to ketoconazole treatment continue, however, to be reported in the literature (5 C, 6c); Svedhem described a reaction (5c), which points to the possibility of a late onset. A 61-year-old woman was suffering from chronic candidiasis of the finger nails. Treatment with 200 mg ketoconazole daily was initiated because of the onychomycosis and a suspected allergy to Candida. Before the start of ketoconazole treatment, and then monthly afterwards, checks were made of the serum concentrations of aspartate aminotransferase (ASAT), alanine aminotmnsferuse (ALAT), alkaline phosphatase (ALP), bilirubin and of ketoconazole. Except for slight nausea a couple of hours after intake occurring only during the first 2 weeks of treatment, the patient seemed to tolerate the ketoconazole, and there were no marked side effects. Serum concentrations of ketoconazole, obtained about 2 hours after intake, varied between 2.6 and 4.0 ug/ml. At the scheduled 4-month check, a moderate rise in serum ASAT and ALAT levels was noted and, as the patient also reported recurrent nausea and fatigue during the preceding 2 days, the treatment was discontinued. The serum bilirubin level began to rise alarmingly a week later, reaching a maximum 1 month after ketoconazole had been withdrawn. Convalescence took 3 months, during which only symptomatic treatment was given, and a rich carbohydrate diet prescribed because of hepatic insufficiency. No liver biopsy was taken. Neither hepatitis B surface antigen and antibodies nor hepatitis A IgM antibodies could be detected, but tests for hepatitis IgG antibodies remained consistently positive. Hollmen et al (6 c) noted an increase in serum ASAT and/or A L A T levels in 4 of 24 patients with onychomycosis during ketoconazole treatment. These data confirm the wisdom of warning patients to stop treatment and have a liver function test performed as soon as they experience any nausea or other discomfort. Some authors have reported the results o f treatment o f vaginal candidosis with
Chapter 28 A. K Astahova oral ketoconazole (7 c , 8t:). Van der Pus et al (7 c ) have evaluated several dose regimens. The 5-day regimens (200 a'ng b.i.d, or 400 mg once daily) seem to be the most appropriate in this infection. Side effects were in their experience minor, 5% o f patients variously developing nausea, headache, epigastric pain, somnolence or weakness. In another report (8) there were 5 patients (out of 56) with side effects. Two women who had received ketoconazole complained of nausea, and one each of dyspepsia, constipation and increased
frequency o f micturition. Further concern was expressed as to the possible hepatic complications of ketoconazole treatment. A statement issued by Britain's Committee on Safety of Medicines to physicians drew attention to the fact that there had up to then been at least 5 deaths and 77 other cases of liver damage, the actual figures perhaps being higher, and stressed the need for intensive monitoring of patients receiving the medicine (9). Miconazole (SED-IO, 521; SEDA-8, 270) Stevens ( 10 cr) has summed up the literature data and his own experience on the efficacy and safety of miconazole in the treatment of coccidioidomycosis. In 4 large series of patients with skin and soft tissue, chronic pulmonary, meningeal and skeletal coccidioidomycosis, response rates of 3 1 - 7 2 % were achieved. C o m m o n side effects of the intravenous miconazole doses needed to attain this result included phlebitis, pruritus,
anemia, thrombocytosis, hyponatremia, nausea, hyperlipidemia, vomiting, central nervous system effects, and rashes. On the basis of comparative evaluation of safety of miconazole, amphotericin B and ketoconazole in the treatment of coccidioidomycosis the author concludes that miconazole is a less toxic drug than amphotericin B, but more toxic than ketoconazole. Enilconazole A 43-year-old woman developed a scaly red patch on the dorsal aspect of the right hand. Her employer considered the lesion as a dermatophyte infection of the skin and gave her the veterinary antimycotic Imaverol, which is a 10% solution o f enilconazole. Two weeks later, she consulted her doctor for an acute eczematous contact der-
Antifungal agents Chapter 28 matitis of the right hand and forearm. After discontinuing Imaverol, the dermatitis healed quickly with wet dressings and topical steroids. Patch tests showed allergy to the imidazole derivatives econazole, enilconazole, isoconazole and miconazole The tests with Imaverol were strongly positive (I 1c). In a previous paper, cross-sensitivity of the imidazole derivatives was described. This new report shows that clinicians can extend the cross-sensitivity patterns of econazole and miconazole to enilconazole and isoconazole. This might have been anticipated since they are ~substituted 1-phenethyl imidazoles. Nifuratel (SEDA-8, 156) Bedello et al (12 C) in a paper incidentally mentioned in the dermatological chapter of the previous Annual have described 1 case of contact dermatitis from nifuratel; such a case has been reported previously. Their 43-year-old patient developed marked edema of the penis and scrotum with early phimosis, beginning approximately 5 hours after application of the ointment. He also had periorbital edema and erythema with mild scaling. Epicutaneous tests were carried out with the standard European series of the ICDRG and with Macmiror ointment (Macmiror being the Italian trade name for preparations containing nifuratel) and a positive result was obtained only to Macmiror ointment. Of the various components of Macmixor o i n t m e n t only nifuratel gave a positive reaction. The first sensitizing contact with allergen had occurred during intercourse with his wife who was being treated with a Macmiror vaginal suppository. The subsequent single application of the ointment to the penis apparently represented the eliciting exposure which produced the severe allergic reaction. INTERACTIONS Smith (13 C) has reported a case in which treatment with ketoconazole potentiated the anticoagulant effect of warfarin. This is the first such published report to date. In the light of this case, when ketoconazole is prescribed for patients being treated with wax-
249 farin, the precautions currently advised for patients being treated with broad-spectrum antibiotics should be taken, namely more frequent monitoring of anticoagulant control and reduction of the warfarin dosage by one third. The combination of amphotericin B and flucytosine (fluorocytosine) is widely used for the treatment of severe fungal infections, in order to secure potentiation of the antifungal effects. Cherfan et al (14 C) observed a case of aplasia of the bone marrow due to amphotericin B and flucytosine therapy in low doses. A 62-year-old woman recovering from a surgical operation was admitted to the reanimation department because of septic shock and renal insufficiency. Torulopsis glabrata was cultured from urine and blood. Treatment with 20 mg/kg/d (total dose 18 g) flucytosine and 30 mg/48 h (total dose 400 mg) amphotericin B was started on the basis of these findings. After 20 days of treatment leukopenia (2100/ mm 3) and thrombocytopenia (165,000/mm 3) developed. After discontinuing the drugs the clinical situation worsened, leukopenia and thrombocytopenia progressing to 500]mm ~ and 46,000]mm 3 respectively. The patient died from septicemia, and autopsy confirmed the bone marrow hypoplasia. Although it is known that amphotericin B can cause anemia, leukopenia and thrombocytopenia are only rarely observed. Flucytosine alone may induce neutropenia and thrombocytopenia. The combination of the 2 drugs apparently increases their toxic effects. In the above case, 2 drugs were applied with great caution; doses were adapted to ereatinine clearance, concentrations of drug in serum were measured and hemodialysis was performed. In view of the complication which nevertheless occurred, the authors recommend avoiding concomitant application of amphotericin B and flucytosine in patients with renal insufficiency. Current scientific literature on the side effects of antifungal drugs relates mostly to old and well-known compounds; most of the topics discussed in these papers are by now familiar and have been reviewed in previous editions of Meyler's Side Effects o f Drugs and in SEDA. The present overview is limited strictly t o a number of subjects on which recent reports have thrown some additional light.
REFERENCES 1. Drutz DJ (1983) Amphotericin B in the treatment of coccidioidomycosis. Drugs, 26, 337. 2 Heidemann HTh, Gerkens JF, Spickard WA et al (1983) Amphotericin B nephrotoxicity
in humans decreased by salt repletion. Am. J.
Med., 75,476. 3. Henry JC (1984) Ketoconazole. Clin., 2, 121.
Dermatol.
Chapter 28
250 4. Galgiani JN (1983) Ketoconazole in the treatment of coccidioidomycosis. Drugs, 26, 355. 5. Svedhem A (1984) Toxic hepatitis following ketoconazole treatment. Scand. J. Infect. Dis., 16, 123. 6. HoUmen A, Lakkakorpi A, V~i/~tainenN (1983) Ketokonatsoli kynsisienen hoidossa. Duodecim, 99, 1046. 7. Van der Pas H, Peeters F, Janssens D et al (1983) Treatment of vaginal candidosis with oral ketoconazole. Eur. J. Obstet. Gynaecol. Reprod. Biol., 14, 399. 8. Scudamore J, Tooley P (1983) The treatment of recurrent vaginal candidiasis in general practice with the orally active antifungal agent ketoconazole. Curr. Ther. Res., 33, 917. 9. Anonymous (1985) Doctors warned of liver risk
A. E Astahova
after five skin drug patients die. The Times, Jan.
5th, London. 10. Stevens DA (1983) Miconazole in the treatment of coccidioidomycosis. Drugs, 26, 347. 11. Hecke E, Vos L (1983) Contact sensitivity to enilconazole. Contact Dermatitis, 9, 144. 12. Bedello PG, Goitre M, Cane D et al (1983) Contact dermatitis from nifuratel. Contact Dermatitis, 9, 166. 13. Smith AG (1984) Potentiation of oral anticoagulants by ketoconazole. Br. Med. J., 288, 188. 14. Cherfan J, Maurier F, Koenig F (1983) Aplasie m6dullaire au cours d'une association amphot6ricine B-fluorocytosine. J. Mkd. Strasbourg, 14, 468.