Cucé, Luiz Carlos

Sampaio, Sebastião A. P.

Wroclawski, Elisabeth L.

English

Cadernos Espinosanos (E-Journal)

Rev. Inst. Med. trop. São Paulo23(2) :82-85, março-abril, 1981TREATMENT OF PARAGOCCIDIOIDOMYCOSIS W¡TH KETOCONAZOLELuiz Carlos CUCE, Elisabeth L. WROCLAWSKI and Sebastião A. P. SAMPAIO (l)SUMMARYThe results of the use of ketoconazole in 3? cases of paracoccidioidomycosisare presented. The drug was administered "per os" in the dose of 400 mg a da.yfor 30 days and 200 mg a day for the following 60 da¡rs. With this treatment ci-catrization of the cutaneous lesions occurred from 3 to 4 weeks in 32 patientsând from 6 to 7 weeks in 4 patients. The direct mycological examinations beca-me negatives in all cases. In 1 patient who had intestinal involvement withoutcutaneous lesions clinical improvement was registered. After the 90 days periodof treatment the patients were divided in two groups. To the first one with 14patients no further medication was given and to the second group with 23 patientswas administered 200 mg of ketoconazole, three times a week. After a follow upperiod of 10 months a relapse wâs ,seen in 7 of 14 patients $0%) of the Group I,who were treated for only 90 days and in 2 of. 23 patients ß.6vo) of the patientsof Group II, who received a maintenance dose of 200 mg three times a week. Keto-conazole is a very effective drug in the treatment of paracoccidioidomycosis,with excellent tolerance. It is the first choice in the therapy of paracoccidioidomy-cosis but the period of administration and the doses will need further studies.UDC 616.992.282Prior to the 1940's and the advent of sulfadrugs 12 paracoccidioidomycorsis carried out analmost hopeless prognosis. The sulfonamidesare fungistatic drugs and must be administeredfor an indefinite period of time. Relapses occurupon cessation of therapy. In a review of 3BB pa-tients 15 treated between 1948 and 19SB with sul-fonamiders, 430/o died of the disease and mosuof the survivors still had the disease. Amphote-ricin B was introduced in 1958s and. since then400 patients have been treated with this antibio-tic in our clinic with one or more series of am-photericin B. The review of these patients show-ed 51.00/o with clinical and serological cure;17.2% with clinical cure but with positive sero-Iogy; 21.6% with ctinical and serological activi-ty of the disease; 76.2ø/o 0L the patients diedfrom the disease or related conditions, includingin this group 2 patients who died from irrever-T NTRODUCT I ONsible renal lesions. The nephrotoxicity of am-photericin B is the main toxic effect 1,2,3,8 of theamphotericin B.Miconazole and clotrimazole, imidazolic de-rivatives have a topical action on superficial my-cosis caused by dermatophytes or yeasts. Theyhave a certain systemic activity in the deepmycosis but the published papers have not pro-vided definite conclusions 4,6,7,e,10,11,13,14.The research works carried out lead to thesynthesis of a new imidazolic derivative, ketoco-nazole, presenting a better absorption by oralroute in relation to the others which have al-rea{y been studied and with excellent "in vitro"antifungal action. The present clinical trial aimsto verify the action of ketoconazole in the treat-ment of paracoccidioidornycosis.(1) From the DÍvision of Dermatology, Department of rropical Medicine and Derma,tology, Faculty of Med.icine, universityof s. Paulo. Reprint requests to: Prof. Sebastião A. P. Sampaio, Divisão de Dermatologia, Hospital das clÍnicas. c.p,8091, São Paulo - S.p. Brasil82cucÉ, L. C.;Rev. fnsú.MATERIALS AND METHODSKetoconazole, imidazolic derivative, is awhite powder, slightþ yellowish, practicallyodorless and tasteless. It rvas administrated o,yoral route in 200 mg tablets, in between mealswithout alkaline agents. This clinical trial wasmade in BT cases of paracoccidioidomycosis.The diagnosis was based on the clinical aspec[s,direct and histopathological examinations. Ra_diological examinations were mad.e according tothe disease and complement fixation and preci_pitin reactions for paracoccidioidorqycosis, (na_va Netto's tests) were performed.The following tests were also made, before,during and after treatment: Complete hemo_gram, urea, creatinine, gþcemia, cholesterol, to_tal lipids, transaminases, protrombine, alkalinephosphatase, bilirubin and urinaþsis.In the 37 cases of paracoccidioidomycosis,36 were males and 1 female; the mean age .was42 years and the disease's d.uration wâs from zmonths to 28 years. Of all B? patients 24 havehad previous treatments.Of the 3Z patients with paracoccidioidomy_cosis, 36 had skin lesions in which ty¡pical formsof parasites were found in the histopathologicaland direct examinations. In 1 patient there wasno skin lesion. This patient had already beensubmitted to treatment and presented skinscars. The existence of intestinal signs of para_coccidioidorr¡ycosis showed through the radio_logical examinations as well as the positive re_sults of the serological reactions justified theirinclusion in the group. The precipitin tests werenegatives in 18 and positives in 19 patients andthe complement fixation tests were positives in34 and negatives in 3 patienús. Out of B? patients,23 presented a radiological pulmonary picturetypical of paracoccidioid.ornycosis in activity.In accordance with the clinical involvement,13 patients had only tegumentary lesions, 28had cutaneous-visceral lesions and I patient hadonly an intestinal involvement.WR,OCLAWSKI, E. L. & SAMPAIO,Med. trop. São Paulo ZB:BZ-95. 1981.S. A. P. - Treatment of paracoccidioidomycosis with ketoconazole.The 37 patients were divided into twogroups: The first group of 14 patients receivedthe ketoconazole for a period of g0 days, 400 mga day for 30 days and 200 mg a day for 60 days.The second group, Group II, of 28 patients afterthe same dosage and period of time of treat_ment received a maintenance d.ose of 200 mg ofketoconazole, three times a week, for a þeriodof 10 months. Both groups were followed withclinical, radiological, serological and other com_plementary examinations in this period of time.RESULTSAfter a period of g0 days of treatment withketoconazole the B? cases of paracoccidioidomy_cosis had the cicatrization of the skin 1e,sions,which occurred from B to 4 weeks in 82 patientsand from 6 to ? weeks in 4 patients, with nega-tive direct mycological examinations. The pa-tient with intestinal involvement but withourcutaneous lesion had clinical improvement. Inaccording with the pulmonary 1esions in the g0days period of treatment, 1 patient had radio_logical remission and the other had improve-meni or unchanged X-rays. The clinical, radiolo_gical and seroiogical re,sults after 10 months ofevolution are presented in Tables I, II and III.The tables showed the following results:Group I - In this group with 14 patientswere observed T cases (80%) of. relapses. Ofthese patients 2 had tegumentary forms, 4 hadtegumentary-lymphatic-visceral forms and t hadthe intestinal form.TABLE IResults of the treatment with ketoconazole in a period of10 monthsGroup IGroup IIPatients with lesionsTABLE IIEvolution of the pulmonary lesions (X-rays) in 28 patientsGroup I: 14 patients treated for g0 days (400 mg a dayfor 30 days and 200 mg a day for 60 days).Number of relapses: ? (50.00/o)Group II: 23 patients treated. with the same dosage for g0days with a fufther maintenance dose of 200 mgof ketoconazole three times a week foÌ 10 months.Number of relapses: Z (8-60/o)16Remission7 (6-20k)fmprovement2 (28.30/o)I (56.2%)Unchanged3 (42.90/o)4 (25.00/o)2 (28.60/o)2 (72.50/o)83CUCE, L. C.; WROCLAWSKI, E. L. & SAMPAIO, S. A. P. - Treatment of paracoccidioidomycosis with ketoconazole.Rev. Inst. Med. trop. São Paulo 23:82-85,1981.Group IGroup IINeg. : negativeDec. ; decreaseUnch.: UnchangedGroup II - In this group with 23 patients,who received the maintenance dose of 200 mg,three times a week, occurred 2 cases (B.6Vo) ofrelapses.fn accordance with the radiological pulmonary studies, 7 patients in the Group I with pul-monary lesions had the following evolution: in2 there'were improvement, in 3 the X-rays wereunchanged and in 2 there were no further con-trol.In the Group II, of 16 patients with pulmo'nary involvement, the radiological studiesshowed disappearance of the lesions int (6.2o/o),improvement in 9 (é6.20/o), unchanged aspectsin 4 (25.0o/o) and without further control 2 pa-tients (12.5%).The serological evolution with the comple-ment fixation and precipitin tests showed inGroup I improvement or negativity in 4 patientsunchanged in 1 and in 2 no further control. Inthe Group II there was negative precipitin in 11patients, decrease in 2 and unchanged in 5. Inthis group, there was fall of the titers of thecomplement fixation tests in 15 and unchangedtiters in 3. In 5 patients further serologicaltests were not performed... COMMENTSFirst of all the excellent results of ketoco-nazole in paracoccidioidornycosis must be point-ed out. It has a therapeutic action comparableto amphotericin B On the other hand, its ex-cellent tolerance and ease of administrationmake ketoconazole the drug of choice for thetreatment of paracoccidioidom¡rcosis. It shouldbe added that the drug was effective in patientsresistent to sulfas and/or in those that had al-ready undergone treatment with amphotericinB.The 90 days period of administration of ke-toconazole is not, sufficient for the treatmentB4Neg.8IIPrecipitin testsTABLE IIIEvolution of the serology in.10 monthsDec.12UnchINeg.3Complement fixation testsD¿c.615since relapses occurred in 7 of 14 patients(50.0%). On the other hand the maintenancedose of 200 mg three times a week is also notsufficient since 2 cases (8.60/o) of relapses occurr-ed in the 10 month period of observatÍon. Theadministration of 200 mg a day ketoconazole fora variable period of time in accordance withthe clinical, radiological and serological evolu-tion should be tried as the maintenance dosasein the therapy of paracoccidioidomycosis.RESUMOTratamento da paracoccidioidomicose comketoconazolOs resultados do tratamento de 37 casos deparacoccidioidomicose pelo ketoconazol sãoapresentados. O medicamento foi administrado"per os" na dose de 400 mg ao dia por 30 diase 200 mg por dia em 60 dias subseqüentes. Comeste tratamento ocorreu cicatrizaçáo das lesõescutâneas em 3 a 4 ,semanas em 32 doentes e em6 a ? semanas em 4 doentes. O exame micológi-co direto das lesões cutâneas tornou-se negativoem todos os casos. Um dos doentes, apresenta-va exclusivamente comprometimento intestinal,tendo tido clinicamente melhora. Após 90 diasde tratamento os doentes foram divididos emdois grupos: o primeiro, com 14 doentes, não re-cebeu mais medicação e o segundo grupo, com23 doentes, recebeu a dose de 200 mg de keto-conazol três vezes por semana. Após um perÍo-do de 10 meses de seguimento, recidiva da mo-léstia foi registrada em 7 dos 14 doentes (50% )do primeiro grupo (500/o) que foram tratadossomente por 90 dias e em 2 dos 23 doentes(8,60/o) do segundo grupo, que receberam a do-se de manutenção de 200 mg, três vezeS por se-mana".Os Autores concluem que o ketoconazol éuma droga efetiva no tratamento da paracoccidioidomicose e com excelente tolerância. Pode.rá ser a primeira escolha no tratamento da mo-Unch13UndonecUcÉ, L' C'; WR'OCLAIVSKI, E. L. & SAMPAIO, S. A. P. - Treatment of paracoccidioidomycosis \a'iilr ketoconazoleBev. Inst. Med. trop. São Par¡lo 23:92.85, 1991.léstia ainda que o tempo de administraçáo e asdoses do medicamento necessitarão de ooste-riores estudos.REFEEENCES1. CHUNG, D. K. & KOENING, M. c. - Reversible car-diac enlargement during treatment with amphotericinB and hydrocortisone. Report of three casês. Am. Rev.Resp. Dis. 103: 831-841, l9?1.2. DILLON, N. L. - lratamenúo da paracoccidioidomi-cose pelâ anfotericina B. Avaliação de 119 doentes numperíodo de 14 anos. lTese de doutoramento]. Sáo Paulo,Faculdade de MedicÍna da Universidade de Sáo pâulo,r972.3. DOUGLAS, J. B. & HEALEY, J. K. - Nephrotic ef.fects of amphotericin B including renal tubular acido-sis. Am. J. Med. 46: 154-162, 1969.4. HOLT, R,. J. & NEWMAN, L. - LaboÌato¡y assessmentof the antimycotÍc dtug clotrÍmazole. J. Clin. paúh.25: 1089-1097. 19?2.5. LACAZ, C. S. & SAMPAIO, S. A. p. - Tratamentoda Blastomicose sul-americana com anfotericina B. Rev.PauI. Med. 52: 443-450, 1958.6, LIMA, N. S.; TEIXEIRA, c. .4.. & MIRANDA, J. L.- Tratamento da Blastomicose sul-americanå pelo mi_conazole o¡al. An, Brasil. Dermaú. 4gt Zg7-244, Lg74-7. LIMA, N. S.; TEIXEIRA, G. A.; MIRANDA, J. &VALLE, A. C. F. - Treatment of South American Bras-tomycosis (Paracoccidioidomycosis) .with miconazole bythe oral ¡oute: An on-going study. proc. Roy. Soc.Med. ?0 (Suppl. 1): 85.89, 19??.MILLER, R. P- & BATES, J. H. - Amphotericin Btoxicity. ¡, follow-up reF,ort of 5A pâtients, Ann. Itìúeuì.Med. ?1: 1089,1095, 1969.NEGRONI, P. Y. & RODRIGUEZ, Z. J. _ Ensayossobre la accion fungostatica y fungicida de miconazol.Bol. Acad. Nac. Med. Argentina 5l: t2B-180, 19?8.NEGRONI, R,.; LIBONATTI, E.; RUBENSTEIN, p.;RAMO, H.; PA.LMIERI, O.; WAISMANN, M.; ELDER,M. & CABLINSKY, E. - Preliminary study of theaction of miconâzo1e on paracoccidioidomvcosis. C¿s.tellania 4: 11-19, 1976.NEGRONI, R,.; RUBINSTEIN, P.; HERRMANN, A.& GIMENEZ, A. - Results of Miconazole therapy intwenty-eight patients with paracoccidioidomycosis (SouthAmerican Blâstomycosis). Proe. Roy. Soc. Med. ?0(Suppl. 1): 24-28, 1911.OLMIRA RIBEIR.O, D. - Nova telapêutica parablastomÍcose. PubI. Med. São Pauto t2: 86-54, 1940.PROENÇA, N. c.; MAIA, M. A. & ALONSO, F. F. ._Miconazole em paracoccidioidomicose. An. Bræil. Der_mat. 53: 2'l'l-284, L978.RODRIGUEZ, H. J. & BOR.ELLI, D. - Miconazoteper os en tiña y micosis profundas. Med, Cut. I.L.A.3: 199-204, 19?6.SAMPAIO, S. A. P. - Tratamento da Blastomicose sut.âmericana com anfoúericina B. lTese de ptofessorado]São Paulo, Fâculdade de Medicina da Universidade deSão Paulo, 1960.10.Recebido para publicação em I /,t/lgBO.B5

Treatment of paracoccidioidomycosis with ketoconazole

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Treatment of paracoccidioidomycosis with ketoconazole

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