Agranulocitosis febril y artropatía reactiva asociada a consumo de cocaína en un paciente HLA B27 positivo / Febrile agranulocytosis and reactive arthropathy associated with cocaine consumption in an HLA B27 positive patient

Resumen La agranulocitosis asociada al consumo de cocaína es un fenómeno vinculado a la presencia de levamisol, un agente antihelmíntico e inmunomodulador, usado como adulterante de la cocaína. Esta reacción puede presentarse con mayor frecuencia en personas con HLA B27. Además de la agranulocitosis, las personas que consumen cocaína adulterada con levamisol pueden desarrollar fiebre, lesiones en piel, artralgias y, menos frecuentemente, artritis y entesitis inflamatoria. Presentamos el caso de un paciente consumidor de cocaína, con genotipo HLA B27, que desarrolló agranulocitosis febril y artropatía reactiva. En sangre se detectó la presencia de ANCA p, ANCA atípico y MPO, y fueron excluidas otras causas de agranulocitosis. Fue tratado con corticoides y posteriormente metotrexato, terapia de deshabituación, con buena evolución.

Abstract Agranulocytosis associated with cocaine use is a phenomenon linked to the presence of levamisole, an anthelminthic and immunomodulating agent, used as an adulterant to cocaine. This reaction has been associated with the presence of HLA B27. In addition to agranulocytosis, people who use levamisole-adulterated cocaine may develop fever, skin lesions, arthralgias, and less frequently, inflammatory enthesitis and arthritis. We present the case of a cocaine-consuming patient with HLA B27 genotype, who developed febrile agranulocytosis and inflammatory arthropathy. The presence of p ANCA, atypical ANCA and MPO was detected in blood, and other causes of agranulocytosis were excluded. He was treated with corticosteroids and later methotrexate, therapy for addiction, with good evolution.

Cocaína adulterada con levamisol: reporte de tres casos clínicos / Levamisole-adulterated cocaine: a report on three clinical cases

El consumo de clorhidrato y pasta base de cocaína en Uruguay tiene una prevalencia de vida del 6,9% y 0,7% respectivamente. Las complicaciones tóxicas secundarias al consumo dependen de la concentración del alcaloide así como de la presencia de adulterantes. El levamisol, antihelmíntico veterinario, reconocido adulterante de la cocaína en Estados Unidos (2003), fue detectado en Uruguay en el año 2013. Este adulterante genera complicaciones tales como neutropenia, vasculitis cutánea, glomerulonefritis, hemorragia pulmonar y leucoencefalopatía. Se describen los tres primeros casos clínicos de complicaciones por levamisol como adulterante de cocaína reportados al Centro de Información y Asesoramiento Toxicológico. Los pacientes eran consumidores crónicos con edades entre los 35 y 40 años. En los tres casos se objetivó un púrpura retiforme con centro necrótico asociado a anticuerpos ANCA positivos con tendencia a presentarse en lóbulos de orejas, mejillas y extremidades, tal como se reporta en las vasculitis por levamisol. Se reportó neutropenia asociada en un caso. Los tres pacientes presentaron anemia. Dos casos presentaron falla renal aguda. El tratamiento principal fue el cese del consumo, lo que produjo una reversión completa de las complicaciones. Todos requirieron debridación o injertos de piel, o ambos. Se discuten y analizan las complicaciones mencionadas así como el riesgo que conlleva la reexposición y los tratamientos propuestos para las mismas, tales como los factores de crecimiento de granulocitos, antibióticos de amplio espectro y los corticoides. Se requiere un alto índice de sospecha para vincular estas manifestaciones clínicas a la presencia de levamisol como adulterante de la cocaína.

Consumption of cocaine hydrochloride and cocaine base paste (CBP) in Uruguay has a lifetime prevalence of 6.9% and 0.7% respectively. Complications associated to toxic side effects of cocaine abuse depend on the concentration of the alkaloid, as well as on the presence of adulterants. Levamisole, a veterinary anthelmintic, a well know cocaine adulterant in the US was identified in Uruguay in 2013. This adulterant results in complications such as neutropenia, skin vasculitis, glomerulonephritis and leukoencephalopathy. The study describes the first three clinical cases of complications resulting from cocaine cut with levamisole reported to the Toxicology Center for Information and Counseling. The patients included were chronic cocaine abusers between 35 and 40 years old. Retiform purpura was detected in the three cases with a necrotic center associated to ANCA antibodies, with a tendency to appear in the earlobes, cheeks, and limbs, as it is reported in levamisole associated vasculitis. Neutropenia was reported in one case. The three patients had anemia. Two of the cases presented acute kidney failure. The main treatment was interruption of consumption, what resulted in a complete reversion of complications. All patients required debridement or skin grafts, or both. The above mentioned complications are discussed and analyzed, as well as the risk re-exposure and the suggested treatments involve, as the granulocytes growth factors, broad spectrum antibiotics and corticoids. A high degree of suspicion is required to associate these clinical manifestations to the presence of levamisole as a cocaine adulterant.

O consumo de cloridrato e pasta base de cocaína no Uruguai tem uma prevalência de vida de 6,9% e 0,7% respectivamente. As complicações tóxicas secundarias ao consumo dependem da concentração do alcaloide como também da presença de adulterantes. O levamisol, anti-helmíntico veterinário, um conhecido adulterante da cocaína nos Estados Unidos (2003), foi detectado no Uruguai em 2013. Este adulterante gera complicações tais como neutropenia, vasculite cutânea, glomerulonefrite, hemorragia pulmonar e leucoencefalopatia. Os três primeiros casos clínicos de complicações por levamisol como adulterante de cocaína informados ao Centro de Información y Asesoramiento Toxicológico são descritos. Os pacientes eram consumidores crônicos com idades entre 35 e 40 anos. Nos três casos se observou púrpura retiforme com centro necrótico associado a anticorpos ANCA positivos com tendência a apresentação nos lóbulos das orelhas, bochechas e extremidades, como estão descritas nas vasculites por levamisol. Em um caso foi observada neutropenia. Três pacientes apresentaram anemia e dois falha renal aguda. O tratamento principal foi a cessação do consumo com reversão total das complicações. Foi necessário realizar debridação ou enxertos de pele, ou ambos em todos os casos. As complicações mencionadas bem como o risco vinculado à reposição e os tratamentos propostos para as mesmas, como por exemplo os fatores de crescimento de granulócitos, antibióticos de amplio espectro e corticoides, são discutidos e analisados. É necesssário um alto índice de suspeita para vincular estas manifestações clínicas à presença de levamisol como adulterante da cocaína.

Cocaine/levamisole-induced systemic vasculitis with retiform purpura and pauci-immune glomerulonephritis

Levamisole has been increasingly used as an adulterant of cocaine in recent years, emerging as a public health challenge worldwide. Levamisole-associated toxicity manifests clinically as a systemic vasculitis, consisting of cutaneous, hematological, and renal lesions, among others. Purpura retiform, cutaneous necrosis, intravascular thrombosis, neutropenia, and less commonly crescentic nephritis have been described in association with anti-neutrophil cytoplasmic antibodies (ANCAs) and other autoantibodies. Here we report the case of a 49-year-old male who was a chronic cocaine user, and who presented spontaneous weight loss, arthralgia, and 3 weeks before admission purpuric skin lesions in the earlobes and in the anterior thighs. His laboratory tests on admission showed serum creatinine of 4.56 mg/dL, white blood count 3,800/μL, hemoglobin 7.3 g/dL, urinalysis with 51 white blood cells/μL and 960 red blood cells/μL, and urine protein-to-creatinine ratio 1.20. Serum ANCA testing was positive (>1:320), as well as serum anti-myeloperoxidase and anti-proteinase 3 antibodies. Urine toxicology screen was positive for cocaine and levamisole, with 62.8% of cocaine, 32.2% of levamisole, and 5% of an unidentified substance. Skin and renal biopsies were diagnostic for leukocytoclastic vasculitis and pauci-immune crescentic glomerulonephritis, respectively. The patient showed a good clinical response to cocaine abstinence, and use of corticosteroids and intravenous cyclophosphamide. Last serum creatinine was 1.97 mg/dL, white blood cell count 7,420/μL, and hemoglobin level 10.8 g/dL. In levamisole-induced systemic vasculitis, the early institution of cocaine abstinence, concomitant with the use of immunosuppressive drugs in severe cases, may prevent permanent end organ damage and associate with better clinical outcomes.

Agranulocitosis por levamisol asociado a cocaína / Agranulocytosis induced by levamisole in association to cocaine

La neutropenia en usuarios de cocaína es una condición de reciente reconocimiento en distintos países. Se debe a la utilización del levamisol, una antigua droga antiparasitaria e inmunomoduladora, como agente de corte. Presentamos el caso de un paciente con agranulocitosis por levamisol asociado a cocaína y una revisión de las características del cuadro, así como del control de estos pacientes. También se tratan los motivos vinculados al agregado cada vez más frecuente de levamisol a la cocaína. Este es el primer caso descrito en nuestro país, si bien es probable que existan muchos casos no reconocidos o no comunicados de esta enfermedad.

Agranulocytosis in cocaine users is a worldwide recently recognized condition. It is due to the utilization as cutting agent of levamisole, an ancient antiparasitic and immunomodulator drug. We describe the case of a patient with agranulocytosis induced by levamisole in association to cocaine and we review clinical and biochemical characteristics of the clinical picture, as well as the management of these patients. We also analyze the reasons related to a more and more frequent practice, the addition of levamisole to cocaine. This is the first case described in our country, although it is probable that there are many not recognized or not described cases related to this pathology.

Levamisol não previne lesões de estomatite aftosa recorrente: um ensaio clínico randomizado, duplo-cego e controlado por placebo / Levamisole does not prevent lesions of recurrent aphthous stomatitis: a double-blind placebo-controlled clinical trial

OBJETIVO: Avaliar a eficácia e a segurança do levamisol no tratamento profilático da afta recorrente, utilizando um protocolo de estudo duplo-cego. MÉTODOS: Quatorze pacientes receberam doses decrescentes de levamisol por via oral por seis meses (dose inicial de 150mg três vezes por semana). Dez pacientes receberam placebo. As avaliações foram mensais. RESULTADOS: Houve tendência à diminuição do número de crises nos dois grupos, mas sem diferenças entre ambos. O número de lesões diminuiu significantemente nos grupos levamisol e placebo, mas na comparação entre eles a diferença não foi significante. A duração das lesões diminuiu significantemente no grupo placebo, porém ao compará-lo com o grupo levamisol a diferença não foi significante durante todo o tratamento. A intensidade da dor foi significantemente menor nos dois grupos, mas ao compará-los a dor foi significantemente menor no grupo placebo. A avaliação global final mostrou melhora em 50 por cento dos pacientes do grupo levamisol e em 70 por cento do Placebo, sem diferença significante entre os dois tratamentos. Não foi observada diferença na frequência de efeitos colaterais entre os grupos. CONCLUSÃO: Levamisol, como usado nesse protocolo, é uma droga segura. Comparado ao placebo, levamisol não é efetivo no tratamento profilático da afta recorrente. O efeito placebo é importante em desordens nas quais fatores emocionais afetam a recorrência ou a expressão de sintomas.

OBJECTIVE: to utilize a double-blind protocol to provide clarification about the safety and effectiveness of levamisole in the treatment of recurrent aphthous stomatitis. METHODS: Fourteen patients took a decreasing dose of oral levamisole for six months (initial dose 150mg three times a week) and ten others were placebo control patients. All were evaluated monthly. RESULTS: The number of crises had a tendency to decrease in both groups, but without a difference between groups. The number of lesions diminished significantly in the two groups, but upon comparison the difference was not significant. Duration of the lesions diminished significantly in the placebo, however when compared to the levamisole group, difference was not significant during treatment. The intensity of pain was significantly lower in the two groups, but upon comparison, pain was significantly lower in the placebo group. The final global evaluation showed improvement in 50 percent of patients of the levamisole group and in 70 percent of the placebo, without a significant difference between treatments. No difference in the frequency of collateral effects was observed between groups. CONCLUSIONS: Levamisole, as used in this protocol, is a safe drug. When compared with the placebo, levamisole is not effective in the prophylactic treatment of recurrent aphthous stomatitis. The placebo effect is important in diseases where emotional factors affect recurrence or expression of symptoms.

Dermatopatía asociada a leucoencefalopatía posterior reversible inducida por levamisol / Dermatopathy associated with levamisole induced reversible posterior leukoencephalopathy

Levamisol es una droga antihelmíntica con propiedades inmunomoduladoras que estimula la formación de anticuerpos y aumenta la respuesta T, la respuesta neutrofílica y laquimiotaxis. Se utiliza en dermatología para el tratamiento de verrugas planas, eritema multiforme, úlceras aftosas, vitíligo y,conjuntamente con prednisolona, en el liquen plano.Con el uso prolongado del medicamento se han comunicadoefectos adversos dermatológicos, como erupciones liquenoides,ulceraciones y vasculitis.Comunicamos el caso de una niña de 9 años que desarrolló uncuadro de erupción cutánea y leucoencefalopatía reversible con un tratamiento breve de levamisol pero con dosis elevadas.

Levamisole is an antihelmintic drug that stimulates antibodies formation increasing both T response, and neutrophilic response, and quimiotaxis. It is used in dermatology for the treatment of plane warts, erythema multiforme, aphtous ulcers and, with prednisone, in lichen planus. With prolonged use this drug has been implicated in adverse dermatological reactions as lichenoid eruptions, ulcers and vasculitis. We present a 9-years old girl who developed a cutaneous eruption and a reverse leucoencephalopathy with a short treatment but high doses of the drug.

Reação farmacodérmica decorrente do uso do levamisol: relato de caso / Pharmacodermic adverse reaction due to levamisole: a case report

Relata-se a ocorrência de um caso de farmacodérmica pelo levamisol e discute-se sobre a manifestação clínica e o estabelecimento do diagnóstico dessa reação cutânea adversa. O animal desenvolveu lesões exsudativas na face, com resolução espontânea após a suspensão do fármaco.

Multifocal Inflammatory Leukoencephalopathy: Use of Thallium-201 SPECT and Proton MRS

In a patient receiving 5-fluorouracil and levamisole, neurologic deficits suggest the cerebral demyelinating syndrome as a differential diagnosis. The authors report a patient diagnosed as multifocal inflammatory leukoencephalopathy for which thallium-201 ((201)Tl) single photon emission computed tomography (SPECT) and proton magnetic resonance spectroscopy (MRS) were employed as noninvasive diagnostic tools. (201)Tl SPECT study was negative and proton MRS showed an increase of choline and lactate and well preserved N-acetylaspartate. These findings support histopathologic findings of multifocal inflammatory leukoencephalopathy revealing demyelination with relative axonal sparing in the patient.

Combination therapy in Kala-azar.

128 untreated cases of Kala-azar were divided in 4 equal groups of 32, Group A was treated with Sodium Stibogluconate (SSG) in the dose of 20 mg/kg/body wt. for 30 days. Group B was treated SSG plus allopurinol in the dose of 20 mg/kg/body wt. orally in divided dosage for 30 days. Group C received SSG plus Ketoconazole 600 mg orally in divided dosage for 30 days. Group D in addition to SSG also received levamisole in single oral daily dose of 13 mg/kg/body wt. for 30 days. Response of Group B, C and D was compared to Group A. Results from this study revealed combination of allopurinol with SSG to be statistically not superior to SSG alone.

Farmacología de las drogas empleadas en el tratamiento del SIDA / Pharmacology of the drugs employee in the treatment of AIDS

En esta revisión (transcripción de la presentación realizada en el Simposio SIDA, Avellaneda 1990) se enumeran las drogas empleadas para: 1)tratar las complicaciones del SIDA (solo algunos ejemplos, incluyendo foscarnet y glanciclovir); 2)realizar la inmunoterapia del SIDA; y 3)inhibir la replicación del HIV (quimioterápicos anti-HIV). En la segunda clase se enfatiza la necesidad de actuar precozmente (por ej., con valores no muy bajos de CD4), y se analizan evidencias preliminares sobre isoprinosina, timopentina y ditiocarb. En la tercera se analiza en detalle el mecanismo de acción de los dideoxinucleósidos, ejemplificando con la zidovudina, sus efectos adversos, sus limitaciones, en particular para tratamiento precoz, y el desarrrollo de resistencia en el HIV tanto in vitro como in vivo. Se analiza, también, el efecto del interferón * sobre la replicación viral y se esbozan los tratamientos más experimentales en farmacología clínica como el CD4 recombinante soluble) e in vitro (como los oligonucleótidos antisense). Pese a disponer de drogas efectivas en cada una de las tres categorías enunciadas, ninguna hace más que retrasar el curso de la infección hacia la destrucción del sistema inmune y muerte del paciente

Study of the thromboxane synthetasa inhibitory effect and antiplatelet action of levamisole

Thromboxane A* release by guinea pig lungs stimulated by AA and ionophore A 23187 was inhibited by levamisole (40 and 120 *g/ml), whereas leukotrienes, Pgl* or PgE* generation were unaffected. Since levamisole (1,5-25 *M) also inhibited plateled aggregation induced by collagen, which is markedly T x A* dependent, we suggest that levamisole acts as a thromboxane synthetase inhibitors

Adelantos terapéuticos en lepra / Progress in leprosy therapeutic

Se comentan los recientes aportes terapéuticos, dividiéndose el trabajo en los siguientes capítulos: I)Resistencia bacteriana a los diversos fármacos, en especial a la D.D.S. en su forma secundaria, así como la primaria. Dosis a emplear con la monoterapia. Causas de aparición de la resistencia (tratamiento irregular y/o bajas dosis). II) Asociación medicamentosa: sus ventajas y los principales esquemas en enfermos vírgenes y en casos de resistencia a las sulfonas. III) Tratamiento de la reacción leprosa. IV) Inmunoterapia en lepra: sus objetivos, los medios más comúnmente empleados, sus riesgos y efectos colaterales

A comparative evaluation of levamisole in leprosy.

Ninety adult leprosy patients attending the skin outpatient department of Institute Hospital of Varanasi, India, were selected for the study. A group of thirty patients including 10 cases of lepromatous, 10 of borderline and 10 cases in reaction of which 5 were of type 1 and 5 of type II reaction were treated with levamisole and DDS. Levamisole was given in the doses of 150 mg. daily for three consecutive days which was repeated after every 12 days. The effects were compared with two similar groups receiving clofazimine plus DDS and DDS alone respectively for six months. It was observed that levamisole was useful in bringing down both the types of reactions in a period shorter than required by clofazimine. Clinical improvement in non-reaction cases was found to be similar in all the three groups. Minor side effects were also seen with levamisole and clofazimine in some cases.

Effect of levamisole on toxoplasmosis during pregnancy in guinea-pigs

The effect of levamisole was tested in guinea-pigs infected with an avirulent strain of Toxoplasma gondii at mid-pregnancy and in two different doses and schedules of administration. With a small short-term dose, the pregnancy terminated rapidly with high foetal wastage, and the severity of infection in the offspring decreased. With a large long-term dose, the pregnancy protracted and the severity of infection in the offspring increased. It was concluded that, during pregnancy, small doses of levamisole cannot be used without harm in the prescribed schedules to reduce the severity of infection. On the other hand large doses are immunosuppressive and can aggravate the severity of infection in the offspring

Levamisole and mebendazole in the treatment of bancroftian infection.

Levamisole and mebendazole, broad spectrum anthelminthic compounds were tested against microfilaria of Wuchereria bancrofti, and the results were compared with similarly treated diethylcarbamazine and untreated group. Levamisole at a dosage of 3 mg/kg daily for 8 days showed marked reduction in both microfilaria rate and microfilaria density and immediately thereafter mf-rate steadily increased almost up to pre-treatment level, the mf-density however showed only marginal increase. Mebendazole at dosage of 6 mg/kg daily for 10 days following 8 days treatment of levamisole also showed marginal increase of mf-rate but no increase of mf-density. Treatment with DEC at a dosage of 6 mg/kg daily for 12 days showed comparatively better results both in respect of reduction in mf-rate and mf-density. The reactions - severity and duration were more among levamisole treated groups as compared to DEC treated group. Thus with the dosages tried, DEC could be considered as a better drug than levamisole and mebendazole. Both the latter compounds had no or very limited effect on the adult worms of W. bancrofti.