Paniculitis secundaria a terapia target en paciente con melanoma, lo que el dermatólogo debe saber: reporte de un caso / Panniculitis in association with target therapy in melanoma patient, what the dermatologist should know: a case report

Las terapias target constituyen hoy en día una alternativa terapéutica cada vez más utilizada para el manejo de pacientes con melanoma metastásico. Sin embargo, se han descrito múltiples efectos farmacológicos adversos asociados a su uso, siendo los cutáneos los de mayor prevalencia. Se presenta el caso de un hombre de 55 años con diagnóstico de melanoma cutáneo metastásico etapa IV, BRAFV600E mutado, en tratamiento con dabrafenib/trametinib que consultó por desarrollo de lesiones nodulares eritematosas sensibles en extremidades superiores e inferiores, asociadas a sensación febril durante el curso del tratamiento. Se descartó alguna infección sobreagregada. Se realizó una biopsia de las lesiones cutáneas, con confirmación diagnóstica histopatológica de una paniculitis mixta de predominio septal, granulomatosa y con vasculitis leucocitoclástica. La paniculitis asociada a esta terapia ha sido descrita en la literatura y se ha considerado un efecto farmacológico inmunomediado adverso, relacionándose a un mejor pronóstico para el melanoma metastásico en tratamiento. Por lo tanto, así como en el caso presentado, se evita la suspensión del fármaco y se asocia terapia sintomática en caso de mayores molestias del paciente. Es de alta relevancia para el dermatólogo conocer e interpretar adecuadamente este efecto adverso farmacológico, y así indicar el manejo más adecuado para el paciente.

Target therapies are currently a therapeutic option increasingly used for the management of patients with metastatic melanoma. However, there are multiple adverse pharmacological effects associated with their use that have been described. Cutaneous adverse reactions are the most frequent. We report the case of a 55-year-old man with a diagnosis of stage IV BRAFV600E-mutated metastatic cutaneous melanoma undergoing treatment with dabrafenib/trametinib, who consulted due to the development of erythematous nodular lesions in the upper and lower limbs associated with febrile sensation during the course of treatment. Infection was ruled out and a biopsy of the skin lesions was done, which provided the histopathological confirmation of a predominantly septal, granulomatous with leukocytoclastic vasculitis, mixed panniculitis. Panniculitis associated with this therapy has been described in the literature and has been considered an immune-mediated pharmacological adverse effect. It is considered to be related to a better prognosis in the treatment of metastatic melanoma. Consequently, as shown in this case report, target therapy should not be discontinued and symptomatic medication should be given to alleviate patient discomfort. The dermatologist should know and properly interpret this adverse effect and prescribe the most appropriate management for the patient.

Manejo de hemorragia asociada a anticoagulantes orales directos: estado actual de las estrategias de reversión / Management of bleeding associated with direct oral anticoagulants: update on reversal strategies

Direct oral anticoagulants (DOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban have at least comparable efficacy as vitamin K antagonists along with a better safety profile, reflected by a lower incidence of intracranial hemorrhage. Specific reversal agents have been developed in recent years. Namely, idarucizumab, a specific antidote for dabigatran, is currently approved in most countries. Andexanet, which reverses factor Xa inhibitors, has been recently approved by the FDA, and ciraparantag, a universal antidote targeted to reverse all DOACs, is still under investigation. In this review we provide an update on the pharmacology of DOACs, the risk of hemorrhagic complications associated with their use, the measurement of their anticoagulant effect and the reversal strategies in case of DOAC-associated bleeding.

Use of direct oral anticoagulants for chronic thromboembolic pulmonary hypertension

OBJECTIVES: Chronic thromboembolic pulmonary hypertension is one of the most prevalent forms of pulmonary hypertension and is a major complication of acute pulmonary embolism. One mainstay of chronic thromboembolic pulmonary hypertension treatment is lifelong anticoagulation. The recent advent of direct oral anticoagulants for acute pulmonary embolism treatment has provided a viable and effective alternative for treating this condition. However, little is known about the efficacy of this new class of drugs for treating chronic thromboembolic pulmonary hypertension. We aimed to evaluate the safety and efficacy of direct oral anticoagulants in the treatment of chronic thromboembolic pulmonary hypertension. METHODS: A cohort of chronic thromboembolic pulmonary hypertension patients who initiated treatment with direct oral anticoagulants between June 2015 and November 2016 were enrolled in this study. RESULTS: Sixteen patients used rivaroxaban, three used dabigatran and one used apixaban for a mean follow-up of 20.9 months. The mean age was 51 years, and eighteen patients were classified as functional class II/III. Eight patients underwent a pulmonary endarterectomy and exhibited clinical, hemodynamic and functional improvement and currently continue to use direct oral anticoagulants. No episode of venous thromboembolism recurrence was identified during the follow-up period, but there was one episode of major bleeding after a traumatic fall. CONCLUSIONS: Although direct oral anticoagulants appear to be a safe and effective alternative for treating chronic thromboembolic pulmonary hypertension, larger studies are needed to support their routine use.

New orally active anticoagulants in critical care and anesthesia practice: The good, the bad and the ugly.

With the adoption of dabigatran, rivaroxaban, and apixaban into clinical practice, a new era has arrived in the practice of oral anticoagulants. Venous thromboembolism (VTE) has traditionally been underdiagnosed and under treated in Asia. With increasing longevity, the diagnosis and the need for management of atrial fibrillation (AF) and VTE is likely to increase significantly. The new orally active anticoagulants (NOACs) have reasonably filled the lacunae that clinicians traditionally faced when treating patients with vitamin K antagonist (VKA). Unlike VKA, NOACs do not need frequent monitoring. Therefore, more patients are likely to get therapeutic effects of anticoagulation and thus reduce morbidity and mortality associated with VTE and AF. However, the clinicians need to be circumspect and exercise caution in use of these medications. In particular (in geriatric population), the clinicians should look out for drug-drug interactions and underlying renal insufficiency. This would ensure therapeutic efficacy and minimize bleeding complications. Here, it is important to note that the antidote for NOACs is not available and is a major concern if emergency surgical procedure is required in their presence.

Comparative clinical evaluation of efficacy and safety of a formulation containing ciclopirox 8% in the form of a therapeutic nail lacquer in two different posologies for the treatment of onychomycosis of the toes / Avaliação clínica comparativa da eficácia e da segurança de formulação contendo ciclopirox a 8% na forma de esmalte terapêutico em duas diferentes posologias no tratamento de onicomicoses dos pododáctilos

BACKGROUND: The use of topical antifungal agents in the treatment of onychomycosis is of great value in clinical practice as there are different limitations regarding the use of systemic treatment. OBJECTIVE: To evaluate the efficacy and safety of a nail lacquer formulation containing ciclopirox 8% in two different posologies: the traditional regimen (3/2/1) and a regimen of weekly use. METHODS: A blind, randomized, comparative trial which included 41 patients divided into 02 groups, with Group I using the nail lacquer once weekly and Group II using the traditional regimen (3/2/1). Both groups applied the medication for 06 months. RESULTS: The species most frequently found in groups I and II were Trichophyton rubrum (55% and 61.9%) and Trichophyton mentagrophytes (30% and 19%). There was a tendency to a higher level of treatment resistance by T. mentagrophytes infection in both groups, without any predilection for sex, age, proportion of the nail affected at the beginning of the study, duration of the clinical disease and quantity of nails affected per person. Both groups had significant levels of mycological cure, clinical response and therapeutic success and there was no statistically significant difference between groups I and II (p >0.05). CONCLUSION: The nail lacquer containing ciclopirox 8% was equally effective at a weekly dose when compared to the traditional dosing (3/2/1), allowing a more comfortable regimen.

FUNDAMENTOS: A utilização de antifúngicos tópicos na terapêutica da onicomicose é de grande valor na prática clínica, visto que há diferentes limitações ao uso das opções terapêuticas sistêmicas. OBJETIVO: Avaliar comparativamente a eficácia e a segurança de uma formulação de esmalte de ciclopirox a 8% em dois diferentes esquemas posológicos: o esquema tradicional (3/2/1) e um esquema posológico de uso semanal. MÉTODOS: Foi realizado um estudo cego, comparativo e randomizado que incluiu 41 pacientes, divididos em dois grupos, sendo o grupo I submetido ao esquema posológico de uma vez por semana e o grupo II submetido ao esquema posológico tradicional (3/2/1). Os grupos utilizaram a medicação por 180 dias. RESULTADOS: As espécies mais frequentemente encontradas nos grupos I e II foram Trichophyton rubrum (55% e 61,9%) e Trichophyton mentagrophytes (30% e 19%). Houve tendência de maior resistência ao tratamento pelo T. mentagrophytes nos dois grupos estudados, sem predileção por sexo, idade, proporção de acometimento ungueal inicial, tempo de evolução do quadro ou número de unhas acometidas por indivíduo. Ambas as modalidades apresentaram índices significativos de cura micológica, resposta clínica e sucesso terapêutico, e não houve diferença estatisticamente significante entre os grupos I e II (p > 0,05). CONCLUSÃO: O esmalte contendo ciclopirox a 8% mostrou-se igualmente eficaz na posologia de uma vez por semana quando comparada à posologia tradicional (3/2/1), permitindo um esquema posológico mais confortável.

Experience with the oral iron chelator deferiprone in transfusion-dependent children.

OBJECTIVE: To establish efficacy and safety of deferiprone. DESIGN: Prospective study. SETTING: The Lady Ridgeway Hospital for Children, Colombo. PATIENTS: Transfusion-dependent children in the age group 1 to 15 years. INTERVENTION: Patients were given 75 mg/kg/day of deferiprone orally in divided doses. MEASUREMENTS: Efficacy of deferiprone therapy was assessed by 4 to 6 monthly serum ferritin (SF) assays. Safety of therapy was assessed by 4-weekly white cell counts and serum alanine aminotransferase (ALT) levels. The Z-score was used to assess the significance of the difference between the mean initial and final SF level. RESULTS: 82 patients received deferiprone therapy for a mean duration of 30 +/- 14 months. Initial SF levels ranged from 1115 to 12,165 micrograms/l with a mean of 5156 +/- 2631 micrograms/l. Final SF levels ranged from 312 to 15,285 micrograms/l with a mean of 2809 +/- 2380 micrograms/l (Z score 5.99; p < 0.001). Two (2.4%) children developed agranulocytosis which reverted to normal on discontinuation of treatment. 41 (50%) developed arthropathy and in 17 this was severe enough to require discontinuation of therapy. Serum ALT levels were raised in 35 (43%) patients but reverted to pretreatment values or lower despite continuation of deferiprone therapy. There was one death in a 9-year old child who developed diabetes mellitus and heart failure despite deferiprone therapy for 3 years. CONCLUSIONS: A final SF level < 2500 micrograms/l was achieved in 52% children. Severe arthropathy and agranulocytosis may necessitate permanent discontinuation of therapy.

Effects of hydroxypyridinone iron chelators in combination with antimalarial drugs on the in vitro growth of Plasmodium falciparum.

Using standard in vitro drug susceptibility methods, we assessed the antimalarial activity of 3 orally administered iron chelators (hydroxypyridinones) alone and in combination with conventional antimalarials drugs (quinine, mefloquine, artesunate, tetracycline, atovaquone) against a chloroquine-resistant Plasmodium falciparum isolate. When tested alone, all iron chelators and antimalarial compounds inhibited the growth of the parasites. IC50 values for iron chelators were 60-70 microM, whereas the IC50 values for antimalarial drugs were in nM ranges, with artesunate being the most potent. The derived isobolograms for the interaction of hydroxypyridinones and antimalarial drugs showed addition or mild antagonism, similar to desferroxamine (Sum of Fractional Inhibitory Concentration, sigma FIC < 0.5 or > 4.0). Despite the absence of synergy with conventional drugs, intrinsic antimalarial activity of hydroxypyridinones supports the continued assessment of these iron chelators as treatment adjuncts.

A trial of deferiprone in transfusion-dependent iron overloaded children.

OBJECTIVE: To determine the efficacy and safety of deferiprone. DESIGN: Prospective study. SETTING: 5 paediatric medical units at the Lady Ridgeway Hospital for Children (LRHC), Colombo. PATIENTS: Transfusion-dependent iron overloaded children in the age group 2 to 15 years. INTERVENTION: Patients were given a total daily dose of 75 mg/kg of deferiprone orally in divided doses. MEASUREMENTS: Efficacy of deferiprone therapy was assessed by 4-monthly serum ferritin assays using the ELISA technique. Safety of deferiprone therapy was assessed by 4-weekly white cell counts, platelet counts and serum transaminase levels. The Z-test was used to assess the significance of the difference between the mean initial serum ferritin level and the mean subsequent serum ferritin level. RESULTS: 54 patients received deferiprone therapy for a mean duration of 9 +/- 3 months. Initial serum ferritin levels ranged from 1500 to 10,700 ng/ml with a mean of 5743. Subsequent serum ferritin levels, obtained in 48 patients ranged from 740 to 7300 ng/ml with a mean of 3558 (p < 0.001). In 47 of the 48 patients subsequent serum ferritin levels were lower than initial levels. One child developed severe neutropaenia, which reverted to normal on discontinuation of treatment. 11 children developed arthropathy, which responded to ibuprofen therapy combined in some cases with a reduction of the dose of deferiprone to 50 mg/kg/day. Serum transaminase levels were raised in 5 patients but reverted to pretreatment values or lower despite continuation of deferiprone therapy. CONCLUSIONS: Deferiprone is a safe and effective oral iron-chelating agent which can be used, under strict supervision, in transfusion-dependent iron overloaded children.

Efficacy and safety of oral iron chelating agent deferiprone in beta-thalassemia and hemoglobin E-beta thalassemia.

OBJECTIVES: To assess efficacy and safety of oral iron chelating agent deferiprone (DFP) in patients with beta thalassemia and hemoglobin E-beta thalassemia. DESIGN: Non-randomized study. SETTING: Hematology Out-Patient Department. SUBJECTS: Forty-one patients of beta thalassemia and hemoglobin E-beta thalassemia. INTERVENTIONS: DFP was given to 20 patients, 10 patients of beta thalassemia and 10 with hemoglobin E-beta thalassemia; the rest were taken as controls. RESULTS: A significant fall in serum ferritin was observed in the study group along with rise in urinary iron excretion (p < 0.05). Adverse effects of DFP were nausea and vomiting (30%), significant arthropathy requiring stopping of the drug (30%), and reversible neutropenia in one patient. All these complications could be managed easily with medical supervision and no death or permanent disability was seen. CONCLUSIONS: DFP is an effective and fairly well tolerated oral iron chelating agent. The side effects that occur can be tackled easily if monitored properly.

Autoantibodies in thalassaemia major: relationship with oral iron chelator L1.

Ninety patients with thalassaemia major were investigated for the occurrence of antinuclear antibodies (ANA), and those with ANA were tested for antibodies to histones (AHA). ANA were detected in 7 of 27 thalassemics on oral iron chelator L1, and in 2 of 63 thalassaemics not on L1 (p < 0.01). AHA were seen in 4 of 7 thalassemics receiving L1 with positive ANA, and in none of the 2 not receiving L1 (p < 0.03). Joint pains were seen in patients receiving L1, but in none of the patients not receiving L1. There was no correlation between hepatitis B or HIV positivity and presence of ANA or joint pains. While some amount of background ANA-positivity was found in patients with thalassaemia major, it was significantly more in patients receiving L1. Laboratory evidence of drug-induced lupus-like reaction was seen only in patients who received L1. In view of serious concerns about the safety of L1 and wide variations in the incidence and severity of adverse reactions reported by different sources, an urgent regulatory audit of all trial centres is essential.

Acute increase in exercise capacity with milrinone: lack of correlation with resting hemodynamic responses

1-The acute administration of milrinone, a positive inotropic vasodilator agent, improves resting hemodynamic function and maximal and submaximal metabolic rsponses to exercice in patients with severe congestive heart failure. 2. to determine whether the improvement in exerecise capacity induced by milrinone administration can be predicted by its acute positive inotropic and/or vasodilator effects at rest, milrinone was adminstered intravenously (progressive doses of 1.5 to 75 microng/Kg) to 15 patients with heart failure (functional classes III and IV, New York Heart Association) at rest, and during maximal upright exercise testing on a cycke ergometer. Serum drug levels were matched for the resting and exercise tests. Drug administration for exercise tests was placebo-controlled and double-blind. 3. At rest, milrinone administration caused substantial decreases in right atrial pressure (-53%), left ventricular end-diastolic pressure (-30%), and systemic vascular resistance (-35%); and increases in cardiac index (+59%), peak positive dP/dt (+20%) and stroke work index (+51%). Administration of milrinone during exercise resulted in a 15% increase in peak oxygen uptake and a 16% increase in anaerobic threshold. However, none of the changes in resting hemodynamic function correlated significantly in magnitude with the changes in peak oxygen uptake and anaerobic threshold. 4. Thus, the acute improvement in exercise capacity that occus with milrinone is not predicted by the positive inotropic or vasodilator effects of the drug at rest

Effect of deltamethrine on trypanosoma cruzy (trypanosomatidae) in triatoma infestans (reduviidae: triatominae)

A aplicaçäo de deltametrina em ninfas de T.Infestans, nas doses de 0,0483 ou 0,0966 mg i. a./g de inseto, em exemplares ja expostos a infecçäo por T.Cruzi,reduz significativamente a taxa de eliminaçäo de tripomastigotas nas dejeçöes. A aplicaçäo de 0,0966 mg/g, 3 ou 7 dias antes da exposiçäo a T. Cruzi, nao influenciou significativamente a taxa de eliminaçäo