Antimalarials and macrolides: a review of off-label pharmacotherapies during the first wave of the SARS-CoV-2 pandemic

Abstract We critically analyzed clinical trials performed with chloroquine (CQ) and hydroxychloroquine (HCQ) with or without macrolides during the first wave of COVID-19 and discussed the design and limitations of peer-reviewed studies from January to July 2020. Seventeen studies were eligible for the discussion. CQ and HCQ did not demonstrate clinical advantages that justified their inclusion in therapeutic regimens of free prescription for treatment or prophylactic purposes, as suggested by health authorities, including in Brazil, during the first wave. Around August 2020, robust data had already indicated that pharmacological effects of CQ, HCQ and macrolides as anti-SARS-CoV-2 molecules were limited to in vitro conditions and largely based on retrospective trials with low quality and weak internal validity, which made evidence superficial for decision-making. Up to that point, most randomized and nonrandomized clinical trials did not reveal beneficial effects of CQ or HCQ with or without macrolides to reduce lethality, rate of intubation, days of hospitalization, respiratory support/mechanical ventilation requirements, duration, type and number of symptoms, and death and were unsuccessful in increasing virus elimination and/or days alive in hospitalized or ambulatory patients with COVID-19. In addition, many studies have demonstrated that side effects are more common in CQ-or HCQ-treated patients.

Acantholytic pityriasis rubra pilaris associated with topical use of imiquimod 5%: case report and literature review

Abstract Topical use of immune response modifiers, such as imiquimod, has increased in dermatology. Although its topical use is well tolerated, it may be associated with exacerbations of generalized cutaneous inflammatory diseases, possibly through the systemic circulation of pro-inflammatory cytokines. This report describes a case of development of pityriasis rubra pilaris, a rare erythematous-papulosquamous dermatosis, in a woman aged 60 years during treatment with imiquimod 5% cream for actinic keratosis. It evolved with erythrodermic conditions and palmoplantar keratoderma, presenting progressive clinical resolution after the introduction of methotrexate. The authors emphasize the importance of recognizing possible systemic reactions associated with the topical use of imiquimod.

Aberraciones cromosomales en bulbos de cebolla Allium cepa inducidas pormoléculas híbridas 4-aminoquinolínicas / Chromosomal aberrations in Allium cepa onion bulbs induced by 4-aminoquinoline hybrid molecules

Se estudiaron las propiedades toxicológicas de los trescompuestos híbridos quinolin-tiazolidinona (FR-72 y FR-121), y acridinepoxiisoindolindiona(FR-154) aplicándolos en el test de las raíces debulbos de cebolla Allium cepa. Las moléculas FR-72, FR-121 y FR-154 fueron sintetizadas de novo según protocolos experimentalesdescritos. Los bulbos de Allium cepa (2n = 16) limpios y sanos,previamente sumergidos en el agua destilada, se secaron con papeltoalla y se colocaron directamente en los tubos de ensayo llenos conla sustancia a evaluar. Los experimentos se realizaron a temperaturaambiente 20 ± 2°C y se mantuvieron en oscuridad. El periodo deexposición de los bulbos fue de 120 horas y las raíces que se utilizaronpara el montaje de genotoxicidad eran en promedio de 2 a 2.5 cmde longitud. La evaluación del comportamiento de las tres moléculasquinolínicas sobre la inhibición del crecimiento promedio de las raícesde bulbos de cebolla Allium cepa se realizó con los tres parámetrosde bioactividad (CE50, IM, ACs) en diferentes concentraciones. Lassustancias evaluadas pueden considerarse aneugénicas, ya que actúana nivel de estructuras celulares y moleculares e impiden la fijación delas fibras del huso acromático, por ende ocasionan el desplazamientode cromosomas en anafase o pérdidas de cromosomas, llegandoincluso a ser inductoras de la apoptosis al sobrepasar la capacidadhomeostática de la célula. El análisis preliminar indicó que la moléculaFR-121 a concentración 10-6 M y la molécula FR-154 a concentración10-3 M resultaron ser potentes agentes fitotóxicos provocando diversasaberraciones claustogénicas y aneugénicas...

The toxicological properties of three hybridcompounds, quinoline-thiazolidinone (FR-72 and FR-121)and acridin-epoxyisoindolindione (FR-154) were studiedby applying named compounds to the test of the rootsof Allium cepa onion bulbs. Molecules FR-72, FR-121 andFR-154 were synthesized de novo according to describedsynthetic protocols. Clean and healthy bulbs of Alliumcepa (2n = 16), previously immersed in distilled water,were dried with paper towels and placed directly into testtubes filled with the test substance. The experiments werecarried out at room temperature 20 ± 2°C and were keptin darkness. The period of exposure of bulbs was 120hours; the roots used for the genotoxicity evaluation wereon average of 2 to 2.5 cm in length. The evaluation of theeffect of the three quinolinic molecules on the growthof onion roots of Allium cepa bulbs was achieved usingdifferent concentrations of the three growth parameters(EC50, IM, ACs) The evaluated substances performedaneugenic actions, operating at cellular and molecularstructure level and preventing the fixing of mitoticspindle fibers, causing the movement of chromosomesin the anaphase or loss of chromosomes, even inducingapoptosis by exceeding the homeostatic capacity of thecell. The preliminary analysis indicated that molecule FR-121 at 10-6 M concentration and molecule FR-154 at 10-3M concentration, proved to be potent phytotoxic agentscausing various claustogenic and aneugenic aberrations...

Foram estudadas as propriedades toxicológicas dos trêscompostos híbridos, quinolina-tiazolidinona (FR-72 e FR-121)e hidroacridin-epoxiisoindolindiona (FR-154) aplicando-os noteste das raízes de bulbos de cebola Allium cepa. As moléculas FR-72, FR-121 e FR-154 foram sintetizadas de novo de acordo com osprotocolos experimentais já descritos. Os bulbos de Allium cepa (2n= 16) limpos e sádios, previamente imersos em água destilada, foramsecos com papel toalha e colocados diretamente em tubos de ensaio,cheios com a substância de teste. Os experimentos foram realizadosà temperatura ambiente 20 ± 2°C e mantiveram-se na escuridão. Operíodo de exposição dos bulbos foi de 120 horas e as raízes usadaspara a montagem de genotoxicidade tinham, em média, de 2 a 2,5 cmde comprimento. A avaliação do comportamento das três moléculasquinolínicas sobre a inibição do crescimento médio das raízes debulbos de cebola Allium cepa foi realizada com os três parâmetrosde bioatividade (EC50, IM, ACs) em diferentes concentrações. Assubstâncias avaliadas podem se considerar aneugénicas, já queatuam ao nível de estruturas celulares e moleculares, e impedem oestabelecimento de fibras do fuso acromático, provocando assim odeslocamento dos cromossomos na anáfase ou perda de cromossomos,chegando, inclusive, a serem indutoras da apoptose ao ultrapassar acapacidade homeostática da célula. A análise preliminar indicou que amolécula FR-121 em concentração de 10-6 M e a molécula de FR-154em concentração de 10-3 M resultaram ser potentes agentes fitotóxicosprovocando várias aberrações claustogénicas e aneugénicas...

Tratamento do papiloma vírus humano na infância com creme de imiquimode a 5 por cento / Treatment of human papillomavirus in childhood with imiquimod 5 percent cream

Lesões decorrentes da infecção pelo papilomavírus humano na infância, em especial as verrugas anogenitais, são um importante problema epidemiológico e terapêutico. O tratamento das verrugas anogenitais na infância é um desafio terapêutico. Os tratamentos convencionais geralmente são dolorosos e necessitam de anestesia geral. O imiquimode, um imunomodulador tópico, constitui uma alternativa terapêutica. Serão descritos quatro casos tratados com sucesso utilizando creme de imiquimode a 5 por cento aplicado topicamente.

In children, lesions caused by the human papillomavirus (HPV) constitute a significant epidemiological issue and a therapeutic dilemma, particularly in the case of anogenital warts. The treatment of anogenital warts in children is a challenge, since standard treatments are generally painful and require the patient to be anesthetized. Imiquimod, a topical immune response modifier, constitutes an alternative therapeutic agent for the treatment of HPV. The present report describes four cases in which treatment with topically applied imiquimod 5 percent cream was implemented with successful results.

Prediction on Inhibitory Activitv of Aminoauinolines on Malaria bv HMEDV / 重庆医科大学学报

Objective: Study the relationship between the activity and structural parameters of aminoquinolines. Methods: A new type of topological indices, called the hydrogen - association classified molecular electrongativity - distance vector ( H - MEDV) developed in our laboratory, has been used to describe the chemical structure of 40 aminoquinolines. Reasonable molecular modeling results were achieved by a multiple linear regression ( MLR). Results; For two sets of aminoquinolines, the correlation coefficient ( R) between the estimated and the observed activities were 0.920 and 0.910 respectively. Conclusion; Hie results suggest the estimation stability and predictive ability of the model based on the H - MEDV descriptors.

ACUTE TOXICITY OF HYDROXYPIPERAQUINE / 第二军医大学学报

Hydroxypiperaquine (HPQ) and its phosphate (HPQP) are a new long-acting antimalarial agent synthesized in our Lab.The 95% fiducial limits of i.g.LD50 of HPQP and chloroquine phosphate (CQP) in mice were 387~491 and 253~330 mg/kg, respectively.The i.v.convulsive doses of HPQP and CQP in dogs were 40 and 8 mg/kg, respectively.The i.g.convulsive doses of HPQP and CQP in dogs were 200 and 40 mg/kg, while their MLD were 600 and 40 mg/kg, respectively.The acute cardiovascular toxicity of HPQP in rabbits was lower than that of CQP significantly.The intoxicated manifestations of HPQP in dogs were characterized by the signs of stimulation of cholinergic and central nervous system such as emesis, excitation, salivation, urination, defecation, tremor and convulsion.The acute toxic manifestations of CQP were similar to those of HPQP but developed more rapidly and markedly.The transient elevated activities of sGPT demonstrated that hepatic function was impaired to some extent and that th; liver may be the toxic target organ.The results obtained show that HPQP has a lower toxicity and a broader margin of safety as compared with CQP.Thess results may be useful for the control of its side effects during clinical use.