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.

Experiencia en cirugía de condilomas anales en mayores de 15 años / Experience in anal condyloma surgery in patients older than 15 years

Resumen Objetivo: Describir la experiencia en cirugía electiva de condilomas anales en pacientes mayores de 15 años en un hospital terciario de la Región Metropolitana. Material y Método: Estudio observacional retrospectivo y descriptivo, en el cual se analizan las intervenciones quirúrgicas electivas realizadas entre 2008 a 2021. Resultados: Dentro del período analizado se obtuvo 165 cirugías de condilomas anales, lo que corresponde a 137 pacientes en total. El 85% de los pacientes son de sexo masculino, el 68% de los pacientes son VIH positivo, un 87% de los pacientes MSM (hombres que tienen sexo con otros hombres) son VIH positivo, el 34% de los pacientes tiene antecedente de ETS, el 46% de los pacientes recibió terapia tópica como tratamiento preoperatorio o posoperatorio. Un 25% de los pacientes presenta recidiva en su historia personal, un 21% de los pacientes presenta lesiones anales intraepiteliales de alto grado, un 6% presenta carcinoma escamoso infiltrante. No hubo mortalidad descrita. Discusión: El presente estudio, describe la experiencia en cirugía de condilomas de un hospital terciario de la Región Metropolitana de Chile, cuya población corresponde a un estrato socioeconómico medio y bajo. Se logra describir a la población que es intervenida de condilomas acuminados, además de sus resultados quirúrgicos precoces y a largo plazo. Conclusión: El presente estudio, presenta una población de 137 pacientes operados de condilomas anales, a partir de los hallazgos de la cirugía. Se cumple el objetivo del estudio de caracterizar en un período de 12 años los resultados quirúrgicos de dicha serie, algo no reportado previamente en la literatura chilena.

Objective: To describe the experience in elective surgery for anal condylomas in patients over 15 years of age in a tertiary hospital in the Metropolitan Region. Materials and Method: Retrospective and descriptive observational study about elective surgical interventions performed between 2008 to 2021. Results: Within the analyzed period, 165 anal warts surgeries were obtained, corresponding to 137 patients. 85% of the patients are male, 68% are HIV positive, 87% of the MSM patients are HIV positive, 34% of the patients have a history of STDs, 46% of the patients received topical therapy as preoperative or postoperative treatment. 25% present recurrence in their personal history, 21% present high-grade anal intraepithelial lesions, 6% present infiltrating squamous carcinoma. There was no reported mortality. Discussion: The present study describes the experience in condyloma surgery in a tertiary hospital in the Metropolitan Region of Chile, whose population corresponds to a medium and low socioeconomic stratum. It is possible to describe the population that undergoes surgery for this reason, in addition to its early and long-term surgical results. Conclusion: The present study presents a population of 137 patients operated on for anal condylomas, based on the findings of the surgery. The objective of the study to characterize the surgical results of this series over a 12-year period is fulfilled, something not previously reported in the Chilean literature.

Eficacia y seguridad de las aminoquinolinas para el tratamiento de infecciones a SARS-CoV-2: Una revisión sistemática de la literatura / Efficacy and safety of aminoquinolines for treating patients infected with SARS-CoV-2: A systematic review of the literature

INTRODUCTION: Amoniquinolines such as hydroxycholorquine have shown to inhibit SARS-CoV2 replication in-vitro. However, their benefit in clinical terms are controversial. OBJECTIVES: To synthesize the available evidence regarding the use of aminoquinolines for treating patients with COVID-19. METHODS: A systematic review was undertaken. Five databases were searched for randomized trials assessing chloroquine o hydroxychloroquine in the treatment of patients infected with SARS-CoV-2. All studies were assessed using the criteria endorsed by the Cochrane Collaboration. Metaanalyses were undertaken whenever possible. RESULTS: The literature search yielded 852 references, and 5 randomized trials were included. All were at high risk of bias. All studies included several cointerventions, such as antibiotics, steroids and antivirals and only two of them included critically-ill patients. When meta-analyses were conducted, aminoquinolines showed no benefit in terms of viral clearance or clinical improvement. However, a significant increase in the incidence of adverse events was observed (RR 3.11,95CI% 1.64-5.89, p < 0.001). DISCUSSION: The inhibitory properties of aminoquinolines do not seem to translate in clinical benefits amongst patients with COVID-19. The perceived high risk of bias of included studies along the significant increase in terms of adverse events recommends against the routine use of these drugs for treating patients with COVID-19.

INTRODUCCIÓN: Las aminoquinolinas como hidroxicloroquina han mostrado eficacia en inhibir la replicación del SARS-CoV-2 in vitro. Sus efectos en pacientes reales son controversiales. OBJETIVOS: Sintetizar la evidencia disponible respecto al uso de aminoquinolinas en el tratamiento de pacientes con COVID-19. METODOLOGÍA: Revisión sistemática de la literatura de ensayos clínicos aleatorizados (ECA) que evaluaron la eficacia de cloroquina o hidroxicloroquina en el tratamiento de pacientes infectados con SARS-CoV-2. Se buscó evidencia en 5 bases de datos, sólo incluyendo ECAs que fueron evaluados mediante los criterios de calidad de la colaboración Cochrane. Los resultados fueron sintetizados en un metaanálisis siempre que fue posible. RESULTADOS: Se evaluaron 852 referencias, incluyéndose 5 ensayos clínicos aleatorizados con alto riesgo de sesgo. Sólo dos estudios incluyeron pacientes críticamente enfermos. No se apreciaron beneficios en términos de aclaramiento viral o mejoría clínica al realizar el metaanálisis. Se detectó un incremento significativo en la incidencia de reacciones adversas (RR 3,11, IC95% 1,64-5,89, p < 0,001), si bien la mayoría fueron reportadas como leves. DISCUSIÓN: Las aminoquinolinas poseen efectos inhibitorios in vitro que no han demostrado traducirse en beneficios clínicos. El incremento significativo en la incidencia de reacciones adversas asociado a la baja calidad de los estudios evaluados no permite recomendar este tratamiento para pacientes con COVID-19.

Case of large lentigo maligna melanoma of the scalp treated with 5% and 3. 75% Imiquimod

Abstract The paper presents a case of lentigo maligna melanoma of the scalp in an elderly patient treated for the nodular part with surgery and the residual melanoma in situ with 5% Imiquimod and subsequently with 3.75% Imiquimod (each concentration for 4 months, 5 times per week), with complete regression of the lesion. 3.75% Imiquimod, which is already used for the treatment of actinic keratosis, could be a useful weapon with the same effectiveness and fewer side effects compared to 5% Imiquimod.

Efficacy and safety of oral pyrotinib in HER2 positive metastatic breast cancer: real-world practice / 北京大学学报(医学版)

OBJECTIVE@#Pyrotinib, a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor, showed promising antitumor activity and acceptable tolerability in phase II and phase III randomized clinical trials. We assessed the activity and safety of oral pyrotinib for human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer patients in the real world.@*METHODS@#We retrospectively analyzed 72 HER2 positive metastatic breast cancer (MBC) patients who received oral pyrotinib based regimens at Beijing Cancer Hospital and other four hospitals (Peking University First Hospital, China-Japan Friendship Hospital, General Hospital of PLA, Peking University Third Hospital) from August 2018 to September 2019. Progression free survival (PFS), objective response rate (ORR), adverse events (AE) of pyrotinib were investigated.@*RESULTS@#Seventy-two patients with HER2 positive MBC were enrolled. The median age of the patients was 55 years (range: 32-79 years). Sixty-nine (95.8%) patients had received anti-HER2 treatment in the metastatic and/or (neo) adjuvant settings; 61 (84.7%) patients had received anti-HER2 treatments in the metastatic setting in terms of trastuzumab 56 (77.8%) patients, lapatinib 36 (50.0%) patients, and T-DM1 4 (5.6%) patients. Among these 72 patients who received oral pyrotinib based regimens, 62 (86.1%) patients received pyrotinib (±trastuzumab) in combination with chemotherapy, 6 (8.3%) patients received pyrotinib (± trastuzumab) in combination with endocrine therapy and 4 (5.6%) patients received pyrotinib (±trastuzumab). Sixty-five (90.3%) patients received 400 mg pyrotinib once daily as initial dose, and 7 (9.7%) patients received 320 mg. OBJECTIVE response and safety to pyrotinib based therapy were evaluable in all the 72 patients. One (1.4%) patient achieved complete response (CR), 18 (25.0%) patients achieved partial response (PR), 41 (56.9%) patients had stable disease (SD), and 12 (16.7%) patients had progressive disease (PD). The ORR (CR+PR) was 26.4% and the median PFS was 7.6 months (95%CI: 5.5-9.7 months). Among the 36 patients with prior lapatinib therapy, the median PFS was 7.9 months (95%CI: 4.1-11.7 months). Among the 15 patients with brain metastasis, the median PFS was 6.0 months (95%CI: 2.2-9.8 months). The main toxicities related to pyrotinib were diarrhea in 57 (79.2%) cases, and 48 (66.7%) cases with grade 1-2 as well as 9 (12.5%) cases with grade 3.@*CONCLUSION@#Pyrotinib based therapy is an effective treatment for patients with HER2 positive MBC, including patients with lapatinib treatment failure and brain metastasis, and the toxicities can be tolerated.

Effect of methotrexate on regulation for the number of regulatory T cells and expression of Foxp3 in psoriasis / 中南大学学报(医学版)

To explore the role of methotrexate (MTX) in regulating the number of regulatory T cells (Treg) and the mRNA expression of transcription factor Foxp3.
 Methods: 1) We analyzed the number of Treg and the mRNA expression of Foxp3 by flow cytometry (FCM) and quantitative real-time PCR (qRT-PCR) respectively in patients with psoriasis vulgaris, patients with psoriasis vulgaris after the 8-week treatment of MTX, and healthy people. 2) BALB/c female mice were smeared with imiquimod (IMQ) cream for 6 days. We recorded the change of the lesion in mice every day. The morphological changes of lesion in mice were evaluated by the psoriasis area and severity index (PASI) and HE staining. 3) The mouse model was randomly divided into a control group and an MTX group. The MTX group was treated with different doses of MTX (38.5 and 77.0 nmol/L) on the third day of this experiment. The morphological changes of lesion in mice were evaluated by PASI and HE staining. We tested the number of Treg and the expression level of Foxp3 mRNA in splenic lymphocytes.
 Results: 1) The number of Treg and the expression level of Foxp3 mRNA were lower in psoriasis vulgaris patients than those in the healthy control group (P<0.05). After 8-week treatment of MTX, the number of Treg was increased (P<0.05) and Foxp3 mRNA level was up-regulated (P<0.01). 2) Typical psoriasis-like skin lesions, such as red scaly skin plaque were found after topical application of IMQ. Both the number of Treg in the splenic lymphocytes of mice and the Foxp3 mRNA level of Treg were reduced by IMQ (P<0.01 and P<0.05). 3) Different doses of MTX for mice showed the ability to improve skin lesion, increase the number of Treg in the spleen of mice and Foxp3 mRNA level in psoriatic dermatitis of mice (P<0.05).
 Conclusion: MTX is able to regulate the number of Treg and Foxp3 mRNA expression in psoriasis.

Dermatoscopy-guided therapy of pigmented basal cell carcinoma with imiquimod

Abstract BACKGROUND: Dermatoscopy is a non-invasive diagnostic tool used to examine skin lesions with an optical magnification. It has been suggested as a useful tool for monitoring therapeutic response in lentigo maligna patients treated with imiquimod. OBJECTIVE: To examine the accuracy of dermatoscopy as a tool to monitor the therapeutic response of pigmented basal cell carcinoma treated with imiquimod. METHOD: The authors designed a prospective study. Patients with pigmented basal cell carcinoma were included and data regarding the dermatoscopy features were collected following the Menzies criteria, prior to initiating the imiquimod treatment. Subsequent dermatoscopic evaluations were performed at weeks 4 and 8, following imiquimod discontinuation. RESULTS: Twenty lesions were included. The most common pigmented dermatoscopy features were large blue-grey ovoid nests (80%), followed by blue-grey globules (50%) and leaf-like areas (30%). No spoke wheel areas were observed. In 17 out of 20 patients, a response was noted during the first evaluation at 4 weeks, while the clearance was noted at the second check-up after 8 weeks. In two patients, the clearance was found at the initial evaluation at 4 weeks, while in one patient, the response remained unchanged. Blue-grey globules were the fastest to exhibit clearance (50% at week 4), followed by leaf-like areas (15%) and large blue-grey ovoid nests (6.25%). CONCLUSION: According to our results, dermatoscopic evaluation enhances the accuracy in the assessment of the clinical response to imiquimod in pigmented basal cell carcinoma.

Quinoline derivative PQ1 combined with cisplatin promotes the proliferation and gap junction communication of prostate cancer PC3 cells / 中华男科学杂志

<p><b>OBJECTIVE</b>To investigate the effects of the quinoline derivative PQ1 combined with cisplatin on the proliferation and gap junction communication of prostate cancer PC3 cells.</p><p><b>METHODS</b>We cultured in vitro prostate cancer PC3 cells and divided them into DMSO blank control, cisplatin control, and cisplatin (10 mg/ml) plus PQ1 (1, 2, 5, 10, and 15 μmol/L) groups. We measured the proliferation of the prostate cancer PC3 cells, determined the expressions of the connexin 43 (Cx43) mRNA and protein by RT-PCR and Western blot, and compared the indexes among different groups.</p><p><b>RESULTS</b>Cisplatin combined with PQl at 1 - 10 μmol/L significantly inhibited the proliferation of the PC3 cells and the inhibition rate rose in a concentration- and time-dependent manner, from (48.72 ± 0.98)% vs (50.33 ± 0.62)% at 0 μmol/L to (77.38 ± 1.12)% vs (83.50 ± 1.05)% at 15 μmol/L at 24 and 48 hours (P < 0.05). Compared with the cisplatin control, cisplatin combined with PQ1 at 1, 2, 5, 10, and 15 μmol/L increased the expression of Cx43 mRNA from 0.379 ± 0.113 to 0.669 ± 0.031, 0.831 ± 0. 127, 0.769 ± 0.100, 0.532 ± 0.086, and 0.475 ± 0.134, respectively (P < 0.05), and cisplatin combined with PQ1 at 1, 2, 5, and 10 μmol/L elevated that of Cx43 protein from 0.138 ± 0.146 to 0.263 ± 0.111, 0.306 ± 0.152, 0.415 ± 0.280, and 0.643 ± 0.310, respectively (P < 0.05).</p><p><b>CONCLUSION</b>The quinoline derivative PQ1 can promote the gap junction communication of prostate cancer PC3 cells and enhance the killing effect of cisplatin on PC3 cells by upregulating the expressions of Cx43 mRNA and protein.</p>

The TLR7 agonist Imiquimod promote the immunogenicity of msenchymal stem cells

BACKGROUND: Mesenchymal stem cells (MSCs) are considered the best candidate in stem cells therapy due to their multipotent differentiation ability, low expression of co-stimulatory molecules (CD80, CD86, CD34 and HLA-II) and immunosuppression effects on in vivo immune responses. MSCs were now widely used in clinical trials but received no encourage results. The major problem was the fate of engrafted MSCs in vivo could not be defined. Some studies indicated that MSCs could induce immune response and result in the damage and rejection of MSCs. As toll like receptors (TLRs) are important in inducing of immune responses, in this study we study the role of TLR7 in mediating the immune status of MSCs isolated from umbilical cord. RESULTS: Our results indicated that TLR7 agonist Imiquimod could increase the proliferation of PBMC isolated from healthy human volunteers and release of lactate dehydrogenase (LDH) in supernatant from PBMC-UCMSCs co-culture system. Flow cytometry and quantitative PCR also confirmed the regulated expression of surface co-stimulatory molecules and pro-inflammatory genes (IL-6, IL-8, IL-12, TGF-β and TNF-α). And the down-regulation expression of stem cell markers also confirmed the loss of stemness of UCMSCs. We also found that the osteo-differentiation ability of UCMSCs was enhanced in the presence of Imiquimod. CONCLUSION: To our knowledge, this is the first report that activation of TLR7 pathway increases the immunogenicity of UCMSCs. Extensive researches have now been conducted to study whether the change of immune status will be help in tumor rejection based on the tumor-tropism of MSCs.

Vulvar vitiligo-like depigmentation and multiple halos of hypomelanosis at the trunk following treatment with imiquimod 5% cream for vulvar condylomata: casual or related events?

A 25-year-old Caucasian female with multiple genital warts involving the vulvar area was treated with imiquimod 5% cream. During follow-up the patient developed areas of hypopigmentation at the site of application of imiquimod cream and areas of hypomelanosis around multiple preexisting nevi of the trunk. At 18 months follow-up genital depigmentation persisted and halo nevi of the trunk were still present. Different mechanisms of imiquimod-induced depigmentation have been reported. Halo nevi are considered expression of an autoimmune response. In the case presented here, it might be conceivable that both vitiligo-like depigmentation at the site of application and halo of hypomelanosis around melanocytic nevi have been induced by the same immunologic mechanism elicited by topical application of imiquimod.

Progress in PDE4 targeted therapy for inflammatory diseases / 浙江大学学报·医学版

cAMP-specific phosphodiesterase type 4 (PDE4) is one of the hot targets for treatment of inflammatory diseases. PDE4 inhibitors can suppress inflammation by increasing the concentration of cAMP in inflammatory cells. The efficacy and safety evaluations of several PDE4 inhibitors are currently carried on in clinical trials, for example GSK256066 in asthma, roflumilast and GSK256066 in chronic obstructive pulmonary disease, tetomilast in inflammatory bowel disease, and apremilast in dermatitis and arthritis etc. This article reviews the recent progress on PDE4-targeted therapy for inflammatory diseases.

Expression of Toll-like receptor 7 in gastric cancer cell lines and effects of TLR7 agonist on proliferation and apoptosis of SGC-7901 cells in vitro / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the expression of Toll-like receptor 7 (TLR7) in gastric cancer cell lines and the effect of imiquimod, a TLR7 agonist, on the proliferation and apoptosis of SGC-7901 cells.</p><p><b>METHODS</b>The protein expression levels of TLR7 were detected with Western blotting in 3 human gastric cancer cell lines (SGC-7901, HGC-27 and MKN-28). The cell line expressing the highest TLR7 level was exposed to different doses of imiquimod for 12-72 h and the cell viability was assessed with MTT assay. The cell apoptosis rate after 100 µg/ml imiquimod treatment for 12 or 24 h was quantified by flow cytometry, and the ultrastructual changes of the cells were observed under electron microscope. The expression of apoptosis-related genes Bcl-2 and Bax were analyzed with real-time PCR.</p><p><b>RESULTS</b>All the 3 cell lines expressed TLR7, among which SGC-7901 cells showed the highest expression level. TLR7 agonist imiquimod dose- and time-dependently reduced the viability of SGC-7901 cells. Exposure to 100 µg/ml imiquimod for 24 h resulted in SGC-7901 cell apoptosis as shown by an increased ratio of early apoptotic cells and significant ultrastructural changes of the cells. Real-time PCR demonstrated that imiquimod treatment for 24 h caused a dose-dependent reduction of Bcl-2 mRNA expression and increment of Bax mRNA expression.</p><p><b>CONCLUSIONS</b>TLR7 protein is expressed in all the 3 gastric cancer lines and its agonist imiquimod can inhibit cell proliferation and induce apoptosis in SGC-7901 cells.</p>

Bowen's disease on finger: A diagnostic and therapeutic challenge.

Bowen's disease commonly presents as a solitary asymptomatic plaque involving head and neck region or lower limbs. We present a case of a sixty seven-year-old man with an itchy, oozy, crusted solitary plaque on the right ring finger of eighteen months duration with histopathology consistent with Bowen's disease. The lesion was initially treated with topical 5% imiquimod but due to relapse and inadequate response to a second course, complete surgical excision followed by full thickness skin grafting was done. Recurrence after about 6 months in the form of a small papule adjacent to the initial site was also treated with excision. This report highlights the potential of Bowen's disease to mimic more common dermatoses and a high index of suspicion, supported by histopathology, is required to diagnose and treat it without delay, which in turn may require a multimodality approach. We also reviewed the current literature on the same.

Mechanism of psoriasis generation in animal models / 药学学报

Psoriasis is a chronic inflammatory disease related to genome-wide and surroundings, it is important to develop a suitable animal model to research psoriasis pathogenesis and evolve pharmacotherapeutics. With the development of transgenetic technology in the past few years, psoriasis virulence gene animal model become a hotspot. Research of animal model of human psoriasis genes is reviewed in the paper.

Expression of NLRP3 inflammasome in BALB/c mice with imiquimod-induced psoriasis-like inflammation and therapeutic effect of mustard seed (Sinapis Alba Linn) / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the role of NLRP3 inflammasome in imiquimod-induced psoriasis-like inflammation in mice and the therapeutic effects of mustard seed (Sinapis Alba Linn).</p><p><b>METHODS</b>Thirty BALB/c mice were randomized equally into blank control group (fed with normal forage and treated with vehicle), model group (fed with normal forage and treated with 5% imiquimod cream), and experimental group (fed with 5% mustard seed forage and treated with 5% imiquimod cream). RT-PCR was used to detect the mRNA expression of NLRP3, ASC, caspase-1, and caspase-11. Immunohistochemistry was performed to determine the expression and distribution of ASC and caspase-1. ELISA was used to test the serum levels of interleukin-1β (IL-1β) and IL-18.</p><p><b>RESULTS</b>Compared with the blank control group, the mice with imiquimod-induced psoriasis-like inflammation showed significantly increased NLRP3, ASC, caspase-1, and caspase-11 mRNA expressions, ASC and caspase-1 protein expressions , and serum levels of IL-1β and IL-18 (P<0.05). These changes were obviously attenuated by feeding the mice with mustard seed.</p><p><b>CONCLUSION</b>NLRP3 inflammasome is involved in imiquimod-induced psoriasis-like inflammation in mice, and mustard seed may suppress the inflammation induced by IL-1β and IL-18 through down-regulating the expression of NLRP3 inflammasome.</p>

New Alternative Combination Therapy for Recalcitrant Common Warts: The Efficacy of Imiquimod 5% Cream and Duct Tape Combination Therapy

No abstract available.