Therapeutic Effects Of Hydroxychloroquine Research Articles

The Gut Microbiota of Pregnant Rats Alleviates Fetal Growth Restriction by Inhibiting the TLR9/MyD88 Pathway.

Fetal growth restriction (FGR) is a prevalent obstetric condition. This study aimed to investigate the role of Toll-like receptor 9 (TLR9) in regulating the inflammatory response and gut microbiota structure in FGR. An FGR animal model was established in rats, and ODN1668 and hydroxychloroquine (HCQ) were administered. Changes in gut microbiota structure were assessed using 16S rRNA sequencing, and fecal microbiota transplantation (FMT) was conducted. HTR-8/Svneo cells were treated with ODN1668 and HCQ to evaluate cell growth. Histopathological analysis was performed, and relative factor levels were measured. The results showed that FGR rats exhibited elevated levels of TLR9 and myeloid differentiating primary response gene 88 (MyD88). In vitro experiments demonstrated that TLR9 inhibited trophoblast cell proliferation and invasion. TLR9 upregulated lipopolysaccharide (LPS), LPS-binding protein (LBP), interleukin (IL)-1β and tumor necrosis factor (TNF)-α while downregulating IL-10. TLR9 activated the TARF3-TBK1-IRF3 signaling pathway. In vivo experiments showed HCQ reduced inflammation in FGR rats, and the relative cytokine expression followed a similar trend to that observed in vitro. TLR9 stimulated neutrophil activation. HCQ in FGR rats resulted in changes in the abundance of Eubacterium_coprostanoligenes_group at the family level and the abundance of Eubacterium_coprostanoligenes_group and Bacteroides at the genus level. TLR9 and associated inflammatory factors were correlated with Bacteroides, Prevotella, Streptococcus, and Prevotellaceae_Ga6A1_group. FMT from FGR rats interfered with the therapeutic effects of HCQ. In conclusion, our findings suggest that TLR9 regulates the inflammatory response and gut microbiota structure in FGR, providing new insights into the pathogenesis of FGR and suggesting potential therapeutic interventions.

Effects of Hydroxychloroquine on Proteinuria in IgA Nephropathy: A Systematic Review and Meta-Analysis.

Introduction The present meta-analysis was to explore the efficacy of hydroxychloroquine (HCQ) in IgA nephropathy patients in terms of proteinuria. Method We systematically searched PubMed and Embase for studies that compared HCQ and other treatments to reduce proteinuria in patients with IgA nephropathy up to June 2021. Mean ± SD of percentage change and level of proteinuria was calculated. Results A total of 5 studies with 587 participants were included. IgA nephropathy patients who received HCQ were at a lower level of mean proteinuria at 6 months. However, there was no statistical difference between HCQ and control group considering percentage reduction in proteinuria. The long-term therapeutic effect of HCQ might be inferior to HCQ and renin-angiotensin-aldosterone system inhibition. Conclusion HCQ might play a role in the reduction of proteinuria in IgA nephropathy patients. The addition of HCQ to other immunosuppressive agents should be clarified further.

Hydroxychloroquine in COVID-19 Patients: Pros and Cons

The pandemic of COVID-19, caused by SARS-CoV-2, has recently overwhelmed medical centers and paralyzed economies. The unparalleled public distress caused by this pandemic mandated an urgent quest for an effective approach to manage or treat this disease. Due to their well-established anti-infectious and anti-inflammatory properties, quinine derivatives have been sought as potential therapies for COVID-19. Indeed, these molecules were originally employed in the treatment and prophylaxis of malaria, and later in the management of various autoimmune rheumatic and dermatologic diseases. Initially, some promising results for the use of hydroxychloroquine (HCQ) in treating COVID-19 patients were reported by a few in vitro and in vivo studies. However, current evidence is not yet sufficiently solid to warrant its use as a therapy for this disease. Additionally, the therapeutic effects of HCQ are not without many side effects, which range from mild gastrointestinal effects to life-threatening cardiovascular and neurological effects. In this review, we explore the controversy associated with the repurposing of HCQ to manage or treat COVID-19, and we discuss the cellular and molecular mechanisms of action of HCQ.

In Vivo Analysis of Therapeutic Effects of Hydroxychloroquine, Azithromycin, Paracetamol, Dexamethasone, Remdesivir and Tocilizumab in Patients Affected with Novel Covid-19

COVID 19 creates pandemic around the globe. This virus spread so rapidly and unfortunately till now there is no authentic treatment available. Based upon the trials various drugs were applied to control the disease. Different drugs found effective including hydroxychloroquine, dexamethasone, azithromycin and remdesivir. In current study 100 patients were participated. The presence of disease was confirmed by PCR based tests. Initials reports represent various abnormal range of WBC’s in patients. Most of them were symptomatic while few were asymptomatic. Gender wise COVID-19 mostly affected males rather than female gender. It was also found that older person were more susceptible than younger one.Effectiveness of the drugs shows there is need to do more work on following components to control the disease prevalence until a vaccine is discovered. Keywords: COVID-19, Dexamethasone, SARS DOI: 10.7176/JHMN/81-06 Publication date: October 31 st 2020

Hydroxychloroquine treatment in COVID-19: A descriptive observational analysis of 30 cases from a single center in Wuhan, China.

Hydroxychloroquine (HCQ) garnered scientific attention in early February following publication of reports showing in vitro activity of chloroquine (CQ) against coronavirus disease 2019 (COVID‐19). While studies are mixed on this topic, the therapeutic effect of HCQ or CQ still need more valid clinical evidence. In this descriptive observational study, we aimed to discuss the treatment response of HCQ in COVID‐19 infected patients and 30 cases were included. The demographic, treatment, laboratory parameters of C‐reactive protein (CRP) and interleukin‐6 (IL‐6) before and after HCQ therapy and clinical outcome in the 30 patients with COVID‐19 were assessed. To evaluate the effect of mediation time point, we also divided these cases into two groups, patients began administrated with HCQ within 7 days hospital (defined as early delivery group) and 7 days after hospital (defined as later delivery group). We found that, the elevated IL‐6, a risk factor in severe patients were reduced to normal level after HCQ treatment. More importantly, patients treated with HCQ at the time of early hospital recovered faster than those who treated later or taken as second line choose for their obvious shorter hospitalization time. In summary, early use of HCQ was better than later use and the effect of IL‐6 and CRP level cannot be ruled out.

Torsades de Pointes in Coronavirus Disease 2019 Infection

A 73-YEAR-OLD MAN (weight 69 kg, height 175 cm) was transferred to the authors’ critical care unit with respiratory and acute renal failure secondary to coronavirus disease 2019 (COVID-19) infection. His past medical history included hypertension, diabetes, and previous stroke, from which he had made a full recovery. The patient was treated with mechanical ventilation and peritoneal dialysis. He was recruited into the hydroxychloroquine arm of the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial. Baseline electrocardiogram (ECG) and subsequent ECG monitoring were normal and did not demonstrate any QT prolongation. Three days later, the patient developed a ventricular tachycardia with a circulatory collapse. Immediate cardiopulmonary resuscitation was initiated and defibrillator pads attached; however, the arrhythmia self-terminated within 2 minutes (Fig 1). After resuscitation, another ECG showed a normal QT interval. Arterial blood gas analysis did not show any signs of respiratory insufficiency or an acid-base disturbance. There were no signs of myocardial ischemia. A full panel of blood tests was performed, which did not demonstrate any relevant abnormalities in full blood count, biochemical studies, or coagulation. Hypomagnesemia and hypokalemia were absent. Echocardiography was normal. What is the diagnosis? Diagnosis: Torsades de pointes ventricular tachycardia presumably resulting from hydroxychloroquine therapy. Review of the telemetry data demonstrated a polymorphic ventricular tachycardia in the pattern of torsades de pointes, with a spontaneous onset and termination. A cardiac electrophysiology review was requested and confirmed the diagnosis of torsades de pointes. Review of ECGs, blood test results, and medication history allowed the authors to conclude that the arrhythmia had most likely been caused by hydroxychloroquine. Recommendations were made for stringent monitoring of serum electrolytes (to prevent hypomagnesemia and hypokalemia) and daily ECGs. No further antiarrhythmic therapy was recommended at this stage. Hydroxychloroquine was discontinued, and the patient's participation in the RECOVERY trial was terminated. No further arrhythmias were reported during the patent's stay. An adverse drug reaction report was submitted to the UK Medicines and Healthcare products Regulatory Agency (UK MHRA) to register the hydroxychloroquine-related life-threatening arrhythmia. In early 2020 during the COVID-19 pandemic, a number of studies reported possible therapeutic effects of hydroxychloroquine, and it was therefore included as 1 of the drugs in the platform UK RECOVERY trial.1Randomised evalution of COVID-19 Therapy (RECOVERY) Availible at: https://www.recoverytrial.net/files/protocol-archive/recovery-protocol-v4-0-2020-04-14.pdfGoogle Scholar However, preliminary data showed no benefit in hospitalized patients with COVID-19, which led to the UK MHRA instruction to stop recruitment into trials using hydroxychloroquine to treat patients with COVID-19.2UK Medicines & Healthcare products Regulatory AgencyMHRA suspends recruitment to COVID-19 hydroxychloroquine trials.2020https://www.gov.uk/government/news/mhra-suspends-recruitment-to-covid-19-hydroxychloroquine-trialsGoogle Scholar Hydroxychloroquine was introduced in 1955 as an anti-malarial drug. It has immunomodulatory properties that include inhibition of chemotaxis and phagocytosis, reduction of cytokine synthesis, inhibition of phospholipase A2, and signaling in lymphocytes.3Ben-Zvi I Kivity S Langevitz P et al.Hydroxychloroquine: From malaria to autoimmunity.Clin Rev Allerg Immunol. 2012; 42: 145-153Crossref PubMed Scopus (398) Google Scholar,4Kalia S Dutz JP. New concepts in antimalarial use and mode of action in dermatology.Dermatol Ther. 2007; 20: 160-174Crossref PubMed Scopus (187) Google Scholar Hydroxychloroquine has a large spectrum of side effects including cardiomyopathy and arrhythmias associated with the prolongation of the QT interval.3Ben-Zvi I Kivity S Langevitz P et al.Hydroxychloroquine: From malaria to autoimmunity.Clin Rev Allerg Immunol. 2012; 42: 145-153Crossref PubMed Scopus (398) Google Scholar Between 1964 and 2020, the UK MHRA registered 916 patients with adverse drug reactions, of whom 679 were classified as serious and 15 as fatal. The most commonly reported adverse drug reactions involved skin (454 cases) and the nervous system, including eye (285) and gastrointestinal tract (165). Cardiac adverse drug reactions were reported in 48 patients and included myocardial and/or pericardial disorders, arrhythmias, and heart failure.5UK Medicines & Healthcare products Regulatory AgencyInteractive drug analysis profile for hydroxychloroquine.2020https://info.mhra.gov.uk/drug-analysis-profiles/dap.html?drug=./UK_EXTERNAL/NONCOMBINED/UK_NON_000544442035.zip&agency=MHRAGoogle Scholar Cardiac arrhythmias were reported in 18 patients. Anesthesiologists should continue to be aware of the importance of a comprehensive drug history and are reminded of potential life-threatening arrhythmias when hydroxychloroquine is used. We declare that we have no known competing interests or relationships that could have influenced the work reported in this paper.

Exploring Repurposing Potential of Existing Drugs in the Management of COVID-19 Epidemic: A Critical Review.

Despite high morbidity and mortality of ongoing coronavirus disease 2019 (COVID-19) pandemic, no specific therapy has been established till date. Though in vitro studies identified various molecules as possible therapies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), these findings call for substantiation by human studies. We conducted this review aiming at reporting evidences on therapies used so far globally for management of COVID-19 in clinical settings. We searched electronic databases as PubMed, Google Scholar, EMBASE and extracted 612 possible studies as on May 31, 2020. We included original studies of any epidemiological design done on human COVID-19 patients and measured clinical outcomes. Finally, following removal of duplicates and studies meeting exclusion criteria, we derived 22 studies, of which eight were clinical trials, seven were case reports and case series, and seven were observational studies. The most reported therapies were hydroxychloroquine (HCQ) (eight studies) and lopinavir/ritonavir (four studies). We conclude from the evidence generated so far that interferon combined with antivirals, remdesivir, umifenovir and favipiravir were mostly associated with better clinical outcomes. The therapeutic effect of HCQ was established initially by two clinical trials; one of them showing a reinforcing effect by azithromycin but subsequent studies did not elicit any effectiveness rather increased rate of adverse events was reported. Lopinavir/ritonavir was found beneficial when administered with interferon and ribavirin, but one clinical trial on its sole use proved contrary. As many clinical trials are in process, we expect to get concrete evidences on repurposing of existing drugs based on less biased, high powered studies.

Hydroxychloroquine Improves Obesity-Associated Insulin Resistance and Hepatic Steatosis by Regulating Lipid Metabolism.

The burden of obesity and associated cardiometabolic diseases has been considered as an important risk factor for lupus patients. Therefore, whether obesity is involved in the over-activation of autoimmune response has attracted more and more attention. Hydroxychloroquine is a synthetic antimalarial drug and has been the clinical treatment of rheumatic diseases irreplaceable first-line drugs. Hydroxychloroquine has been suggested to have beneficial effects on lipids and insulin sensitivity, which may contribute in lowering high cardiovascular risk in SLE patients. However, its mechanism on insulin sensitivity and lipid disorders is far from being completely understood. In the present study, the therapeutic effects of hydroxychloroquine were evaluated under pathological conditions in vivo. Obesity was induced in C57BL/6 mice fed with high-fed diet, or in mice fed with high-fat diet and hydroxychloroquine. In addition, healthy mice that received normal chow diet were also monitored. The present results revealed that hydroxychloroquine reduced weight, hepatic steatosis, glucose, and insulin resistance. Furthermore, hydroxychloroquine downregulated the expression of peroxisome proliferator-activated receptor gamma in the liver. According to these present results, genes about lipid metabolism went down in high-fat mice liver. Hydroxychloroquine shows potential in ameliorating obesity-induced pathology, which acts though PPARγ to facilitate the healthy function of hepatic tissues. This evidence shows that hydroxychloroquine plays a role in improving obesity-induced lipotoxicity and insulin resistance though the peroxisome proliferator-activated receptor gamma pathway.

Histiocytic Necrotizing Lymphadenitis, a Benign Mimic of Lymphoma Presenting with B Symptoms

IntroductionHistiocytic necrotizing lymphadenitis (HNL), also known as Kikuchi Fujimoto disease, is a disorder of unknown etiology. Diagnosis is made only with histological examination and is frequently misdiagnosed as lymphoma. Our objective is to maintain high index of suspicion to diagnose HNL and to emphasize on the role of hydroxychloroquine (HCQ) for management of complicated cases.Case48 year old male with a past medical history of ankylosing spondylitis, uveitis, and hypothyroidism initially presented 4 years ago with fever, night sweats, vomiting and weight loss of 10 pounds over the past 1 month. The physical exam was significant for tender, mobile left supraclavicular lymphadenopathy with no hepatosplenomegaly. Laboratory findings revealed leukopenia, anemia and elevated liver enzymes, lactate dehydrogenase, erythrocyte sedimentation rate and C-reactive protein. He was given broad spectrum antibiotics with no improvement. Computed tomography of the chest/abdomen demonstrated mediastinal, hilar and abdominal lymphadenopathy. Further infectious and autoimmune workup was negative. The patient then underwent a left supraclavicular lymph node excision which was consistent with HNL (Figure 1). Flow cytometry of the lymph node revealed no diagnostic evidence of a lymphoproliferative disorder. He was started on prednisone and his symptoms resolved. He had multiple episodes of recurrence in the last 4 years, manifesting as high grade fever, fatigue and lymphadenopathy. He was treated each time with prednisone. No provoking factors including viral infection or flare of uveitis was evidenced. Most recently, he had 3 episodes within 12 month span. Eventually he was treated with HCQ and since, has had no recurrence.DiscussionHNL is most commonly reported among young Asian females. The exact entity of this disease is unclear including its pathogenesis and treatment. No signs or symptoms are pathognomonic, making it a difficult diagnosis. Awareness of this disorder by clinicians would help prevent unnecessary treatment with antibiotics and allow earlier initiation of HCQ.Characteristic histopathologic findings of HNL include irregular paracortical areas of coagulative necrosis with karyorrhectic focus, distorting the nodal architecture. The foci are formed by predominantly histiocytes and plasmacytoid monocytes, also immunoblasts and lymphocytes. Neutrophils are absent and plasma cells are either absent or scarce. The histiocytes express antigens such as CD163 and CD68.Most cases of HNL have a self-limited clinical course, although 3-7% of patients experience recurrent episodes. Treatment is generally directed towards symptomatic relief. Use of short term administration of corticosteroids and nonsteroidal anti-inflammatory drugs may be effective. However preventing recurrence has been a challenge. Several reports have proposed a close association between HNL and autoimmune disorders. Therefore, it has been speculated that HCQ would be useful for treating HNL. Our patient had 3 recurrences within 4 years and with the use of HCQ, remission was finally achieved.ConclusionIn past 1 year, two articles discussed the use of HCQ in HNL. Lin et al. presented a retrospective review of 40 children diagnosed with HNL over approximately 15 years. Corticosteroids and HCQ were administered in 15.6% of patients. There were neither recurrences nor relevant major adverse effects in cases treated with HCQ. Honda et al. reported a case of a 42 year old female with multiple recurrences following tapering dose of prednisone. Continuous remission was achieved by concomitant use of HCQ with prednisolone. Several other cases have been reported suggesting that HCQ is effective for treating HNL patients with Systemic lupus erythematosus (SLE). Despite our patient not meeting the American College of Rheumatology criteria of SLE, he still responded to HCQ and has been able to avoid unnecessary use of steroids. Further research is needed regarding management of HNL flares which do not present with obvious autoimmune symptoms.Lin, YC et al., Pediatric Kikuchi-Fujimoto disease: A clinicopathologic study and the therapeutic effects of hydroxychloroquine; https://doi.org/10.1016/j.jmii.2017.08.023Honda et al; Recurrent Kikuchi-Fujimoto Disease Successfully Treated by the Concomitant Use of Hydroxychloroquine and Corticosteroids; Intern Med. 2017 Dec 15; 56(24): 3373-3377. DisclosuresNo relevant conflicts of interest to declare.

Pediatric Kikuchi-Fujimoto disease: A clinicopathologic study and the therapeutic effects of hydroxychloroquine.

To investigate the clinical features of Kikuchi-Fujimoto disease (KFD) in children, and place an emphasis on the therapeutic effects of hydroxychloroquine as monotherapy. We retrospectively reviewed the medical records of all children diagnosed with KFD during the period January 1992 to September 2016at a tertiary medical center in Taiwan. 40 patients were histopathologically confirmed as KFD, and the mean age of the patients was 13.9±3.1 years. The male to female ratio was 1:1. The lymph node involvements were often cervical (95%) with features of unilateral predisposition (75%), polyadenopathy (84.4%) and tenderness (56.3%). Fever, cough, rhinorrhea, and tonsillitis were other common presentations. Laboratory findings included leukopenia (56.5%), monocytosis (63.6%), with positive results of EB-VCA IgG (88.9%), EB-VCA IgM (22.2%), EBEA IgG (22.2%) and EBNA IgG (88.9%). The univariate analyses of prolonged fever with lymphopenia, monocytosis, thrombocytopenia and necrotizing type in histopathology were disclosed as statistically significant (P<0.05). Corticosteroids and hydroxychloroquine were administered in 15.6% of patients respectively, along with symptomatic treatments for the rest. Recurrence occurred in 13.0% of patients without corticosteroids or hydroxychloroquine treatment. There were neither recurrences nor relevant major adverse effects in all the five KFD cases treated with hydroxychloroquine. KFD should be suspected in children with febrile cervical lymphadenopathy, especially when concomitant with leukopenia and monocytosis. Lymphopenia, monocytosis, thrombocytopenia and necrotizing type in histopathology are reliable predictors for prolonged fever. Hydroxychloroquine may be an alternative choice to corticosteroids for its favorable effects and safety.

Therapeutic effect of hydroxychloroquine on colorectal carcinogenesis in experimental murine colitis

Chronic inflammation in the intestine is a strong risk factor for colitis-associated colorectal cancer (CAC). Hydroxychloroquine (HCQ) is widely used as an anti-inflammatory drug in the treatment of immune-mediated inflammatory disorders and various tumors. However, little is known regarding the effects of HCQ on colitis-associated tumorigenesis. In this study, mice treated with HCQ showed a significant reduction in early-stage colitis following azoxymethane (AOM)/dextran sodium sulfate (DSS) administration, as well as a remarkable inhibition of colonic tumorigenesis and tumor growth at late stages of CAC. Mechanistically, the therapeutic effects of HCQ were attributed to inhibition of inflammatory responses and production of mutagenic reactive oxygen species (ROS) in immune cells and subsequent promotion of apoptosis and cell cycle arrest in tumor cells. Furthermore, we found that HCQ inhibited the production of inflammatory cytokines and ROS in response to toll-like receptor 4 (TLR4) activation in macrophages. Our data presented herein may help guide the clinical use of HCQ as a prevention and treatment strategy for CAC.

Therapeutic effects of hydroxychloroquine combined with butyli flufenamatum ointment and other drugs for the treatment of polymorphous light eruption: a comparison study

Objective To evaluate the efficacy and safety of hydroxychloroquine combined with butyli flufenamatum ointment and other drugs for the treatment of polymorphous light eruption (PLE). Methods A total of 48 patients with PLE were randomly and equally classified into group 1 and group 2. Both groups took hydroxychloroquine 200 mg twice a day and loratadine 10 mg per day for the initial 4 weeks, then took hydroxychloroquine 100 mg twice a day alone for another 4 weeks. Group 1 also topically applied butyli flufenamatum ointment twice a day during the 8 weeks, while group 2 applied mometasone furoate cream twice a day for the first 2 weeks followed by butyli flufenamatum ointment twice a day for another 6 weeks. Each treatment cycle lasted 2 weeks, and both groups received 4 cycles of treatment. Patients were evaluated for the response rate at the end of each cycle, and for the total symptom score and erythema score before and after the 8-week treatment. Statistical analysis was carried out using t test, chi-square test, Fisher's exact test and repeated-measures analysis of variance with the SPSS17.0 software. Results On day 14, 28, 42 and 56, the total score improved in 0, 3, 12 and 19 patients in group 1 respectively, and in 1, 4, 12 and 20 patients in group 2 respectively; the erythema score improved in 1, 5, 13 and 18 patients in group 1 respectively, and in 0, 5, 11 and 17 patients in group 2 respectively. No significant difference was observed between the two groups in response rates at any of the above four time points (P > 0.05). Both the total score and erythema score significantly decreased after the 8-week treatment in both groups compared with the pretreatment scores (both P < 0.05). No serious adverse reaction was observed in either of the two groups. Conclusions Hydroxychloroquine combined with loratadine and butyli flufenamatum ointment shows high efficacy and safety for the treatment of PLE. Topical butyli flufenamatum ointment is highly effective for the treatment of PLE, especially for PLE cases mainly presenting with erythema. Key words: Hydroxychloroquine; Loratadine; Flufenamate acid; Treatment outcome; Comparative effectiveness research; Erythema; Polymorphic sun light eruption