Synthetic Antimalarials Research Articles

WHAT TO EXPECT FROM MICROBLADING OF THE EYEBROWS

Microblading of the eyebrows, a kind of cosmetic tattooing that has become very popular in the last decade, it can nevertheless cause adverse skin reactions at the tattoo site, including infections, allergic reactions, and even sarcoid reactions. These reactions can lead to a reduction in the quality of life. We report tow cases of adverse reactions following microblading of the eyebrows, the first patient 40-year-old women presenting with a 7 -month history of erythematous lesions on the eyebrow, A biopsy was performed, which came back a sarcoidosis granulomatous reaction, Our patient was put on intralesional corticosteroid and synthetic antimalarials with good improvement, the second patient have 38 year-old women consulting for erythematous, oozing, pruritic lesions after 3 days of application microblading of the eyebrows, . The dermatological examination revealed the presence of edematous erythematous plaques surmounted by vesicles with crumbling contours located on both eyebrows. The diagnosis of contact eczema was retained, and the patients was put on a low-class topical corticosteroid for 10 days with good improvement.

Promising 8-Aminoquinoline-Based Metal Complexes in the Modulation of SIRT1/3-FOXO3a Axis against Oxidative Damage-Induced Preclinical Neurons.

The discovery of novel bioactive molecules as potential multifunctional neuroprotective agents has clinically drawn continual interest due to devastating oxidative damage in the pathogenesis and progression of neurodegenerative diseases. Synthetic 8-aminoquinoline antimalarial drug is an attractive pharmacophore in drug development and chemical modification owing to its wide range of biological activities, yet the underlying molecular mechanisms are not fully elucidated in preclinical models for oxidative damage. Herein, the neuroprotective effects of two 8-aminoquinoline-uracil copper complexes were investigated on the hydrogen peroxide-induced human neuroblastoma SH-SY5Y cells. Both metal complexes markedly restored cell survival, alleviated apoptotic cascades, maintained antioxidant defense, and prevented mitochondrial function by upregulating the sirtuin 1 (SIRT1)/3-FOXO3a signaling pathway. Intriguingly, in silico molecular docking and pharmacokinetic prediction suggested that these synthetic compounds acted as SIRT1 activators with potential drug-like properties, wherein the uracil ligands (5-iodoracil and 5-nitrouracil) were essential for effective binding interactions with the target protein SIRT1. Taken together, the synthetic 8-aminoquinoline-based metal complexes are promising brain-targeting drugs for attenuating neurodegenerative diseases.

Idiopathic Pulmonary Hemosiderosis in Pediatric in Patients: Report of Four Cases in Rabat, Morrocco

Idiopathic pulmonary hemosiderosis (IPH) is a rare cause of diffuse alveolar hemorrhage. Patients with IPH usually present with the classical triad: hemoptysis, and iron deficiency anemia, and pulmonary infiltrates on chest imaging, the diagnosis is often delayed by years.
 We report four IPH pediatrics cases of children diagnosed at the children’s hospital of Rabat, Morocco. The aim of this study is to review the clinical manifestations, diagnostic tools and treatment of this affection.
 All the four patients were presented with the classical triad, the diagnosis was based on the Clinical, radiologic and biologic findings. Bronchoalveolar lavage was performed to all the patients and confirmed the diagnosis by the identification of siderophages.
 High doses of Corticosteroids, by an induction therapy with an intravenous methylprednisolone (20 mg/kg/day for 3 days) followed by oral prednisone (1 mg/kg/day) had shown a good therapeutic response. One patient was treated first with oral corticosteroid and switched over to synthetic antimalarial drugs, because he had side effects from long-term cortico therapy. Then the clinical condition has been improved. The evaluation of response to the therapy included the clinical symptoms and signs, laboratory data and chest x ray. The prognosis of IPH is influenced by several factors, including the time of diagnosis, early initiation of treatment, and the presence of comorbidities.

In Vitro Effect on Plasmodium falciparum and In Vivo Effect on Plasmodium berghei of Annomaal, an Oily Fraction Obtained from the Seeds of Annona squamosa.

Malaria remains a life-threatening health problem and is responsible for the high rates of mortality and morbidity in the tropical and subtropical regions of the world. The increasing threat of drug resistance to available artemisinin-based therapy warrants an urgent need to develop new antimalarial drugs that are safer, more effective, and have a novel mode of action. Natural plants are an excellent source of inspiration in searching for a new antimalarial agent. This research reports a systematic investigation for determining the antimalarial potential of the seeds of A. squamosa. The study shows that the crude seed extract (CSE), protein, saponin, and the oily fractions of the seeds were nontoxic at a 2000 mg/kg body weight dose when tested in Wistar rats, thus revealing high safety is classified as class 5. The oily fraction, Annomaal, demonstrated pronounced antimalarial activity with low IC50 (1.25 ± 0.183 μg/mL) against P. falciparum in vitro. The CSE and Annomaal significantly inhibited the growth of P. berghei parasites in vivo with 58.47% and 61.11% chemo suppression, respectively, while the standard drug artemether showed chemo suppression of 66.75%. Furthermore, the study demonstrated that oral administration of Annomaal at a daily dose of 250 mg/kg/day for 3 days was adequate to provide a complete cure to the P. berghei-infected mice. Annomaal thus holds promise as being patient-compliant due to the shorter treatment schedule, eliminating the need for frequent dosing for extended time periods as required by several synthetic antimalarial drugs. Further studies are needed to determine the active compounds in the oily fraction responsible for antimalarial activity.

Screening for toxic retinopathy due to antimalarial drugs in Tunisia.

Toxic retinopathy due to antimalarial drugs is characterized by structural anomalies associated with severe, irreversible visual loss. The advantage of ophthalmologic monitoring is to detect these anomalies at an asymptomatic, preclinical stage, so that the recommended dose can be adjusted before the ophthalmologic manifestations appear. Cross-sectional study carried out in the ophthalmology department of Habib Bourguiba University Hospital, Sfax, between August 2016 and February 2018. All patients treated in the internal medicine department of Hedi Chaker University Hospital with synthetic antimalarial drugs for at least 1 year were included. A complete ophthalmologic examination and specialized retinal testing (fundus autofluorescence, 10-2 automated visual field and swept source OCT) were performed for all patients. Fifty-six patients treated with antimalarial drugs were analyzed. The main indication was systemic lupus erythematosus (80.3%). Fifty-three patients (94.64%) were treated with hydroxychloroquine, and 3 patients (5.4%) with chloroquine. Thirteen patients (23.2%) exhibited signs of retinal toxicity, with fundus autofluorescence alterations in 8% of cases, fundus anomalies in 12.5% of cases, 10-2 automated visual field defects in 16% of cases, and SS-OCT alterations in 23.2% of cases. We did not find a statistically significant association between retinal toxicity, weight, age, sex and renal insufficiency (p values of 0.8, 0.6, 0.66 and 0.7 respectively). Furthermore, the association between the cumulative dose and retinal toxicity was statistically significant (p=0.02). The prevalence of toxic retinopathy was identified as 5% at 5 years, 25% at 10 years and 70% at 20 years. A better understanding of the risk factors for retinal toxicity is necessary when prescribing synthetic antimalarial drugs. Screening should be systematic. It should be based on a combination of functional and anatomic tests. The frequency of screening depends on the associated risk factors.

Historical 8-Aminoquinoline Combinations: Not All Antimalarial Drugs Work Well Together.

Since their first use in the 1920s, 8-aminoquinolines have been known to have important toxicities such as methemoglobinemia and hemolysis. An empiric pamaquine (plasmochin) combination with quinine was widely used in the British military with relatively little toxicity. Attempts to use pamaquine with a new synthetic antimalarial drug (atabrine, quinacrine) in the 1930-1940s, however, resulted in hemolytic reactions and some deaths from renal failure. An improved 8-aminoquinoline, primaquine, was particularly effective against Plasmodium vivax relapses when combined with either quinine or chloroquine. When used in reduced daily doses (15 mg) over 2 weeks, it was safely given to many thousands of U.S. soldiers returning from Korea. CP tablets (chloroquine 300 mg, primaquine 45 mg weekly) were widely used during the Vietnam War with few hemolytic reactions and no known deaths. Efficacy and toxicity of 8-aminoquinolines is determined in part by the selection of appropriate partner drugs.

L’hydroxychloroquine pour la sarcoïdose extra-pulmonaire non-sévère

Sarcoidosis can develop into a chronic disease in about 30% of cases. When general treatment is indicated, corticosteroids are the first-line treatment. More than one third of patients treated with corticosteroids receive a steroid-sparing agent. Although methotrexate is the most commonly used sparing agent, synthetic antimalarials have been used for more than fifty years on the basis of small, randomised, therapeutic trials. Despite this low level of evidence, chloroquine or more often hydroxychloroquine are used in daily practice, particularly to treat skin, bone and joint sarcoidosis, as well as hypercalcemia and certain types of uveitis.This review summarises the state of knowledge on steroid-sparing therapy in sarcoidosis, particularly in its extra-pulmonary form. These data support the need for good quality therapeutic trials to validate the use of hydroxychloroquine in this specific indication.

Peroxide Antimalarial Drugs Target Redox Homeostasis in Plasmodium falciparum Infected Red Blood Cells.

Plasmodium falciparum causes the most lethal form of malaria. Peroxide antimalarials based on artemisinin underpin the frontline treatments for malaria, but artemisinin resistance is rapidly spreading. Synthetic peroxide antimalarials, known as ozonides, are in clinical development and offer a potential alternative. Here, we used chemoproteomics to investigate the protein alkylation targets of artemisinin and ozonide probes, including an analogue of the ozonide clinical candidate, artefenomel. We greatly expanded the list of proteins alkylated by peroxide antimalarials and identified significant enrichment of redox-related proteins for both artemisinins and ozonides. Disrupted redox homeostasis was confirmed by dynamic live imaging of the glutathione redox potential using a genetically encoded redox-sensitive fluorescence-based biosensor. Targeted liquid chromatography-mass spectrometry (LC-MS)-based thiol metabolomics also confirmed changes in cellular thiol levels. This work shows that peroxide antimalarials disproportionately alkylate proteins involved in redox homeostasis and that disrupted redox processes are involved in the mechanism of action of these important antimalarials.

Nephrotic syndrome associated with Libman–Sacks endocarditis as a first manifestation of systemic lupus

Libman–Sacks endocarditis is a rare cardiac manifestation of systemic lupus erythematosus, in which there is sterile vegetation in the heart valves with a significant risk of infective endocarditis. Patient aged 29, presents with a deep nephrotic syndrome, associated with microscopic hematuria, we find in his history a notion of inflammatory arthritis of the ankles, wrists and knees, with alteration of the general state in a long-term febrile context, associated with a chronic inflammatory left subpalpebral cellulitis. The patient was in average general condition, asthenic, with exertional dyspnoea, oedema of the lower limbs rising to the legs and the cardiac examination found a significant murmur at the aorto-mitral focus. Biologically: a deep nephrotic syndrome was found. Inflammatory syndrome with PRC at 80 mg and SR at +++. Inflammatory anaemia and lymphopenia. An echocardiography done, finds a mitro-aortic valve thickening, with the presence of fine vegetations on the aortic side of the posterior sigmoid, in addition to an important mitral and aortic leak. The immunological work-up was strongly positive for antiphospholipid syndrome with IgG anti-cardiolipin antibodies (+), IgG anti-B2GP1 antibodies (+), antinuclear factor antibodies (+) with a speckled appearance; a renal biopsy was performed and was consistent with lupus glomerulonephritis. High-dose corticosteroids combined with double antibiotic therapy significantly improved the patient's clinical and biological parameters. Our observation is quite exceptional because cardiac involvement usually occurs years after the onset of SLE, but in this observation the onset is quite nasty, first in a male subject, associating renal involvement, endocarditis and SAPL. Treatment was based on a combination of antibiotics, corticoids and synthetic antimalarials.

Artemisinin inspired synthetic endoperoxide drug candidates: Design, synthesis, and mechanism of action studies.

Artemisinin combination therapies (ACTs) have been used as the first-line treatments against Plasmodium falciparum malaria for decades. Recent advances in chemical proteomics have shed light on the complex mechanism of action of semi-synthetic artemisinin (ARTs), particularly their promiscuous alkylation of parasite proteins via previous heme-mediated bioactivation of the endoperoxide bond. Alarmingly, the rise of resistance to ART in South East Asia and the synthetic limitations of the ART scaffold have pushed the course for the necessity of fully synthetic endoperoxide-based antimalarials. Several classes of synthetic endoperoxide antimalarials have been described in literature utilizing various endoperoxide warheads including 1,2-dioxanes, 1,2,4-trioxanes, 1,2,4-trioxolanes, and 1,2,4,5-tetraoxanes. Two of these classes, the 1,2,4-trioxolanes (arterolaneand artefenomel) and the 1,2,4,5-tetraoxanes (N205 andE209) based antimalarials, have been explored extensively and are still in active development. In contrast, the most recent publication pertaining to the development of the 1,2-dioxane, Arteflene, and 1,2,4-trioxanes fenozan-50F, DU1301, and PA1103/SAR116242 was published in 2008. This review summarizes the synthesis, biological and clinical evaluation, and mechanistic studies of the most developed synthetic endoperoxide antimalarials, providing an update on those classes still in active development.

Enantioselective Synthesis and Profiling of Potent, Nonlinear Analogues of Antimalarial Tetraoxanes E209 and N205.

Synthetic endoperoxide antimalarials, such as 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes, are promising successors for current front-line antimalarials, semisynthetic artemisinin derivatives. However, limited solubility of second-generation analogues in biological-relevant media represents a barrier in clinical development. We present methodology for the synthesis of nonlinear analogues of second-generation tetraoxane antimalarials E209 and N205 to investigate reduced molecular symmetry on in vitro antimalarial activity and physicochemical properties. While maintaining good antimalarial activity and metabolic stability, head-to-head comparison of linear and nonlinear counterparts showed up to 10-fold improvement in FaSSIF solubility for three of the four analogues studied. Pharmacokinetic studies in rats comparing a selected nonlinear analogue 14a and its parent N205 showed improvement on oral absorption and exposure in vivo with more than double the AUC and a significant increase in oral bioavailability (76% versus 41%). These findings provide support for further in vivo efficacy studies in preclinical animal species.

AB0899-HPR THE IMPACT OF CORONAVIRUS (COVID-19) PANDEMIC ON THERAPEUTIC MAINTENANCE IN PATIENTS WITH CHRONIC INFLAMMATORY RHEUMATIC DISEASES

Background:The Coronavirus pandemic caused many consequences on well being, access to care and therapeutic maintenance in patients with chronic diseases.Objectives:To assess the impact of COVID-19 on therapeutic maintenance of patients with Chronic Inflammatory Rheumatic Diseases (CIRD) and to identify related factors to difficulties in access to rheumatologist care during the COVID-19 pandemic.Methods:A cross-sectional study was conducted among patients with rheumatic diseases using a questionnaire providing information on patients and disease characteristics, impact of COVID-19 on access to rheumatologist care and therapeutic maintenance during the confinement. Reasons of therapeutic interruption and of diificulties in access to healthcare were precised.Results:We received answers from 350 patients (female sex of 68%, mean age of 46,1 ± 14,4 years) suffering from Chronic Inflammatory Rheumatic Diseases (CIRD):rheumatic arthritis (RA) (62.3%), spondyloarthropathies (34.3%), and undifferentiated CIRD (3.4%). The global average disease evolution was 12,1 ± 9,7 years.The patients were treated with conventional Disease-modifying anti-rheumatic drugs (cDMARDs) and biologic Disease-modifying anti-rheumatic drugs (bDMARDs) in respectively 67.4% and 30.6% of cases. Corticosteroids and Nonsteroidal Anti-Inflammatories (NSAIDs) intake was noted in 39.1 and 33.7% of patients.Difficulties to access to rheumatologist care appointments were reported in 82.9% of the participants. Reasons of thoses difficulties are summurized in Figure 1.Figure 1.Causes of difficulties of access to Rheumatologist care during COVID-19 pandemic.Half of patients declared that the pandemic had affected their therapeutic compliance. Discontinued drugs were in decreasing order: Synthetic antimalarials (68.4%), NSAIDs (45.8%), Methotrexate (43.8%), bDMARDs (25.2%), Sulfasalazine (18.2%) and Corticosteroids (10,2%).Causes of treatments interruption are summarized in Table I.Table 1.Causes of treatments interuption in patients with CIRDDrugsNot found in pharmaciesThe pharmacy refuses to give me the treatment without a recent prescriptionTo avoid the decrease in immunity and therefore to avoid catching Covid-19I stopped the follow-up, and so I stopped the treatment...Other reasonsNSAIDS027.874.144.427.8Corticosteroids014.392.957.150Methotrexate70.1310.416.422.4Sulfasalazine012.52575100Synthetic antimalarial69.20023.161.5Leflunomide00000bDMARDs07.440.744.451.9Conclusion:The COVID-19 pandemic impacted heavly on therapeutic maintenance in CIRD patients in our country. Patients expressed many difficulties in access to appropiate management. Facing to all thoses consequences, we need to devolopp as soon as possible adequate solutions adapted in such health crisis, especially therapeutic education and telemedecine.Disclosure of Interests:None declared

Drug repurposing of dermatologic medications to treat coronavirus disease 2019: Science or fiction?

No pharmaceutical products have been demonstrated to be safe and effective to specifically treat coronavirus disease 2019 (COVID-19); therefore, the therapy administered to infected patients remains symptomatic and empiric. Alongside the development of new, often high-cost drugs, a different tactic is being applied in parallel, investigating long-established, inexpensive medications originally designed for a variety of diseases to study their potential in treating COVID-19.The skin is the largest organ of the human body. With more than 3,000 skin conditions identified, the specialty of dermatology offers a rich armamentarium of systemic therapeutic agents aimed to treat the various chronic immunologically mediated, metabolic, infectious, occupational, inherited, or paraneoplastic dermatoses. Dermatologists have extensive experience with many drugs that have demonstrated promising in vitro antiviral action (directly targeting the viral replication). Many of these drugs have been used as nonspecific immunosuppressive strategies, such as glucocorticoids, synthetic antimalarials, colchicine, or other immunomodulators, and a number of targeted therapeutics have been directed at controlling hyperinflammatory processes similar to the “cytokine storm” associated with COVID-19 infection. We discuss several dermatologic drugs that have already been used or may have a promising role in the treatment of COVID-19.

Acridine-Based Antimalarials-From the Very First Synthetic Antimalarial to Recent Developments.

Malaria is among the deadliest infectious diseases in the world caused by Plasmodium parasites. Due to the high complexity of the parasite’s life cycle, we partly depend on antimalarial drugs to fight this disease. However, the emergence of resistance, mainly by Plasmodium falciparum, has dethroned most of the antimalarials developed to date. Given recent reports of resistance to artemisinin combination therapies, first-line treatment currently recommended by the World Health Organization, in Western Cambodia and across the Greater Mekong sub-region, it seems very likely that artemisinin and its derivatives will follow the same path of other antimalarial drugs. Consequently, novel, safe and efficient antimalarial drugs are urgently needed. One fast and low-cost strategy to accelerate antimalarial development is by recycling classical pharmacophores. Quinacrine, an acridine-based compound and the first clinically tested synthetic antimalarial drug with potent blood schizonticide but serious side effects, has attracted attention due to its broad spectrum of biological activity. In this sense, the present review will focus on efforts made in the last 20 years for the development of more efficient, safer and affordable antimalarial compounds, through recycling the classical quinacrine drug.

Identification of bioactive molecule from Withania somnifera (Ashwagandha) as SARS-CoV-2 main protease inhibitor

SARS-CoV-2 is the causative agent of COVID-19 and has been declared as pandemic disease by World Health Organization. Lack of targeted therapeutics and vaccines for COVID-2019 have triggered the scientific community to develop new vaccines or drugs against this novel virus. Many synthetic compounds and antimalarial drugs are undergoing clinical trials. The traditional medical practitioners widely use Indian medicinal plant Withania somnifera (Ashwagandha) natural constituents, called withanolides for curing various diseases. The main protease (Mpro) of SARS-CoV-2 plays a vital role in disease propagation by processing the polyproteins which are required for its replication. Hence, it denotes a significant target for drug discovery. In the present study, we evaluate the potential of 40 natural chemical constituents of Ashwagandha to explore a possible inhibitor against main protease of SARS-CoV-2 by adopting the computational approach. The docking study revealed that four constituents of Ashwagandha; Withanoside II (-11.30 Kcal/mol), Withanoside IV (-11.02 Kcal/mol), Withanoside V (-8.96 Kcal/mol) and Sitoindoside IX (-8.37 Kcal/mol) exhibited the highest docking energy among the selected natural constituents. Further, MD simulation study of 100 ns predicts Withanoside V possess strong binding affinity and hydrogen-bonding interactions with the protein active site and indicates its stability in the active site. The binding free energy score also correlates with the highest score of −87.01 ± 5.01 Kcal/mol as compared to other selected compounds. In conclusion, our study suggests that Withanoside V in Ashwagandha may be serve as a potential inhibitor against Mpro of SARS-CoV-2 to combat COVID-19 and may have an antiviral effect on nCoV. Communicated by Ramaswamy H. Sarma

System-wide biochemical analysis reveals ozonide antimalarials initially act by disrupting Plasmodium falciparum haemoglobin digestion.

Ozonide antimalarials, OZ277 (arterolane) and OZ439 (artefenomel), are synthetic peroxide-based antimalarials with potent activity against the deadliest malaria parasite, Plasmodium falciparum. Here we used a “multi-omics” workflow, in combination with activity-based protein profiling (ABPP), to demonstrate that peroxide antimalarials initially target the haemoglobin (Hb) digestion pathway to kill malaria parasites. Time-dependent metabolomic profiling of ozonide-treated P. falciparum infected red blood cells revealed a rapid depletion of short Hb-derived peptides followed by subsequent alterations in lipid and nucleotide metabolism, while untargeted peptidomics showed accumulation of longer Hb-derived peptides. Quantitative proteomics and ABPP assays demonstrated that Hb-digesting proteases were increased in abundance and activity following treatment, respectively. Ozonide-induced depletion of short Hb-derived peptides was less extensive in a drug-treated K13-mutant artemisinin resistant parasite line (Cam3.IIR539T) than in the drug-treated isogenic sensitive strain (Cam3.IIrev), further confirming the association between ozonide activity and Hb catabolism. To demonstrate that compromised Hb catabolism may be a primary mechanism involved in ozonide antimalarial activity, we showed that parasites forced to rely solely on Hb digestion for amino acids became hypersensitive to short ozonide exposures. Quantitative proteomics analysis also revealed parasite proteins involved in translation and the ubiquitin-proteasome system were enriched following drug treatment, suggestive of the parasite engaging a stress response to mitigate ozonide-induced damage. Taken together, these data point to a mechanism of action involving initial impairment of Hb catabolism, and indicate that the parasite regulates protein turnover to manage ozonide-induced damage.

Effects of Anti-Malarial Drug, Hydroxychloroquine, on Glucose and Lipid Metabolism in Japanese Population

Background: Hydroxychloroquine (HCQ) is a synthetic anti-malarial drug and has been used for the treatment of rheumatic diseases. Recently, HCQ has been reported to improve lipid and glucose metabolism in patients with rheumatic diseases. However, effects of HCQ on lipid and glucose metabolism in Japanese remain unknown. Methods: We picked up patients who had been prescribed HCQ for 1 month or longer between September 2015 and August 2018. We compared the data at baseline and at 1 - 11 months after the start of HCQ. We excluded patients who discontinued to take HCQ due to adverse reaction, and patients who had taken daily more than 20 mg of prednisolone with HCQ. Results: We found 40 patients, and excluded nine patients who discontinued to take HCQ due to adverse reactions and five patients who had taken daily more than 20 mg of prednisolone in addition to HCQ, and we analyzed 26 patients. Twenty-two systemic lupus erythematosus (SLE) patients and 4 rheumatoid arthritis (RA) patients had been prescribed HCQ. Hemoglobin A1c (HbA1c) showed a significant decrease and tendency to decrease at 5 and 6 months after the start of HCQ, respectively. At other time points, HbA1c showed non-significant decrease. Serum triglyceride showed a significant decrease at 1, 3, 7, 8 and 11 months after the start of HCQ. At other time points, serum triglyceride showed non-significant decrease. Serum high-density lipoprotein-cholesterol (HDL-C) did not show any significant changes at every time point. Serum low-density lipoprotein-cholesterol (LDL-C) showed a significant decrease at 2 months after the start of HCQ and showed tendency to decrease after 7 and 10 months. At other time points, serum LDL-C showed non-significant decrease. Serum non-HDL-C showed a significant decrease at 2, 3 and 7 months after the start of HCQ and showed tendency to decrease after 1 and 5 months. At other time points, serum non-HDL-C showed non-significant decrease. Conclusion: HCQ was associated with reduction of HbA1c, serum triglyceride, LDL-C and non-HDL-C levels in SLE and RA patients. J Endocrinol Metab. 2019;9(5):159-164 doi: https://doi.org/10.14740/jem611

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.

High blood pressure and Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune systemic disease affecting young women and associated with high cardiovascular risk. Hypertension during SLE is more frequent than in the general population and occurs earlier. Its pathophysiology remains unclear. The purpose of our study is to report the clinical data of hypertensive patients with SLE. Our retrospective study included 24 patients with lupus and hypertension among 67 lupus patients hospitalized in the internal medicine department between 2011 and 2017. Our patients were 22 women and 2 men (mean age 46 years old). SLE had been evolving for an average of 12 years. Lupus nephropathy was present in 15 cases and 8 patients had renal failure. The treatment was based on steroids for all patients, 20 of them received synthetic antimalarial drugs, 18 patients had immune suppressors and 2 patients received a biotherapy. The average age of onset of hypertension was 37 years; 5 years after SLE diagnosis. Hypertension was essential in 8 cases, attributable to SLE in 14 cases, corticoid-induced in 17 cases and secondary to renal failure in 7 cases. A multiple origin was retained in half of the cases. Each patient had an average of 5 cardiovascular risk factors in addition to hypertension and SLE. Treatment relied primarily on angiotensin converting enzyme inhibitors, calcium channel blockers and beta-blockers. Monotherapy was used in 8 cases. A blood pressure control was obtained in 17 patients. Seven developed complications such as hypertensive heart disease ( n = 6) and retinopathy ( n = 3). Ten patients had atherosclerosis, 6 of whom had a cardiovascular complication. The average age of the latter group was 46 years. Hypertension during SLE is frequent and multifactorial. It is associated with accelerated atherosclerosis and a high risk of cardiovascular disease. A better understanding of the pathophysiology of hypertension during SLE would improve the prognosis.

CARDIOVASCULAR RISK FACTORS IN SYSTEMIC LUPUS ERYTHEMATOSUS WITH HYPERTENSION

Objective: Systemic lupus erythematosus (SLE) is a systemic disease that affects the young women with predilection. It is associated with a high cardiovascular risk related to atherosclerosis accelerated by different mechanisms, thus increasing morbidity and mortality during SLE. Design and method: This is a retrospective study of the 67 patients with SLE hospitalized at least once in the internal medicine department of Sahloul Hospital in Sousse between January 1st, 2011 and January 1st, 2017. Results: Twenty-four patients were found with hypertension: 22 women and 2 men. The occurrence of hypertension was on average 5.4 [0 - 21] years after of the diagnosis of SLE. The plausible etiology was attributable to SLE in 14 cases, corticoid-induced in 17 cases and secondary to renal failure in 7 cases. SLE has been evolving in our patients for an average of 12 years [3–28]. The occurrence after the age of 40 was noted in seven cases. Lupus nephropathy was present in 15 cases. Treatment was based on long-term corticosteroid therapy (n = 24), synthetic anti-malarials (n = 20), immuno-suppressants (n = 18), and biotherapy (n = 2). Eight patients were taking non-steroidal anti-inflammatory drugs for at least 3 years. Several other cardiovascular risk factors were found in this hypertensive population. Two patients were smoking. Seven were diabetic with an average evolution of 7.3 years. Obesity was noted in 12 patients. Dyslipidemia was found in 9 cases and hyper-homocysteinemia in 6 cases. A sedentary lifestyle was reported in 23 cases. Chronic renal failure was found in 7 patients. The number of cardiovascular risk factors was 4.9 [2 - 8] per patient. Ten patients had atherosclerosis. In 4 of them, it was documented by a carotid ultrasound imaging. The remaining six had ischemic heart disease (n = 5) and / or cerebrovascular accident (n = 3). Conclusions: SLE is associated with accelerated atherosclerosis and a high risk of developing cardiovascular disease in young patients, especially when associated with hypertension. A better understanding of the pathophysiology of hypertension during SLE would improve the prognosis.