Diacerein Research Articles

Diacerein-loaded surface modified iron oxide microparticles (SMIOMPs): an emerging magnetic system for management of osteoarthritis via intra-articular injection.

Osteoarthritis (OA) is regarded as one of the most prevealent irreversible joint degenerative disorder worldwide. Recently, considerable interest in utilizing intra-articular (IA) injections for managing OA has been raised. In this study, IA injectable surface modified iron oxide microparticles (SMIOMPs) loaded with Diacerein (DCN) were developed. The effects of formulation parameters on particle size, entrapment efficiency, and zeta potential were explored using factorial design. The optimized formulation was characterized regarding morphology and in vitro release. Differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR) were done to assess interactions. Further, sterilization and in vivo performance in rats with induced arthritis has been performed for the optimized formulation. The selected optimized system included 2M FeCL3 and 1% chitosan as a surface modifier achieved high drug entrapment of 85.25% with a PS of 1.54 µm and sustained DCN release. Morphological examination of the optimized formulation revealed spherical particles with chitosan coat. DSC and FTIR results indicated the absence of undesired interactions between DCN and the used components. No significant change in the measured parameters was observed following sterilization using gamma radiation. In vivo assessment revealed superior performance for the optimized formulation in reducing cartilage inflammation and degradation. Plasma levels of tumor necrosis factor α and Interleukin-1 beta, as well as knee diameter, were significantly reduced in the treated groups compared to the untreated ones. Overall, the results suggest that the proposed DCN-loaded SMIOMPs represent a promising advancement in the arena of cartilage regeneration.

Diacerein ameliorates amiodarone-induced pulmonary fibrosis via targeting the TGFβ1/α-SMA/Smad3 pathway.

This study is aimed at investigating the possible protective effect of diacerein (DIA) against AMD-induced pulmonary fibrosis in rats. Rats were classified into 4 groups: a normal group that received distilled water, control group that received AMD (100 mg/kg, p.o.) for 21 days to induce pulmonary fibrosis, and 2 treatment groups that received diacerein, in 2 dose levels (50 and 100 mg/kg, p.o., respectively) in addition to AMD (100 mg/kg, p.o.), for 21 days. Lung function test was assessed using a spirometer; serum and tissue were collected. Biochemical, real-time PCR, histopathological, and immunohistopathological analyses were carried out. AMD reduced tidal volume (TV), peripheral expiratory rate (PER), forced vital capacity (FVC), serum reduced glutathione (GSH) levels, Beclin, and LCII, while it elevated transform growth factor (TGF-β1) gene expression, serum malondialdehyde (MDA) level, alpha-smooth muscle actin (α-SMA), Smad3, phosphorylated signal transducer and activator of transcription (p-STAT3), and p62 lung content. Also, AMD elevated tumor necrosis factor-alpha (TNF-α) and caspase-3 protein expression. DIA elevated TV, PER, FVC, serum GSH level, Beclin, and LCII, while it reduced TGF-β1 gene expression, serum MDA level, α-SMA, Smad3, p-STAT-3, and p62 lung content. Moreover, DIA reduced TNF-α and caspase-3 protein expression. DIA attenuated AMD-induced pulmonary fibrosis via alleviating the TGF1/α-SMA/Smad3 pathway, reducing STAT-3 activation, and combating oxidative stress and inflammation in addition to promoting autophagy and abrogating apoptosis.

Diacerein mitigates endocrine and cardio-metabolic disruptions in experimental PCOS mice model by modulating AdipoR1/ PON 1

BackgroundThis study aimed to explore the impact of Diacerein (DIC) on endocrine and cardio-metabolic changes in polycystic ovarian syndrome (PCOS) mouse model.MethodsA total of 18 adult female mice (Parkes strain), aged 4–5 weeks, were randomly assigned to three groups, each comprising 6 animals, as follows: Group I (control), received normal diet and normal saline as vehicle for 51 days; Group II received Letrozole (LET; 6 mg/kg bw) for 21 days to induce PCOS; Group III received LET, followed by daily oral gavage administration of DIC (35 mg/kg bw) for 30 days.ResultsThis study indicates that treatment with LET resulted in PCOS with characteristics such as polycystic ovaries, elevated testosterone, weight gain, visceral adiposity, high levels of insulin as well as fasting blood glucose in addition to insulin resistance, improper handling of ovarian lipids, atherogenic dyslipidemia, impaired Na + /K + -ATPase activity and serum, cardiac, and ovarian oxidative stress. Serum/ovarian adiponectin levels were lowered in LET-treated mice. In mice treated with LET, we also discovered a reduction in cardiac and serum paraoxonase 1 (PON1). Interestingly, DIC restored ovarian andcardio-metabolic abnormalities in LET-induced PCOS mice. DIC prevented the endocrine and cardio-metabolic changes brought on by letrozole-induced PCOS in mice.ConclusionThe ameliorative effects of DIC on letrozole-induced PCOS with concurrent oxidative stress, abdominal fat deposition, cardiac and ovarian substrate mishandling, glucometabolic dysfunction, and adiponectin/PON1 activation support the idea that DIC perhaps, restore compromised endocrine and cardio-metabolic regulators in PCOS.

Uncovering the Cardioprotective Potential of Diacerein in Doxorubicin Cardiotoxicity: Mitigating Ferritinophagy-Mediated Ferroptosis via Upregulating NRF2/SLC7A11/GPX4 Axis.

Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a life-threatening clinical issue with limited preventive approaches, posing a substantial challenge to cancer survivors. The anthraquinone diacerein (DCN) exhibits significant anti-inflammatory, anti-proliferative, and antioxidant actions. Its beneficial effects on DIC have yet to be clarified. Therefore, this study investigated DCN's cardioprotective potency and its conceivable molecular targets against DIC. Twenty-eight Wister rats were assigned to CON, DOX, DCN-L/DOX, and DCN-H/DOX groups. Serum cardiac damage indices, iron assay, oxidative stress, inflammation, endoplasmic reticulum (ER) stress, apoptosis, ferritinophagy, and ferroptosis-related biomarkers were estimated. Nuclear factor E2-related factor 2 (NRF2) DNA-binding activity and phospho-p53 immunoreactivity were assessed. DCN administration effectively ameliorated DOX-induced cardiac cytomorphological abnormalities. Additionally, DCN profoundly combated the DOX-induced labile iron pool expansion alongside its consequent lethal lipid peroxide overproduction, whereas it counteracted ferritinophagy and enhanced iron storage. Indeed, DCN valuably reinforced the cardiomyocytes' resistance to ferroptosis, mainly by restoring the NRF2/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling axis. Furthermore, DCN abrogated the cardiac oxidative damage, inflammatory response, ER stress, and cardiomyocyte apoptosis elicited by DOX. In conclusion, for the first time, our findings validated DCN's cardioprotective potency against DIC based on its antioxidant, anti-inflammatory, anti-ferroptotic, and anti-apoptotic imprint, chiefly mediated by the NRF2/SLC7A11/GPX4 axis. Accordingly, DCN could represent a promising therapeutic avenue for patients under DOX-dependent chemotherapy.

Capped flexosomes for prominent anti-inflammatory activity: development, optimization, and ex vivo and in vivo assessments

This study aimed to formulate diacerein (DCN)-loaded flexosomes for enhanced efficacy against osteoarthritis. A 23 D-optimal design was employed, investigating the impact of surfactant type (A), surfactant concentration (%w/v) (B), and oleylamine amount (mg) (C). Flexosomes were formulated using a rotary evaporator, and Design-Expert® software was utilized to statistically analyze entrapment efficiency (EE%), zeta potential (ZP), poly-dispersity index (PDI), and particle size (PS) to determine the optimum formula. The selection criteria prioritized increased ZP (as absolute value) and EE%, coupled with decreased PDI and PS. Rigorous physicochemical, in vivo, and ex vivo tests were conducted to validate the safety, stability, and activity of the optimal formula. Physicochemical assessments encompassed pH measurement, transmission electron microscopy, differential scanning calorimetry, release profiles, storage effects, and Fourier transform infrared spectroscopy. In vivo tests included permeation studies, histopathology, anti-inflammatory activity, and skin irritancy, while ex vivo tests focused on permeation parameters and skin deposition. The optimum formula demonstrated high desirability (0.931), along with favorable EE% (90.93%), ZP (− 40.4 mV), particle size (188.55 nm), and sustained behavior. Notably, improved in vivo permeation (132 µm), skin deposition (193.43 µg/cm2), and antinociceptive activity (66%) compared to DCN suspension (48 µm, 66.31 µg/cm2, and 26%, respectively) were observed. The optimal formula also exhibited excellent safety and storage characteristics. In conclusion, DCN-loaded flexosomes exhibit significant potential for effectively managing osteoarthritis.Graphical

Cardioprotective role of diacerein in diabetic cardiomyopathy via modulation of inflammasome/caspase1/interleukin1β pathway in juvenile rats

Diabetes mellitus is a common metabolic disorder affecting different body organs; one of its serious complications is diabetic cardiomyopathy (DCM). Thus, finding more cardiopreserving agents to protect the heart against such illness is a critical task. For the first time, we planned to study the suspected role of diacerein (DIA) in ameliorating DCM in juvenile rats and explore different mechanisms mediating its effect including inflammasome/caspase1/interleukin1β pathway. Four-week-aged juvenile rats were randomly divided into groups; the control group, diacerein group, diabetic group, and diabetic-treated group. Streptozotocin (45 mg/kg) single intraperitoneal (i.p.) dose was administered for induction of type 1 diabetes on the 1st day which was confirmed by detecting blood glucose level. DIA was given in a dose of 50 mg/kg/day for 6 weeks to diabetic and non-diabetic rats, then we evaluated different inflammatory, apoptotic, and oxidative stress parameters. Induction of DCM succeeded as there were significant increases in cardiac enzymes, heart weights, fasting blood glucose level (FBG), and glycosylated hemoglobin (HbA1c) associated with elevated blood pressure (BP), histopathological changes, and increased caspase 3 immunoexpression. Furthermore, there was an increase of malondialdehyde (MDA), inflammasome, caspase1, angiotensin II, nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNFα), and interleukin 1β (IL1β). However, antioxidant parameters such as reduced glutathione (GSH) and total antioxidant capacity (TAC) significantly declined. Fortunately, DIA reversed the diabetic cardiomyopathy changes mostly due to the observed anti-inflammatory, antioxidant, and anti-apoptotic properties with regulation of blood glucose level.DIA has an ability to regulate DCM-associated biochemical and histopathological disturbances.

Role of Nrf2/HO-1, PPAR-γ, and cytoglobin signals in the pathogenesis of methotrexate-induced testicular intoxication in rats and the protective effect of diacerein.

Methotrexate (MTX) is an inhibitor of folic acid reductase used in managing a variety of malignancies. Testicular injury by MTX is one of its serious adverse effects. The current investigation aims to assess the protective effects of diacerein (DIA) on testicular injury by MTX and clarify the possible underlying mechanisms. Testicular injury in rats was induced by a single injection of 20mg/kg body weight of MTX. DIA was given in 25mg/kg body weight/day and 50mg/kg body weight/day doses for 10days. Compared to the MTX group, DIA attenuated testicular intoxication as evidenced by improvement of testicular histopathological abnormalities and increased serum testosterone and luteinizing hormone. DIA attenuated testicular oxidative stress changes by lowering testicular MDA and boosting GSH content and SOD activity. Moreover, administration of DIA attenuated MTX-induced testicular inflammation, as proved by decreased TNF-α and IL-6. At the molecular level, DIA induced significant upregulation in Nrf2, HO-1, PPAR-γ, and cytoglobin protein expression. The present results proved that DIA, in a dose-dependent manner, exhibited notable amelioration of testicular toxicity induced by MTX through augmentation of anti-inflammatory and antioxidant effects combined by upregulating Nrf2/HO-1, PPAR-γ, and cytoglobin signaling.

Diacerein provokes apoptosis, improves redox balance, and downregulates PCNA and TNF-α in a rat model of testosterone-induced benign prostatic hyperplasia: A new non-invasive approach.

One of the most prevalent chronic conditions affecting older men is benign prostatic hyperplasia (BPH), causing severe annoyance and embarrassment to patients. The pathogenesis of BPH has been connected to epithelial proliferation, inflammation, deranged redox balance, and apoptosis. Diacerein (DIA), the anthraquinone derivative, is a non-steroidal anti-inflammatory drug. This study intended to investigate the ameliorative effect of DIA on the prostatic histology in testosterone-induced BPH in rats. BPH was experimentally induced by daily subcutaneous injection of testosterone propionate for four weeks. The treated group received DIA daily for a further two weeks after induction of BPH. Rats' body and prostate weights, serum-free testosterone, dihydrotestosterone, and PSA were evaluated. Prostatic tissue was processed for measuring redox balance and histopathological examination. The BPH group had increased body and prostate weights, serum testosterone, dihydrotestosterone, PSA, and oxidative stress. Histologically, there were marked acinar epithelial and stromal hyperplasia, inflammatory infiltrates, and increased collagen deposition. An immunohistochemical study showed an increase in the inflammatory TNF-α and the proliferative PCNA markers. Treatment with DIA markedly decreased the prostate weight and plasma hormones, improved tissue redox balance, repaired the histological changes, and increased the proapoptotic caspase 3 expression besides the substantial reduction in TNF-α and PCNA expression. In conclusion, our study underscored DIA's potential to alleviate the prostatic hyperplastic and inflammatory changes in BPH through its antioxidant, anti-inflammatory, antiproliferative, and apoptosis-inducing effects, rendering it an effective, innovative treatment for BPH.

Diacerein Loaded Novasome for Transdermal Delivery: Prepartion , In-Vitro Characterization and Factors Affecting Formulation

Diacerein (DCN) is a semi-synthetic anthraquinone derivative of Rhein that is indicated for the management of osteoarthritis. Diacerein exhibits poor dissolution in the GIT fluids and suffers from low bioavailability upon oral administration in addition to the laxative effect of Rhein metabolites. The aim of the present study was to develop novasomal vesicles with optimized entrapment efficiency and size to serve as a carrier for transdermal delivery of diacerein. Novasomal vesicles were prepared by thin film hydration method thin film hydration. The prepared vesicles were optimized utilizing different surfactant to cholesterol molar ration, sonication type, different sonication times and varying fatty acid level. The prepared vesicles were characterized for drug entrapment efficiency, vesicle size and PDI. The best formula was further investigated for zeta potential ten TEM and compatibility study by FTIR analysis. Results showed that F6 was the best formula regarding it vesicle size 275.2± 2.68nm , entrapment efficiency 69.415± 0.234 % and PDI 0.309± 0.016. In conclusion , novasomal dispersion could be successfully formulated with thin film hydration method. Keywords: Diacerein , Novasome , Transdermal Delivery ,Vesicular System .

Evaluation of Diacerein Efficacy on Colitis as Anti-inflammatory and Anti-oxidant and its Role in Enhancing of Colon Barrier in Mice

Ulcerative colitis (UC) is a prevalent disorder characterized by oxidative stress and the release of pro-inflammatory cytokines that disturb the colonic mucosa. Currently, available medicines for UC remain unsatisfactory. Diacerein (DIAC) has exhibited anti-oxidant and anti-inflammatory properties in wide inflammatory disorders. However, the limited understanding of DIAC's role in bowel inflammation has necessitated the investigation of its efficacy in dextran sodium sulfate (DSS)-induced UC in Balb/c mice in this study. Fifty mice were equally divided into five groups. Except for the control, all groups were given DSS for seven days to induce the colitis model. The model was treated with 25 and 50mg/kg/day of DIAC and 00mg/kg/day of 5-aminosalicylic acid (5-ASA) for ten days. Several clinical, molecular and biochemical parameters were evaluated. Following the exposure to DSS, there was a significant upregulation in the pro-inflammatory cytokines (IL-1β, IL-6, IL-17 and TNF-α) and oxidative stress index (MDA). Meanwhile, the concentration of anti-oxidative stress indices (SOD, GPx and CAT) and the levels of IL-10, mucin-1 and 2 and tight junction proteins (TJs) ZO-1 and occludin were markedly suppressed. The colon length and body weight were reduced while DAI and myeloperoxidase (MPO) were elevated. Conversely, DIAC 50mg and 5-ASA significantly reversed the altered pro-inflammatory cytokines, oxidative stress and MPO. Moreover, they significantly restored body weight, colon length, DAI, TJs, mucin-1 and 2 and IL-10. No significant results were found with DIAC 25mg. In conclusion, DIAC exhibited therapeutic effectiveness against colitis. This research may provide hope for testing its effectiveness against UC in humans

Rhein methotrexate-decorated solid lipid nanoparticles altering adjuvant arthritis progression through endoplasmic reticulum stress-mediated apoptosis

Methotrexate (MTX) and diacerein (DIA) are two of the most potent disease-modifying anti-rheumatic drugs used for the treatment of rheumatoid arthritis (RA). DIA has reflected some GIT and hepatobiliary manifestations in numerous cases. It undergoes biotransformation in the liver into the active metabolite rhein (RH) which is characterized by its excellent anti-inflammatory activity and lower side effects. However, RH's hydrophobic nature and low bioavailability do not encourage its use in RA. The current study aims to use RH in combination with MTX in targeted solid lipid nanoparticles (RH-MTX-SLNs) for better effectiveness and shadowing light on its possible mechanistic pathways. RH-MTX-SLNs were prepared and assessed for their quality attributes. The effect of the formulation was assessed in-vivo in an adjuvant arthritis animal model investigating the role of the endoplasmic reticulum stress (ERS)-induced apoptosis. Results revealed that RH-MTX-SLNs were in the suitable nanosized range with high negative zeta potential indicating good stability. In-vivo, RH-MTX-SLNs significantly improved all measured inflammatory and arthritic markers, confirmed by electron microscopy and histology examination of the joints. Besides, the formulation was able to alter the ERS-mediated apoptosis. In conclusion, RH-MTX-SLNs can represent a promising therapeutic approach for RA showing significant anti-arthritic activity.Graphical abstract

Sustainable multi-analyte HPTLC estimation of meloxicam, diclofenac and diacerein along with its major degradation product and official impurity; rhein: Comprehensive greenness and whiteness evaluation

A sustainable HPTLC method has been developed for the simultaneous determination of Meloxicam (MLX), Diclofenac (DCF) with Diacerein (DCN), and its pharmacopoeial impurity and main degradation product, Rhein (RIN). Reviewing the literature revealed that no HPTLC method has been reported for the simultaneous determination of the three cited drugs along with RIN. Merck TLC plates precoated with 60F 254 silica gel on aluminium sheet were used as stationary phase and were developed with a green mobile phase composed of ethyl acetate: ethanol: water (9.5: 1: 0.5 v/v/v respectively). Densitometric scanning was performed at 259 nm for DCN and RIN, while MLX and DCF were detected at 360 nm and 281 nm, respectively. The proposed method was validated according to the ICH guidelines regarding linearity, range, accuracy, precision, specificity, and robustness. Additionally, the environmental impact of the developed method was assessed using the analytical eco-scale (AES), the green analytical procedure index (GAPI) and the Analytical GREEnness calculator (AGREE). Moreover, the method’s sustainability was evaluated and compared with previously published methods using the novel RGB 12 model in terms of the 12 white analytical chemistry (WAC) perspectives. Finally, successful application of the proposed method was carried out for the estimation of the cited compounds in their combined formulations as well as for the detection and quantification of DCN impurity; RIN, at concentrations below its pharmacopoeial limit. The present study represents the first sustainable and economic HPTLC separation and determination of the four cited compounds simultaneously as well as a sensitive method for testing the purity of DCN in bulk form and combined formulations.

Development of solid lipid nanoparticles of diacerein in a stable oral liquid dosage form using a central composite design

Diacerein (DCN) is used mainly to treat degenerative diseases, such as osteoarthritis. DCN is marketed commercially in solid dosage forms. Liquid formulations of diacerein (DCN) have been hindered by its poor chemical stability in aqueous media. This work aims to develop a novel, stable, oral, liquid preparation of DCN having a concentration of 50 mg/5 ml. Solid lipid nanoparticles (SLNs) of DCN were prepared using cetyl alcohol as the lipid matrix and Tween 80® as a surfactant. A quality-by-design approach was utilized to optimize DCN-SLNs. The optimum DCN-SLNs were dispersed in a structured vehicle to formulate the liquid dosage form. This liquid preparation was subjected to accelerated stability studies at 40 °C and 75% RH for 6 months. The potential of the liquid preparation to minimize the diarrheal effect of DCN was assessed. Optimum concentrations of cetyl alcohol (2%) and Tween 80® (0.9%) were chosen to obtain the desired characteristics of SLNs. Interestingly, we determined that 0.05% of citric acid was the maximum concentration that can be added to the liquid preparation of diacerein to modify its pH without compromising its stability. The results of the stability studies show that the liquid preparation was robust and it withstood storage conditions (40 °C, 75% RH) for 6 months. The encapsulation of diacerein helps to protect it from degradation and significantly reduced the occurrence of diarrhea as a side effect (p < 0.0001). Liquid preparations of DCN-SLNs can thus be marketed as a new dosage form.

Diacerein modulates TLR4/ NF-κB/IL-1β and TRPC1/CHOP signalling pathways in gentamicin-induced parotid toxicity in rats.

The present study aimed to identify the possible protective effect of diacerein (DIA) on gentamicin (GNT)-induced parotid toxicity in rats. DIA was administered in the presence and absence of GNT. Thirty-two Wistar adult male rats were randomly arranged into four groups: control, DIA (50 mg/kg/day), GNT (100 mg/kg) and GNT+DIA groups for 8 days. Parotid oxidative stress parameters, besides inflammatory and apoptotic biomarkers, were evaluated. Salivary flow rate, transient receptor potential canonical 1 (TRCP1), and C/EBP homologous protein (CHOP) in parotid tissue were measured. A parotid histopathological examination and an interleukin-1 beta (IL-1β) immunohistochemical study were also performed. GNT significantly increased parotid oxidative stress, inflammatory, apoptotic and CHOP biomarkers with decreased salivary flow rate and TRCP1 level. A histopathological picture of parotid damage and high IL-1β immunoexpression were detected. DIA significantly normalized the distributed oxidative, inflammatory and apoptotic indicators, CHOP and TRCP1, with a prompt improvement in the histopathological picture and a decrease in IL-1β immunoexpression. These results reported that DIA protects against GNT-induced parotid toxicity via modulation of TLR4/NF-κB/IL-1β and TRPC1/CHOP signalling pathways.

A New Stability-Indicating RP-HPLC Method for Simultaneous Quantification of Diacerein and Aceclofenac in Novel Nanoemulgel Formulation and Commercial Tablet Dosage Form in the Presence of their Major Degradation Products Using DoE Approach.

The present study aimed to develop a simple, robust, sensitive and effective stability-indicating reversed-phase high-performance liquid chromatography method for simultaneous quantification of diacerein (DCN) and aceclofenac (ACE) in novel nanoemulgel formulation and commercial tablets in the presence of their main degradation product: rhein (RH) and diclofenac sodium (DLS), respectively. A fractional factorial design was used to screen the crucial independent factors, whereas a central composite design was used for the optimization of the chromatographic conditions. The separation was carried out on Phenomenex C18 column (5μm, 250 × 4.6mm), using a mobile phase consisting of phosphate buffer pH3 (0.1% v/v orthophosphoric acid) and acetonitrile (40:60v/v) at a flow rate of 1mL/min with detection at 264nm. The analytes were exposed to a variety of stress conditions, including heat, alkali, acid, oxidation, photochemical, humidity and hydrolysis. DCN, ACE, RH and DLS were found to have retention times of 4.32 ± 0.15, 5.77 ± 0.07, 8.28 ± 0.20 and 9.10 ± 0.18min, respectively. The percent recovery for all four analytes was found to be between 98 and 102, and the procedure was discovered to be linear in the range of 0.1-64μg/mL with R2 value > 0.999. The established method was validated as per ICH guidelines and successfully used to assay DCN and ACE in their combined marketed tablet dosage form and developed nanoemulgel formulation.

Role of diacerein on steroidogenesis and folliculogenesis related genes in ovary of letrozole-induced PCOS mice

Polycystic ovary syndrome (PCOS), an intricate and multifaceted metabolic-endocrine disorder that typically affects 6–20% of women of reproductive age and accounts for 70–80% of all occurrences of infertility globally. In this study we focussed on the effect of diacerein (DIC) on steroidogenesis and follicle development in addition to the basic metabolic and endocrine problems which are associated with PCOS. Eighteen mature female parkes strain mice were separated into three groups at random with 6 animals in a group as follows: Group I, received water and normal diet for 66 days; group II received letrozole (LETZ) (6 mg/kg bw) for the induction of PCOS; Group III received LETZ (6 mg/kg) for 3 weeks followed by the administration of DIC (35 mg/kg) for 45 days. In our study we observed that mice with PCOS had irregular estrous cycle with increased LH/FSH, estrogen level and decline in expression of Kitl, Bmp, Cyp11a1, CYP19a1, Ar, lhr, Fshr and Esr1 as well as decreased SOD and CAT activity in ovary. Moreover, we observed increase in the expression of CYP17a1, as well as increase in serum cholesterol, triglycerides, testosterone, LH, VEGF and insulin levels. All these changes were reversed after the administration of DIC in PCOS mice. Diacerin administration reversed abnormalities in mice with PCOS by modulating the regulation of genes which are related to steroidogenesis and folliculogenesis.

Diacerein Mitigates Renal Ischemia/Reperfusion Injury via Inhibition of Renal Inflammation, Dendritic Cells Maturation and Apoptosis: The Role of TLR4/NF-kB/NLRP3/IL-1&amp;#946; Signaling Pathway

One of the reasons for acute kidney damage is renal ischemia. Nevertheless, there are limited protective and therapeutic approaches for this problem. Diacerein is an anti-inflammatory drug characterized by numerous biological activities. We aimed to determine the ameliorative impact of diacerein on renal ischemia/reperfusion injury (I/R) condition, exploring the underlying mechanisms. Twenty-four male rats were allotted into four groups (n= 6): sham group; Diacerein (DIA) group; I/R group, in which a non-crushing clamp occluded the left renal pedicle for 45 min, and the right kidney was nephrectomized for 5 min before the reperfusion process; I/R + diacerein group, injected intraperitoneally with 50 mg diacerein/kg i.m 30 minutes prior to I/R operation. Ischemia/ reperfusion was found to affect renal function and induce histopathological alterations. The flow cytometry analysis demonstrated an elevated expression of innate and mature dendritic cells in I/R renal tissues. Moreover, upregulation in the expression of the inflammatory genes (TLR4, Myd88, and NLRP3), and overexpression of the pro-inflammatory cytokines (IL-1β), apoptotic (caspase-3) and pyroptotic (caspase-1) markers were observed in I/R-experienced animals. The aforementioned deteriorations were mitigated by pre-I/R diacerein treatment. Diacerein alleviated I/R-induced inflammation and apoptosis. Thus, it could be a promising protective agent against I/R.

Drug repositioning: diacerein as a new therapeutic approach in a mice model of sciatic nerve injury.

Peripheral nerve injuries negatively impact the quality of life of patients, with no effective treatment available that accelerates sensorimotor recovery and promotes functional improvement and pain relief. The aim of this study was to evaluate the effects of diacerein (DIA) in an experimental mice model of sciatic nerve crush. In this study, male Swiss mice were used, randomly separated into six groups as follows: FO (false-operated + vehicle); FO + DIA (false-operated + diacerein 30mg/kg); SNI (sciatic nerve injury + vehicle); SNI + DIA in doses of 3, 10 and 30mg/kg (sciatic nerve injury + treatment with diacerein in doses of 3-30mg/kg). DIA or vehicle was administered 24h after the surgical procedure, intragastrically, twice a day. The lesion of the right sciatic nerve was generated by crush. We found that the treatment of animals with DIA accelerated sensorimotor recovery of the animal. In addition, animals in the sciatic nerve injury + vehicle (SNI) group showed hopelessness, anhedonia, and lack of well-being, which were significantly inhibited by DIA treatment. The SNI group showed a reduction in the diameters of nerve fibers, axons, and myelin sheaths, while DIA treatment recovered all these parameters. In addition, the treatment of animals with DIA prevented an increase the levels of interleukin (IL)-1β and a reduction in the levels of the brain-derived growth factor (BDNF). Treatment with DIA reduces hypersensitivity and depression like behaviors in animals. Furthermore, DIA promotes functional recovery and regulates IL-1β and BDNF concentrations.

Assessment of formulation variables of poor water soluble diacerein for its improved loading and anti-inflammatory activity.

Dissolving microneedles have become a popular method for percutaneous administrationof drugs. However, loading poorly soluble drugs into water-based dissolving microneedles remains a challenge. In view of this, we aimed to improve Diacerein (DCN) solubility formulating dissolving microneedles. DCN microsuspension was created by high-speed homogenization with organic solvents or wet milling with Tween 80 as a stabilizer (LD1). They were analyzed for particle size and saturation solubility. Subsequently, the organic solvent-based microneedles were prepared under vacuum, whereas LD1 was mixed with HPMC (8% w/w) and PVP (30% w/w) matrix to concentrate the drug in acral fraction through centrifugation. DCN microsuspension in DMSO had the highest drug solubility with an average particle size of 6 µm, whereas LD1 had a particle size of 3.28 µm showing improved solubility. TD-3 had the highest drug loading and the least amount of drug migration into the blank baseplate. Within 5 min, these microneedles dissolved completely in an agarose-gel block. LD1 was likewise put in the baseplate to generate TD3-B. Within 24 h, 74.39% of the medication was released from TD3-B, with only a small amount remaining in the baseplate. TLC examination indicated the conversion of DCN to Rhein in the skin, whereas DSC and TGA studies revealed amorphous features. DCN microneedles showed no sign of skin irritancy but showed anti-inflammatory response on carrageenan-induced paw edema model. Microneedles remained stable during accelerated stability testing. Wet milling in the presence of a stabilizer can be an effective approach for enhancing DCN solubility for improved drug loading in dissolving microneedles. Improvement in solubility of Diacerein for subsequent loading in Dissolving Microneedle for percutaneous delivery.

Betaine- and L-Carnitine-Based Ionic Liquids as Solubilising and Stabilising Agents for the Formulation of Antimicrobial Eye Drops Containing Diacerein.

The therapeutic efficacy of topically administered drugs, however powerful, is largely affected by their bioavailability and, thus, ultimately, on their aqueous solubility and stability. The aim of this study was to evaluate the use of ionic liquids (ILs) as functional excipients to solubilise, stabilise, and prolong the ocular residence time of diacerein (DIA) in eye drop formulations. DIA is a poorly soluble and unstable anthraquinone prodrug, rapidly hydrolysed to rhein (Rhe), for the treatment of osteoarthritis. DIA has recently been evaluated as an antimicrobial agent for bacterial keratitis. Two ILs based on natural zwitterionic compounds were investigated: L-carnitine C6 alkyl ester bromide (Carn6), and betaine C6 alkyl ester bromide (Bet6). The stabilising, solubilising, and mucoadhesive properties of ILs were investigated, as well as their cytotoxicity to the murine fibroblast BALB/3T3 clone A31 cell line. Two IL-DIA-based eye drop formulations were prepared, and their efficacy against both Staphylococcus aureus and Pseudomonas aeruginosa was determined. Finally, the eye drops were administered in vivo on New Zealand albino rabbits, testing their tolerability as well as their elimination and degradation kinetics. Both Bet6 and Carn6 have good potential as functional excipients, showing solubilising, stabilising, mucoadhesive, and antimicrobial properties; their in vitro cytotoxicity and in vivo ocular tolerability pave the way for their future use in ophthalmic applications.