Oral Psoriasis Therapies.

Oral psoriasis therapies include both older traditional immunosuppressants, such as methotrexate, cyclosporine, and acitretin, as well as newer, more targeted agents, such as apremilast, deucravacitinib, and oral interleukin-23 receptor antagonists. Patients may prefer oral therapies to injectable therapies based on the route of administration. Both older and newer oral psoriasis therapies can be utilized effectively in the treatment of psoriasis. Here, we will review oral agents used in the treatment of psoriasis as well as provide commentary on their role in our current, evolving psoriasis treatment paradigm.

Impact of P-gp inhibition on systemic exposure of pralsetinib and dosing considerations.

A study to determine the impact of cyclosporine (Neoral), an inhibitor of P-gp, on the pharmacokinetics of pralsetinib (trade name GAVRETO®) was conducted in 15 healthy adult volunteers. A single 200 mg dose of pralsetinib was administered orally alone and in combination with cyclosporine with a 9-day washout between treatments. Co-administration with cyclosporine resulted in a clinically relevant increase in pralsetinib maximum plasma concentration (Cmax) and area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞) with associated geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of 148% (109, 201) and 181% (136, 241), respectively. These findings provide insight into concomitant dosing of pralsetinib with inhibitors of P-gp given the increases in pralsetinib exposure observed when administered with cyclosporine. Based on these results, co-administration of pralsetinib with P-gp inhibitors is not recommended. In the event that co-administration cannot be avoided, it is recommended that the dose of pralsetinib be reduced.

[The place of ciclosporin A cationic emulsion 0.1% in the therapy of xerophthalmia]. / Mesto kationnoi emul'sii tsiklosporina A 0,1% v terapii kseroftal'mii.

Dry eye disease (DED) is pathogenetically based on inflammation of the ocular surface. A step-by-step approach to DED treatment involves early initiation of anti-inflammatory therapy, including instillation of cyclosporine A (CsA). However, recommendations for the use of topical CsA in clinical practice are limited. This article presents an expert consensus on practical recommendations for the management of patients with DED, including indications, time of initiation and duration of CsA therapy, comparison of CsA forms currently registered in the Russian Federation, as well as issues of patient education.

Association Between FEV1 Decline Rate and Mortality in Long-Term Follow-Up of a 21-Patient Pilot Clinical Trial of Inhaled Liposomal Cyclosporine Plus Standard-of-Care Versus Standard-of-Care Alone for Bronchiolitis Obliterans Syndrome After Lung Transplantation.

BACKGROUND The association between forced expiratory volume in 1 second (FEV1) trajectory and mortality in bronchiolitis obliterans syndrome (BOS) is not well defined. Using long-term data from a prior clinical trial of inhaled liposomal cyclosporine A (L-CsA-I) for lung transplant patients with BOS, this study examined the association between longitudinal FEV1 change and mortality. MATERIAL AND METHODS We analyzed long-term data from a clinical trial which randomized 21 patients with BOS (³20% decrease in FEV1 from personal maximum) to receive L-CsA-I plus standard-of-care (n=11) or standard-of-care (SOC) alone (n=10) for 24 weeks. A joint statistical model, combining a linear mixed model for FEV1 change and Cox regression for mortality, was utilized to examine the overall association between FEV1 trajectory and mortality during follow-up. RESULTS The 21 trial participants (10 single, 11 double lung recipients) had a mean FEV1 of 1.7±0.6 Liters at randomization. Median follow-up post-randomization was 35 months. In joint model analysis, 1 percent FEV1 decline predicted 1.076-fold increased mortality risk (95% confidence interval: -0.998 to 1.160, p=0.058). FEV1 decline was reduced by 2.6% per year in L-CsA-I patients compared to SOC (p=0.210), and overall survival at 1/3/5 years was 91%/64%/27% vs 90%/20%/0% for L-CsA-I versus SOC, respectively (p=0.164). CONCLUSIONS In BOS patients, greater longitudinal FEV1 decline predicts increased mortality. Trends towards prolonged stabilization of FEV1 and improved survival were observed with L-CsA-I receipt. Further analyses will aid in evaluating the utility of FEV1 change as a survival predictor, having implications in BOS management and future trial design.

Combination of PEGylation and Cationization on Phospholipid-Coated Cyclosporine Nanosuspensions for Enhanced Ocular Drug Delivery.

Strong precorneal clearance mechanisms including reflex blink, constant tear drainage, and rapid mucus turnover constitute great challenges for eye drops for effective drug delivery to the ocular epithelium. In this study, cyclosporine A (CsA) for the treatment of dry eye disease (DED) was selected as the model drug. Two strategies, PEGylation for mucus penetration and cationization for potent cellular uptake, were combined to construct a novel CsA nanosuspension (NS@lipid-PEG/CKC) by coating nanoscale drug particles with a mixture of lipids, DSPE-PEG2000, and a cationic surfactant, cetalkonium chloride (CKC). NS@lipid-PEG/CKC with the mean size ∼173 nm and positive zeta potential ∼+40 mV showed promoted mucus penetration, good cytocompatibility, more cellular uptake, and prolonged precorneal retention without obvious ocular irritation. More importantly, NS@lipid-PEG/CKC recovered tear production and goblet cell density more efficiently than the commercial cationic nanoemulsion on a dry eye disease rat model. All results indicated that a combination of PEGylation and cationization might provide a promising strategy to coordinate mucus penetration and cellular uptake for enhanced drug delivery to the ocular epithelium for nanomedicine-based eye drops.

A sterilizable platform based on crosslinked xanthan gum for controlled-release of polymeric micelles: Ocular application for the delivery of neuroprotective compounds to the posterior eye segment.

TPGS (D-α-tocopheryl polyethylene glycol 1000 succinate) polymeric micelles show interesting properties for ocular administration thanks to their solubilization capability, nanometric size and tissue penetration ability. However, micelles formulations are generally characterized by low viscosity, poor adhesion and very short retention time at the administration site. Therefore, the idea behind this work is the preparation and characterization of a crosslinked film based on xanthan gum that contains TPGS micelles and is capable of controlling their release. The system was loaded with melatonin and cyclosporin A, neuroprotective compounds to be delivered to the posterior eye segment. Citric acid and heating at different times and temperatures were exploited as crosslinking approach, giving the possibility to tune swelling, micelles release and drug release. The biocompatibility of the platform was confirmed by HET-CAM assay. Ex vivo studies on isolated porcine ocular tissues, conducted using Franz cells and two-photon microscopy, demonstrated the potential of the xanthan gum-based platform and enlightened micelles penetration mechanism. Finally, the sterilization step was approached, and a process to simultaneously crosslink and sterilize the platform was developed.

Silk Fibroin Formed Bioadhesive Ophthalmic Gel for Dry Eye Syndrome Treatment.

PURPOSE: Dry eye syndrome (DES), arising from various etiologic factors, leads to tear film instability and ocular surface damage. Given its anti-inflammatory effects, cyclosporine A (CsA) has been widely used as a short-term treatment option for DES. However, poor bioavailability and solubility of CsA in aqueous phase make the development of a cyclosporine A-based eye drop for ocular topical application a huge challenge. METHODS: In this study, a novel strategy for preparing cyclosporine A-loaded silk fibroin nanoemulsion gel (CsA NBGs) was proposed to address these barriers. Additionally, the rheological properties, ocular irritation potential, tear elimination kinetics, and pharmacodynamics based on a rabbit dry eye model were investigated for the prepared CsA NBGs. Furthermore, the transcorneal mechanism across the ocular barrier was also investigated. RESULTS: The pharmacodynamics and pharmacokinetics of CsA NBGs exhibited superior performance compared to cyclosporine eye drops, leading to a significant enhancement in the bioavailability of CsA NBGs. Furthermore, our investigation into the transcorneal mechanism of CsA NBGs revealed their ability to be absorbed by corneal epithelial cells via the paracellular pathway. CONCLUSION: The CsA NBG formulation exhibits promising potential for intraocular drug delivery, enabling safe, effective, and controlled administration of hydrophobic drugs into the eye. Moreover, it enhances drug retention within the ocular tissues and improves systemic bioavailability, thereby demonstrating significant clinical translational prospects.

Nanoceria-Mediated Cyclosporin A Delivery for Dry Eye Disease Management through Modulating Immune-Epithelial Crosstalk.

Dry eye disease (DED) affects a substantial worldwide population with increasing frequency. Current single-targeting DED management is severely hindered by the existence of an oxidative stress-inflammation vicious cycle and complicated intercellular crosstalk within the ocular microenvironment. Here, a nanozyme-based eye drop, namely nanoceria loading cyclosporin A (Cs@P/CeO2), is developed, which possesses long-term antioxidative and anti-inflammatory capacities due to its regenerative antioxidative activity and sustained release of cyclosporin A (CsA). In vitro studies showed that the dual-functional Cs@P/CeO2 not only inhibits cellular reactive oxygen species production, sequentially maintaining mitochondrial integrity, but also downregulates inflammatory processes and repolarizes macrophages. Moreover, using flow cytometric and single-cell sequencing data, the in vivo therapeutic effect of Cs@P/CeO2 was systemically demonstrated, which rebalances the immune-epithelial communication in the corneal microenvironment with less inflammatory macrophage polarization, restrained oxidative stress, and enhanced epithelium regeneration. Collectively, our data proved that the antioxidative and anti-inflammatory Cs@P/CeO2 may provide therapeutic insights into DED management.

Efficacy of a new water-free topical cyclosporine 0.1% solution for optimizing the ocular surface in patients with dry eye and cataract.

This is a pooled analysis from 2 phase III clinical trials investigating a water-free topical cyclosporine 0.1% for the treatment of moderate to severe dry eye. The analyses included 1162 patients: 35% with cataract, 20% with pseudophakia, and 45% without cataract. Demographics or baseline characteristics were comparable across groups except for age and vision. The cyclosporine-treated patients achieved large mean improvements from baseline by day 15: -3.7 in patients without cataract, -3.2 in patients with cataract, and -3.1 in pseudophakic patients. These improvements were statistically significantly higher compared with the respective vehicle groups. In the cataract subgroup, 59% of patients treated with cyclosporine achieved ≥3 grade improvements in corneal staining score, as early as day 15. The magnitude of the effect and early onset of action make this new cyclosporine solution a promising candidate for preoperative management of ocular surface in patients undergoing cataract surgery.

Rhabdomyolysis and acute kidney injury potentiated by a drug-drug interaction between cyclosporine, leflunomide, and rosuvastatin in a kidney transplant recipient: A missed opportunity for pharmacist involvement.

BACKGROUND: This study aimed to describe a case of rhabdomyolysis and acute kidney injury potentiated by a drug-drug interaction (DDI) between cyclosporine, leflunomide, and rosuvastatin in a kidney transplant recipient. CASE SUMMARY: A 74-year-old male with end-stage kidney disease secondary to type 2 diabetes mellitus and hypertension received a deceased by cardiac death kidney transplant. The patient's medical history included coronary artery disease and hyperlipidemia for which he was receiving rosuvastatin 40 mg daily. Five months after transplant, the patient developed BK viremia, which required multiple changes in immunosuppression and resulted in the initiation of leflunomide and cyclosporine modified. The patient used multiple pharmacies and coupon cards that delayed the identification of the DDIs between leflunomide, cyclosporine, and rosuvastatin. Approximately, 13 months after transplant, the biopsy report of the patient's allograft kidney showed acute cellular rejection Banff IB, hypertensive changes, and transplant glomerulopathy. This prompted the patient to receive a 3-day course of methylprednisolone 250 mg intravenous at the outpatient infusion center. Two weeks later, the patient presented to the transplant clinic with lightheadedness, dizziness, weakness, fatigue, bilateral eye drainage, and a decrease in appetite and was admitted to the hospital for further workup. On admission, creatine kinase was 2080 IU/L with myoglobin of 7601 ng/mL. The patient's diagnosis was statin myopathy with possible rhabdomyolysis acute kidney injury. Likely contributing factors included cyclosporine, leflunomide, and rosuvastatin DDI and administration of high-dose methylprednisolone. PRACTICE IMPLICATIONS: This case demonstrates the importance of pharmacist involvement throughout all phases of care in a kidney transplant recipient.

Outcomes of Antithymocyte Globulin-Post-Transplantation Cyclophosphamide-Cyclosporine-Based versus Antithymocyte Globulin-Based Prophylaxis for 10/10 HLA-Matched Unrelated Donor Allogeneic Hematopoietic Cell Transplantation.

In 2015, dual T cell depletion with antithymocyte globulin (ATG) and post-transplantation cyclophosphamide (PTCy) combined with cyclosporine A (CsA) replaced our prior institutional graft-versus-host disease (GVHD) prophylaxis regimen of 4.5 mg/kg ATG, CsA, and mycophenolate mofetil (MMF) (ATG-based) in 10/10 HLA-matched unrelated donor (MUD) peripheral blood allogeneic hematopoietic stem cell transplantation (allo-HCT). The initial ATG dose of 4.5 mg/kg [ATG(4.5)/PTCy] was reduced to 2 mg/kg [ATG(2)/PTCy] in 2018. This study compares the results obtained from 444 adults undergoing MUD allo-HCT at our institution who received ATG(4.5)/PTCy (n = 127) or ATG(2)/PTCy (n = 223) with those who received ATG-based prophylaxis without PTCy (n = 84). The rates of grade II-IV and grade III-IV acute GVHD (aGVHD) at day +100 and moderate/severe chronic GVHD (cGVHD) at 1 year were 35.7%, 21.6%, and 14.7%, respectively, in patients receiving ATG-based prophylaxis without PTCy; 16.5%, 4.9%, and 4.3% in patients receiving ATG(4.5)/PTCy; and 23.3% (P = .004), 8.0% (P < .001), and 14.1% (P =.006) in patients receiving ATG(2)/PTCy. One-year overall survival (OS), nonrelapse mortality (NRM), and GVHD-free relapse-free survival (GRFS) were 69.8%, 25.3%, and 52.0%, respectively, for patients receiving ATG-based prophylaxis without PTCy; 82.7%, 17.3%, and 59.8% for patients receiving ATG(4.5)/PTCy; and 78.3% (P = .446), 14.7% (P = 101), and 56.2% (P = .448) for patients receiving ATG(2)/PTCy. On univariate analyses, the use of ATG(2)/PTCy was associated with a lower risk of NRM (hazard ratio, .54; P = .023) compared with the use of ATG-based prophylaxis without PTCy. ATG(2)/PTCy prophylaxis effectively prevents GVHD and is associated with comparable relapse risk, OS, and GRFS as seen with ATG(4.5)/PTCy and ATG-based prophylaxis without PTCy.

Initial dosage optimisation of cyclosporine in Chinese paediatric patients undergoing allogeneic haematopoietic stem cell transplantation based on population pharmacokinetics: a retrospective study.

OBJECTIVE: Improved understanding of cyclosporine A (CsA) pharmacokinetics in children undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT) is crucial for effective prevention of acute graft-versus-host disease and medication safety. The aim of this study was to establish a population pharmacokinetic (Pop-PK) model that could be used for individualised therapy to paediatric patients undergoing allo-HSCT in China. DESIGN, SETTING AND PARTICIPANTS: A retrospective analysis of 251 paediatric HSCT patients who received CsA intravenously in the early post transplantation period at Women and Children's Medical Center in Guangzhou was conducted. ANALYSIS MEASURES: The model building dataset from 176 children was used to develop and analyse the CsA Pop-Pk model by using the nonlinear mixed effect model method. The basic information was collected by the electronic medical record system. Genotype was analysed by matrix-assisted time-of-flight mass spectrometry. The stability and predictability of the final model were verified internally, and a validation dataset of 75 children was used for external validation. Monte Carlo simulation is used to adjust and optimise the initial dose of CsA in paediatric allo-HSCT patients. RESULTS: The typical values for clearance (CL) and volume of distribution ([Formula: see text]) were 14.47 L/hour and 2033.53 L, respectively. The body weight and haematocrit were identified as significant variables for V, while only body weight had an impact on CL. The simulation based on the final model suggests that paediatrics with HSCT required an appropriate intravenous dose of 5 mg/kg/day to reach the therapeutic trough concentration. CONCLUSIONS: The CsA Pop-PK model established in this study can quantitatively describe the factors influencing pharmacokinetic parameters and precisely predict the intrinsic exposure to CsA in children. In addition, our dosage simulation results can provide evidence for the personalised medications TRIAL REGISTRATION NUMBER: ChiCTR2000040561.

Impact of Topical Cyclosporine-A or Topical Chloroquine on Post-LASIK Ocular Surface Stability - A Randomized Controlled Trial.

PURPOSE: To compare effect of topical cyclosporine-A 0.05% (CsA) and chloroquine phosphate 0.03% (CHQ) as an adjunct to standard therapy in maintaining post-laser assisted in situ keratomileusis (LASIK) ocular surface stability. METHODS: Randomized controlled trial on 100 eyes undergoing femtosecond-LASIK randomized into three groups: 33 eyes in Group I (Standard Treatment group), 34 eyes in Group II (CsA group) and 33 eyes in Group III (CHQ group). Standard treatment included topical moxifloxacin, topical prednisolone and carboxymethyl cellulose. Group II received topical CsA 0.05% twice daily for three months and group III received topical CHQ 0.03% twice daily for three months in addition to standard treatment. Primary outcome measure was change in ocular surface disease index (OSDI) at 6 months. Secondary outcome measures were tear break up time (TBUT), Schirmer-I score, tear film osmolarity, tear film MMP-9 and visual acuity. Follow-up was performed at postoperative 1, 3 and 6 months. RESULTS: At 6 months, OSDI score, MMP-9, tear osmolarity, TBUT and Schirmer score were significantly better in both CsA and CHQ groups as compared with controls (p < 0.001). OSDI, Tear osmolarity, TBUT, MMP-9 levels were comparable in CsA and CHQ group (p > 0.05). In CsA group, tear film MMP-9 levels at 6 months were comparable to preoperative baseline (p = 0.09). There was no significant change in the Schirmer score from baseline in the CsA group; in addition, the Schirmer score was significantly better than the CHQ group at 6 months (p = 0.02). Visual acuity was comparable in all three groups. Adverse effects including burning sensation, stinging, pain and redness were reported by ten patients (CsA group- 3, CHQ group-7; p = 0.28). CONCLUSION: Both CsA and CHQ are useful adjuncts to standard therapy in maintaining ocular surface stability after refractive surgery. Cyclosporine A has more potent and sustained anti-inflammatory effect with less ocular irritative effects.

Ciclosporin A Cationic Emulsion 0.1% for the Management of Dry Eye Disease: Facts That Matter for Eye-Care Providers.

Dry eye disease (DED) is a chronic inflammatory disease of the ocular surface requiring long-term therapy. Severe forms of DED generally do not respond to tear substitutes alone or combined, and often require treatment with topical anti-inflammatory agents to break the vicious circle of inflammation. This review summarises data from randomised controlled trials and real-world evidence on the efficacy and safety of ciclosporin A 0.1% cationic emulsion (Ikervis®) for the management of DED. Improvements in clinical signs and symptoms were reported from as early as 4 weeks after treatment initiation, although it can take a few months to reach the full benefits. Treatment periods of up to 12 months provide sustained benefit to patients. In the most responsive patients, treatment discontinuation is possible with no further substantial relapse over 12 months in over 65% of patients. Transient local ocular effects are the most commonly reported adverse events.

Haemophagocytic lymphohistiocytosis associated with liver injury in systemic sarcoidosis.

Hepatic involvement in sarcoidosis, though common, is usually asymptomatic. Hepatomegaly and deranged liver function tests are the usual manifestations. However, unexplained hepatomegaly in sarcoidosis not responding to immunosuppressive therapy could indicate an alternative pathology. Haemophagocytic lymphohistiocytosis (HLH), although seldom reported in sarcoidosis, can cause hepatosplenomegaly and cytopenias. HLH occurring concomitantly with hepatic sarcoidosis is extremely rare. We report a patient of systemic sarcoidosis who presented with fever, hepatosplenomegaly and jaundice despite being on steroid therapy. He was subsequently diagnosed with HLH. The clinical response to treatment with pulse steroid and oral cyclosporine was dramatic.

A Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union.

The current regulatory criterion for bioequivalence of narrow therapeutic index (NTI) drugs in the European Union requires that the 90% confidence interval for the ratio of the population geometric means of the test product compared with the reference for area under the plasma concentration-time curve (AUC), and in certain cases maximum plasma drug concentration (Cmax ), to be included within the tighter acceptance range of 90.00-111.11%. As a consequence, sponsors need to recruit a higher number of subjects to demonstrate bioequivalence and this may be seen as increasing the burden for the development of generics. This "one-size-fits-all" criterion is particularly questionable when the within-subject variability of the reference product is moderate to high. As an alternative, we propose a further refined statistical approach where the acceptance range is narrowed based on the within-subject variability of the reference product of the NTI drug, similar to the one used for widening the standard 80.00-125.00% acceptance range for highly variable drugs. The 80.00-125.00% acceptance range is narrowed, only if the within-subject variability is lower than 30%, down to the current NTI acceptance range of 90.00-111.11% when the within-subject variability is 13.93% or lower. Examples within the current European Medicines Agency list of NTI drugs show a considerable reduction in required sample size for drugs like tacrolimus and colchicine, where the predicted within-subject variability is 20-30%. In these cases, this approach is less sample size demanding without any expected increase in the therapeutic risks, since patients treated with reference products with moderate to high within-subject variability are frequently exposed to bioavailability differences larger than 10%.

Transition from Amorphous Cyclosporin A Nanoparticles to Size-Reduced Stable Nanocrystals in a Poloxamer 407 Solution.

Amorphous drug nanoparticles usually exhibit low storage stability. A comprehensive understanding of the molecular states and physicochemical properties of the product is indispensable for designing stable formulations. In the present study, an amorphous cyclosporin A (CyA) nanosuspension with a mean particle size of approximately 370 nm was prepared by wet bead milling with poloxamer 407 (P407). Interestingly, the prepared amorphous CyA nanoparticles were transformed into uniform CyA nanocrystals with a reduced mean particle size of approximately 200 nm during storage at 25 °C. The CyA nanocrystals were stably maintained for at least 1 month. The particle morphologies and molecular structures of the CyA nanosuspensions before and after storage were thoroughly characterized by cryogenic transmission electron microscopy and magic-angle spinning nuclear magnetic resonance spectroscopy, respectively. They revealed that the freshly prepared amorphous CyA nanoparticles (∼370 nm) were secondary particles composed of aggregated primary particles with an estimated size of 50 nm. A portion of P407 was found to be entrapped at the gaps between the primary particles due to aggregation, while most of P407 was dissolved in the solution either adsorbing at the solid/liquid interface or forming polymeric micelles. The entrapped P407 is considered to play an important role in the destabilization of the amorphous CyA nanoparticles. The resultant CyA nanocrystals (∼200 nm) were uniform single crystals of Form 2 hydrate and showed corner-truncated bipyramidal features. Owing to the narrow particle size distribution of the CyA nanocrystals, the rate of Ostwald ripening was slow, giving long-term stability to the CyA nanocrystals. This study provides new insights into the destabilization mechanism of amorphous drug nanoparticles.

A comprehensive review on possibilities of treating psoriasis using dermal cyclosporine.

Psoriasis is an autoimmune, chronic proliferative, inflammatory skin disease with high comorbidity. Psoriasis is not a curable disease; it can only be managed. Cyclosporine A (CyA) is one of the FDA-approved immunosuppressant drug used in severe Psoriasis. Till date only oral route is used for its administration. Administration of CyA by this route causes serious side effects such as hypertension and renal toxicity. Due to these side effects, a number of researches have been done and taking place in the current times for the dermal delivery of CyA for the management of psoriasis. Dermal delivery of CyA is not an easy task because of its physiochemical properties like high molecular weight, lipophilicity and resistance offered by stratum corneum (SC). Because of the above problems in the dermal delivery a number of new approaches such as nanolipid carriers, microemulsion, liposomes, niosomes etc. are explored. To those deep findings for psoriasis management with dermal delivery of CyA have not been discussed. This comprehensive review includes all the studies, advancements and their critical findings which took place in the recent times for the dermal delivery of CyA and along with the suitable modification needed for the efficient dermal delivery of CyA are also suggested.