Formulation of Folate Receptor-Targeted Silibinin-Loaded Inhalable Chitosan Nanoparticles by the QbD Approach for Lung Cancer Targeted Delivery.

Aim: Targeted delivery of chemotherapeutics by functionalized nanoparticles exhibits a wonderful prospect for cancer treatment. The main objective of this research was to develop folate receptor-targeted silibinin (SB)-loaded inhalable polymeric nanoparticles (FA-CS-SB-NPs) for the treatment of lung cancer. Method: The qbD approach was implemented to prepare SB-loaded nanoparticles. Folic acid was conjugated by electrostatic conjugation in an optimized batch. The therapeutic potentials of formulations were determined using a lung cancer cell-bearing rat model. Result: Optimized formulation exhibited a spherical surface with a mean particle size of 275 ± 1.20 nm, a PDI of 0.234 ± 0.07, a ζ-potential of 32.50 ± 0.21, an entrapment efficiency of 75.52 ± 0.87%, and a CDR of 63.25 ± 1.21% at 48 h. Aerodynamic behaviors such as the mass median aerodynamic diameter (MMAD) and geometric size distribution (GSD) were found to be 2.75 ± 1.02 and 3.15 ± 0.88 µm, respectively. After 24 h of incubation with FA-CS-SB-NPs, the IC50 value was found to be 24.5 g/mL. FA-SB-CS-NPs maintained a significantly higher deposition of SB in lung tissues. Conclusions: Thus, the noninvasive nature and target specificity of FA-CS-SB-NPs pave the way for pulmonary delivery for treating lung cancer.

Polymicrobial anaerobic sepsis due to Bacteroides fragilis, Eggerthella lenta, Ruminoccocus gnavus, and Bilophila wadsworthia in a patient with myeloproliferative neoplasm.

We report a rare case of polymicrobial anaerobic bacteremia caused by four different gut anaerobes: Bacteroides fragilis, Eggerthella lenta, Bilophila wadsworthia, and Ruminococcus gnavus. Early initiation of appropriate therapy and species identification with matrix assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF MS) resulted in full recovery from the infection. Our case highlights the clinical significance of polymicrobial cultures and the importance of performing anaerobic cultures for blood specimens to ensure proper identification and treatment.

Graft-Versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplant: SARS-CoV-2 Vaccine as a Potential Trigger.

Allogeneic hematopoietic stem cell transplant (AHSCT) recipients are at a risk of developing immune-mediated tissue damage from activation of the donor's immunocompetent T cells by the recipient's normally expressed antigens, a phenomenon called graft-versus-host disease (GVHD). With the emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), new vaccines have been developed to prevent morbidity and mortality, including the highly vulnerable hematologic malignancy patients after undergoing AHSCT. The early pathophysiologic events in GVHD include priming the donor T cells with molecules that are endogenous or pathogenic. In this case series, we present two cases of AHSCT recipients in which the SARS-CoV-2 vaccination series proceeded the development of GVHD manifesting with oral mucosal symptoms and derangement in the liver function tests. Our experience raises the question if any of the vaccine components serve as a molecular trigger for GVHD, making the current SARS-CoV-2 vaccines a risk factor for activating the immune system and developing GVHD.

RP-HPLC method development, validation and pharmacokinetic applicability in preclinical evaluation of rhein treated with novel diacerein eutectics.

The current study represents a bioanalytical method for the estimation of rhein (Rh, an active metabolite of diacerein, DIA) in rats treated with novel DIA eutectics to investigate the pharmacokinetics of DIA. A simple protein precipitation technique was used to extract Rh and the internal standard (IS), p-aminobenzoic acid, injected into a Phenomenex Gemini C18 column. The separation was achieved by a gradient elution comprising ammonium acetate (10 mm; pH 3.0) and acetonitrile in an 18 min run time at a flow rate of 0.8 ml/min with retention times of 11.8 min (Rh) and 5.9 min (IS). The results revealed that the proposed method is linear over a range of 200-20,000 ng/ml (r2 > 0.9988) of Rh and is precise and accurate. The method was fully validated as per the US Food and Drug Administration guidelines and a pharmacokinetic study in rats was performed for Rh following oral administration of the pure DIA and newly developed eutectics. Therefore, the present method could be used to estimate DIA to illustrate a comparative pharmacokinetic analysis. This can also be applied to its related multicomponent formulations for future studies.

Lung cancer targeting efficiency of Silibinin loaded Poly Caprolactone /Pluronic F68 Inhalable nanoparticles: In vitro and In vivo study.

Silibinin (SB) is shown to have an anticancer properties. However, its clinical therapeutic effects have been restricted due to its low water solubility and poor absorption after oral administration. The aim of this study was to develop SB-loaded PCL/Pluronic F68 nanoparticles for pulmonary delivery in the treatment of lung cancer. A modified solvent displacement process was used to make nanoparticles, which were then lyophilized to make inhalation powder, Nanoparticles were characterized with DSC, FTIR,SEM and In vitro release study. Further, a validated HPLC method was developed to investigate the Biodistribution study, pharmacokinetic parameters. Poly Caprolactone PCL / Pluronic F68 NPs showed the sustained release effect up to 48 h with an emitted (Mass median Aerodynamic diameter)MMAD and (Geometric size distribution)GSD were found to be 4.235 ±0.124 and 1.958±1.23 respectively. More specifically, the SB Loaded PCL/Pluronic F 68 NPs demonstrated long circulation and successful lung tumor-targeting potential due to their cancer-targeting capabilities. SB Loaded PCL/Pluronic F68 NPs significantly inhibited tumour growth in lung cancer-induced rats after inhalable administration. In a pharmacokinetics study, PCL/ Pluronic F68 NPs substantially improved SB bioavailability, with a more than 4-fold rise in AUC when compared to IV administration. These findings indicate that SB-loaded PCL/PluronicF68 nanoparticles may be a successful lung cancer therapy delivery system.

T-cell prolymphocytic leukaemia associated with immune checkpoint inhibitor (pembrolizumab).

We describe the case of a man in his 60s with squamous cell carcinoma of the lung with brain metastasis treated with pembrolizumab who subsequently developed T-cell prolymphocytic leukaemia. He was transferred to our hospital with worsening dyspnoea, suspected hyperviscosity syndrome and tumour lysis syndrome. He was intubated and admitted to our critical care unit. Emergent leucapheresis was started due to worsening renal function in the setting of tumour lysis and hyperviscosity syndromes. He continued to deteriorate and required continuous renal replacement therapy. Unfortunately, he eventually died from haemodynamic decompensation. There are only a few anecdotal cases pointing at a possible association between the use of immune checkpoint inhibitors and the progression or exacerbation of secondary haematological malignancies. The poor prognosis of these haematological malignancies warrants further investigation to determine if checkpoint inhibitors increase the risk of developing or propagating these potentially fatal diseases.

Silibinin loaded inhalable solid lipid nanoparticles for lung targeting.

AIM: In the current study, efforts are being made to prepare Inhalable Silibinin loaded solid lipid nanoparticles (SLNs) with narrow size distribution with improved bioavailability. METHODS: SLNs were formulated by high shear homogenisation method SLNs were characterised, including Differential Scanning Calorimetry (DSC), Fourier transform infra-red spectroscopy (FTIR), particle size analysis, entrapment efficiency with Aerodynamic behaviour. The MTT assay was performed against A549 cell line, to measure their anticancer cell activity with In vivo study. RESULTS: Optimized formulation exhibited spherical surface with a mean particle size of 221 ± 1.251 nm, PI of 0.121 ± 0.081, zeta potential of -4.12 ± 0.744. Aerodynamic behaviour such as Mass median aerodynamic diameter (MMAD) and Geometric size distribution (GSD) were found to be 5.487 ± 0.072 and 2.321 ± 0.141 respectively proved formulation is suitable for inhalation. In vitro cellular efficacy against A549 cells, revealed that the optimised formulations were more effective and potent. CONCLUSION: The Inhalable SLNs approach was successfully engineered and administered to the lungs safely without causing any problems.

Serum sickness reaction to obinutuzumab in a patient with chronic lymphocytic leukaemia.

Serum sickness (SS) is a known phenomenon; however, it is commonly missed due to vague symptoms, and is usually confounded by other aetiologies that present similarly. Obinutuzumab is a novel anti-CD20 antibody agent that has been approved for chronic lymphocytic leukaemia (CLL) treatment. At the time of approval, it was not linked to SS; however, this phenomenon has been recognised with other anti-CD20 agents like rituximab. SS remains a rare entity, but it is important to be recognised accurately and quickly in the appropriate circumstances, so that effective treatment with corticosteroids can be initiated to alleviate inflammatory symptoms. Here we present a patient with CLL who developed maculopapular rash, fever and polyarthritis and elevated inflammatory markers consistent with serum sickness triggered by obinutuzumab and was effectively treated with corticosteroids.

Application of a Validated RP-HPLC Method in Solubility and Dissolution Testing for Simultaneous Estimation of Diacerein and Its Active Metabolite Rhein in Presence of Coformers in the Eutectic Tablet Formulation.

The present study aimed to develop and validate a novel reversed-phase high-performance liquid chromatography method for simultaneous estimation of Diacerein (DIA) and Rhein (Rh, alkaline degradation product and active metabolite) in the presence of various coformers used to prepare eutectic oral formulation. Chromatographic separations were achieved on a Phenomenex Gemini C18 column (250 mm × 4.6 mm, 5 µm) placed in the thermostated column oven at 40°C. The mobile phase, comprising of acetonitrile and 10 mM ammonium acetate (pH 3.0), was eluted through the gradient system with 0.8 mL/min flow rate at 254 nm detection and analytical run time of 14 min. Additionally, the method was validated for specificity, linearity, precision, accuracy, selectivity, limit of quantitation, limit of detection and robustness as per International Conference on Harmonization guideline. The developed method was applied for the comparison of drug release profiles of pure DIA and from prepared eutectic formulations for the quantitation of DIA and Rh in the multicomponent adducts. The achieved method advocated their applicability in routine quality control analysis of DIA formulations without interference of degraded product and excipients.

Congenital dysfibrinogenaemia presented with preterm premature rupture of the membranes and vaginal bleeding.

A 26-year-old woman was found to have congenital dysfibrinogenaemia after presenting to our hospital with premature rupture of the membranes and vaginal bleeding. Given the absence of clear guidelines for the management of pregnancy complicated by dysfibrinogenaemia, we followed expert consensus that exists among published works, with some modifications. This case was managed by a multidisciplinary team of obstetrics-gynaecology, haematology and paediatric haematology. Here we review how the patient presented, the investigations that led to the diagnosis and the treatment options.

Concurrent Diagnosis of Acute Myeloid Leukemia and COVID-19: A Management Challenge.

The emergence of coronavirus disease 2019 (COVID-19) has created new challenges in the management of serious diseases. We describe a 41-year-old male who presented with fever, watery diarrhea, and epistaxis. Initial workup revealed pancytopenia with >50% blasts on the peripheral smear raising suspicion of acute myeloid leukemia (AML) (later confirmed by bone marrow biopsy as AML with myelodysplasia-related changes) and a positive polymerase chain reaction (PCR) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the extraordinary risk, he was treated with remdesivir and convalescent plasma for COVID-19. On admission day 8, repeat PCR for SARS-CoV-2 returned negative and the patient was deemed stable for chemotherapy. Therefore, induction was done with liposomal daunorubicin and cytarabine. However, he did not respond to the therapy and was started on re-induction therapy with decitabine and venetoclax. In our discussion, we review the current principles of treatment of patients with concurrent COVID-19 and AML.

Intractable hypercalcemia in a patient with multiple myeloma: An infectious etiology.

Hypercalcemia is a common laboratory finding in patients with malignancy, as well as with granulomatous disease. We report the case of a 75-year-old man with multiple myeloma (MM) who presented with generalized weakness, fever, and intractable hypercalcemia. The hypercalcemia proved difficult to treat despite well-controlled MM, as well as adequate use of bisphosphonates and calcitonin. Biopsy of sub-centimeter mesenteric adenopathy was significant for Histoplasma capsulatum and negative for malignancy, suggesting disseminated gastrointestinal histoplasmosis as the sole etiology for uncontrolled hypercalcemia. He was successfully treated with voriconazole. Disseminated histoplasmosis can be fatal if left untreated and warrants vigilance of non-malignant etiologies of hypercalcemia. While hypercalcemia is a common clinical manifestation of MM, our patient is an exemplar of maintaining a broader differential diagnosis in immunocompromised hosts.

HTLV-positive adult T-cell leukaemia/lymphoma with Epstein-Barr virus and hepatitis B coinfection.

Human T-cell lymphotropic virus (HTLV) is a human oncoretrovirus known to cause adult T-cell leukaemia/lymphoma (ATLL). Coinfection of human T-lymphotropic virus type 1 with Epstein-Barr virus (EBV) results in enhanced expression of the HTLV virus and leads to aggressive organ involvement from T-cell malignancy. It has also been observed that the prevalence of hepatitis B infection has been higher in patients with HTLV ATLL as compared with the general population in certain countries. We describe a case of a 34-year-old man who initially presented with leucocytosis, fatigue and conjunctival erythema. His radiological images revealed significant generalised adenopathy, and his flow cytometry analysis came back positive for CD4-positive T-cell lymphoma. He was subsequently diagnosed with HTLV-positive ATLL. Ultimately the patient was also diagnosed with acute hepatitis B and EBV. We describe a unique case of ATLL with coinfection with two other viruses, the association of which can be of potential prognostic value in guiding the treatment strategies for ATLL.

Blastic plasmacytoid dendritic cell neoplasm in the background of myeloproliferative disorder and chronic lymphocytic leukaemia.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare haematological malignancy defined by concurrent expression of CD4, CD56, BCL-2 and CD123. The disease has a very poor prognosis and there are no well-established treatment guidelines. We describe a case of BPDCN in a 65-year-old female patient with myeloproliferative disorder (essential thrombocythemia) and chronic lymphocytic leukaemia. She presented with rapidly progressive facial and scalp lesions. Skin biopsy confirmed BPDCN and the imaging revealed widespread disease. Patient was started on hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) and intrathecal methotrexate. Due to progression on initial treatment, she was treated with decitabine and venetoclax (BCL-2 inhibitor). However, patient continued to deteriorate and died after 4 months from initial diagnosis. We emphasise on the clinical features, emerging treatment modalities and prognosis of BPDCN.

Spontaneous Subdural Hematoma in Patient with Polycythemia Vera.

BACKGROUND: Polycythemia vera (PV) is a myeloproliferative disorder usually characterized by an increase tendency toward thromboembolic events. Spontaneous hemorrhage/bleeding in PV patients is seldom reported in neurosurgical literature. CASE DESCRIPTION: We report the case of a 76-year-old male with PV who developed a spontaneous subdural hematoma requiring surgical evacuation. He improved significantly after the resolution of brain compression and mass effect caused by the hematoma. CONCLUSIONS: Sporadic reports of hemorrhage within the central nervous system in the setting of PV exist and are attributed to microvascular thrombotic events with hemorrhagic conversion. Though rare, spontaneous central nervous system hemorrhage in the absence of vascular malformation or an inciting event such as trauma can occur in the setting of myeloproliferative disorders like PV.

An unusual presentation of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a B-cell lymphocytic neoplasm with indolent clinical course. If identified early, observation is opted. Many variables lead to the initiation of treatment. Authors describe a 62-year-old male presenting with shortness of breath and found to have white cell count of 1360 × 109/L and subsequently was diagnosed with CLL/SLL. The patient received leukapheresis along with tumor lysis treatment and systemic chemotherapy with fludarabine, cyclophosphamide, and rituximab regimen. His course was complicated with deep venous thrombosis, extensive cutaneous, and sinus mucosa involvement by CLL/SLL. The patient clinically improved and on follow-up clinic visits documented normalization of his white cell counts. The case report brings up a rare presentation of CLL/SLL with such an extreme high white cell count, leukostasis symptoms and extramedullary involvement of disease and encourages providers to be vigilant of rare presentation of CLL/SLL.

Sarcoidosis-like syndrome and lymphadenopathy due to checkpoint inhibitors.

Immunotherapy with checkpoint inhibitors has revolutionized the management of metastatic melanoma. These checkpoints, namely the cytotoxic T lymphocyte antigen 4 and the programmed T cell death 1 receptor, possess an inhibitory effect on the T cell function. Pharmacologic inhibition of cytotoxic T lymphocyte antigen 4 with ipilimumab and programmed T cell death 1 with either pembrolizumab or nivolumab has resulted in long-term sustained responses among patients with metastatic melanoma. The adverse events of these medications are predominantly immune related. Sarcoidosis-like syndrome/lymphadenopathy represents a challenging adverse event to the oncologist as it can be mistaken for progressive disease. Hence, awareness of such adverse event and obtaining a biopsy of the enlarged lymph nodes will confirm the diagnosis and avoid the unnecessary change of current therapies for those with stage IV disease or adding new ones for those with stage III disease. We report three cases of immunotherapy-related sarcoidosis-like syndrome/lymphadenopathy; two cases occurred during adjuvant ipilimumab for stage III surgically resected melanoma and one case during pemprolizumab for stage IV metastatic melanoma.

Development of loteprednol etabonate-loaded cationic nanoemulsified in-situ ophthalmic gel for sustained delivery and enhanced ocular bioavailability.

A novel cationic nanoemulsified in-situ ophthalmic gel of loteprednol etabonate (LE) was developed to improve the permeability and retention time of formulations for overall improvement of drug's ocular bioavability. Capryol 90 (oil phase), tween 80 (surfactant) and transcutol P (cosurfactant) was selected as formulation excipients to construct pseudoternary phase diagrams and nanoemulsion region was recognized from diagrams. Spontaneous emulsification method was used to manufacture LE nanoemulsion and it was optimized using 32 factorial design by considering the amount of oil and the ratio of surfactant to cosurfactant (Smix) as independent variables and evaluated for various physicochemical properties. Optimized NE was dispersed in Poloxamer 407 and 188 solution to form nanoemulsified sols that were predictable to transform into in-situ gels at corneal temperature. Drug pharmacokinetics of sterilized optimized in situ NE gel, NE-ISG2 [0.69% w/w Capryol 90, 0.99%w/w Smix (3:1), 13% Poloxamer 407, 4% w/w Poloxamer 188] and marketed formulation were assessed in rabbit aqueous humor. The in-situ gels were clear, shear thinning in nature and displayed zero-order drug release kinetics. NE-ISG2 showed the minimum ocular irritation potential and significantly (p < 0.01) higher Cmax and AUC(0-10 h), delayed Tmax, extended mean residence time and improved (2.54-fold times) bioavailability compared to marketed formulation.

Dissolution enhancement of chlorzoxazone using cogrinding technique.

PURPOSE: The aim of the present work was to improve rate of dissolution and processing parameters of BCS class II drug, chlorzoxazone using cogrinding technique in the presence of different excipients as a carrier. MATERIALS AND METHODS: The drug was coground with various carriers like polyethylene glycol (PEG 4000), hydroxypropyl methylcellulose (HPMC) E50LV, polyvinylpyrrolidone (PVP)K30, Kaolin and Neusilin US2 using ball mill, where only PEG 4000 improved dissolution rate of drug by bringing amorphization in 1:3 ratio. The coground mixture after 3 and 6 h was evaluated for various analytical, physicochemical and mechanical parameters. RESULTS: The analysis showed conversion of Chlorzoxazone from its crystalline to amorphization form upon grinding with PEG 4000. Coground mixture as well as its directly compressed tablet showed 2.5-fold increment in the dissolution rate compared with pure drug. Directly compressible tablets prepared from pure drug required a large quantity of microcrystalline cellulose (MCC) during compression. The coground mixture and formulation was found stable in nature even after storage (40°C/75% relative humidity). CONCLUSIONS: Cogrinding can be successfully utilized to improve the rate of dissolution of poorly water soluble drugs and hence bioavailability.

Yttrium-90 radioembolization of hepatic metastases from colorectal cancer.

Liver metastases from colorectal cancer (CRC) result in substantial morbidity and mortality. The primary treatment is systemic chemotherapy, and in selected patients, surgical resection; however, for patients who are not surgical candidates and/or fail systemic chemotherapy, liver-directed therapies are increasingly being utilized. Yttrium-90 (Y-90) microsphere therapy, also known as selective internal radiation therapy (SIRT) or radioembolization, has proven to be effective in terms of extending time to progression of disease and also providing survival benefit. This review focuses on the use of Y-90 microsphere therapy in the treatment of liver metastases from CRC, including a comprehensive review of published clinical trials and prospective studies conducted thus far. We review the methodology, outcomes, and side effects of Y-90 microsphere therapy for metastatic CRC.