Glenmark Pharmaceuticals (India)

Dear Editor, In recent years, India has seen a significant rise in the prescription of itraconazole for the management of dermatophytosis [1]. However, its pharmacokinetic variability has often led to inconsistent clinical outcomes. To address these challenges, a newer formulation-Super-Bioavailable Itraconazole (SB-ITZ) has been commercialized in India [2]. Although SB-ITZ has supportive pharmacokinetic and clinical data, large scale real world evidence remains limited. We therefore undertook a retrospective, record based evaluation of SB ITZ in Indian patients with dermatophytosis.

Using metal free solid acid catalyst in chemical reactions is essential for the development of a new organic synthesis approach. Herein, we demonstrate the use of sulfonated reduced graphene oxide (GO-SO3H, SGO) metal free catalyst, which is emerging as a popular catalyst. The metal free catalyst was prepared as an anchored aryl diazonium salt of sulfanilic acid free radicals onto its surface by sonication. As such synthesized SGO catalyst was structurally elucidated by various analytical techniques. An effective one-pot synthesis of 2, 5-diarylsubstituted1, 3, 4-oxadiazoles was reported here. Initially, benzohydrazides were condensed with substituted carboxylic acids in the presence of O-(benzotriazol-1-yl)-N, N, Nʹ, Nʹ-tetramethyluronium tetrafluoroborate (TBTU) to obtain diacylhydrazine. Later, the diacylhydrazines underwent sulfonated graphene oxide (SGO) catalyzed cyclodehydration reaction to obtain targeted heterocyclic molecules. This work exemplifies numerous benefits in work-up methods and environmental friendliness. The obtained 1,3,4-oxadiazoles were evaluated successfully for their antibacterial activities. SGO attracts the scientific community and its catalytic applications in synthesis of 1,3,4-oxadiazoles and other organic transformations.

Abstract Background: ISB 2001 is the first trispecific antibody that simultaneously targets BCMA and CD38 on MM cells, and CD3 to engage T-cells, forming tumor/immune cell synapses (TICS) that cause tumor cytotoxicity. Since ISB 2001 lacks cross-reactivity to common preclinical toxicology species including monkeys, no preclinical toxicology studies were conducted to inform the FIH dose calculation. The conventional minimal anticipated biological effect level (MABEL) approach for FIH dose derivation for T-cell engagers (TCE) often results in exposing patients to non-therapeutic doses. Instead, we developed a QSP model to predict an optimal FIH dose and efficacious dose range. This informed the design of the ongoing phase 1 dose escalation study of ISB 2001 in RRMM patients (NCT05862012), starting at 5 µg/kg subcutaneously with the initial three single-patient cohorts followed by standard 3+3 cohorts beginning at 150 µg/kg. Method: A QSP model utilizing binding affinities, target expressions, cell counts, and preclinical pharmacokinetic (PK) data was developed to characterize TICS profiles in the tumor compartment. Normalized TICS formation was linked to tumor cytotoxicity, and the model was calibrated with ISB 2001 in vivo efficacy data to enable efficacy predictions. This QSP model was benchmarked with teclistamab’s clinical data to derive the minimal pharmacologically active dose (MPAD) of ISB 2001[1]. The MPAD was further adjusted using in vitro cytokine secretion data to establish the FIH dose, which was preceded by fractionated step-up doses to mitigate potential cytokine release syndrome concerns. Serum concentration of ISB 2001 across doses up to 1200 µg/kg were quantified using a validated electrochemiluminescence assay and compared with the model predictions. Results: No CRS was observed in the FIH cohort, and only one grade 1 case was reported at doses up to 15 µg/kg in third cohort, supporting the QSP model-based FIH dose selection while acknowledging the limited sample size. As predicted, objective tumor responses were observed at dose levels as low as 50 µg/kg, just 10-fold higher than the FIH dose. Measured ISB 2001 serum concentration time profiles across multiple dose levels up to 1200 µg/kg (n=20) aligned well with model simulations. Conclusion: Despite the absence of monkey PK and toxicology data, this QSP-guided approach successfully predicted an optimal FIH dose, clinical PK, safety, and efficacy, while minimizing patient exposure to non-therapeutic doses. With this method, TCEs can be optimized solely for activity against human tumors without requiring cross-reactivity to animal species. Overall, the QSP based FIH calculation approach offers an effective pathway for designing phase 1 studies for future TCEs.

ABSTRACT Introduction The rising challenge of carbapenem-resistant Enterobacterales (CRE) infections in Indian healthcare settings calls for clear clinical guidance on the management of these infections. The Indian consensus on the management of CRE infection in critically ill patients (ICONIC-II) is a follow-up of the ICONIC-I study, which was undertaken in 2019. Areas Covered A modified Delphi method was used to build expert consensus on CRE management in India, involving online surveys, face-to – face expert meetings, and a literature review. A panel of 12 experts was formed to develop potential clinical consensus statements (CCSs), which were rated through two survey rounds. The CCSs were finalized in a final face-to – face discussion. The finalized CCSs were categorized as consensus, near consensus, and no consensus. Expert Opinion The outcomes included 46 CCSs (consensus: 40; near consensus: 3; and no consensus: 3). The expert panel discussed and achieved consensus on various strategies for managing CRE infections, emphasizing the significance of existing and emerging resistance mechanisms, prompt and tailored empiric therapy, and use of combination therapies. The consensus statements based on the collective expertise of the panel can potentially assist clinicians in the management of CRE infections that lack high-level evidence.

[This corrects the article DOI: 10.7759/cureus.56447.].

BackgroundChemotherapy-induced nausea and vomiting is a common and unpleasant treatment-related side effect reported by cancer patients receiving chemotherapy. Akynzeo® or NEPA (NEtupitant + PAlonosetron) is the first fixed combination of netupitant and palonosetron that targets both critical pathways involved in emesis while providing a convenient, single oral dose therapy. The current study aimed to assess the effectiveness and safety of NEPA in a real-world setting in India.MethodologyThis was an open-label, multicenter, prospective, single-arm study conducted at six different locations across India. The study included patients of either gender, aged ≥18 years, naive to chemotherapy, scheduled to receive highly or moderately emetogenic chemotherapy (HEC/MEC), and scheduled to receive oral NEPA, as determined by the investigator.ResultsA total of 360 people were screened and enrolled in the study. HEC was prescribed to 289 (81.64%) patients, while MEC was prescribed to 65 (18.36%) patients. Complete response was achieved in 94.92% of patients during the acute phase, 95.20% during the delayed phase, and 93.22% during the overall phase. During the overall phase, 92.73% and 95.38% of patients on the HEC and MEC regimens, respectively, achieved complete response. Adverse events were reported in 3.88% of patients.ConclusionsOral NEPA was found to be effective in the Indian real-world setting, eliciting a >90% complete response with HEC and MEC regimens across the acute, delayed, and overall phases.

Topical calcineurin inhibitors (TCIs) and topical corticosteroids (TCS) are the mainstays of flare management for atopic eczema or atopic dermatitis (AD). Tacrolimus (an immunomodulator), belongs to the class of calcineurin inhibitors, with promising efficacy in AD. We performed this systematic review to obtain an up-to-date coverage map of controlled clinical trials of sequential or intermittent treatments with TCI as a therapeutic intervention for AD. Articles of interest were retrieved from PubMed, Google Scholar, and EMBASE published between between January 2000 and March 2023. Key words were "calcineurin inhibitors," "corticosteroids," "atopic dermatitis," "pruritus," "sequential," "intermittent" and "consecutive" while fixed language search consisted of "Intermittent topical calcineurin inhibitors AND topical corticosteroids AND atopic dermatitis OR eczema" AD patients who were administered sequential and/or intermittent applications of TCI for management of atopic eczema were included. Outcome measures included but were not limited to Scoring of Atopic Dermatitis (SCORAD) and the Eczema Area Severity Score (EASI). Four clinical trials were considered for the purpose of review. A total of 101 patients with AD were analysed. The risk of bias was low in two studies, while the other two had an unclear risk of bias. Overall, pooled data from two trials revealed that sequential therapy with TCS/TCI was comparable to monotherapy or emollients, as the test for overall effect determined was non-significant with a p-value of 0.33. The two studies were highly heterogeneous, as indicated by a very high I2 of 92% and an extremely significant p-value (p=0.0005).Sequential therapy with TCS and TCIs was effective and well tolerated in the management of AD and it may be considered an important treatment approach during the initial period.

Background: Obesity is considered one of the risk factors for dermatophytosis and warrants systemic therapy. Itraconazole is the most commonly used antifungal, but owing to pharmacokinetic challenges, super-bioavailable itraconazole (SITZ) was approved globally, recently. For the management of dermatophytosis in obese patients, there are mixed opinions regarding the dosing of systemic antifungals. Materials and Methods: This study was conducted to compare the efficacy and safety of SITZ-130 mg once daily in glabrous tinea or dermatophytosis in obese and non-obese patients for a total duration of 10 weeks on 87 eligible patients. Efficacy and safety assessments were done at weeks 3 and 6 with follow-up at week 10 for relapse. The primary objective was to assess the proportion of patients achieving complete cure at week 6 with the assessment of safety, clinical, and mycological cure rates as secondary objectives. Results: Out of 87 patients, 80 were considered for analysis. At week 6, 22/35 (63%) and 33/45 (73%) patients in obese and non-obese groups were completely cured (P = 0.47). Similarly, there was no statistically significant difference for mycological and clinical cure in both the groups (P = 0.17 and P = 0.61, respectively). Four patients in the obese group (18% of completely cured), while one patient in the non-obese group (3% of completely cured), relapsed within 4 weeks of completion of treatment (P = 0.14). The therapy was well tolerated by both groups, with only one patient in the non-obese group experiencing pruritus. Conclusion: SITZ-130 mg once daily achieved desired and similar clinical response in obese patients as of non-obese patients suffering from dermatophytosis, and hence, a higher dose may not require in obesity.

Background: Calotropis procera (Aiton) (Apocynaceae) is a traditional Indian medicinal plant and used in folk medicine for the past decade for the treatment of gastrointestinal disorders. Therefore the current investigation was undertaken to explore the gastroprotective effect of C. procera (Aiton) leaves extract using pylorus ligation-induced gastric ulcer in rats. Methods: The crude powder material was successively extracted with different solvents and concentrated at reduced pressure in a rotary evaporator. The current investigation was carried out by a pylorus ligation-induced gastric ulcer model in rats. Omeprazole, 20 mg/kg and 100, 250, and 500 mg/kg ethanol extract of C. procera (Aiton) leaves were administered orally for 15 consecutive days, on the last day six hours after pylorus ligation animals were sacrificed and the amount of gastric juice, pH, total and free acidity, ulcer index, and pro-inflammatory cytokines along with antioxidant parameters and total protein were also studied. Results: Pretreatment of C. procera (Aiton) leaf extract at the doses 250 and 500 mg/kg, significantly (p < 0.001) decrease the volume of gastric juice, free and total acidity as well as gastric lesions, and secretion of pro-inflammatory cytokine. On the other hand, the pH of gastric juice, mucin content, and total protein was also significantly decreased. Moreover, pretreatment of C. procera (Aiton) significantly (p < 0.001) boost the enzymatic activity and level of different antioxidant markers and attenuated the pylorus ligation-induced level of MDA (p < 0.05) in experimental animals. Conclusion: From this study, it is concluded that the ethanol leaf extract of C. procera (Aiton) extract possess considerable antiulcer and antioxidant potential. For further research findings, it is necessary to explore the mechanism of action for anti-ulcer activity.