A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an αVß3 Binder for the Treatment of Multiple Cancer Types

To improve tumor selectivity of cytotoxic agents, we designed VIP236, a small molecule–drug conjugate consisting of an αVβ3 integrin binder linked to a modified camptothecin payload (VIP126), which is released by the enzyme neutrophil elastase (NE) in the tumor microenvironment (TME). The tumor targeting and pharmacokinetics of VIP236 were studied in tumor-bearing mice by in vivo near-infrared imaging and by analyzing tumor and plasma samples. The efficacy of VIP236 was investigated in a panel of cancer cell lines in vitro, and in MX-1, NCI-H69, and SW480 murine xenograft models. Imaging studies with the αVβ3 binder demonstrated efficient tumor targeting. Administration of VIP126 via VIP236 resulted in a 10-fold improvement in the tumor/plasma ratio of VIP126 compared with VIP126 administered alone. Unlike SN38, VIP126 is not a substrate of P-gp and BCRP drug transporters. VIP236 presented strong cytotoxic activity in the presence of NE. VIP236 treatment resulted in tumor regressions and very good tolerability in all in vivo models tested. VIP236 represents a novel approach for delivering a potent cytotoxic agent by utilizing αVβ3 as a targeting moiety and NE in the TME to release the VIP126 payload—designed for high permeability and low efflux—directly into the tumor stroma.

Plasmalemmal V-ATPase as a Potential Biomarker for Lactoferrin-Based Anticancer Therapy

Lactoferrin (Lf) is a milk-derived protein with well-recognized potential as a therapeutic agent against a wide variety of cancers. This natural protein exhibits health-promoting effects and has several interesting features, including its selectivity towards cancer cells, good tolerability in humans, worldwide availability, and holding a generally recognized as safe (GRAS) status. To prompt the rational clinical application of this promising anticancer compound, previous works aimed to unveil the molecular mechanisms underlying its selective anticancer activity, where plasmalemmal V-ATPase was identified as an Lf target in cancer cells. V-ATPase is a proton pump critical for cellular homeostasis that migrates to the plasma membrane of highly metastatic cancer cells contributing to the acidity of the tumor microenvironment. Cancer cells were found to be susceptible to Lf only when this proton pump is present at the plasma membrane. Plasmalemmal V-ATPase can thus be an excellent biomarker for driving treatment decisions and forecasting clinical outcomes of Lf-based anticancer strategies. Future research endeavors should thus seek to validate this biomarker by thorough preclinical and clinical studies, as well as to develop effective methods for its detection under clinical settings.

Nanocrystalline chloroxine possesses broad-spectrum antimicrobial activities and excellent skin tolerability in mice

Background: Antimicrobial submicrometer particles are being studied as promising interventions against a wide range of skin conditions, such as fungal or bacterial infections. Aims: To submicronize chloroxine, the crystalline compound 5,7-dichloro-8-hydroxyquinoline, by nanoprecipitation and characterize the resulting assemblies. Methods: The chloroxine particles were stabilized by a nonionic surfactant and were studied by a broth microdilution assay against 20 medically important bacteria and fungi. The intervention was studied using a murine model of skin irritation. Results & conclusions: Chloroxine nanoparticles with a diameter of 600–800 nm exhibit good tolerability in terms of skin irritation in vivo and good antimicrobial activity. Thus, the fabricated formulation shows great promise for interventions for both cutaneous infection control and prophylaxis.

Localized peripheral neuropathic pain: topical treatment with lidocaine 700 mg medicated plaster in routine clinical practice

Aim: To provide real-world evidence for the effectiveness and tolerability of lidocaine 700 mg medicated plaster (LMP) in localized peripheral neuropathic pain (l-PNP) treatment compared with first-line oral medications (OM). Patients & methods: This was a noninterventional, retrospective 6-month cohort study in patients refractory to at least one recommended OM, using anonymized medical care data from the German Pain eRegistry. Treatment groups were matched by propensity scoring, considering seven predefined confounding factors. The primary effectiveness end point was the absolute change in average pain intensity index from baseline at weeks 4, 12 and 24 of treatment and over the treatment period. Results: A total of 3081 datasets were retained per treatment group. LMP provided superior pain reductions and significantly greater improvements in pain-related impairments of daily living and quality of life with significantly better tolerability (p < 0.001 for all parameters) than OM. Conclusion: These real-world data confirm the effectiveness and good tolerability of LMP for l-PNP treatment under routine medical care.

Efficacy and Tolerability of Methotrexate in the Treatment of Severe Paediatric Alopecia Areata

<b><i>Introduction:</i></b> Alopecia areata (AA) is a chronic, autoimmune condition affecting hair follicles, and its occurrence in the paediatric population is associated with poorer prognosis and limited treatment options compared to adults. Treatment with oral methotrexate (MTX) has been documented in adults, but there is a paucity of data for its use in the paediatric population. We aimed to study the efficacy and tolerability of MTX in severe paediatric AA. <b><i>Methods:</i></b> We performed a retrospective review on paediatric patients with severe AA who were treated with MTX in our centre from January 2019 to December 2020. <b><i>Results:</i></b> Thirteen patients were included (6 boys and 7 girls) aged between 4 and 16 years at the initiation of MTX (mean age of 8.8 years). The interval from diagnosis of AA to commencement of MTX was between 8 months and 9 years (mean duration of 3.3 years). Oral MTX was administered once weekly with a mean maximal dose of 0.4 mg/kg/dose. Out of 12 assessable patients, 5 were considered treatment success as they had more than 50% regrowth, while the other 7 were treatment failures. No serious side effects were reported. <b><i>Conclusion:</i></b> MTX was shown to have variable efficacy for the treatment of paediatric AA with overall good tolerability. MTX can be considered in the treatment of severe refractory AA for children.

Immunogenicity of the drug "Live intranasal vaccine for the prevention of pertussis" (GamLPV) with a single use in healthy volunteers

Introduction. A significant increase in the incidence of pertussis in the world, including among adolescents and adults, the prevalence of mild forms of the disease and asymptomatic carrier of bacteria B. pertussis, and the resulting need for mass revaccination of different age groups determine the demand for new vaccines against B. pertussis. In N.F. Gamaleya Federal Research Center for Epidemiology and Microbiology, a live intranasal pertussis vaccine for the prevention of pertussis (GamLPV) has been developed. The GamLPV vaccine underwent preclinical studies that proved its safety and effectiveness in experiments on small laboratory animals and nonhuman monkeys. Safety of vaccine is shown in clinical studies on healthy volunteers.The aim of the study is to assess the immunogenicity of different doses of the drug GamLPV when first used in healthy volunteers.Materials and methods. The study was conducted as randomized placebo-controlled, blind trial with consistent volunteer inclusion and dose escalation. Study ID in clinicaltrials.gov database: NCT03137927 (A Phase I Clinical Study of a GamLPV, a Live Intranasal Bordetella Pertussis Vaccine). The following parameters of humoral and cellular immune responses were assessed in dynamics: levels of specific IgM, IgG and IgA antibodies in blood serum of volunteers and the number of cytokines interleukin-17, tumor necrosis factor-α, interferon-γ produced after specific induction in vitro of blood mononuclears of vaccinated volunteers. Dynamics of attenuated bacteria persistence in nasopharynx of vaccinated volunteers was evaluated.Results. Intranasal vaccination of volunteers with the drug Gam LPV resulted in the formation of a specific humoral (IgG and IgA) and cellular immune response. The dose-dependent nature of immunoglobulin and cytokine production was shown. Attenuated bacteria persisted for a long time in the nose/oropharynx of vaccinated volunteers.Discussion. Good tolerability of all tested doses of the drug justifies the choice for further investigation of a vaccine dose equal to 4 × 109 CFU. At the next stage, the safety and immunogenicity of two-time vaccination of volunteers will be studied.

Safety assessment of a new anti-tuberculosis drug in silico and with the participation of healthy volunteers

Relevance. In connection with the increase in the number of cases of multidrug-resistant tuberculosis (MDR-TB), the search for new anti-tuberculosis drugs (ATD) is necessary. The assessment of its effect on the human body outside the aspect of the therapeutic effect is one of the main directions in the development of anti-TB drugs.Aim. Evaluation of the possible toxicity of thiosonide, a new domestic anti-TB drug, combining a consistent study of this side of the drug using a bioinformatics approach and an analysis of the results of a clinical safety study.Methods. The bioinformatic assessment was carried out using web services and models to predict the toxicity of thiosonide. The safety assessment in relation to healthy volunteers was carried out as part of a clinical study according to the protocol: «An open-label study of the pharmacokinetics, safety and tolerability of the drug thiozonide, capsule 100 mg with a single dose of increasing doses by various groups of healthy volunteers.» (2013, Permit No. 187 to conduct a clinical trial dated March 22, 2013, issued by the Ministry of Health of the Russian Federation).Results. Potential unwanted targets were identified, the predicted activity value for which was greater than 7. The results obtained indicate the likelihood of the effect of thiosonide on these protein targets and, possibly, the ability of the latter to cause side effects associated with changes in the activity of these molecules. The cytotoxic and carcinogenic effect of thiosonide is not predicted. During a clinical study, the drug thiosonide showed good tolerance and safety, since the identified adverse events did not show a definite or reliable relationship with the study drug. The resolution of all adverse events was complete, and dose escalation did not affect the number, severity of AEs and association with the study drug.Conclusion. The safety analysis of thiosonide demonstrated its good tolerability both during in silico assessment and in a study with the participation of healthy volunteers.

Efficacy of a Retinoid, Keratolytic, Anti-Inflammatory and Antibacterial Gel and Spray Formulations in Mild Common Acne

Background and Objectives: For the treatment of mild/moderate acne, topical retinoids and antibacterial molecules are used in monotherapy or in combination. An exfoliating and anti-inflammatory action can increase the clinical efficacy of this therapeutic approach. A topical product in Gel and Spray Formulations (GF and SF) with retinoids (hydroxypinacolone retinoate and encapsulated retinol), with anti-inflammatory (niacinamide), antibacterial (biopep15) and keratolytic (glycolic and salicylic acids) activity has recently been developed. Topical retinoids have anti-inflammatory, anti-seborrheic and anticomedone-formation properties. Biopep15 is an oligopeptide with antibacterial action that can interfere with lipoteichoic acid, a component of the wall of Cutibacterium acnes. In addition, Biopep15 can perform also an antagonistic action against the Toll-Like-Receptor 2, involved in the pathogenesis of acne. Niacinamide has a well-known anti-inflammatory action. Salicylic and glycolic explain keratolytic and exfoliating activities. In this study the objective was to determine the efficacy and tolerability of GF and SF in mild/ moderate comedogenic acne. Methods: In a 4-week, open-label, prospective trial, 32 patients between the ages of 15 and 30 have been evaluated. All participants gave their written consent. Treatment with gel (for facial lesions) and spray (for lesions located on thorax, back and shoulder) applied twice daily were used. To assess clinical efficacy, a count of comedogenic lesions (open and closed comedones; non-inflammatory lesions: NIL) and inflammatory lesions (IL; papules, and pustules) was performed and the reduction in the number of lesions after 2 and 4 weeks of treatment was evaluated. An evaluation of Total lesions count (TL; NIL+IL) was also performed.The lesion count data were analysed with a paired Student's t test.We evaluated also the exfoliating/keratolytic activity and the effect on sebum production assessed at baseline, after 2 and 4 weeks of treatment. Finally, to evaluate Cutibacterium acnes (C. acnes) skin colonization, we performed a fluorescence detection of skin porphyrin content at baseline and at day 28, by mean of Visiopor PP 34 camera. Results: All patients completed the trial. At baseline the NIL, IL and TL count were 14.3, 8.7 and23, respectively. After 2 weeks of GF/SF treatment, NIL, IL and TL significantly decreased to 9.7 (-32%), 6.8 (-22%) and 16.5 (-29%), respectively. At the end of the treatment, a significant reduction in comparison with baseline was observed for NIL (-49%) IL (-63%) and TL (-54%). The exfoliating index evaluated in comparison with baseline value improved not significantly by 13% at day 14, and significantly (p=0.05) by 18% at day 24. The Cutibacterium acnes skin colonization area was significantly (p=0.02) reduced by 28% in comparison with baseline. Treatment was well tolerated, and local tolerability was assessed as optimal by all patients. Conclusion: This new anti-acne combination formula based on retinoids, antibacterial oligopeptide, keratolytic and anti-inflammatory agents have shown high clinical efficacy and good tolerability in patients with mild to moderate acne. The treatment shows also a keratolytic effect and a significant reduction of C. acnes skin colonization.

Extended Disease Control with Unconventional Cabozantinib Dose Increase in Metastatic Renal Cell Carcinoma

BACKGROUND: Cabozantinib is among the most potent tyrosine kinase inhibitors (TKIs) FDA-approved for metastatic renal cell carcinoma (mRCC). Effective treatments after progression on cabozantinib salvage therapy are limited. Dose escalation for other TKIs has been shown to afford added disease control. OBJECTIVE: We sought to evaluate whether dose escalation of cabozantinib (Cabometyx®) from conventional doses in selected patients with limited treatment options offered additional disease control. We asked how cabozantinib dose increases may affect circulating drug levels. METHODS: We identified patients with mRCC at the University of Texas Southwestern Medical Center who were treated with cabozantinib dose escalation to 80 mg after progressing on conventional cabozantinib 60 mg. We then queried leading kidney cancer investigators across the world to identify additional patients. Finally, we reviewed pharmacokinetic (PK) data to assess how higher doses impacted circulating levels by comparison to other formulations (Cometriq® capsules). RESULTS: We report six patients treated at two different institutions with cabozantinib-responsive disease and good tolerability, where cabozantinib was dose escalated (typically to 80mg, but as high as 120 mg) after progression on 60 mg, a strategy that resulted in added disease control (median duration, 14 months; 95% Confidence Interval [CI]: 8 –Not Estimable[NE]). Four patients (66.7%) had disease control lasting at least 1 year. No grade III/IV adverse events were identified. A comparison of PK data to FDA-approved cabozantinib 140 mg capsules suggest that cabozantinib 80 mg tablets results in comparable exposures. CONCLUSIONS: mRCC patients with cabozantinib responsive disease and reasonable tolerability may benefit from dose escalation at progression.

The effectiveness of combined topical product with fluocortolone pivalate and lidocaine for hemorrhoids: results of a multicenter observational study

AIM: to assess the changes in hemorrhoids symptoms and satisfaction with treatment against the background of treatment with a combined topical product Relief® Pro.PATIENTS AND METHODS: multicenter prospective non-interventional cohort study was done in 13 clinical centers in Russia. The study included patients aged 18 to 65 years with acute hemorrhoids of stages 1–2 treated with the combined product Relief® Pro (rectal suppositories, cream or a combination thereof). The follow-up period was up to 14 days (in the case of 2 visits to the clinical center after receiving the initial data). The analysis was performed on the basis of data obtained at Visit 2 (5–7 days of therapy) and Visit 3 (10–14 days of therapy) vs the initial data (Visit 1). Following criteria were used: the severity of hemorrhoid symptoms on the Sodergren scale, the severity of hemorrhoid symptoms (pain, bleeding, itching, edema, the presence of discharge, a feeling of discomfort), the size of the largest hemorrhoid node, the satisfaction of the doctor and the patient with treatment, assessment of the patient’s adherence to recommendations for lifestyle changes and treatment, evaluation of the use of the drug Relief® were evaluated as endpoints About the treatment process and patient preferences regarding the dosage form of the prescribed drug. In addition, adverse events were evaluated.RESULTS: the study included 1000 patients aged 18 to 65 years (men — 54.5%, women — 45.5%) Patients had grade 1 acute hemorrhoids (330 patients), grade 2 acute hemorrhoids (345 patients) and exacerbation of chronic hemorrhoids (325 patients). The drug Relief® Pro rectal cream was used by 333 patients; suppositories — 383 patients; joint therapy with both dosage forms — 284 patients. During follow-up (visits 2 and 3), positive dynamics was observed in patients — a decrease in the severity of hemorrhoid symptoms both during objective examination and according to patient questionnaires. So, according to the patients’ estimates, the use of Relief® Pro, regardless of the form, led to a decrease in the severity or disappearance of the main symptoms of hemorrhoids — bleeding, itching, edema, the presence of discharge, discomfort already by Visit 2 and in almost all patients by the end of observation. A similar change of the symptoms due the digital examination: by day 5–7, the severity of edema and bleeding in the perianal region, bleeding decreased. About 96% of patients and about 97% of doctors were satisfied with the treatment. Application of both forms of Relief® The ABM was characterized by good tolerability: there were no adverse events associated, according to the researcher, with the studied drug.CONCLUSIONS: combined topical product Relief® Pro is effective for hemorrhoids.