Regulatory Considerations in the Approval of Rezafungin (REZZAYO) for the Treatment of Candidemia and Invasive Candidiasis in Adults.

On March 22, 2023, the FDA approved rezafungin (REZZAYO) for the treatment of candidemia and invasive candidiasis in adults with limited or no alternative treatment options. Rezafungin is an echinocandin that supports weekly dosing, enabling outpatient parenteral treatment that potentially avoids the need for a central venous catheter. Approval of rezafungin was based on a single adequate and well-controlled phase 3 study designed with a Day 30 all-cause mortality primary endpoint and 20% noninferiority margin, which demonstrated that rezafungin is noninferior to the comparator echinocandin. Nonclinical studies of rezafungin in non-human primates identified a neurotoxicity safety signal; however, rezafungin's safety profile in the completed clinical studies was similar to other FDA-approved echinocandins. Here we describe the rationale for this approval and important considerations during the review process for a flexible development program intended to expedite the availability of antimicrobial therapies to treat serious infections in patients with limited treatment options.

Do differences in cell lines and methods used for calculation of IC50 values influence categorisation of drugs as P-glycoprotein substrates and inhibitors?

In vitro bidirectional assays are employed to determine whether a drug is a substrate and/or inhibitor of P-glycoprotein (P-gp) transport. Differences between cell lines and calculation methods can lead to variations in the determination of efflux ratios (ER) and IC50 values used to classify a drug as a P-gp substrate and inhibitor, respectively.Information was collected from the literature on ER and IC50 values with digoxin as the probe substrate using different cell lines and inhibition calculation methods. Predictive performance was evaluated by comparing [Igut]/IC50 ratios versus reported in vivo results.For known P-gp substrates, 50% of the drugs had their highest ER value in MDCK-MDR1 cells while 81% had their lowest ER value in Caco-2 cells. For 30 drugs with inhibition data, lower mean IC50 values were often observed with the Caco-2 cells and calculations based on ER. Based on the cut-off criteria of [Igut]/IC50 ≥ 10, there were no significant differences in positive or negative predictive values based on either cell line or calculation method for the drugs.Within this limited dataset, differences between cell lines or IC50 calculation methods do not seem to impact the prediction of in vivo P-gp inhibitor classification.

Variations in pharmacokinetic-pharmacodynamic target values across MICs and their potential impact on determination of susceptibility test interpretive criteria.

BACKGROUND: An antibacterial drug's susceptibility test interpretive criteria (STIC) are determined by integrating clinical, microbiological and pharmacokinetic-pharmacodynamic (PK-PD) data. PTA analysis plays a pivotal or supportive role in STIC determination and is heavily dependent on the PK-PD target values determined from animal PK-PD studies. Therefore, variations in PK-PD target values may impact STIC determination. Factors contributing to variation in the PK-PD target values include the number of and MICs for bacterial isolates used in animal PK-PD studies. OBJECTIVES: To analyse the relationship between PK-PD target values and MICs, describe the variations in PK-PD target values of isolates and evaluate whether the proposed/target STICs were within the ranges of the MICs for isolates used in animal PK-PD studies. METHODS: A database was compiled for this research by screening animal PK-PD study reports submitted to the FDA from 10 new drug applications (NDAs). RESULTS: A relationship evaluation between PK-PD target values and MICs for tested isolates for seven drugs (that used AUC/MIC ratio as the PK-PD index) showed that, generally, the AUC/MIC values decreased with an increase in MIC. These target values were highly variable, with the percentage coefficient of variation ranging between 1% and 132% for isolates having the same MIC. For 16/27 (59%) drug/bacteria combinations from all 10 drugs, the proposed/target STICs were higher than the highest MIC for bacteria isolates evaluated, while 6/27 (22.5%) were lower. CONCLUSIONS: This research suggests that careful considerations related to selection of bacterial isolates for animal PK-PD studies could strengthen the STIC determination process.

FDA Public Workshop Summary: Advancing Animal Models for Antibacterial Drug Development.

The U.S. Food and Drug Administration (FDA) hosted a public workshop entitled "Advancing Animal Models for Antibacterial Drug Development" on 5 March 2020. The workshop mainly focused on models of pneumonia caused by Pseudomonas aeruginosa and Acinetobacter baumannii The program included discussions from academic investigators, industry, and U.S. government scientists. The potential use of mouse, rabbit, and pig models for antibacterial drug development was presented and discussed.

Effect of microporation on passive and iontophoretic delivery of diclofenac sodium.

Skin pretreatment with a microneedle roller (microporation (MP)) appears a simple and inexpensive technique to increase transdermal delivery of topically applied drug products. This study investigates the effect of MP on the passive and iontophoretic delivery of diclofenac (DCF) by quantifying dermis and plasma levels of DCF in a rabbit model. New Zealand albino female rabbits received either: (i) a topical application of 4 g of Voltaren® 1% gel with or without pretreatment with a microroller (0.5 mm needle length; density 23 microneedles per cm(2) area) or (ii) a DCF solution (40 mg/2.5 mL) via iontophoresis (IOMED transQ(E) medium size patch), with or without microroller pretreatment. A 300 µA/cm(2) cathodic current was applied for 20 min for a total of 80 mA. DCF concentrations were monitored in dermis with microdialysis sampling every 20 min for 5 h. Plasma samples were collected over the same period. In the passive delivery studies, microroller pretreatment increased Cmax by 1.5- and 2.0-fold in skin and plasma, respectively, and AUC by 1.5- and 2.4-fold in skin and plasma, respectively. In the iontophoresis delivery studies, microporation increased Cmax by 2.0-fold both in skin and in plasma, and AUC by 1.1- and 1.8-fold in skin and plasma, respectively. In conclusion, microneedle pretreatment increased significantly the systemic exposure of DCF from either passive or iontophoretic delivery, whereas the effect in skin was less pronounced.

Dual photo-detector system for low phase noise microwave generation with femtosecond lasers.

Low phase noise microwave signals can be generated by photo-detecting the pulse train of an optical frequency comb locked to a high spectral purity continuous-wave optical reference. Amplitude-to-phase noise conversion is, however, a well-known limitation to this technique. Great care is usually required to overcome this constraint due to its strong dependence on the impinging optical power. Here we demonstrate the combined use of "magic point" operating conditions of photodetectors, pulse repetition rate multipliers, and coherent addition of microwave signals to realize a microwave extraction device largely immune to amplitude-to-phase conversion effects over a large range of impinging optical powers.

Social capital in a time of uncertainty: A case study of COVID-19 in Maharashtra state, India.

A novel coronavirus disease (COVID-19) was reported in India in late January 2020, less than 50 days after the first case was reported in Wuhan, China. Knowingly or unknowingly, almost all aspects of humankind around the world are affected, including physical, mental, and financial aspects. We set out to investigate how local communities take preventive action and have a meaningful role in dealing with these impacts of COVID-19. This community role is absolutely based on trust, regular communication, and social networking among community members. We collected data from India to determine whether the community-level response to COVID-19 during the peak phase of the pandemic (January 1st to February 1st, 2021) depended on the level of social capital. The source of information on COVID-19 is one of the significant issues during the pandemic. People prefer to depend on and trust family members, who represent the only trustworthy source of information irrespective of where they bring the information. In general, regular participation in local activities plays a major role in preventing COVID-19 at the local level.

Expert Opinion Guidance on the Detection of Early Connective Tissue Diseases in Interstitial Lung Disease.

There is a significant variation in symptoms and clinical presentation of connective tissue disorders (CTD) associated with interstitial lung disease (ILD) (CTD-ILD). This presents difficulties in the diagnosis and treatment of CTD-ILD. Early detection and treatment of CTD-ILD using a multidisciplinary approach have been shown to enhance patient outcomes. This exercise aims to explore clinical components to develop a screening tool for pulmonologists for early detection of CTD in ILD and to provide a framework for a multidisciplinary approach in managing CTD-ILD. This in turn will lead to early treatment of CTD-ILD in collaboration with rheumatologists. A panel of 12 leading rheumatologists from the Middle East and North Africa (MENA) region met virtually to select the most relevant clinical findings to aid in identifying CTD-ILD. Twelve panellists opted to investigate seven of the most common inflammatory autoimmune disorders. The panel discussed how to improve the early detection of CTD-ILD. Clinical characteristics were categorized, and a nine-item questionnaire was created. A biphasic algorithm was developed to guide early referral to a rheumatologist based on the presence of one of nine clinical features of CTD (Phase 1) or the presence of CTD-specific antibodies (Phase 2). A brief questionnaire has been developed to serve as a simple and practical screening tool for CTD-ILD detection. Additional research is needed to validate and evaluate the tool in longitudinal cohorts.

Comprehensive description of the prevalence, serological and clinical characteristics, and visceral involvement of systemic sclerosis (scleroderma) in a large cohort from the United Arab Emirates Systemic Sclerosis Registry.

Systemic sclerosis is an autoimmune condition characterized by a wide range of clinical presentations. Registries may serve to expand understanding about systemic sclerosis and aid in patient care and follow-up. The objective of this study was to analyze the prevalence of systemic sclerosis in a large cohort from the United Arab Emirates Systemic Sclerosis Registry and find the significant similarities and differences between the different subsets. All scleroderma patients in the United Arab Emirates were included in this multicenter national retrospective analysis. Data on demographics, comorbidities, serological characteristics, clinical aspects, and treatment were collected and analyzed, highlighting the most common traits identified. A total of 167 systemic scleroderma patients from diverse ethnic backgrounds were enrolled. Overall, 54.5% (91/167) of the patients were diagnosed with diffuse cutaneous systemic sclerosis, and 45.5% (76/167) with limited cutaneous systemic sclerosis. The prevalence of systemic sclerosis was 1.66 per 100,000 for the total registry and 7.78 per 100,000 for United Arab Emirates patients. Almost all patients in the diffuse cutaneous systemic sclerosis and limited cutaneous systemic sclerosis groups tested positive for the immunofluorescence antinuclear antibody. Antibodies against Scl-70 were significantly more associated with diffuse cutaneous systemic sclerosis, whereas anticentromere antibodies were significantly more associated with the limited cutaneous systemic sclerosis group (p < 0.001). Sclerodactyly, shortness of breath, and digital ulcers were more common in diffuse cutaneous systemic sclerosis patients compared with the limited cutaneous systemic sclerosis subtype in terms of clinical symptoms and organ involvement. Telangiectasia was much more common in the limited cutaneous systemic sclerosis group. Furthermore, diffuse cutaneous systemic sclerosis patients had more lung fibrosis (interstitial lung disease) than limited cutaneous systemic sclerosis patients (70.5% vs 45.7%), and pulmonary arterial hypertension was twice as common in limited cutaneous systemic sclerosis patients as it was in diffuse cutaneous systemic sclerosis patients. Local registries are paramount to understanding the clinical/serological characteristics of scleroderma. This study emphasizes the importance of raising disease awareness and distinguishing between the various systemic sclerosis subsets to implement patient-tailored strategies for early detection, better management, and higher quality of care.

Quantification of dermal and transdermal delivery of meloxicam gels in rabbits.

BACKGROUND: This study was designed to quantify the effects of penetration enhancers on systemic bioavailability of 0.3% meloxicam (MLX) hydroxypropylcellulose gels. Cutaneous microdialysis was also performed to assess dermis availability and to better understand the penetration process. The gels tested were a 1% oleic acid gel, a 5% menthol gel, and a control gel without penetration enhancers. METHODS: To assess systemic bioavailability, three female rabbits received according to a crossover design 0.135 g/cm(2) of gel applied to a 7.5 × 7.5 cm area of their shaved back and a short (5 min) infusion of 1 mg. In each experiment, blood samples were collected serially for 36 h and analyzed by a validated HPLC method. For skin bioavailability studies, 0.135 g/cm(2) of the same gels were applied to a 1 × 2 cm area on top of a microdialysis probe previously inserted in the dermis. Dialysate samples were collected for 6 h every 30 min. RESULTS: Systemically, the 5% menthol gel delivered 3.93 ± 0.85 mg of MLX versus the 1.41 ± 0.24 mg of the oleic acid gel. Only traces of MLX were detectable from the control gel. In dermis, substantial concentrations of MLX were detected only after the application of the menthol gel, whereas skin concentration from the control gel and the 1% oleic acid gel were always below the lowest limit of quantification (LLOQ). CONCLUSIONS: The 5% menthol gel can possibly deliver therapeutically relevant amount of MLX in vivo. Dermis concentrations can be predictive of systemic plasma levels.

Pharmacokinetics and Pharmacological Properties of Chloroquine and Hydroxychloroquine in the Context of COVID-19 Infection.

Chloroquine and hydroxychloroquine are quinoline derivatives used to treat malaria. To date, these medications are not approved for the treatment of viral infections, and there are no well-controlled, prospective, randomized clinical studies or evidence to support their use in patients with coronavirus disease 2019 (COVID-19). Nevertheless, chloroquine and hydroxychloroquine are being studied alone or in combination with other agents to assess their effectiveness in the treatment or prophylaxis for COVID-19. The effective use of any medication involves an understanding of its pharmacokinetics, safety, and mechanism of action. This work provides basic clinical pharmacology information relevant for planning and initiating COVID-19 clinical studies with chloroquine or hydroxychloroquine, summarizes safety data from healthy volunteer studies, and summarizes safety data from phase II and phase II/III clinical studies in patients with uncomplicated malaria, including a phase II/III study in pediatric patients following administration of azithromycin and chloroquine in combination. In addition, this work presents data describing the proposed mechanisms of action against the severe acute respiratory distress syndrome coronavirus-2 and summarizes clinical efficacy to date.

Lower back pain as a manifestation of acute gouty sacroiliitis: Utilization of dual-energy computed tomography (DECT) in establishing a diagnosis.

Gout is the most common inflammatory arthritis which initially presents as a monoarthritis that usually favours peripheral joints namely the 1st MTP. It was reported in the literature to rarely involve the axial joint, such as the sacroiliac joint, and often mimics seronegative spondyloarthritis (SpA). Gout is a male disease and after menopause the risk in females is equal to males. Previous reports describe male patients developing gout involving the SI joint. We report a lady with a history of gout presenting with acute onset lower back pain. MRI of the sacroiliac joints revealed unilateral sacroilitis. With the help of Dual-Energy Computed Tomography (DECT) which is a newer imaging technique, a diagnosis of gout involving the sacroiliac joint was established. Gout involving the sacroiliac joints is rare, however it should be considered in the differential diagnosis in patients with unilateral sacroilitis given the similarity in presentation to SpA. Utilization of newer imaging modalities including DECT can highly guide in establishing a diagnosis and providing the correct treatment.

Demographic and Clinical Patterns of Rheumatoid Arthritis in an Emirati Cohort from United Arab Emirates.

This retrospective cohort study aimed to assess the demographic and clinical characteristics of rheumatoid arthritis (RA) in Emirati patients attending Cleveland Clinic Abu Dhabi, a large tertiary center in the Middle East. In this study, 414 Emirati patients with RA were evaluated over a 3-year period from April 2015 to April 2018. All patients fulfilled the 2010 RA ACR/EULAR criteria and were assessed for demographic and clinical characteristics. The estimated RA prevalence rate in our population cohort was 2.72%. Females showed predominance (80%) with a higher body mass index (31.4 ± 6.61, P = 0.0001) compared to males (28.8 ± 6.03, P = 0.0001). The most frequent comorbidity observed was dyslipidemia (43.5%) followed by hypertension (37.9%), diabetes mellitus (34.5%), and gastroesophageal reflux disease (33.1%). Xerophthalmia was the most frequent extra-articular manifestation. Rheumatoid factor and anti-citrullinated peptide were detected in 63.3% and 41.5% patients, respectively, while both were present in 33.3% of patients. Methotrexate, adalimumab, and rituximab were the most frequently prescribed disease modifying agents. In this study, we describe disease features that are unique to United Arab Emirates (UAE) patients and demonstrate that RA has a significant disease burden. Our findings highlight the need for a RA national registry to improve the quality of care of these patients in UAE.

Prevalence and real-world assessment of central aortic blood pressure in adult patients with essential hypertension uncontrolled on single anti-hypertensive agents.

OBJECTIVE: To assess the prevalence of high central aortic pressure (CAP) in Indian patients with uncontrolled essential hypertension while on anti-hypertensive monotherapy. Also, to determine correlation between brachial blood pressure (BBP) and CAP, and ascertain if it is impacted by anti-hypertensive drug class and patients' age. METHODS: In this real-world, observational, prospective study, patients (30-70 years) with uncontrolled BBP (systolic BP [SBP] ≥140 mmHg or diastolic BP [DBP] ≥90 mmHg) were enrolled. Treatment was adjusted at Visit 1 (baseline), based on BBP and at treating physicians' discretion. Primary endpoint was proportion of patients with uncontrolled central aortic SBP (>125 mmHg) at baseline. Secondary endpoints were comparison of BBP and CAP across drugs classes and age groups at baseline and Visit 2 (End-of-study, ∼8 weeks post-baseline), and proportion of patients with uncontrolled central SBP at end-of-study. RESULTS: Of 2030 patients screened, 1949 patients reported at baseline and 1740 patients completed end-of-study visit. Central SBP was >125 mmHg for 84.3% patients at baseline, and 48% patients at end-of-study. Interestingly, at end-of-study, 6.6% patients still had uncontrolled brachial SBP and controlled central SBP, while 13.6% patients had uncontrolled central SBP and controlled brachial SBP. At both visits, brachial SBP and central SBP showed positive correlation across most drug classes and age groups. At baseline, ACE inhibitors showed better efficacy than other drug classes. At end-of-study, BP control was better with fixed-dose combinations, though free-drug combinations were more frequently prescribed. CONCLUSION: Measurement of CAP along with BBP can be vital in management of hypertension. CTRI REGISTRATION NUMBER: CTRI/2015/10/006302.

Pharmacokinetic applications of cutaneous microdialysis: Continuous+intermittent vs continuous-only sampling.

INTRODUCTION: Microdialysis is a technique that allows interstitial-fluid sampling with minimal tissue-damage. In a microdialysis study, samples are collected serially (continuous microdialysis, CMD) and participant's movements are reduced for the entire study. Intermittent Cutaneous Microdialysis (IMD) is a modified version of CMD, which allows for unrestrained periods in between samples. However, in separate experiments, pharmacokinetic parameters estimated with IMD showed higher variability than with CMD. The purpose of this study is to simultaneously assess and compare the skin pharmacokinetic profiles obtained with a combination of CMD and IMD with those obtained with traditional CMD sampling only, in the same experiment. METHODS: Two linear microdialysis (MD) probes were inserted into the shaved dorsal skin of three rabbits. Following the oral administration of three different doses (20, 40 and 80mg/kg) of ciprofloxacin (CPLX), for the first 2h, samples were collected from both probes according to traditional CMD in order to assess intrinsic differences between the two sites. After 2h, one of the probes was switched to IMD schedule. Skin-exposure parameters were estimated with non-compartmental analysis. RESULTS: Two of the nine experiments showed a difference larger than 30% between the concentrations measured from the two probes when both were on the CMD schedule. Otherwise, the skin concentration profiles were almost superimposable. Pharmacokinetic parameters were not statistically different. CONCLUSION: The results of this study show that skin pharmacokinetic parameters measured via a combination of CMD and IMD were not statistically different from those estimated via traditional CMD sampling alone.

Cutaneous Penetration-Enhancing Effect of Menthol: Calcium Involvement.

Menthol is a naturally occurring terpene used as a penetration enhancer in topical and transdermal formulations. Literature shows a growing interest in menthol's interactions with the transient receptor potential melastatin 8. A decrease in extracellular Ca2+ due to the activation of the transient receptor potential melastatin 8 receptor produces inhibition of E-cadherin expression that is responsible for cell-cell adhesion. Because calcium is present in the entire epidermis, the purpose of this study is to evaluate whether the aforementioned properties of menthol are also related to its penetration-enhancing effects. We formulated 16 gels: (i) drug-alone (diphenhydramine or lidocaine), (ii) drug with menthol, (iii) drug, menthol, and calcium channel blocker (CCB; verapamil or diltiazem), and (iv) drug and CCB. In vitro studies showed no effect of the CCB on the release of the drugs either with or without menthol. In vivo experiments were performed for each drug/menthol/CCB combination gel by applying 4 formulations on a shaved rabbit's dorsum on the same day. Dermis concentration profiles were assessed with microdialysis. The gels containing menthol showed higher penetration of drugs than those without whereas the addition of the CCB consistently inhibited the penetration-enhancing effects of menthol. In summary, these findings strongly support the involvement of calcium in the penetration-enhancing effect of menthol.

Gemigliptin: Newer Promising Gliptin for Type 2 Diabetes Mellitus.

The dipeptidyl peptidase-4 (DPP-4) inhibitors have facilitated the management of type 2 diabetes mellitus (T2DM) owing to their superior efficacy and safety with low incidence of adverse effects. Gemigliptin is a new member of this family of drugs, and studies have revealed certain advantages of gemigliptin use compared to its previous congeners. Besides, this drug has also been studied for the treatment of T2DM as monotherapy, in combination with metformin or other oral antidiabetic drugs and in T2DM with moderate-to-severe renal failure. In this review, we explore the published data highlighting the pharmacology, efficacy, and safety of gemigliptin along with its recommendations for use in patients with T2DM.

Kaposi sarcoma in a patient with giant cell arteritis.

Kaposi sarcoma usually occurs in immunosuppressed patients. A classic type has been reported in elderly men of Jewish and Mediterranean origin. We report a case of an elderly woman with giant cell arteritis (GCA) who developed Kaposi sarcoma while on a double blind trial for GCA with an anti-tumor-necrosis-factor medication. Our patient had none of the risk factors for Kaposi sarcoma, and when she was withdrawn from the study it was found that she was receiving only placebo along with the moderate, tapering doses of corticosteroids.

Transdermal Delivery of Etoposide Phosphate II: In Vitro In Vivo Correlations (IVIVC).

A dependable in vitro in vivo correlation (IVIVC) is a vital tool to optimize drug formulation and expedite product development time. Although many IVIVC examples are available for oral delivery systems, IVIVC for transdermal delivery is far less common, especially for electrical-assisted delivery. The objective of this study was to develop an IVIVC for the iontophoretic delivery of the anticancer drug etoposide. Iontophoresis was performed at 4 current densities (100, 200, 300, and 400 µA/cm(2)) both in vitro using a standard Franz-cell apparatus with excised porcine skin as membrane, and in vivo in a rabbit model. There was strong correlation between the in vitro % permeated across porcine skin and in vivo absorption (AUC, Cmax) in the range 100-300 µA/cm(2). The correlation between in vitro flux and in vivo input rate (R0) permitted to predict the R0 from a different set of in vitro data (external validation). Convolution of such input rate accurately predicted in vivo plasma profiles (PE% <15) in the absorption phase, whereas the elimination phase was slightly under-predicted (PE% >20). In vivo absorption profiles obtained with deconvolution did not overlap directly with the in vitro profiles; however, correction for the lag time and the application of a scaling factor estimated from Levy' s plots resulted in excellent correlation.

Transdermal Delivery of Etoposide Phosphate I: In Vitro and In Vivo Evaluation.

Cancer chemotherapy frequently requires long periods of multiple intravenous infusions that often results in patients opting out of treatment. The main purpose of this study was to investigate the feasibility of delivering one of these anticancer agents: etoposide phosphate (ETP) transdermally using iontophoresis and a combination of iontophoresis/microporation. The iontophoresis conditions for ETP were first optimized in vitro then tested in vivo in a rabbit model. Both ETP and its active form etoposide (VP) were quantified in dermis (via microdialysis sampling) and in plasma, with a specially developed high-performance liquid chromatography method. In vitro, the amount of total etoposide permeated and the steady state flux increased (p < 0.05) with increase in iontophoretic current densities (100-400 µA/cm(2)). At 300 µA/cm(2), microporation/iontophoresis further improved both parameters by 2- and 2.8-fold, respectively. In vivo, exposure increased proportionally to current density in plasma, whereas dermal concentration dropped significantly at the highest current density. Microporation led to a 50% increase in Cmax and AUClast values in both skin and plasma. In conclusion, a mild current density (300 µA/cm(2)) and a small surface area (10.1 cm(2)) achieved and maintained the minimum effective concentration for the entire duration of electrical current delivery; microporation further increased the plasma concentrations at the same current density.