New Horizons: Next-Generation Insulin Analogs: Structural Principles and Clinical Goals

Design of “first-generation” insulin analogs over the past three decades has provided pharmaceutical formulations with tailored pharmacokinetic (PK) and pharmacodynamic (PD) properties. Application of a molecular tool-kit—integrating protein sequence, chemical modification and formulation—has thus led to improved prandial and basal formulations for the treatment of diabetes mellitus. Although PK/PD changes were modest in relation to prior formulations of human and animal insulins, significant clinical advantages in efficacy (mean glycemia) and safety (rates of hypoglycemia) were obtained. Continuing innovation is providing further improvements to achieve ultra-rapid and ultra-basal analog formulations in an effort to reduce glycemic variability and optimize time in range. Beyond such PK/PD metrics, next-generation insulin analogs seek to exploit therapeutic mechanisms: glucose-responsive (“smart”) analogs, pathway-specific (“biased”) analogs, and organ-targeted analogs. Smart insulin analogs and delivery systems promise to mitigate hypoglycemic risk, a critical barrier to glycemic control, whereas biased and organ-targeted insulin analogs may better recapitulate physiologic hormonal regulation. In each therapeutic class considerations of cost and stability will impact utilization and global distribution. This review highlights structural principles underlying next-generation design efforts, their respective biological rationale and potential clinical applications.

Price versus clinical guidelines in primary care statin prescribing: a retrospective cohort study and cost simulation model

Objective To investigate the relative impact of generic entry and National Institute for Health and Care Excellence clinical guidelines on prescribing using statins as an exemplar. Design Retrospective analysis of statin prescribing in primary care and cost simulation model. Setting Royal College of General Practitioners Research and Surveillance Centre (RCGP R&SC) database and Prescription Cost Analysis (PCA) database. Participants New patients prescribed statins for the first time between July 2003 and September 2018. Results General trends of statin’ prescriptions were largely driven by a decrease in acquisition costs triggered by patent expiration, preceding NICE guidelines which themselves did not seem to affect prescription trends. Significant heterogeneity is observed in the prescription of the most cost-effective statin across GPs. A cost simulation shows that, between 2004 and 2018, the NHS could have saved £2.8bn (around 40% of the £6.3bn spent on statins during this time) if all GP practices had prescribed only the most cost-effective treatment. Conclusions There is potential for large savings for the NHS if new and, whenever possible, ongoing patients are promptly switched to the first medicine that becomes available as generic within a therapeutic class as long as it has similar efficacy to still-patented medicines.

Patient Demographics, Clinical Characteristics, and Medication Adherence to Treatment Among Patients on Oral Tyrosine Kinase Inhibitors in a Retail Pharmacy Setting

INTRODUCTION Previous studies have demonstrated the importance of adherence to oral tyrosine kinase inhibitors in improving outcomes, including achieving a complete cytogenic response. Patients with chronic myeloid leukemia (CML) that had a suboptimal response were more likely to be non-adherent. Early identification and intervention based on predictors of non-adherence may lead to improved outcomes for patients in the non-trial setting. This research aimed to determine the rate of adherence and persistence to oral tyrosine kinase inhibitors (TKI) and to assess associated effect of patient characteristics using real world data from a retail pharmacy setting. METHODS This retrospective analysis of administrative pharmacy claims data included a random sample of 5000 patients who filled at least one TKI medication (bosutinib, dasatinib, imatinib, nilotinib) from national retail pharmacy chain in the study period of May 1, 2018 to April 30, 2021. Data elements included prescription fill attributes, patient-level demographics, medication adherence by therapeutic class (TKI, antidiabetics, antihypertensives and antihyperlipidemics), as well as patient health conditions and diagnoses. Patient adherence barrier data were also analyzed for a subset of patients who received select clinical interventions. This research was reviewed and approved by Advarra IRB as exempt (Pro00044844). Medication adherence was measured using the proportion of days covered (PDC) metric. For each therapeutic class, PDC was measured from first fill date for that class from May 01 2018 to April 30 2021, followed for maximum of 365 days, and calculated as the ratio of the number of days of medication available and the measurement period. A cut-off to indicate suboptimum adherence of <85% was used for TKI and <80% for other classes. Length of therapy was measured as number of days a patient had underline medication coverage from the index date to the start date of medication gap that was>45 days. PDC and length of therapy and their influential factors were assessed using generalized linear models. Persistency rates were calculated descriptively and using Kaplan-Meier analyses. Associations among PDCs in TKI and common chronic medications were assessed using multivariate correlation statistics. All statistics were conducted using SAS 9.4. RESULTS The random sample of patients had a mean age of 61.7 years (median=65.6, IQR= =51, 75) and 49.9% were male. TKI use in our sample was predominantly imatinib (2,857, 57.1%) and dasatinib (1,428, 28.6%) with fewer patients on nilotinib (556, 11.1%) or bosutinib (159, 3.2%). Among those patients with adherence barrier data, the average number of barriers was 1.7. Among TKI users, 38.3% also had hypertension, 13.6% had diabetes and 15.6% had hyperlipidemia. Percent of TKI users who had common chronic conditions and who were taking corresponding therapies were 38.2%, 33.9%, and 33.3% for hypertension, hyperlipidemia, and diabetes, correspondingly. Mean TKI PDC was 0.797 (95% CL 0.789 to 0.804) with a median of 0.889. Over half of patients (55% patients) had a PDC>=.85. Mean TKI length of therapy was 18.3 months with a median of 15 months with differences by therapy. Correlation of TKI PDC to three common chronic therapy PDC were all low: 0.095 for antidiabetics; 0.032 for antihypertensives; 0.083 for antilipidemics) and not statistically significant. Age was a significant predicator of PDC, with every 10-year increase in age associated with a 2% increase in PDC. When a patient had previously stated adherence barriers, PDC was estimated to decrease by 1.7% for each barrier faced by the patient. Only a small portion (33%-38%) of TKI patients, who had a diagnosis for a common chronic condition, had a claim for the corresponding therapeutic class. CONCLUSIONS Adherence to TKI was influenced by non-modifiable risk such as age and modifiable risks such as the number of adherence barriers. Many patients on TKI who also had a common chronic condition were not taking medications for their chronic condition, noting a discordance in care. Ongoing capture of barrier data beyond specialty medications will help predict patient adherence behavior and identify targeted interventions. Disclosures No relevant conflicts of interest to declare.

Formulation, optimization, qualitative and quantitative analysis of new dosage form of corticosteroid

Background The objective of the present research work is to develop the entirely new drug product formulation (Ophthalmic Suspension) which belongs to the therapeutic class of steroids drugs (Corticosteroid). There are different dosage forms of Triamcinolone acetonide to treat different systemic as well as topical diseases as per patient symptomatic conditions. Due to non-availability of this active drug (Triamcinolone acetonide) ophthalmic dosage form in the national and international market research work is carried out to enter in this dosage form. Results In the formulation design and development, different inactive like polysorbate 30 mg/mL, PEG-12 glyceryl dimyristate 70 mg/mL, ethyl alcohol 10 µL/mL, citric acid 1 mg/mL, sodium citrate 3.5–4.0 mg/mL, BKC 0.15 mg/mL and water for injection have been used at different stages in different proportions during the manufacturing procedure. Gradient HPLC, C18 column, 5 µm, 100 A, 3.9 mm × 300 mm, detector UV/Vis @ 254 nm, column oven, auto-sampler, degasser, is used and this analytical testing method is validated to obtain the accurate results. The excipients play different roles including solvent, antioxidant, solubilizer, emulsifier, antibacterial, preservative, anticoagulant, antimicrobial agent, surfactant and buffers in the stability of active drug for its excellent therapeutic output results. Correlation coefficient factor is greater than 0.999 which indicates that the method has good linearity at proposed concentration against triamcinolone acetonide. Conclusions Excellent physical and chemical properties like physical appearance, pH, specific gravity, viscosity, re-suspendability, sedimentation volume is accomplished to meet the requirements of the eye treatment products. On the basis of experimental results achieved during validation process, it can be assumed that the current analysis method is more accurate, precise, specific, linear and consistency indicating in the range of 70 to 130% of the analyte concentration. From the physical, chemical behaviors and chemical assay of the newly developed drug formulation of corticosteroid (triamcinolone acetonide) it is concluded that it can be probably put for further clinical trial in different phases for human use.

Abiraterone acetate – 10 clinically relevant facts

Prostate cancer is one of the most frequently diagnosed cancers in men. Number of newly diagnosed cases is increasing due to several factors and the most important ones seem to be: population ageing and more sensitive diagnostic procedures. Secondary – the higher efficacy of treatment with its influence on improving patients’ overall survival and the specific mechanism of action of drugs used in systemic therapy lead to growing population of men suffering from prostate cancer in general and, specifically – patients with castration resistance. It is hormone therapy to play the key role in systemic treatment of prostate cancer with increasing significance of novel drugs focused on inhibition of molecular signal transduction mediated by androgen receptor. Abiraterone acetate is the representative of this therapeutic class. The paper describes the most clinically relevant data regarding the drug.

An audit of Black Box Warnings (BBWs) in the United States Food and Drug Administration (US-FDA) database - a five-year analysis

Background: The black-box warning (BBW) is the most serious warning that US-FDA can ask for on a drug’s labelling. BBWs represent key safety concerns uncovered either during dossier review or post-approval. We have conducted the present study with the primary objective of assessing BBWs issued by the US-FDA. Methods: BBW’s were identified on US-FDA’s website from 1st January 2015 to 31st December 2019. Prescribing information was used to identify and characterize BBWs into new and minor/major update on a previous BBW. The therapeutic class of the drug, nature [Biological/New Molecular entity (NME)], formulation type, expected duration of use along with the year of first approval of the molecule with BBWs were evaluated. Results: A total of n = 167 BBWs were issued by FDA of which 53 (31.7%) had major updates, 57(34.1%) had minor updates and 57(34.1%) were new BBWs. A total of 137(82%) of BBWs were with NME’s whereas 30(18%) were with biologics. Drugs for neurology 40(25.5%)had the highest number of BBWs followed by oncology 38(24.2%). Among type of BBWs, cardiovascular risk 31 (15%) were the highest. Conclusion: Practicing physicians need to understand that benefit-risk of a drug is dynamic and keep abreast of new data related to it.

About Sacubitril/Valsartan: A Clinically-Oriented Primer for Internists

The medical therapy of heart failure (HF) has been traditionally based on inhibiting the main pathophysiologic mechanisms: the adrenergic and renin-angiotensin-aldosterone systems. Introducing the therapeutical triad of beta-blockers, angiotensin converting enzyme inhibitors and mineralocorticoid receptor antagonists in the treatment of HF patients almost 40 years ago marked an important step since they were not only addressing the symptoms of HF, but also the prognosis and life- expectancy of these patients. Although many discoveries have been made in the past years, no other therapeutic class was able to increase survival among HF patients, until recently, when th SA e benefits of modulating the natriuretic peptide system were brought to the attention of the scientific community. Increasing the levels of natriuretic peptides with Sacubitril/ Valsartan (SV) led to several benefits for the reduced ejection fraction HF population, including less long and short term complications, increased survival and a reduced symptom burden. As this article is being written, it is estimated that more than 2.8 million patients are being treated with SV(1). Therefore, SV is an important and validated therapy for HF patients and internists should be aware of its indications, benefits and management in clinical practice.

Nano intervention in topical delivery of corticosteroid for psoriasis and atopic dermatitis—a systematic review

Atopic dermatitis (AD) and psoriasis are highly prevalent, complex, chronic inflammatory skin diseases that immensly affect the patient’s quality of life. While there is no definitive cure for these conditions, suppressive medications aim at managing the symptoms of these diseases. The application of emollients accompanied by symptomatic anti-inflammatory therapy consisting of topical corticosteroids (TCS) is extensively employed for controlling the symptoms among general practitioners making this therapeutic class an indispensable pillar of dermatotherapeutics. The first TCS, hydrocortisone (HC) introduced in the early 1950s led to the development of different steroidal moieties of varying potencies by inducing chemical modifications to the basic steroid structure. The wide spectrum of the available range of formulations and potency provides flexibility to treat all patient groups, different phases of the diseases, and different anatomical sites. Conventional TCS therapy suffers from drawbacks such as low drug permeation and retention rate. Thus, novel nanoformulations have been developed to overcome these problems. This review provides an insight into the current state of nanocarrier-mediated topical delivery of corticosteroids monotherapy and combination therapy with special emphasis on targeting psoriasis and AD.

Clinical and molecular analysis of smoothened inhibitors in SHH medulloblastoma

Background Smoothened inhibitors (SMOi) have shown activity in Sonic Hedgehog (SHH) medulloblastoma, however this therapeutic class was not developed in children due to severe effects reported on growth. We hereby report long-term follow up of young patients treated with SMOi for recurrent medulloblastoma. Methods Clinical data on response and toxicity from patients treated with vismodegib or sonidegib from 2011 to 2019 for a SHH medulloblastoma were retrospectively reviewed. Methylation analysis and whole exome sequencing were performed whenever possible. Results All patients with a somatic PTCH1 mutation responded to SMOi (6/8), including two prolonged complete responses. One patient was free of disease 8.2 years after treatment. SMOi was challenged again for three patients. Two of them had a response, one with SMOi alone, the other one in combination with temozolomide despite previous progression under monotherapy. SMO resistance mutations were found in patients from biopsy at relapse. Combination with temozolomide or surgery plus radiotherapy was associated with very long disease control in two patients. The most severe adverse events were myalgia and growth plate fusion with metaphyseal sclerosis. Normal growth velocity was recovered for one patient although her final height was below estimated target height. Conclusion Targeting SMO in mutated PTCH1 is an interesting strategy for long-term responses. Combination of SMOi with chemotherapy or surgery and local radiotherapy is an appealing strategy to prevent early resistance and diminish SMOi exposure, especially in young patients. Inhibition of SHH pathway causes growth and development impairment but partial recovery of the growth velocity is possible.

Evidence for a bacterial Lands cycle phospholipase A: Structural and mechanistic insights into membrane phospholipid remodeling

Cells steadily adapt their membrane glycerophospholipid (GPL) composition to changing environmental and developmental conditions. While the regulation of membrane homeostasis via GPL synthesis in bacteria has been studied in detail, the mechanisms underlying the controlled degradation of endogenous GPLs remain unknown. Thus far, the function of intracellular phospholipases A (PLAs) in GPL remodeling (Lands cycle) in bacteria is not clearly established. Here, we identified the first cytoplasmic membrane-bound phospholipase A1 (PlaF) from Pseudomonas aeruginosa involved in the Lands cycle. PlaF is an important virulence factor, as the P. aeruginosa ΔplaF mutant showed strongly attenuated virulence in Galleria mellonella and macrophages. We present a 2.0-Å-resolution crystal structure of PlaF, the first structure that reveals homodimerization of a single-pass transmembrane (TM) full-length protein. PlaF dimerization, mediated solely through the intermolecular interactions of TM and juxtamembrane regions, inhibits its activity. A dimerization site and the catalytic sites are linked by an intricate ligand-mediated interaction network which likely explains the product (fatty acid) feedback inhibition observed with the purified PlaF protein. We used molecular dynamics simulations and configurational free energy computations to suggest a model of PlaF activation through a coupled monomerization and tilting of the monomer in the membrane, which constrains the active site cavity into contact with the GPL substrates. Thus, these data show the importance of the GPL remodeling pathway for virulence and pave the way for the development of a novel therapeutic class of antibiotics targeting PlaF-mediated membrane GPL remodeling.