Indication-Specific Generic Uptake of Imatinib Demonstrates the Impact of Skinny Labeling

PURPOSE Generic competition can be delayed if brand-name manufacturers obtain additional patents on supplemental uses. The US Food and Drug Administration allows generic drug manufacturers to market versions with skinny labels that exclude patent-protected indications. This study assessed whether use of generic versions of imatinib varied between indications included and excluded from the skinny labels. METHODS In this cross-sectional study, we identified adult patients covered by commercial insurance or Medicare Advantage plans who initiated imatinib from February 2016 (first generic availability) to September 2020. Generic versions were introduced with skinny labels that included indications covering treatment of chronic myelogenous leukemia (CML) but excluded treatment of gastrointestinal stromal tumors (GISTs) because of remaining patent protections. Logistic regression was used to determine whether use of generic versus brand-name imatinib differed between patients with a diagnosis of CML or GIST, adjusting for demographics, insurance type, prior use of brand-name drugs, and calendar month. RESULTS Among 2,000 initiators, 934 (47%) had CML and 686 (34%) had GIST. Within 3 years after generics entered the market, more than 90% of initiators in both groups used generic imatinib. Initiation of generic imatinib was slightly lower among patients with GIST than among patients with CML (85% v 88%; adjusted odds ratio 0.56; 95% CI, 0.39 to 0.80; P ≤ .001). CONCLUSION Generic versions of imatinib were dispensed frequently for indications both included (CML) and excluded (GIST) from the skinny labeling, although patients with GIST were slightly less likely to receive a generic version. The skinny labeling pathway allowed generics to enter the market before patent protection for treating patients with GIST expired, facilitating lower drug prices.

Effect of Oxycations in Clay Mineral on Adsorption—Vanadyl Exchange Bentonites and Their Ability for Amiloride Removal

The presence of drugs in aquatic bodies is a prevailing issue, and their removal by adsorption is an effective treatment. Among the adsorbents, those based clay minerals have been proposed. Bentonite is a clay mineral that is widely studied as an adsorbent due to its unique physicochemical properties, such as cation exchange capacity (CEC), intercalation, and adsorption. The properties of bentonites can be improved through chemical modifications, such as the incorporation of organic and/or inorganic compounds. These modifications allow for the efficient removal of different contaminants, including pharmaceutical compounds. In this work, raw sodium bentonite (Na+-Bent) and vanadyl bentonites were prepared using 100 (BentV1), 300 (BentV3), and 500% (BentV5) of the cationic exchange capacity of the Na+-Bent and further used for amiloride removal from aqueous solution. Analysis of X-ray fluorescence and Na+ in solution after interaction indicated that the principal mechanism of interaction between bentonite and ions was the ion exchange between sodium of the matrix and vanadyl in solution. Infrared spectroscopy suggested the contribution of coordination of the interlayer water with the vanadyl ions and hydrogen bonding between vanadyl and structural OH. X-ray diffraction analysis indicated that vanadyl ions were incorporated onto Na+-Bent. Amiloride adsorption was better at pH 5.8, using a solid dosage of 75 mg of Na+-Bent, 25 mg of BentV1 and BentV5, and 50 mg of BentV3. The adsorption occurred briefly until 20 min, and maximum removal values were 457.08, 374.64, 102.56, and 25.63 mg·g−1 for Na+-Bent, BentV1, BentV3, and BentV5, respectively. At lower drug concentrations (48.78 and 91.24 mg·g−1 for Na+-Bent and BentV3), the best performance was obtained for the BentV3 sample.

A family of cell wall transglutaminases is essential for appressorium development and pathogenicity in Phytophthora infestans

Transglutaminases (TGases) are enzymes highly conserved among prokaryotic and eukaryotic organisms, where their role is to catalyse protein cross-linking. One of the putative TGases of Phytophthora infestans has previously been shown to be localised to the cell wall. Based on sequence similarity we were able to identify six more genes annotated as putative TGases and show that these seven genes group together in phylogenetic analysis. All of the seven proteins are predicted to contain transmembrane helices and both a TGase domain and a MANSC domain, the latter of which was previously shown to play a role in protein stability. Chemical inhibition of transglutaminase activity and silencing of the entire family of the putative cell wall TGases are both lethal to P. infestans indicating the importance of these proteins in cell wall formation and stability. The intermediate phenotype obtained with lower drug concentrations and less efficient silencing displays a number of deformations to germ tubes and appressoria. Both chemically treated and silenced lines show lower pathogenicity than the wild type in leaf infection assays. Finally, we show that appressoria of P. infestans possess the ability to build up turgor pressure and that this ability is decreased by chemical inhibition of TGases.

Will the Volume-Based Procurement Policy Promote Pharmaceutical Firms’ R&D Investment in China? An Event Study Approach

Innovation is the key to the development of the pharmaceutical industry. The pilot program of China’s “4 + 7” volume-based procurement policy (“4 + 7” procurement policy) brings the drug price back to a reasonable level through trading procurement quantities for lower drug prices. The policy manages to reduce the burden of the health care system, improve efficiency, and push the pharmaceutical industry to transform and update from the era of high gross profit of generic drugs to innovative drugs. So far, few studies have investigated the influence of the volume-based procurement policy on the innovation of pharmaceutical firms. By combining the event study and Difference-in-Difference (DiD) methodology, this study finds that the abnormal return (AR) of firms with high R&D intensity is lower than that of firms with low R&D intensity during the event window period. Moreover, further analysis identifies the moderating effect of firm size and firm type. Specifically, the results show that the negative influence of high R&D intensity on abnormal return (AR) during the announcement of the “4 + 7” procurement policy is stronger in large firms and innovative pharmaceutical firms. Finally, we discuss the policy implications of our study.

Measurement of Anticoagulation in Patients on Dabigatran, Rivaroxaban and Apixaban Therapy by Novel Automated Thrombelastography

Background: Direct-acting oral anticoagulants (DOACs) do not require monitoring. Measurement of DOAC effect would be useful in the event of bleeding, trauma, and thromboembolism while on anticoagulation. We evaluated the effectiveness of the investigational DOAC assays on the TEG®6s Hemostasis Analyzer to assess the anticoagulant effect of DOACs in patients treated for atrial fibrillation or DVT. Methods: Patients on treatment for a minimum of 7 days with standard doses of dabigatran, rivaroxaban and apixaban were included. DOAC plasma concentrations and TEG®6s R-time were measured and correlated. The sensitivity, specificity and negative predictive value (NPV) of R-time to detect DOAC concentrations of ≥ 30, ≥ 50 and ≥ 100 ng/mL were calculated. Results: 189 Subjects were included, (n=50) on apixaban, (n= 62) on rivaroxaban, (n=53) on dabigatran and (n=24) on no DOAC were studied. Using the direct thrombin inhibitor (DTI) channel, R-time demonstrated strong linear correlation with dabigatran levels (r = 0.93, p < 0.0001). Using the anti-factor Xa (AFXa) channel, R-time demonstrated strong non-linear correlation with rivaroxaban and apixaban levels (rs = 0.92 and 0.84 respectively, p < 0.0001 for both). R-time revealed strong sensitivity and NPV in detecting low DOAC levels for the predefined concentrations. Conclusion: R-time measured by TEG®6s DOAC Specific cartridge has a strong correlation with concentrations of the most commonly used DOACs, with high sensitivity and NPV for detecting lower drug levels that are considered clinically relevant for patients in need of antidote, or prior to urgent surgery. Further studies to determine the relation of R-time to clinical outcomes are warranted.

Ionic and Enzymatic Multiple-Crosslinked Nanogels for Drug Delivery

Both ionic and enzymatic crosslink are efficient strategies for constructing network materials of high biocompatibility. Here chitosan was modified firstly and then crosslinked by these two methods for complementary advantages. The preparation methods and ionic crosslinkers can regulate the size and uniformity of the multiple-crosslinked nanogels. The multiple-crosslinked nanogels with the smallest size and the best uniformity was selected for the drug delivery. The drug-loading content and encapsulation efficiency were up to 35.01 and 66.82%, respectively. Their release behaviours are correlated with the pH value and the drug dosage. In general, the lower pH value and the lower drug dosage promoted the drug release. With the assistance of several kinetic models, it is found that drug diffusion plays a preponderant role in drug release, while polymer relaxation has a subtle effect. The multiple-crosslink resulting from ionic compounds and enzymes may provide a new perspective on developing novel biocompatible materials.

Impact of Drug Loading Method on Drug Release from 3D-Printed Tablets Made from Filaments Fabricated by Hot-Melt Extrusion and Impregnation Processes

The purpose of this study was to investigate the impact of the drug loading method on drug release from 3D-printed tablets. Filaments comprising a poorly water-soluble model drug, indomethacin (IND), and a polymer, polyvinyl alcohol (PVA), were prepared by hot-melt extrusion (HME) and compared with IND-loaded filaments prepared with an impregnation (IMP) process. The 3D-printed tablets were fabricated using a fused deposition modeling 3D printer. The filaments and 3D printed tablets were evaluated for their physicochemical properties, swelling and matrix erosion behaviors, drug content, and drug release. Physicochemical investigations revealed no drug–excipient interaction or degradation. IND-loaded PVA filaments produced by IMP had a low drug content and a rapid drug release. Filaments produced by HME with a lower drug content released the drug faster than those with a higher drug content. The drug content and drug release of 3D-printed tablets containing IND were similar to those of the filament results. Particularly, drug release was faster in 3D-printed tablets produced with filaments with lower drug content (both by IMP and HME). The drug release of 3D-printed tablets produced from HME filaments with higher drug content was extended to 24 h due to a swelling-erosion process. This study confirmed that the drug loading method has a substantial influence on drug content, which in turn has a significant effect on drug release. The results suggest that increasing the drug content in filaments might delay drug release from 3D-printed tablets, which may be used for developing dosage forms suited for personalized medicine.

Mandatory Minimum Reforms, Sentencing, and Racial-Ethnic Disparities

Over the last 20 years, numerous states and the federal government enacted mandatory minimum reforms, especially for drug offenses. Yet little is known about how effective these reforms have been at the state-level in lowering drug sentences. Using quasi-experimental methods and administrative data, this study evaluates the impact of state-level mandatory minimum reforms on drug sentences and their concomitant racial-ethnic disparities. We find that state-level mandatory minimum reforms do not lower drug sentences in general or change racial-ethnic disparities statistically significantly. These findings suggest that the profound racial-ethnic bias sparked by state-level mandatory minimums are not fully ameliorated by subsequent state-level reforms.

Local Therapies and Modulation of Tumor Surrounding Stroma in Malignant Pleural Mesothelioma: A Translational Approach

Malignant Pleural Mesothelioma (MPM) is a rare and aggressive neoplasm of the pleural mesothelium, mainly associated with asbestos exposure and still lacking effective therapies. Modern targeted biological strategies that have revolutionized the therapy of other solid tumors have not had success so far in the MPM. Combination immunotherapy might achieve better results over chemotherapy alone, but there is still a need for more effective therapeutic approaches. Based on the peculiar disease features of MPM, several strategies for local therapeutic delivery have been developed over the past years. The common rationale of these approaches is: (i) to reduce the risk of drug inactivation before reaching the target tumor cells; (ii) to increase the concentration of active drugs in the tumor micro-environment and their bioavailability; (iii) to reduce toxic effects on normal, non-transformed cells, because of much lower drug doses than those used for systemic chemotherapy. The complex interactions between drugs and the local immune-inflammatory micro-environment modulate the subsequent clinical response. In this perspective, the main interest is currently addressed to the development of local drug delivery platforms, both cell therapy and engineered nanotools. We here propose a review aimed at deep investigation of the biologic effects of the current local therapies for MPM, including cell therapies, and the mechanisms of interaction with the tumor micro-environment.

Modelling the ability of mass drug administration to interrupt soil-transmitted helminth transmission: Community-based deworming in Kenya as a case study

The World Health Organization has recommended the application of mass drug administration (MDA) in treating high prevalence neglected tropical diseases such as soil-transmitted helminths (STHs), schistosomiasis, lymphatic filariasis, onchocerciasis and trachoma. MDA—which is safe, effective and inexpensive—has been widely applied to eliminate or interrupt the transmission of STHs in particular and has been offered to people in endemic regions without requiring individual diagnosis. We propose two mathematical models to investigate the impact of MDA on the mean number of worms in both treated and untreated human subpopulations. By varying the efficay of drugs, initial conditions of the models, coverage and frequency of MDA (both annual and biannual), we examine the dynamic behaviour of both models and the possibility of interruption of transmission. Both models predict that the interruption of transmission is possible if the drug efficacy is sufficiently high, but STH infection remains endemic if the drug efficacy is sufficiently low. In between these two critical values, the two models produce different predictions. By applying an additional round of biannual and annual MDA, we find that interruption of transmission is likely to happen in both cases with lower drug efficacy. In order to interrupt the transmission of STH or eliminate the infection efficiently and effectively, it is crucial to identify the appropriate efficacy of drug, coverage, frequency, timing and number of rounds of MDA.