Lessons for deprescribing from a nonessential medication hold policy in US nursing homes.

BACKGROUND: At the height of the COVID-19 pandemic, a large nursing home chain implemented a policy to temporarily hold potentially unnecessary medications. We describe rates of held and discontinued medications after a temporary hold policy of potentially unnecessary or nonessential medications. METHODS: This retrospective cohort study uses electronic health record (EHR) data on 3247 residents of 64 nursing homes operated by a multistate long-term care provider. Medications were documented in the electronic medication administration record. Overall medication held and discontinued incidences are reported. Hierarchical Bayesian modeling is used to determine individual probabilities for medication discontinuation within each facility. RESULTS: In total, 3247 residents had 5297 nonessential medications held. Multivitamins were most likely to be held, followed by histamine-2 receptor antagonists, antihistamines, and statins. At the end of the hold policy, 2897 of 5297 (54%) were permanently discontinued, including probiotics (73%), histamine-2 receptor antagonists (66%), antihistamines (64%), and statins (45%). Demographics, cognitive and functional impairment were similar between residents with medications who were discontinued versus continued. For most medications, more than 50% of the variance in whether medications were discontinued was explained by facility rather than resident-level factors. CONCLUSION: A temporary medication hold policy implemented during the CoVID-19 pandemic led to the deprescribing of a plurality of 'nonessential' medications. This type of organization-wide initiative may be an effective mechanism for altering future prescribing behaviors to reduce the use of unnecessary medications.

Hybrid inhibitors of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR): design, synthesis, and superior antitumor activity of novel wortmannin-rapamycin conjugates.

Hyperactivation of the PI3K/AKT/mTOR signaling pathway is common in cancer, and PI3K and mTOR act synergistically in promoting tumor growth, survival, and resistance to chemotherapy. Thus, combined targeting of PI3K and mTOR presents an opportunity for robust and synergistic anticancer efficacy. 17-Hydroxywortmannin (2a) analogues conjugated to rapamycin (3a) analogues via a prodrug linker are uniquely positioned for this approach. Our efforts led to the discovery of diester-linked conjugates that, upon in vivo hydrolysis, released two highly potent inhibitors. Conjugate 7c provided enhanced solubility relative to 3a and to an equivalent mixture of 3a and 9a and demonstrated profound activity in U87MG mouse xenografts, achieving an MED of 1.5 mg/kg, following weekly intravenous dosing. At 15 mg/kg, 7c completely inhibited the growth of HT29 tumors, whereas an equivalent mixture of the inhibitors was poorly tolerated. In the A498 renal tumor model, 7c exhibited superior efficacy over 3a or 9a when administered as a single agent or in combination with bevacizumab. Thus, we have uncovered a novel approach to target both PI3K and mTOR via hybrid inhibitors, leading to a broader and more robust anticancer efficacy.

Synthesis and structure-activity relationships of ring-opened 17-hydroxywortmannins: potent phosphoinositide 3-kinase inhibitors with improved properties and anticancer efficacy.

The phosphoinositide 3-kinase (PI3K) signaling pathway is frequently up-regulated in human cancer and is a promising target for the treatment of cancer. Wortmannin and its analogues are potent inhibitors of PI3K but suffer from inherent defects such as instability, insolubility, and toxicity. Opening of the reactive furan ring of 17-hydroxywortmannin with amines gives compounds with improved properties such as greater stability and aqueous solubility and a larger therapeutic index. Ring-opened analogues such as compound 13 containing basic amine groups have significantly increased PI3K inhibitory potency and greater efficacy in nude mouse xenograft assays.