James Watt, of Steam Engine Fame, Offered Inhaled Carbon Monoxide for Putative Therapeutic Action.

James Watt (1736-1819) is remembered as a steam engine innovator and industrial magnate. A polymath, he was also a hands-on contributor to the Medical Pneumatic Institution of Thomas Beddoes. Watt recruited Humphry Davy, who there discovered analgesic action of inhaled nitrous oxide in 1799. Watt also built pneumatic equipment, and he introduced a gas mixture, dubbed hydro-carbonate, as a medical tonic. The bioactive component was carbon monoxide, a readily-lethal inhibitor of the transport and utilization of respiratory oxygen. Despite appreciable toxicity, carbon monoxide is an endogenous product of heme catabolism, and low doses of the gas are under laboratory investigation for therapeutic purposes. However, Watt's hydro-carbonate constituted a setback in the development of pharmacologically useful gases.

Efficacy and safety of PD-1 and PD-L1 inhibitors combined with chemotherapy in randomized clinical trials among triple-negative breast cancer.

Background: The combination of immune checkpoint inhibitors (ICIs) and chemotherapy (CT) is a new strategy to explore cancer treatment in recent years, and it is also practiced in triple-negative breast cancer (TNBC). However, several published randomized controlled trials (RCTs) reported heterogeneous results. We conducted this meta-analysis to yield insights into the efficacy and safety of the combination of ICIs and CT for TNBC patients in both the adjuvant and neoadjuvant settings. Method: EMBASE, PUBMED, Cochrane, and www.clinicaltrials.gov databases were searched to determine potential eligible studies from the inception to 20 May 2022. Published RCTs on PD-1/PD-L1 ICIs combined with CT for TNBC patients were included. Result: This meta-analysis included six double-blind RCTs comprising 4,081 TNBC patients treated with PD-1 or PD-L1 ICIs plus CT or placebo plus CT. The combination strategy benefited a better pathologic complete response (pCR) by 29% (RR = 1.29; 95% CI: 1.17-1.41; I2 = 0%) and a better progression-free survival (PFS) (HR = 0.82; 95% CI: 0.74-0.90; I2 = 0%) in the neoadjuvant and the adjuvant settings, respectively, especially in PD-L1-positive population (HR = 0.71; 95% CI: 0.62-0.81; I2 = 13%). The safety profiles were generally tolerable in both settings but the combination treatment will increase the risk of severe adverse events in the adjuvant setting (RR = 1.33; 95% CI 1.08-1.62, I2 = 0%). Additionally, the combination will increase the risk of any-grade hypothyroidism, hyperthyroidism, pneumonia, and rash in the adjuvant setting, and the risk of any-grade hypothyroidism, hyperthyroidism, infusion-related reactions, and severe cutaneous reactions in the neoadjuvant setting. Conclusion: This meta-analysis demonstrated a significant pCR benefit and confirms the PFS benefit with PD-1/PD-L1 ICIs plus CT in TNBC patients with tolerable safety events in both neoadjuvant and adjuvant settings.

Impact of Matrix Surface Area on Griseofulvin Release from Extrudates Prepared via Nanoextrusion.

We aimed to examine the impact of milling of extrudates prepared via nanoextrusion and the resulting matrix surface area of the particles on griseofulvin (GF, a model poorly soluble drug) release during in vitro dissolution. Wet-milled GF nanosuspensions containing a polymer (Sol: Soluplus®, Kol: Kolliphor® P407, or HPC: Hydroxypropyl cellulose) and sodium dodecyl sulfate were mixed with additional polymer and dried in an extruder. The extrudates with 2% and 10% GF loading were milled-sieved into three size fractions. XRPD-SEM results show that nanoextrusion produced GF nanocomposites with Kol/HPC and an amorphous solid dispersion (ASD) with Sol. For 8.9 mg GF dose (non-supersaturating condition), the dissolution rate parameter was higher for extrudates with higher external specific surface area and those with 10% drug loading. It exhibited a monotonic increase with surface area of the ASD, whereas its increase tended to saturate above ~30 × 10-3 m2/cm3 for the nanocomposites. In general, the nanocomposites released GF faster than the ASD due to greater wettability and faster erosion imparted by Kol/HPC than by Sol. For 100 mg GF dose, the ASD outperformed the nanocomposites due to supersaturation and only 10% GF ASD with 190 × 10-3 m2/cm3 surface area achieved immediate release (80% release within 30 min). Hence, this study suggests that ASD extrudates entail fine milling yielding > ~200 × 10-3 m2/cm3 for rapid drug release, whereas only a coarse milling yielding ~30 × 10-3 m2/cm3 may enable nanocomposites to release low-dose drugs rapidly.