Immune-checkpoint inhibitor toxicity during a pandemic: Overcoming patient fears to provide care. A case report.

BACKGROUND: Pembrolizumab is a humanized monoclonal antibody that is used to treat a variety of cancers. It exerts its mechanism of action by blocking the programmed death receptor-1 (PD-1). Toxicity concerns include immune-related toxicities, including colitis, hepatitis, pneumonitis, nephritis, endocrine toxicities and more rarely, myocarditis and other organ system toxicities. OBJECTIVE: To review a real-world case involving immunotherapy induced myocarditis after a patient received pembrolizumab and discuss how the current pandemic created complexity in toxicity management. DISCUSSION: An 83 year old male with metastatic lung cancer developed fatal myocarditis after receiving 2 doses of pembrolizumab. Applying the Naranjo score, the likelihood of pembrolizumab causing the myocarditis is probable, with a score of 6. Severe cardiac toxicities are rare with pembrolizumab, but can still occur. It is vital to be aware of these toxicities, and educate patients on signs and symptoms. Complicating the situation even further was the global pandemic, which created fear and hesitation in the patient and the patient's family to seek medical treatment out of fear of exposure. This pandemic adds another layer to the complexity of care for patients with cancer and management of toxicities. Pharmacists play a significant role in ensuring the safety and efficacy of medications, especially oncology agents. CONCLUSION: Proper education of patients regarding symptoms and when to report are paramount to assisting in early detection and intervention for immunotherapy-related adverse events. New management and treatment strategies will need to be discussed and implemented considering the changing landscape around the SARS-CoV-2 pandemic.

Damming the rivers of the Amazon basin.

More than a hundred hydropower dams have already been built in the Amazon basin and numerous proposals for further dam constructions are under consideration. The accumulated negative environmental effects of existing dams and proposed dams, if constructed, will trigger massive hydrophysical and biotic disturbances that will affect the Amazon basin's floodplains, estuary and sediment plume. We introduce a Dam Environmental Vulnerability Index to quantify the current and potential impacts of dams in the basin. The scale of foreseeable environmental degradation indicates the need for collective action among nations and states to avoid cumulative, far-reaching impacts. We suggest institutional innovations to assess and avoid the likely impoverishment of Amazon rivers.

Thermal decomposition kinetics of hydrazinium cerium 2,3-Pyrazinedicarboxylate hydrate: a new precursor for CeO2.

The thermal decomposition kinetics of N(2)H(5)[Ce(pyrazine-2,3-dicarboxylate)(2)(H(2)O)] (Ce-P) have been studied by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), for the first time; TGA analysis reveals an oxidative decomposition process yielding CeO(2) as the final product with an activation energy of approximately 160 kJ mol(-1). This complex may be used as a precursor to fine particle cerium oxides due to its low temperature of decomposition.

Crystallization kinetics of amorphous nifedipine studied by model-fitting and model-free approaches.

The crystallization of amorphous nifedipine was studied using hot-stage microscopy (HSM), powder X-ray diffractometry (PXRD), and differential scanning calorimetry (DSC). The kinetic data obtained from DSC studies under isothermal and nonisothermal conditions were examined using both model-fitting and model-free approaches. Evaluation of 16 different models showed that model A4 (Avrami-Erofeev, n = 4) to be most appropriate for crystallization in the conversion range 0.05-0.80. This choice was based on the goodness of fit, the residual plots, and the guidance provided by the model-free approach. The model-free approach indicated that the activation energy decreases slightly as the crystallization proceeds. This variation of the activation energy with the extent of conversion determines the range of conversion over which a model can be fit, and the magnitude of the activation energy helps in the selection of the best model. The model-free approach gives much better predictions than the model of best fit and allows the experimental kinetic function to be numerically evaluated. At the early stage (alpha = 0-0.6), the numerically reconstructed model is almost identical to A4, but gradually approaches A3 (Avrami-Erofeev, n = 3) as the crystallization progresses (alpha = 0.6-0.8) and deviates from both models near the end of the reaction. This behavior may be explained by the relative contributions of nucleation and crystal growth at different stages of the reaction.

Model-free treatment of the dehydration kinetics of nedocromil sodium trihydrate.

The conventional model-fitting approach to kinetic analysis assumes a fixed mechanism throughout the reaction and therefore may be too simplistic for many solid-state reactions. Even for a reaction with a fixed mechanism, model fitting sometimes cannot identify the reaction model uniquely. The alternative model-free approach is sufficiently flexible to allow for a change of mechanism during the course of a reaction and therefore provides a more realistic treatment of solid-state reactions kinetics. The application of model-free analysis to solid-state dehydrations was investigated using the two consecutive dehydration reactions of nedocromil sodium trihydrate. The complexity of such reactions is illustrated by the variation of the activation energy as each dehydration proceeds. The 1st-step dehydration follows one-dimensional phase boundary kinetics until the fraction dehydrated reaches 0.75, and deviates from this model thereafter. The 2nd-step dehydration follows a mechanism intermediate between two- and three-dimensional diffusion that cannot be described by any of the common models. The model-free approach is clearly better than the model-fitting approach for understanding the details of these solid-state dehydration reactions.

Dehydration kinetics of neotame monohydrate.

The dehydration of neotame monohydrate was monitored at various temperatures by differential scanning calorimetry (DSC), thermogravimetry (TGA), hot-stage microscopy (HSM), powder X-ray diffractometry (PXRD), and (13)C solid-state nuclear magnetic resonance (SSNMR) spectroscopy. This work emphasizes kinetic analysis of isothermal TGA data by fitting to various solid-state reaction models and by model-free kinetic treatment. The dehydration of neotame monohydrate follows the kinetics of a two-dimensional phase boundary reaction (R2) at 40-50 degrees C with an activation energy of 75 +/- 9 kJ/mol, agreeing well with 60-80 kJ/mol from model-free kinetics. At a low heating rate in DSC and TGA, neotame monohydrate undergoes dehydration to produce anhydrate Form E, which then converts to anhydrate Form A, followed by the melting of A. Neotame monohydrate under dry nitrogen purge at 50 mL/min undergoes partial isothermal dehydration at 50 degrees C to produce neotame anhydrate Form A. When neotame monohydrate is heated very slowly from 50 to 65-70 degrees C over 24 h, pure Form A is obtained.

Hard to swallow dry: kinetics and mechanism of the anhydrous thermal decomposition of acetylsalicylic acid.

The methods of thermal analysis and mass spectrometry have been used to study the kinetics and mechanism of the anhydrous thermal decomposition of acetylsalicylic acid. Both thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) show that decomposition occurs in two steps. Mass-spectrometric analysis of the residue left after the first decomposition step (approximately equal to 60% mass loss) suggests that in the condensed phase, acetylsalicylic acid decomposes by first forming linear oligomers that are further converted into cyclic oligomers. Model-free isoconversional kinetic analysis of TGA traces has been used to determine global activation energies as a function of the extent of reaction. This method of analysis has also been used to make kinetic predictions of shelf life at ambient temperatures (20-40 degrees C) under anhydrous conditions for acetylsalicylic acid. Our estimate of a shelf life of 876 days (approximately equal to 2.4 years) for 5% decomposition at 30 degrees C is in good agreement with shelf lives of 2-3 years that are stamped on over-the-counter aspirin bottles. Hence, this approach can be used to systematically study the factors that determine the decomposition kinetics of aspirin and may be used for express screening of pharmaceuticals in order to identify those with desirable thermal stabilities.