Prescribing for pregnancy: inflammatory rheumatic disease.

Inflammatory rheumatic disease during pregnancy requires careful management. Key factors for successful pregnancy outcome are disease remission at the time of conception and optimal disease control during pregnancy. This article forms part of a series on prescribing for pregnancy and discusses the impact of inflammatory arthritis on pregnancy and the influence pregnancy may have on inflammatory arthritis. It highlights the importance of prepregnancy care and collaborative working between obstetric and rheumatology specialties as well as focusing on prescribing before, during and after pregnancy.

Effect of Concurrent Proton Pump Inhibitors With Palbociclib Tablets for Metastatic Breast Cancer.

BACKGROUND: Palbociclib is indicated for the treatment of hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC) in combination with an aromatase inhibitor or fulvestrant. Two retrospective studies found that concurrent proton pump inhibitor (PPI) use with palbociclib capsules significantly reduced progression free survival (PFS) versus patients without a PPI. Palbociclib tablets were released in 2020 without restriction on PPI use. No study to date has evaluated the combination of palbociclib tablets with concurrent PPI use. METHODS: Patients were retrospectively evaluated after they received palbociclib tablets for the treatment of HR+ HER2- MBC in the first line setting with or without a PPI. Patients were assigned to the no PPI use arm if they never used a PPI and the PPI use arm if they used a PPI for >50% of the duration of palbocicib therapy. The primary endpoint was PFS. The secondary endpoints included overall survival (OS) and adverse events. RESULTS: Eighty-two patients were identified; 50 in the no PPI use group and 32 in the PPI use group. The median PFS was 20.6 months (95% confidence interval [CI], 16.07 to not estimable) in the no PPI use arm versus 21.0 months (95% CI, 15.15 to not estimable) in the PPI use arm (P = 0.95). Median OS was not reached in either arm. Adverse effects did not differ between arms. CONCLUSION: Use of a concurrent PPI with palbociclib tablets does not significantly reduce PFS in patients treated for HR+ HER2- MBC.

Case series of COVID-19 infection in pregnancy complicated by ketoacidosis and symptomatic breathlessness.

Background: The differential diagnosis of acute shortness of breath in a pregnant woman with COVID-19 is broad. Pregnancy is a ketosis-prone state, which can result in metabolic acidosis and tachypnoea. Methods: We describe four pregnant women with COVID-19 and breathlessness where ketoacidosis was found to contribute to symptomatic tachypnoea. Results: One patient did not have associated COVID-19 pneumonitis, but presented with severe tachypnoea and metabolic acidosis; three women had pneumonitis and metabolic acidosis. Corrective treatment for the metabolic abnormalities resulted in resolution of the ketoacidosis in all cases. No women had coexistent diabetes. Conclusion: This is the first series of COVID-19 in pregnancy complicated by ketoacidosis and symptomatic tachypnoea. Ketoacidosis associated with COVID-19 is an important cause of tachypnoea requiring specific treatment, which should not be overlooked. Potential mechanisms for this are discussed with a framework for interpretation of blood gas results during pregnancy.

Induction of heart valve lesions by small-molecule ALK5 inhibitors.

Aberrant signaling by transforming growth factor-ß (TGF-ß) and its type I (ALK5) receptor has been implicated in a number of human diseases and this pathway is considered a potential target for therapeutic intervention. Transforming growth factor-ß signaling via ALK5 plays a critical role during heart development, but the role of ALK5 in the adult heart is poorly understood. In the current study, the preclinical toxicology of ALK5 inhibitors from two different chemistry scaffolds was explored. Ten-week-old female Han Wistar rats received test compounds by the oral route for three to seven days. Both compounds induced histopathologic heart valve lesions characterized by hemorrhage, inflammation, degeneration, and proliferation of valvular interstitial cells. The pathology was observed in all animals, at all doses tested, and occurred in all four heart valves. Immunohistochemical analysis of ALK5 in rat hearts revealed expression in the valves, but not in the myocardium. Compared to control animals, protein levels of ALK5 were unchanged in the heart valves of treated animals. We also observed a physeal dysplasia in the femoro-tibial joint of rats treated with ALK5 inhibitors, a finding consistent with a pharmacological effect described previously with ALK5 inhibitors. Overall, these findings suggest that TGF-ß signaling via ALK5 plays a critical role in maintaining heart valve integrity.

Pregnancy in women known to be living with a single kidney.

There is a paucity of data on pregnancy outcome in women living with a single kidney from all causes. Current thinking is extrapolated from living kidney donors, a group biased by strict selection criteria. We present a cohort of 26 women with a solitary functioning kidney; 11 women had an acquired single kidney of whom only 1 was a living donor and 15 had a congenital single kidney. Median time living with a single kidney was 28 years. None booked with hypertension or proteinuria. Urinary tract infection complicated 50% of pregnancies. Worryingly, 35% developed pre-eclampsia, gestational proteinuria or gestational hypertension. We propose pre-conceptual counselling, education on how to protect their single kidney, pre eclampsia prophylaxis with low-dose aspirin and close monitoring for urinary tract infection, hypertension and proteinuria with lower thresholds for pharmaceutical management. We have devised a Patient Information leaflet - 'Living with a single kidney, pregnancy and beyond'.

AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models.

Constitutive activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway in human cancers is often associated with mutational activation of BRAF or RAS. MAPK/ERK kinase 1/2 kinases lie downstream of RAS and BRAF and are the only acknowledged activators of ERK1/2, making them attractive targets for therapeutic intervention. AZD6244 (ARRY-142886) is a potent, selective, and ATP-uncompetitive inhibitor of MAPK/ERK kinase 1/2. In vitro cell viability inhibition screening of a tumor cell line panel found that lines harboring BRAF or RAS mutations were more likely to be sensitive to AZD6244. The in vivo mechanisms by which AZD6244 inhibits tumor growth were investigated. Chronic dosing with 25 mg/kg AZD6244 bd resulted in suppression of growth of Colo-205, Calu-6, and SW-620 xenografts, whereas an acute dose resulted in significant inhibition of ERK1/2 phosphorylation. Increased cleaved caspase-3, a marker of apoptosis, was detected in Colo-205 and Calu-6 but not in SW-620 tumors where a significant decrease in cell proliferation was detected. Chronic dosing of AZD6244 induced a morphologic change in SW-620 tumors to a more differentiated phenotype. The potential of AZD6244 in combination with cytotoxic drugs was evaluated in mice bearing SW-620 xenografts. Treatment with tolerated doses of AZD6244 and either irinotecan or docetaxel resulted in significantly enhanced antitumor efficacy relative to that of either agent alone. These results indicate that AZD6244 has potential to inhibit proliferation and induce apoptosis and differentiation, but the response varies between different xenografts. Moreover, enhanced antitumor efficacy can be obtained by combining AZD6244 with the cytotoxic drugs irinotecan or docetaxel.

An antibody panel for immunohistochemical analysis of the retina in Davidson's-fixed, paraffin-embedded eyes of rats.

Unlike most other tissues, the optimal fixative for preserving eye morphology is considered to be Davidson's fixative or modified Davidson's rather than formalin. However, the methodology for antibodies to be used in tissues fixed this way is not normally outlined in current antibody datasheets. Additionally, where eyes have been stored in Davidson's fixative, the efficacy of retrospective analysis of eye morphology by immunohistochemistry is largely unknown. The aim of this study was to compare a panel of six antibodies in both Davidson's-fixed and formalin-fixed pigmented and non-pigmented rat eyes, in order to provide optimal methods for future retinal immunohistochemical evaluation with image analysis. The antibodies evaluated were raised against rhodopsin, synaptophysin, glutamine synthetase, glial fibrillary acidic protein (GFAP), cleaved caspase-3 and phospho-histone H3 (PH3). Overall, the staining quality of these antibodies was found to be optimal in Davidson's compared to formalin-fixed tissues after a time period of up to 4 days in fixative. The methods outlined thus provide a platform for future detailed analysis of retinal pathology in Davidson's-fixed eyes.