Objectives Glucagon-like peptide 1 receptor agonists (GLP1-RA) are indicated for the treatment of type 2 diabetes and more recently for weight loss. The aim of this study was to assess the risks associated with GLP1-RA exposure during early pregnancy. Design This multicentre, observational prospective cohort study compared pregnancy outcomes in women exposed to GLP1-RA in early pregnancy either for diabetes or obesity treatment with those in two reference groups: (1) women with diabetes exposed to at least one non-GLP1-RA antidiabetic drug during the first trimester and (2) a reference group of overweight/obese women without diabetes, between 2009 and 2022. Setting Data were collected from the databases of six Teratology Information Services. Participants This study included 168 pregnancies of women exposed to GLP1-RA during the first trimester, alongside a reference group of 156 pregnancies of women with diabetes and 163 pregnancies of overweight/obese women. Results Exposure to GLP1-RA in the first trimester was not associated with a risk of major birth defects when compared with diabetes (2.6% vs 2.3%; adjusted OR, 0.98 (95% CI, 0.16 to 5.82)) or to overweight/obese (2.6% vs 3.9%; adjusted OR 0.54 (0.11 to 2.75)). For the GLP1-RA group, cumulative incidence for live births, pregnancy losses and pregnancy terminations was 59%, 23% and 18%, respectively. In the diabetes reference group, corresponding estimates were 69%, 26% and 6%, while in the overweight/obese reference group, they were 63%, 29% and 8%, respectively. Cox proportional cause-specific hazard models indicated no increased risk of pregnancy losses in the GLP1-RA versus the diabetes and the overweight/obese reference groups, in both crude and adjusted analyses. Conclusions This study offers reassurance in cases of inadvertent exposure to GLP1-RA during the first trimester of pregnancy. Due to the limited sample size, larger studies are required to validate these findings.

Background: Increased expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL is involved in the development and progression of many tumors. We recently reported that the bcl-2/bcl-xL-bispecific antisense oligonucleotide 4625 induces apoptosis in lung carcinoma cells. To further assess the therapeutic potential of oligonucleotide 4625, we investigated its effect on a series of human tumor cell lines of diverse histologic origins in vitro and in vivo. Methods: Oligonucleotide 4625-mediated inhibition of bcl-2 and bcl-xL expression in vitro was measured in breast carcinoma cells with the use of reverse transcription–polymerase chain reaction (PCR), real-time PCR, and western blotting. Cytotoxicity was assessed in several different cell lines by measurement of tumor cell growth, propidium iodide uptake, and nuclear apoptosis. The in vivo activity of oligonucleotide 4625 was determined by the inhibition of growth of established tumor xenografts in nude mice, immunohistochemical staining of Bcl-2 and Bcl-x proteins in the tumors, and western blotting of tumor lysates. Apoptosis in tumor xenografts was detected with the use of in situ TUNEL (i.e., terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick end labeling) staining. All statistical tests are two-sided. Results: In breast carcinoma cells, oligonucleotide 4625 treatment reduced bcl-2 and bcl-xL messenger RNA levels in a dose-dependent manner. At 600 nM, oligonucleotide 4625 reduced Bcl-2 and Bcl-xL protein levels to 25% (95% confidence interval [CI] = 16% to 34%) and 20% (95% CI = 14% to 26%), respectively, of the levels in untreated cells and it decreased viability in all cell lines mainly by inducing apoptosis. In vivo, oligonucleotide 4625 statistically significantly inhibited the growth of breast and colorectal carcinoma xenografts by 51% (95% CI = 28% to 74%) and 59% (95% CI = 44% to 74%), respectively, relative to those treated with control oligonucleotide 4626; it also reduced Bcl-2 and Bcl-xL protein levels and induced tumor cell apoptosis. Conclusion: The bcl-2/bcl-xL-bispecific antisense oligonucleotide 4625 merits further study as a novel compound for cancer therapy.

The inhibitor of apoptosis protein (IAP) survivin is overexpressed in many tumors but is absent in most normal adult tissues. We report high levels of survivin expression in small cell lung cancer (SCLC), and describe the role of the phosphatidylinositol 3‐kinase (PI3K)/Akt pathway in survivin upregulation. Moreover, the cytoprotective function of survivin in response to the anti‐cancer agent cisplatin (CDDP) was investigated. Negative modulation of PI3K/Akt using pharmacological inhibitors or dominant negative Akt (DN‐Akt) decreased Akt kinase activity and resulted in decreased survivin expression and phosphorylation on Thr34, whereas transfection of constitutively active Akt (CA‐Akt) increased survivin expression and phosphorylation. Interestingly, we found that treatment of SCLC cells with CDDP further increased survivin expression in a cell cycle independent manner by activation of Akt. CA‐Akt or lentiviral survivin also inhibited apoptosis induced by CDDP, whereas DN‐Akt or survivin‐specific RNA interference sensitized cells to CDDP. We identified survivin as an anti‐apoptotic protein in SCLC cells that is regulated by Akt, and demonstrate that treatment with the DNA damaging agent CDDP activates the PI3K/Akt/survivin pathway that in part protects cells from drug‐induced apoptosis.

Bryophyllum pinnatum (syn. Kalanchoe pinnata) is a succulent perennial plant native to Madagascar that was introduced in anthroposophic medicine in the early 20th century. In recent years, we conducted a large collaborative project to provide reliable data on the chemical composition, pharmacological properties, and clinical efficacy of Bryophyllum. Here, we comprehensively review the phytochemistry, as well as the pharmacological and clinical data. As to the pharmacology, special emphasis is given to properties related to the use in anthroposophic medicine as a treatment for “hyperactivity diseases”, such as preterm labor, restlessness, and sleep disorders. Studies suggesting that B. pinnatum may become a new treatment option for overactive bladder syndrome are also reviewed. Tolerability is addressed, and toxicological data are discussed in conjunction with the presence of potentially toxic bufadienolides in Bryophyllum species. The few data available on two related species with medicinal uses, Bryophyllum daigremontianum and Bryophyllum delagoense, have also been included. Taken together, current data support the use of B. pinnatum for the mentioned indications, but further studies are needed to fully understand the modes of action, and to identify the pharmacologically active constituents. ^* Dedicated to Professor Dr. Dr. h. c. mult. Kurt Hostettmann in recognition of his outstanding contribution to natural product research.