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Antibiotics: The Need for Innovation
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Despite been discovered in 1928, it was not until 1941 that effective methods of isolating penicillin were developed by Florey and Chain. This drug revolutionised the battle against infection. However, penicillin is not effective against all types of infections. Since it was discovered that penicillin is a toxic fungal metabolite that kills bacteria and allows the fungi to compete for nutrients, it encouraged scientists to investigate microbial cultures from across the globe in search of other possible therapeutic agents. In 1944, the systematic search of soil microbes revealed the antibiotic streptomycin, which extended the range of therapy to the tubercle bacillus and a variety of gram-negative bacteria. Continued research led to the discovery of the other major classes of antibiotic: peptide antibiotics, tetra-cycline antibiotics, macrolide, and cyclic peptide; and synthetic agents including cephalosporin C, isoniazid, nalidixic acide, ciprofloxacin, and many others.
Transforming Growth Factor-β: A Cytokine Paradigm
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Michelle R. Frazier-Jessen, Nancy McCartney-Francis, Sharon M. Wahl
In addition, TGF-β1 is a potent inhibitor of B lymphocyte proliferation, effectively blocking progression of the cell cycle in the mid-Gt phase. Not only does TGF-β reduce c-myc mRNA levels; it also appears to block the phosphorylation of Rb, an anti-oncogene that regulates cell cycle progression and is differentially phosphorylated during the cell cycle [23]. Hypophosphorylated Rb reversibly arrests cell cycle progression in G1. In addition, TGF-β reduces the levels of E2F mRNA, a downstream transcription factor for Rb [24]. It can inhibit proliferation via inactivation of cyclin/cyclin dependent kinase (CDK) association, such as cyclin E/CDK2 via the inhibitory protein p27kipl [25,26] and cyclin D/CDK4 via the inhibitor p15lnk4B [27]. in addition to inhibiting cell growth, TGF-β1 can promote apoptosis, particularly in resting B lymphocytes [28], which also could provide a mechanism for deletion of self-reactive clones at all stages of B lymphocyte maturation.
Steroidal control of cell proliferation in the breast and breast cancer
Published in Barry G. Wren, Progress in the Management of the Menopause, 2020
E. A. Musgrove, R. L. Sutherland
The increase in cyclin D1 mRNA following progestin treatment was accompanied by an increase in cyclin D1 protein abundance (Figure 4). Little effect was apparent within 3 h but by 6 h cyclin D1 levels had increased by three- to four-fold (Musgrove and colleagues, in preparation). This response preceded entry into S phase, which began after > 9 h treatment The induction of cyclin D1 protein was accompanied by a corresponding increase in the abundance of cyclin D1/Cdk4 complexes and an increase in the relative amount of pRB in the hyperphosphorylated form (Figure 5). In contrast with the marked increase in cyclin D1 abundance, cyclin E abundance and kinase activity increased by at most two-fold (Figure 4). Overall, the data indicate substantial induction of cyclin D1 but more modest effects on cyclin E, consistent with induction of cyclin D1 being a critical component of the mitogenic response to progestins.
A patent and literature review of CDK12 inhibitors
Published in Expert Opinion on Therapeutic Patents, 2022
Ruijun Tang, Jing Liu, Shuyao Li, Junjie Zhang, Chunhong Yu, Honglu Liu, Fang Chen, Lu Lv, Qian Zhang, Kai Yuan, Hao Shao
Bayer Aktiengesellschaft reported three classes of molecular glue cyclin K degrader, which are structurally close to compounds 2–4 and 25, represented by 26 (189 in WO2021/116,178, IC50 = 10.9 nM for CDK12/cyclin K with 2 mM ATP in the assay) [61], 27 (29 in WO2021/176,045, IC50 = 40.5 nM for CDK12/cyclin K) [62] and 28 (50 in WO2021176045, IC50 = 617 nM for CDK12/cyclin K) [63] (Figure 5), respectively. Compounds from patent WO2021176045 represented by 28 were the least potent among the three series. Example compounds were characterized by 1H-NMR and LCMS. All the compounds were tested against CDK12/cyclin K, CDK13/cyclin K, CDK2/cyclin E and CDK9/cyclin T1 in biochemical assays. Most compounds were also tested in a high-content Cyclin K and CDK12 degradation assay with low nM DC50. Different with 25, these compounds were found to degrade both cyclin K and CDK12. Selected compounds were evaluated for their anti-proliferative activities against two breast cancer cell lines.
Neuro-Ophthalmic Literature Review
Published in Neuro-Ophthalmology, 2021
David A. Bellows, Noel C.Y. Chan, John J. Chen, Hui-Chen Cheng, Peter W. MacIntosh, Jenny A. Nij Bijvank, Michael S. Vaphiades, Konrad P. Weber, Sui H. Wong
There were several significant characteristics that distinguish the two groups including sex distribution, symptoms, cerebrospinal fluid pressure, comorbidities, and outcomes. The older age group showed a lower preponderance of females (78.5% vs. 92.3%). In regards to symptoms the older group of patients had fewer headaches (50.8% vs. 80%). However, the incidence of other symptoms such as pulse-synchronous tinnitus, vision changes, transient visual obscurations, and diplopia were similar in both cohorts. The older age group had a higher rate of comorbidities (hypertension, diabetes, and thyroid disease) but there was no difference between the groups in the rates of sleep apnoea, anaemia, or polycystic ovarian syndrome. Older patients were less likely to be on cycline-type antibiotics (0% vs. 10.8%). Interestingly, an older age was not found to be associated with a worse outcome as determined by mean deviation on perimetry or need for surgical intervention.
Emerging antibiotics for community-acquired pneumonia
Published in Expert Opinion on Emerging Drugs, 2019
Adamantia Liapikou, Catia Cilloniz, Andrea Palomeque, Toni Torres
Solithromycin benefits from having multiple binding sites in the 50S ribosome, making it more potent than other macrolides. Its oral formulation appears to be clinically effective, well tolerated, and to be suitable for once daily dosing over 5 days. We anticipate that its development will be pursued to treat infections in children and pregnancy given its desirable antibacterial activities and safety profile in preclinical studies. Omadacycline (a newly approved cycline) offers a single-agent parenteral or oral alternative to traditional empirical therapy in bacterial CAP. Additionally, it is significantly more active than doxycycline or minocycline against Enterobacteriaceae and A. baumannii, and meets the FDA criterion for susceptibility of K. pneumoniae. Unfortunately, patients with severe CAP (Fine class V) or those who presented in septic shock were excluded from the RCTs of solithromycin and omadacycline, so we lack clinical data for their use in those patients.