BioDrugs

Halothane hepatitis is a very rare but clinically important adverse drug reaction that may cause fatal liver failure. The liver damage appears to arise as a consequence of immune responses to novel hepatic protein antigens that are produced via cytochrome P450-mediated bioactivation of halothane to CF3COCl. This reactive metabolite binds covalently to hepatic proteins, apparently via ε-amino groups of lysine residues, yielding trifluoroacetylated proteins. Seven distinct trifluoroacetylated hepatic protein antigens have been identified and characterised to date. These are modified forms of proteins normally resident in the lumen of the endoplasmic reticulum. Apparently all halothane-exposed individuals express the antigens, but only individuals who develop halothane hepatitis mount the antibody response. Why this should be so is unclear. Analogous immune processes may underlie the hepatitis reported in patients exposed to the structurally related anaesthetics enflurane and isoflurane. Diagnosis of anaesthetic-induced hepatitis is based upon clinical criteria and exclusion of other possible causes of liver damage, and may be verified by testing for antibodies to the metabolite-modified antigens. Although most patients recover relatively uneventfully, some develop fulminant liver failure that may progress to severe hepatic encephalopathy. These latter patients have a very poor prognosis and should be referred to specialist centres, where orthotopic liver transplantation should be considered. Patients thought to be sensitised to halothane must never be re-exposed to the drug. The majority of halothane-sensitised individuals may be anaesthetised safely with isoflurane or enflurane. However. some individuals who are sensitised to halothane exhibit cross-sensitisation to these other agents.

The new generation of biological products are largely the result of genetic engineering. The qualitative and quantitative demand for recombinant proteins is steadily increasing. Molecular biologists are constantly challenged by the need to improve and optimise the existing expression systems, and also develop novel approaches to face the demands of producing the complex proteins of tomorrow. This continuous evolution is paralleled by growing concerns about the safety of these novel pharmaceuticals, with health authorities setting high standards for certification. One of the strategies used by researchers in this field involves sourcing new genetic elements for incorporation into expression systems by systematically analysing the rich natural diversity of microorganisms and plant-based expression systems. There are, in addition, numerous tools for modifying microorganisms and for re-engineering existing biological pathways or processes to meet the needs of the pharmaceutical industry. The aim of this review is to present the conventional and alternative expression systems, focusing on prokaryotic expression systems and briefly exploring other complementary recombinant protein production systems and their unique features.

The inflammatory bowel diseases (IBDs) are chronic immune-mediated inflammatory disorders, including ulcerative colitis (UC) and Crohn’s disease (CD). IBD results from a complex interplay between environmental, microbial, and genetic factors to create an abnormal immunological response leading to intestinal inflammation. Many pathways driving inflammation have been described, and different pathways may predominate in an individual patient. The interleukin (IL)-23 pathway plays a key role in IBD pathogenesis through promoting a pathological Th17 response. Targeting IL-23 is effective in the treatment of IBD. Ustekinumab, a monoclonal antibody targeting the shared p40 subunit of IL-12/23, is approved for treatment of moderate-to-severe CD and UC. Specific IL-23p19 antagonists are in development and promising results from phase II trials of mirikizumab and risankizumab underscore the potential for this class of treatment. In this review, we summarize the mechanisms of action and the evidence from clinical trials supporting the efficacy and safety of different IL-23 antagonists for IBD.

Trials in rheumatoid arthritis have been difficult to perform and interpret due to disagreement over what to measure. This paper reviews the most frequently used measures and their validity against the background of the Outcome Measures in Rheumatology (OMERACT) consensus conferences. These conferences have resulted in the adoption of a core set of end-points to be used as a minimum in all clinical trials in rheumatoid arthritis. These are known as the World Health Organization/International League of Associations for Rheumatology (WHOIILAR) core set. p ]This set of measures comprises: (i) pain; (ii) patient global assessment; (iii) physical disability; (iv) swollen joints; (v) tender joints; (vi) acute phase reactants; (vii) physician (assessor) global assessment; and, in studies of 1 or more years duration, (viii) radiographs of joints. Other developments include a renewed interest in aggregate end-points (indices) such as response criteria, and in the measurement of adverse effects and economic costs. In sum, measurement methodology in rheumatoid arthritis has been improved in time to take advantage of expected important advances in treatment.

Felty’s syndrome is a complication of rheumatoid arthritis whereby patients develop neutropenia of varying severity. Although the main clinical concern is the development of serious infections, often patients remain asymptomatic or continue with clinical problems related to the rheumatoid arthritis and not to the neutropenia. There is now considerable clinical experience with the use of the recombinant human haemopoietic growth factors granulocyte and granulocytemacrophage colony-stimulating factors (G-CSF and GM-CSF) in the treatment of patients with Felty’s syndrome. The only indication for the use of either growth factor for Felty’s syndrome is the onset of infectious complications, which may be recurrent and serious. In general, when this occurs, the neutropenia is severe (<108 cells/L). The mechanism(s) underlying development of the neutropenia in Felty’s syndrome is similar to that in other forms of immune-mediated neutropenia, and in general is associated with a terminal defect in neutrophil maturation. It is likely that the maturational defect is a consequence of ‘immune based’ inhibition, although we lack detailed understanding of this inhibitory process. Growth factor therapy does not relieve the defect in terminal maturation, but in general may induce a significant improvement in the peripheral white cell count. Instances where growth factor therapy does not work appear to be due to an inability to overcome the maturational defect. Thus, the level of granulopoietic inhibition mediated by the rheumatoid process varies in severity among patients. To date, treatment options for Felty’s syndrome have included disease-modifying antirheumatic drugs, corticosteroids and splenectomy. The addition of growth factor therapy is a welcome addition to these less than optimal treatment options. However, all of the above therapies fail on occasion. Moreover, the dosage and frequency of growth factors must be titrated to keep the white blood cell count <5 × 109 cells/L, since overshoot may result in complications, the most common being exacerbation of the rheumatoid arthritis. Another mechanism by which these drugs may exacerbate rheumatoid arthritis is through activation of neutrophils. The addition of disease-modifying drugs may relieve the maturational defect, improve the peripheral white cell count and minimise disease exacerbation by limiting neutrophil exposure to the administered haemopoietic growth factor. However, long term monotherapy with G-CSF has been successfully employed without requiring disease-modifying therapy.

Salmonella typhimurium is the main cause of gastrointestinal illness in humans, and treatment options are decreasing because drug-resistant strains have emerged. The objective of this study was to use computational drug repurposing to identify a novel candidate with an effective mechanism of action to circumvent the drug resistance. We used the Mantra 2.0 database to initially screen drug candidates that share similar gene expression profiles to those of quinolones. Data were further reduced using pharmacophore mapping theory. Finally, we employed molecular-simulation studies to calculate the binding affinity of the screened candidates with DNA gyrase, alongside an analysis of side effects. A total of 16 drug candidates from the Mantra 2.0 database were screened. The pharmacophoric features of the screened candidates were examined and nalidixic acid features compared using the PharamGist program. A total of 11 compounds with the highest pharmacophore score were considered for binding energy calculation. Finally, we analysed the side effects of the eight drug candidates that showed significant binding affinity in the simulation study. Overall, flufenamic acid and sulconazole may be potential drug candidates that could be studied in vitro to assess their resistance profile against Salmonella enterica Typhimurium.