This paper introduces the concept and practice of "pharma-cology" which argues that future prescribers as well as established clinicians need to understand pharma sales tactics at a deeper level. The case of a drug rep from the late 1990s is highlighted as he successfully introduced and sold Trovan by manipulating and leveraging social relationships within a teaching hospital - a drug eventually removed from the US market by the FDA due to safey concerns. These specific sales tactics are pulled through to the contemporary scene, showing similarities with the promotion of opioids, which caused great harm to patients, and the GLP-1s, such as Ozempic (semaglutide), which are the most recent class of blockbuster pharmaceuticals to benefit from intensive marketing campaigns and the activies of drug reps.

No information is available on the clinical use of alatrofloxacin during breastfeeding. Fluoroquinolones have traditionally not been used in infants because of concern about adverse effects on the infants' developing joints. However, recent studies indicate little risk.[1,2] The calcium in milk might prevent absorption of the small amounts of fluoroquinolones in milk,[3] but insufficient data exist to prove or disprove this assertion. Use of alatrofloxacin is acceptable in nursing mothers with monitoring of the infant for possible effects on the gastrointestinal flora, such as diarrhea or candidiasis (thrush, diaper rash). However, it is preferable to use an alternate drug for which safety information is available.

No information is available on the clinical use of trovafloxacin during breastfeeding; however, amounts in breastmilk appear to be low. Fluoroquinolones have traditionally not been used in infants because of concern about adverse effects on the infants' developing joints. However, recent studies indicate little risk.[1,2] The calcium in milk might prevent absorption of the small amounts of fluoroquinolones in milk,[3] but insufficient data exist to prove or disprove this assertion. Use of trovafloxacin is acceptable in nursing mothers with monitoring of the infant for possible effects on the gastrointestinal flora, such as diarrhea or candidiasis (thrush, diaper rash). However, it is preferable to use an alternate drug for which safety information is available.

The world is facing the COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Likewise, other viruses of the Coronaviridae family were responsible for causing epidemics earlier. To tackle these viruses, there is a lack of approved antiviral drugs. Therefore, we have developed robust computational methods to predict the repurposed drugs using machine learning techniques namely Support Vector Machine, Random Forest, k-Nearest Neighbour, Artificial Neural Network, and Deep Learning. We used the experimentally validated drugs/chemicals with anticorona activity (IC50/EC50) from 'DrugRepV' repository. The unique entries of SARS-CoV-2 (142), SARS (221), MERS (123), and overall Coronaviruses (414) were subdivided into the training/testing and independent validation datasets, followed by the extraction of chemical/structural descriptors and fingerprints (17968). The highly relevant features were filtered using the recursive feature selection algorithm. The selected chemical descriptors were used to develop prediction models with Pearson's correlation coefficients ranging from 0.60 to 0.90 on training/testing. The robustness of the predictive models was further ensured using external independent validation datasets, decoy datasets, applicability domain, and chemical analyses. The developed models were used to predict promising repurposed drug candidates against coronaviruses after scanning the DrugBank. Top predicted molecules for SARS-CoV-2 were further validated by molecular docking against the spike protein complex with ACE receptor. We found potential repurposed drugs namely Verteporfin, Alatrofloxacin, Metergoline, Rescinnamine, Leuprolide, and Telotristat ethyl with high binding affinity. These 'anticorona' computational models would assist in antiviral drug discovery against SARS-CoV-2 and other Coronaviruses.

Fluoroquinolones (FQs) are a common class of antibiotic used for the treatment of infections, including those of the respiratory tract. However, the use of FQs has been controversial as certain types are associated with antibiotic resistance and adverse events. Antibiotic resistance is of significant concern due to the broad-spectrum nature and common use of FQs, and FQ resistance occurs through a number of potential individual or combined mechanisms. Recent global surveillance studies have found increasing rates of FQ resistance among almost all species of bacteria, and this has been demonstrated in urinary tract infection, respiratory tract infections, intraabdominal infections, skin and skin structure infections, and sexually transmitted infections., FQ resistance has likely been driven by the widespread use of the antibiotic, and adjustments clinical practice guidelines may be warranted to limit misuse of FQs. Common adverse events include gastrointestinal and central nervous system toxicities, while other adverse events include rashes and other allergic reactions, tendinitis and tendon rupture, QT prolongation, hypoglycemia and hyperglycemia, and hematologic toxicity. Several FQs have been withdrawn from the market due to adverse events. In the United States, examples include the withdrawal of grepafloxacin in 1999 due to fatal cardiovascular events, temafloxacin in 1992 due to severe adverse reactions (e.g. hemolytic anemia, acute renal failure, hepatotoxicity, and death), and alatrofloxacin in 2006 due to liver toxicity and death. The association of FQ use with serious adverse events has led to reevaluations of the use of FQs for uncomplicated infections in several jurisdictions. In 2016, the United Sates Food and Drug Administration (FDA) released a statement advising the restriction of FQ use in patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections who have other treatment options, because the risk of serious side effects generally outweighed the benefits. As a result, Health Canada undertook a review of FQs and associated adverse events, and posted the results in their Summary Safety Review in January 2017. The review concluded that adverse events associated with FQ use may be persistent and disabling in rare cases, and that Health Canada would collaborate with drug manufacturers to update product safety information to reflect this potential risk. There remains uncertainty in the use of FQs for the treatment of infections. This report is an extension of a previous Rapid Response report, which identified evidence for the clinical effectiveness, cost-effectiveness, and guidelines for FQs in pneumonia and chronic obstructive pulmonary disease (COPD). The report found inconsistent results in the systematic reviews of the clinical effectiveness of FQ use in pneumonia, while there was a limited volume of evidence in the clinical effectiveness in COPD, and cost-effectiveness of FQ use in pneumonia. The current report aims to identify and synthesize the evidence describing the clinical effectiveness, cost-effectiveness and guidelines for the use of FQs in other respiratory tract infections (excluding COPD, pneumonia, cystic fibrosis and tuberculosis).

Trovafloxacin (TVX) is a fluoroquinolone antibiotic whose therapeutic use was severely restricted due to an unacceptable risk of idiosyncratic liver injury. Oxidative stress and mitochondrial injury have been implicated in fluoroquinolone toxicity, but the mechanisms underlying liver injury are poorly understood. Because TVX-induced hepatotoxicity cannot be modeled in normal healthy rodents, we asked whether an underlying genetic defect (heterozygous deficiency in mitochondrial superoxide dismutase, Sod2) might aggravate TVX-induced mitochondrial adverse effects. Wild-type and Sod2(+/-) mice were treated with vehicle or alatrofloxacin (the prodrug of TVX, 33mg/kg/day, ip) for 28 days. We found that hepatic protein carbonyls were increased by 2.5-fold and hepatic mitochondrial aconitase activity was decreased by 20% in mutant, but not wild-type mice. Because aconitase is a major target of peroxynitrite, we determined the extent of nitrotyrosine residues in hepatic mitochondrial proteins. Trovafloxacin significantly increased nitrotyrosine in Sod2(+/-) mice only. Using the NO-selective probe DAF-2, we found that TVX increased the production of mitochondrial NO in immortalized human hepatocytes. Similarly, mitochondrial Ca(2+) was increased by TVX, suggesting Ca(2+)-dependent activation of mitochondrial NOS activity. Furthermore, the transcript levels of the mtDNA-encoded gene Cox2/mtCo2 were decreased in Sod2(+/-) mice only, while the expression of nDNA-encoded mitochondrial genes was not significantly altered in both genotypes, suggesting selective effects on mtDNA expression. The amount of mtDNA (copy number) was, however, unchanged. These data indicate that TVX enhances hepatic mitochondrial peroxynitrite stress in mice with underlying increased basal levels of superoxide, leading to the disruption of critical mitochondrial enzymes and gene regulation.

Emerging trends in nursing have broadened the traditional scope of nursing practice with growing demands for ethical considerations in clinical judgments. Nurses are experiencing more ethical dilemmas in areas such as end of life issues, organ donation and transplantation, and truth telling among others. It is expected that these challenges will continue to increase and even become more complex. Despite this, the academic and professional preparation of nurses in Africa to cope with these issues is doubtful. The myriad of peculiar socioeconomic and political problems in many African societies present potential threat to the adoption of ethical standards in health care practice. Many health care workers including nurses attach little importance to consumer rights in making informed decisions in issues related to clinical care and research participation. The alleged participation of nurses in the inhuman treatment of the children recruited during the Pfizer's clinical trial of Trovan for cerebrospinal meningitis in northern Nigeria exemplifies this. Such conducts could reduce patients' worth as persons, and at the same time an indictment of nurses' moral sanctity. This paper reviews the current ethical challenges facing professional nurses in Nigeria. The concept and critical relevance of clinical ethics in giving adequate information to patients, relatives and other health workers upon which ethically sound informed decision making is done in clinical situations were highlighted.

The ethics of conducting research in epidemic situations have yet to account fully for differences in the proportion and acuteness of epidemics, among other factors. While epidemics most often arise from infectious diseases, not all infectious diseases are of epidemic proportions, and not all epidemics occur acutely. These and other variations constrain the generalization of ethical decision-making and impose ethical demands on the individual researcher in a way not previously highlighted. This paper discusses a number of such constraints and impositions. It applies the ethical principles enunciated by Emmanuel et al.(1) to the controversial Pfizer study in Nigeria in order to highlight the particular ethical concerns of acute epidemic research, and suggest ways of meeting such challenges. The paper recommends that research during epidemics should be partly evaluated on its own merits in order to determine its ethical appropriateness to the specific situation. Snap decisions to conduct research during acute epidemics should be resisted. Community engagement, public notification and good information management are needed to promote the ethics of conducting research during acute epidemics. Individual consent is most at risk of being compromised, and every effort should be made to ensure that it is maintained and valid. Use of data safety management boards should be routine. Acute epidemics also present opportunities to enhance the social value of research and maximize its benefits to communities. Ethical research is possible in acute epidemics, if the potential challenges are thought of ahead of time and appropriate precautions taken.

To participate in health research, there is a need for well-administered informed consent. Understanding of informed consent, especially in international health research, is influenced by the participants' understanding of information and the meaning attached to the information communicated to them regarding the purpose and procedure of the research. Incorrect information and the power differential between researcher and participants may lead to participants becoming victims of harmful research procedures. Meningitis epidemics in Kano in early 1996 led to a response from drug companies, especially Pfizer, as well as humanitarian workers from Médecins Sans Frontiers, which resulted in an unethical trial. Pfizer's drug trial during the epidemics has left a lasting controversy, which has yet to be resolved. This paper examines the key issues surrounding the controversy, discusses the context of informed decision-making, the ethical issues and implications of the incident, and concludes with some recommendations. Relevant texts, journals, Internet materials, newspaper articles and documentary materials on the conduct of the Pfizer's Trovan trial have been consulted. Four types of action (act intuitively, act rationally, act ignorantly, and act contextually - based on information provided) are identified as possible options for decision making. Participants most likely acted in ignorance due to poor understanding of the information contained in the verbal informed consent administered, thereby raising ethical issues. It is concluded that health research ethics committees have an important role to play nationally and locally in overseeing research, and in avoiding future occurrences.

Trovafloxacin (Trovan) is a fluoroquinolone antibiotic drug with a long half-life and broad-spectrum activity. Since its entry into the market in 1998, trovafloxacin has been associated with numerous cases of hepatotoxicity, which has limited its clinical usefulness. Trovafloxacin possesses two substructural elements that have the potential to generate reactive intermediates: a cyclopropylamine moiety and a difluoroanilino system. The results presented here describe the in vitro metabolic activation of a synthetic drug model (DM) of trovafloxacin that contains the cyclopropylamine moiety. Cyclopropylamine can be oxidized to reactive ring-opened products-a carbon-centered radical and a subsequently oxidized alpha,beta-unsaturated aldehyde. Experiments with monoamine oxygenases, horseradish peroxidase, flavin monooxygenase 3, and cDNA-expressed P450 isoenzymes revealed that P450 1A2 oxidizes DM to a reactive alpha,beta-unsaturated aldehyde, M 1. Furthermore, myeloperoxidase (MPO) was also demonstrated to oxidize DM in the presence of chloride ion to produce M 1. DM proved to be a suicide inhibitor of MPO while showing no inhibition of P450 1A2. The structure of the reactive metabolite was confirmed by LC-MS/MS analysis by comparison with a synthetic standard. M 1 was further shown to react with glutathione and the related thiol nucleophile, 4-bromobenzyl mercaptan, suggesting the potential of this intermediate to react with protein nucleophiles. In summary, these data provide evidence that trovafloxacin-induced hepatotoxicity may be mediated through the oxidation of the cyclopropylamine substructure to reactive intermediates that may form covalent adducts to hepatic proteins, resulting in damage to liver tissue.