Population pharmacokinetics of primaquine and its metabolites in African males.

BACKGROUND: Primaquine (PQ) is the prototype 8-aminoquinoline drug, a class which targets gametocytes and hypnozoites. The World Health Organization (WHO) recommends adding a single low dose of primaquine to the standard artemisinin-based combination therapy (ACT) in order to block malaria transmission in regions with low malaria transmission. However, the haemolytic toxicity is a major adverse outcome of primaquine in glucose-6-phosphate dehydrogenase (G6PD)-deficient subjects. This study aimed to characterize the pharmacokinetic properties of primaquine and its major metabolites in G6PD-deficient subjects. METHODS: A single low-dose of primaquine (0.4-0.5 mg/kg) was administered in twenty-eight African males. Venous and capillary plasma were sampled up to 24 h after the drug administration. Haemoglobin levels were observed up to 28 days after drug administration. Only PQ, carboxy-primaquine (CPQ), and primaquine carbamoyl-glucuronide (PQCG) were present in plasma samples and measured using liquid chromatography mass spectrometry. Drug and metabolites' pharmacokinetic properties were investigated using nonlinear mixed-effects modelling. RESULTS: Population pharmacokinetic properties of PQ, CPQ, and PQCG can be described by one-compartment disposition kinetics with a transit-absorption model. Body weight was implemented as an allometric function on the clearance and volume parameters for all compounds. None of the covariates significantly affected the pharmacokinetic parameters. No significant correlations were detected between the exposures of the measured compounds and the change in haemoglobin or methaemoglobin levels. There was no significant haemoglobin drop in the G6PD-deficient patients after administration of a single low dose of PQ. CONCLUSIONS: A single low-dose of PQ was haematologically safe in this population of G6PD-normal and G6PD-deficient African males without malaria. Trial registration NCT02535767.

Pharmacology education in the medical curriculum: Challenges and opportunities for improvement.

The knowledge and application of pharmacology is essential for safe prescribing and administration of drugs. In this narrative review, the challenges to pharmacology education in the medical curricula were broadly identified to include issues around content and pedagogies. The increasing number of approved drugs and drug targets, expanding field of pharmacology and the often-changing treatment guidelines and board-defined competencies can make pharmacology education in the medical curriculum daunting. There has been a consensus around the deployment of innovative medical curricula with emphasis on vertical and horizontal integration. This strategy, effective as it has been, presents new challenges to pharmacology education. As a discipline often perceived by students to be hard-to-learn, the future of pharmacology education must include heavy reliance on active learning strategies. The continuing utilization of problem-based, team-based and case-based learning can be complemented with personalized learning which aims to identify the learning gaps in individual students. Technology-inspired student engagement can foster pharmacology learning and retention. Early exposure to pharmacology from premedical preparation through an enduring across-the-level integration can be an effective way to enhance pharmacology learning in the medical curricula.

Rare Heterogeneous Adverse Events Associated with mRNA-Based COVID-19 Vaccines: A Systematic Review.

Background: Since the successful development, approval, and administration of vaccines against SARS-CoV-2, the causative agent of COVID-19, there have been reports in the published literature, passive surveillance systems, and other pharmacovigilance platforms of a broad spectrum of adverse events following COVID-19 vaccination. A comprehensive review of the more serious adverse events associated with the Pfizer-BioNTech and Moderna mRNA vaccines is warranted, given the massive number of vaccine doses administered worldwide and the novel mechanism of action of these mRNA vaccines in the healthcare industry. Methods: A systematic review of the literature was conducted to identify relevant studies that have reported mRNA COVID-19 vaccine-related adverse events. Results: Serious and severe adverse events following mRNA COVID-19 vaccinations are rare. While a definitive causal relationship was not established in most cases, important adverse events associated with post-vaccination included rare and non-fatal myocarditis and pericarditis in younger vaccine recipients, thrombocytopenia, neurological effects such as seizures and orofacial events, skin reactions, and allergic hypersensitivities. Conclusions: As a relatively new set of vaccines already administered to billions of people, COVID-19 mRNA-based vaccines are generally safe and efficacious. Further studies on long-term adverse events and other unpredictable reactions in close proximity to mRNA vaccination are required.

A Retrospective Study of the Seroprevalence of Dengue Virus and Chikungunya Virus Exposures in Nigeria, 2010-2018.

Arboviruses are important public health threats in many regions of the world. Nigeria has experienced outbreaks of arboviruses over the past decades, leading to concerns of widespread endemicity, which are frequently misdiagnosed. This study aimed to determine the seroprevalence of dengue virus (DENV) (a flavivirus) and chikungunya virus (CHIKV) (an alphavirus) infections in three major population centers of Nigeria. A convenience sample of 701 sera was collected from both healthy and febrile participants between August 2010 and March 2018. Sera were tested for prior exposure to CHIKV virus and DENV using indirect IgG ELISA. Results showed that 54.1% (379/701) of participants were seropositive for anti-DENV antibodies, 41.3% (290/701) were seropositive for anti-CHIKV antibodies, and 20.1% (141/701) had previous exposure to both. The seropositivity for prior CHIKV exposure and prior exposure to DENV and CHIKV was significantly associated with age (CHIKV: OR = 2.7 (95% CI: 1.7-4.3); DENV and CHIKV: OR = 2.2 (95% CI: 1.2-4.0) for adults compared to participants under 18 years old). Overall, the high seropositivity across all age groups suggests that arboviral infections are prevalent in Nigeria and indicates that surveillance and further epidemiological studies are required to determine the true burden of these infections and the spectrum of diseases associated with these exposures.

A systematic review and meta-analysis of published literature on prevalence of non-O157 Shiga toxin-producing Escherichia coli serogroups (O26, O45, O103, O111, O121, and O145) and virulence genes in feces, hides, and carcasses of pre- and peri-harvest cattle worldwide.

OBJECTIVE: The objective of this study was to summarize peer-reviewed literature on the prevalence and concentration of non-O157 STEC (O26, O45, O103, O111, O121, and O145) serogroups and virulence genes (stx and eae) in fecal, hide, and carcass samples in pre- and peri-harvest cattle worldwide, using a systematic review of the literature and meta-analyses. DATA SYNTHESIS: Seventy articles were eligible for meta-analysis inclusion; data from 65 articles were subjected to random-effects meta-analysis models to yield fecal prevalence estimates. Meta-regression models were built to explore variables contributing to the between-study heterogeneity. RESULTS: Worldwide pooled non-O157 serogroup, STEC, and EHEC fecal prevalence estimates (95% confidence interval) were 4.7% (3.4-6.3%), 0.7% (0.5-0.8%), and 1.0% (0.8-1.1%), respectively. Fecal prevalence estimates significantly differed by geographic region (P < 0.01) for each outcome classification. Meta-regression analyses identified region, cattle type, and specimen type as factors that contribute to heterogeneity for worldwide fecal prevalence estimates. CONCLUSIONS: The prevalence of these global foodborne pathogens in the cattle reservoir is widespread and highly variable by region. The scarcity of prevalence and concentration data for hide and carcass matrices identifies a large data gap in the literature as these are the closest proxies for potential beef contamination at harvest.

Comparative single dose pharmacokinetics and metabolism of racemic primaquine and its enantiomers in human volunteers.

Primaquine (PQ) is a racemic drug used in treatment of malaria for six decades. Recent studies suggest that the two enantiomers of PQ are differentially metabolized in animals, and this results in different pharmacological and toxicological profiles. The current study characterizes the pharmacokinetic (PK) properties, metabolism and tolerability of the individual enantiomers of PQ in healthy human volunteers with normal glucose-6-phosphate dehydrogenase (G6PD) activity. Two cohorts (at two dose levels), each with 18 subjects, participated in three study arms in a crossover fashion: a single dose of the (-)-R enantiomer (RPQ), a single dose of the (+)-S enantiomer (SPQ), and a single dose of racemic PQ (RSPQ). PQ and its key metabolites carboxyprimaquine (cPQ) and PQ-N-carbamoyl glucuronide (PQ-N-CG) were analyzed. Clear differences were observed in PK and metabolism of the two enantiomers. Relative PQ exposure was higher with SPQ as compared to RPQ. PQ maximum plasma concentration (Cmax) and area under the plasma concentration-time curve were higher for SPQ, while the apparent volume of distribution and total body clearance were higher for RPQ. Metabolism of the two enantiomers showed dramatic differences: plasma PQ-N-CG was derived solely from SPQ, while RPQ was much more efficiently converted to cPQ than was SPQ. Cmax of cPQ and PQ-N-CG were 10 and 2 times higher, respectively, than the parent drugs. The study demonstrates that the PK properties of PQ enantiomers show clear differences, and metabolism is highly enantioselective. Such differences in metabolism suggest potentially distinct toxicity profiles in multi-dose regimens, especially in G6PD-deficient subjects.

Factors Associated with Antimicrobial Stewardship Practices on California Dairies: One Year Post Senate Bill 27.

BACKGROUND: The current study is aimed at identifying the factors associated with antimicrobial drug (AMD) use and stewardship practices on conventional California (CA) dairies a year after CA Senate Bill 27. METHODS: Responses from 113 out of 1282 dairies mailed a questionnaire in 2019 were analyzed to estimate the associations between management practices and six outcomes including producer familiarity with medically important antimicrobial drugs (MIADs), restricted use of MIADs previously available over the counter (OTC), use of alternatives to AMD, changes in on-farm management practices, changes in AMD costs, and animal health status in dairies. RESULTS: Producers who reported having a veterinarian-client-patient relationship (VCPR) and tracking AMD withdrawal intervals had greater odds of being familiar with the MIADs. Producers who began or increased the use of preventive alternatives to AMD in 2019 had higher odds (OR = 3.23, p = 0.04) of decreased use of MIADs previously available OTC compared to those who did not. Changes in management practices to prevent disease outbreak and the use of diagnostics to guide treatment were associated with producer-reported improved animal health. In addition, our study identified record keeping (associated with familiarity with MIADs), use of alternatives to AMD (associated with management changes to prevent diseases and decreased AMD costs), and use of diagnostics in treatment decisions (associated with reported better animal health) as factors associated with AMD stewardship. CONCLUSIONS: Our survey findings can be incorporated in outreach education materials to promote antimicrobial stewardship practices in dairies.

Comparative pharmacokinetics and tissue distribution of primaquine enantiomers in mice.

BACKGROUND: Primaquine (PQ) has been used for the radical cure of relapsing Plasmodium vivax malaria for more than 60 years. PQ is also recommended for prophylaxis and prevention of transmission of Plasmodium falciparum. However, clinical utility of PQ has been limited due to toxicity in individuals with genetic deficiencies in glucose 6-phosphate dehydrogenase (G6PD). PQ is currently approved for clinical use as a racemic mixture. Recent studies in animals as well as humans have established differential pharmacological and toxicological properties of the two enantiomers of PQ. This has been attributed to differential metabolism and pharmacokinetics of individual PQ enantiomers. The aim of the current study is to evaluate the comparative pharmacokinetics (PK), tissue distribution and metabolic profiles of the individual enantiomers in mice. METHODS: Two groups of 21 male Albino ND4 Swiss mice were dosed orally with 45 mg/kg of S-(+)-PQ and R-(-)PQ respectively. Each of the enantiomers was comprised of a 50:50 mixture of 12C- and 13C- stable isotope labelled species (at 6 carbons on the benzene ring of the quinoline core). Three mice were euthanized from each group at different time points (at 0, 0.5, 1, 2, 4, 8, 24 h) and blood was collected by terminal cardiac bleed. Liver, spleen, lungs, kidneys and brain were removed, extracted and analysed using UPLC/MS. The metabolites were profiled by tandem mass (MS/MS) fragmentation profile and fragments with 12C-13C twin peaks. Non-compartmental analysis was performed using the Phoenix WinNonLin PK software module. RESULTS: The plasma AUC0-last (µg h/mL) (1.6 vs. 0.6), T1/2 (h) (1.9 vs. 0.45), and Tmax (h) (1 vs. 0.5) were greater for SPQ as compared to RPQ. Generally, the concentration of SPQ was higher in all tissues. At Tmax, (0.5-1 h in all tissues), the level of SPQ was 3 times that of RPQ in the liver. Measured Cmax of SPQ and RPQ in the liver were about 100 and 40 times the Cmax values in plasma, respectively. Similar observations were recorded in other tissues where the concentration of SPQ was higher compared to RPQ (2× in the spleen, 6× in the kidneys, and 49× in the lungs) than in the plasma. CPQ, the major metabolite, was preferentially generated from RPQ, with higher levels in all tissues (> 10× in the liver, and 3.5× in the plasma) than from SPQ. The PQ-o-quinone was preferentially formed from the SPQ (> 4× compared to RPQ), with higher concentrations in the liver. CONCLUSION: These studies show that in mice, PQ enantiomers are differentially biodistributed and metabolized, which may contribute to differential pharmacologic and toxicity profiles of PQ enantiomers. The findings on higher levels of PQ-o-quinone in liver and RBCs compared to plasma and preferential generation of this metabolite from SPQ are consistent with the higher anti-malarial efficacy of SPQ observed in the mouse causal prophylaxis test, and higher haemolytic toxicity in the humanized mouse model of G6PD deficiency. Potential relevance of these findings to clinical use of racemic PQ and other 8-aminoquinolines vis-à-vis need for further clinical evaluation of individual enantiomers are discussed.

Molecular electronics sensors on a scalable semiconductor chip: A platform for single-molecule measurement of binding kinetics and enzyme activity.

For nearly 50 years, the vision of using single molecules in circuits has been seen as providing the ultimate miniaturization of electronic chips. An advanced example of such a molecular electronics chip is presented here, with the important distinction that the molecular circuit elements play the role of general-purpose single-molecule sensors. The device consists of a semiconductor chip with a scalable array architecture. Each array element contains a synthetic molecular wire assembled to span nanoelectrodes in a current monitoring circuit. A central conjugation site is used to attach a single probe molecule that defines the target of the sensor. The chip digitizes the resulting picoamp-scale current-versus-time readout from each sensor element of the array at a rate of 1,000 frames per second. This provides detailed electrical signatures of the single-molecule interactions between the probe and targets present in a solution-phase test sample. This platform is used to measure the interaction kinetics of single molecules, without the use of labels, in a massively parallel fashion. To demonstrate broad applicability, examples are shown for probe molecule binding, including DNA oligos, aptamers, antibodies, and antigens, and the activity of enzymes relevant to diagnostics and sequencing, including a CRISPR/Cas enzyme binding a target DNA, and a DNA polymerase enzyme incorporating nucleotides as it copies a DNA template. All of these applications are accomplished with high sensitivity and resolution, on a manufacturable, scalable, all-electronic semiconductor chip device, thereby bringing the power of modern chips to these diverse areas of biosensing.

Herb-drug Interactions in Neuropsychiatric Pharmacotherapy - A Review of Clinically Relevant Findings.

The management of neuropsychiatric disorders relies heavily on pharmacotherapy. The use of herbal products as complimentary medicine, often concomitantly, is common among patients taking prescription neuropsychiatric drugs. Herb-drug interaction, a clinical consequence of this practice, may jeopardize the success of pharmacotherapy in neuropsychiatry. Besides the wellknown ability of phytochemicals to inhibit and/or induce drug-metabolizing enzymes and transport proteins, several phytoconstituents are capable of exerting pharmacological effects on the central nervous system. This study reviewed the relevant literature and identified 13 commonly used herbal products - celery, echinacea, ginkgo, ginseng, hydroxycut, kava, kratom, moringa, piperine, rhodiola, St. John's wort, terminalia/commiphora ayurvedic mixture and valerian - which have shown clinically relevant interactions with prescription drugs used in the management of neuropsychiatric disorders. The consequent pharmacokinetic and pharmacodynamic interactions with orthodox medications often result in deleterious clinical consequences. This underscores the importance of caution in herb-drug co-medication.

2019 Survey of Antimicrobial Drug Use and Stewardship Practices in Adult Cows on California Dairies: Post Senate Bill 27.

Antimicrobial resistance (AMR) is a global issue for both human and animal health. Antimicrobial drug (AMD) use in animals can contribute to the emergence of AMR. In January 2018, California (CA) implemented legislation (Senate Bill 27; SB 27) requiring veterinary prescriptions for medically important AMD use in food animals. The objective of our survey was to characterize AMD use, health management, and AMD stewardship practices of adult cows on CA dairies since the implementation of SB 27. In 2019, we mailed a questionnaire to 1282 California dairies. We received a total of 131 (10.2%) survey responses from 19 counties in CA. Our results showed that 45.6% of respondents included a veterinarian in their decision on which injectable AMD to purchase. Additionally, 48.8% of dairy producers included a veterinarian in their decision on which AMDs were used to treat sick cows. The majority (96.8%) of dairy producers were aware that all uses of medically important AMDs require a prescription. Approximately 49% of respondents agreed or strongly agreed that AMD use in livestock does not cause problems in humans. The survey documents antimicrobial use and stewardship practices in CA's dairy industry and focus areas for future research and education.

2018 Survey of antimicrobial drug use and stewardship practices in adult cows on California dairies: post-Senate Bill 27.

BACKGROUND: A survey of California (CA) dairies was performed in spring 2018 to characterize antimicrobial stewardship practices, antimicrobial drug (AMD) use, and health management of adult cows on CA dairies since the implementation of the Veterinary Feed Directive (VFD) and the CA Senate Bill 27 (SB 27). Effective January 1, 2017, the U.S. Food and Drug Administration (FDA) implemented regulatory changes requiring veterinary oversight for therapeutic uses of medically-important antimicrobial drugs (MIADs) administered in feed (VFD) and water (veterinary prescription). Similarly, effective January 1, 2018, the CA legislature enacted California Food and Agricultural Code (FAC) 14400-14408, formerly known as Senate Bill 27 (SB 27) requiring veterinary prescriptions for all other dosage forms of MIADs. METHODS: The questionnaire consisted of 43 questions partitioned into three sections to assess herd information, management practices, and AMD use and perspectives. The questionnaire was mailed to 1,282 grade A licensed dairies in CA and 149 responses (11.6%) were collected from 19 counties across the three defined regions of CA: Northern CA (NCA), Northern San Joaquin Valley (NSJV), and Greater Southern CA (GSCA). RESULTS: Most dairies reported treating all dry cows with intramammary AMD and/or teat sealant at the end of a lactation (87.2%). In 92.3% of dairies, producers relied on the veterinarian for information about AMD used to treat cows. Treatment duration for cows treated with AMD was based on the drug manufacturer's label and veterinarian's instructions in most dairies (98.6%). Most respondents to the survey confirmed having a valid veterinarian-client-patient-relationship (VCPR) for their dairies (91.7%), participated in animal welfare audit programs (81.8%) and dairy quality assurance programs (52.9%). Approximately 98.6% respondents were aware that all uses of MIADs in livestock required a veterinary feed directive (VFD) or prescription and are no longer sold over-the-counter (OTC) in CA since January 1, 2018. Multiple factor analysis (MFA) was performed and identified seven components composed of 21 variables (questions) that explained 99.7% of the total variance in the data. Hierarchical cluster analysis on the principal coordinates of the MFA based on conventional dairy survey responses identified two clusters characterized as large conventional dairies (median herd size: 1,265 cows) and mid-sized conventional dairies (median herd size: 715 cows) mostly in GSCA and NSJV. The organic dairies grouped into a single cluster of median herd size of 325 cows mostly in NCA. CONCLUSIONS: The survey results contribute to the knowledge of AMD use and antimicrobial stewardship practices on CA dairies since the implementation of the SB 27 and VFD laws and provide useful information for future evaluation of resistance-related risk in adult cows.

2018 Survey of factors associated with antimicrobial drug use and stewardship practices in adult cows on conventional California dairies: immediate post-Senate Bill 27 impact.

BACKGROUND: Antimicrobial drugs (AMD) are critical for the treatment, control, and prevention of diseases in humans and food-animals. Good AMD stewardship practices and judicious use of AMD are beneficial to the preservation of animal and human health from antimicrobial resistance threat. This study reports on changes in AMD use and stewardship practices on California (CA) dairies, following the implementation of CA Senate Bill 27 (SB 27; codified as Food and Agricultural Code, FAC 14400-14408; here onward referred to as SB 27), by modeling the associations between management practices on CA conventional dairies and seven outcome variables relating to AMD use and stewardship practices following SB 27. METHODS: A survey questionnaire was mailed to 1,282 grade A licensed dairies in CA in spring of 2018. Responses from 132 conventional dairies from 16 counties were included for analyses. Multivariate logistic regression models were specified to explore the associations between survey factors and six outcome variables: producers' familiarity with the Food and Drug Administration's (FDA), Silver Spring, WA, USA medically important antimicrobial drugs (MIAD) term; change in over-the-counter (OTC) AMD use; initiation or increased use of alternatives to AMD; changes to prevent disease outbreaks; changes in AMD costs; and better animal health post SB 27. We employed machine learning classification models to determine which of the survey factors were the most important predictors of good-excellent AMD stewardship practices of CA conventional dairy producers. RESULTS: Having a valid veterinary-client-patient-relationship, involving a veterinarian in training employees on treatment protocols and decisions on AMDs used to treat sick cows, tracking milk and/or meat withdrawal intervals for treated cows, and participating in dairy quality assurance programs were positively associated with producers' familiarity with MIADs. Use or increased use of alternatives to AMDs since 2018 was associated with decreased use of AMDs that were previously available OTC prior to SB 27. Important variables associated with good-excellent AMD stewardship knowledge by CA conventional dairy producers included having written or computerized animal health protocols, keeping a drug inventory log, awareness that use of MIADs required a prescription following implementation of SB 27, involving a veterinarian in AMD treatment duration determination, and using selective dry cow treatment. CONCLUSIONS: Our study identified management factors associated with reported AMD use and antimicrobial stewardship practices on conventional dairies in CA within a year from implementation of SB 27. Producers will benefit from extension outreach efforts that incorporate the findings of this survey by further highlighting the significance of these management practices and encouraging those that are associated with judicious AMD use and stewardship practices on CA conventional dairies.

Clinical Management of COVID-19: A Review of Pharmacological Treatment Options.

Since the outbreak and subsequent declaration of COVID-19 as a global pandemic in March 2020, concerted efforts have been applied by the scientific community to curtail the spread of the disease and find a cure. While vaccines constitute a vital part of the public health strategy to reduce the burden of COVID-19, the management of this disease will continue to rely heavily on pharmacotherapy. This study aims to provide an updated review of pharmacological agents that have been developed and/or repurposed for the treatment of COVID-19. To this end, a comprehensive literature search was conducted using the PubMed, Google Scholar, and LitCovid databases. Relevant clinical studies on drugs used in the management of COVID-19 were identified and evaluated in terms of evidence of efficacy and safety. To date, the FDA has approved three therapies for the treatment of COVID-19 Emergency Use Authorization: convalescent plasma, remdesivir, and casirivimab/imdevimab (REGN-COV2). Drugs such as lopinavir/ritonavir, umifenovir, favipiravir, anakinra, chloroquine, hydroxychloroquine, tocilizumab, interferons, tissue plasminogen activator, intravenous immunoglobulins, and nafamosat have been used off-label with mixed therapeutic results. Adjunctive administration of corticosteroids is also very common. The clinical experience with these approved and repurposed drugs is limited, and data on efficacy for the new indication are not strong. Overall, the response of the global scientific community to the COVID-19 pandemic has been impressive, as evident from the volume of scientific literature elucidating the molecular biology and pathophysiology of SARS-CoV-2 and the approval of three new drugs for clinical management. Reviewed studies have shown mixed data on efficacy and safety of the currently utilized drugs. The lack of standard treatment for COVID-19 has made it difficult to interpret results from most of the published studies due to the risk of attribution error. The long-term effects of drugs can only be assessed after several years of clinical experience; therefore, the efficacy and safety of current COVID-19 therapeutics should continue to be rigorously monitored as part of post-marketing studies.

Epidemiology of antimicrobial resistance (AMR) on California dairies: descriptive and cluster analyses of AMR phenotype of fecal commensal bacteria isolated from adult cows.

BACKGROUND: This study describes the occurrence of antimicrobial resistance (AMR) in commensal Escherichia coli and Enterococcus/Streptococcus spp. (ES) isolated from fecal samples of dairy cows and assesses the variation of AMR profiles across regions and seasons following the implementation of the Food and Agricultural Code (FAC) Sections 14400-14408 (formerly known as Senate Bill, SB 27) in California (CA). METHODS: The study was conducted on ten dairies distributed across CA's three milk sheds: Northern California (NCA), Northern San Joaquin Valley (NSJV), and the Greater Southern California (GSCA). On each study dairy, individual fecal samples were collected from two cohorts of lactating dairy cows during the fall/winter 2018 and spring/summer 2019 seasons. Each cohort comprised of 12 cows per dairy. The fecal samples were collected at enrollment before calving (close-up stage) and then monthly thereafter for four consecutive time points up to 120 days in milk. A total of 2,171 E. coli and 2,158 ES isolates were tested for antimicrobial susceptibility using the broth microdilution method against a select panel of antimicrobials. RESULTS: The E. coli isolates showed high resistance to florfenicol (83.31% ± 0.80) and sulphadimethoxine (32.45%), while resistance to ampicillin (1.10% ± 0.21), ceftiofur (1.93% ± 0.29), danofloxacin (4.01% ± 0.42), enrofloxacin (3.31% ± 0.38), gentamicin (0.32% ± 0.12) and neomycin (1.61% ± 0.27) had low resistance proportions. The ES isolates were highly resistant to tildipirosin (50.18% ± 1.10), tilmicosin (48% ± 1.10), tiamulin (42%) and florfenicol (46% ± 1.10), but were minimally resistant to ampicillin (0.23%) and penicillin (0.20%). Multidrug resistance (MDR) (resistance to at least 1 drug in ≥3 antimicrobial classes) was observed in 14.14% of E. coli isolates and 39% of ES isolates. Escherichia coli isolates recovered during winter showed higher MDR prevalence compared to summer isolates (20.33% vs. 8.04%). A higher prevalence of MDR was observed in NSJV (17.29%) and GSCA (15.34%) compared with NCA (10.10%). CONCLUSIONS: Our findings showed high rates of AMR to several drugs that are not labeled for use in lactating dairy cattle 20 months of age or older. Conversely, very low resistance was observed for drugs labeled for use in adult dairy cows, such as cephalosporins and penicillin. Overall, our findings identified important differences in AMR by antimicrobial class, region and season.

Sexually Transmitted Neisseria gonorrhoeae Infections-Update on Drug Treatment and Vaccine Development.

Background: Sexually transmitted gonorrhea, caused by the Gram-negative diplococcus Neisseria gonorrhoeae, continues to be a serious global health challenge despite efforts to eradicate it. Multidrug resistance among clinical N. gonorrhoeae isolates has limited treatment options, and attempts to develop vaccines have not been successful. Methods: A search of published literature was conducted, and information extracted to provide an update on the status of therapeutics and vaccine development for gonorrheal infection. Results: Recommended pharmacological treatment for gonorrhea has changed multiple times due to increasing acquisition of resistance to existing antibiotics by N. gonorrhoeae. Only broad-spectrum cephalosporin-based combination therapies are currently recommended for treatment of uncomplicated urogenital and anorectal gonococcal infections. With the reported emergence of ceftriaxone resistance, successful strategies addressing the global burden of gonorrhea must include vaccination. Century-old efforts at developing an effective vaccine against gonorrhea, leading to only four clinical trials, have not yielded any successful vaccine. Conclusions: While it is important to continue to explore new drugs for the treatment of gonorrhea, the historical trend of resistance acquisition suggests that any long-term strategy should include vaccine development. Advanced technologies in proteomics and in silico approaches to vaccine target identification may provide templates for future success.

Quantitative determination of primaquine-5,6-ortho-quinone and carboxyprimaquine-5,6-ortho-quinone in human erythrocytes by UHPLC-MS/MS.

The antimalarial drug primaquine (PQ) causes methemoglobinemia and hemolysis in individuals with a genetic deficiency of glucose 6-phosphate dehydrogenase. Reactive oxygen species (ROS) generated by redox cycling of the metabolite primaquine-5,6-orthoquinone (POQ) in erythrocytes has been attributed to be responsible for the toxicity of PQ. Carboxyprimaquine (CPQ), the major human plasma metabolite of PQ, can also form the analogous carboxyprimaquine-5,6-orthoquinone (CPOQ) metabolite, which can also generate ROS in erythrocytes by redox cycling, thus contributing to the hematotoxicity of this drug. In order to study these pathways and characterize such effects in vivo, methods are needed for characterization and quantification of POQ and CPOQ in human erythrocytes. The purpose of this work was to develop a validated method for the quantitative determination of CPOQ and POQ metabolites in human erythrocytes, suitable for clinical studies of PQ metabolism. Several liquid-liquid extraction methods using different organic solvents had been investigated. The solvent mixture of water-methanol-acetonitrile (9:9:5, v/v) was shown to yield the best results for the two analytes. Chromatographic analysis of POQ and CPOQ in human erythrocytes was achieved on a high strength silica (HSS) column and gradient elution (water and acetonitrile, both containing 0.1% formic acid) by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). Quantitative estimation of POQ and CPOQ was executed by monitoring ion pairs of m/z 260.23 > 175.03 and m/z 275.19 > 175.04, respectively. The method, which was validated for precision, accuracy, selectivity, and linearity, was successfully applied for the quantitative determination of POQ and CPOQ, the key metabolites of PQ in human erythrocytes in PQ clinical study.

Pitolisant and Other Histamine-3 Receptor Antagonists-An Update on Therapeutic Potentials and Clinical Prospects.

Background: Besides its well-known role as a peripheral chemical mediator of immune, vascular, and cellular responses, histamine plays major roles in the central nervous system, particularly in the mediation of arousal and cognition-enhancement. These central effects are mediated by the histamine-3 auto receptors, the modulation of which is thought to be beneficial for the treatment of disorders that impair cognition or manifest with excessive daytime sleepiness. Methods: A database search of PubMed, Google Scholar, and clinicaltrials.gov was performed in June 2020. Full-text articles were screened and reviewed to provide an update on pitolisant and other histamine-3 receptor antagonists. Results: A new class of drugs-histamine-3 receptor antagonists-has emerged with the approval of pitolisant for the treatment of narcolepsy with or without cataplexy. At the recommended dose, pitolisant is well tolerated and effective. It has also been evaluated for potential therapeutic benefit in Parkinson disease, epilepsy, attention deficit hyperactivity disorder, Alzheimer's disease, and dementia. Limited studies have shown pitolisant to lack abuse potential which will be a major advantage over existing drug options for narcolepsy. Several histamine-3 receptor antagonists are currently in development for a variety of clinical indications. Conclusions: Although limited clinical studies have been conducted on this new class of drugs, the reviewed literature showed promising results for future additions to the clinical indications of pitolisant, and the expansion of the list of approved drugs in this class for a variety of indications.

Preterm Babies: Management and Challenges Associated with Survival in a Resource-Limited Setting.

BACKGROUND: Preterm babies have constituted a major constraints on human and material resources due to early mortality and long term disability among survivors. Rates of disability among survivors have increased over the period, with high rates of broncho-pulmonary dysplasia. OBJECTIVE: To determine the survival and management challenges of preterm babies in University of Maiduguri Teaching Hospital, Maiduguri Borno State REUSLTS: Of the 1129 preterm babies managed in the Special Care Baby Unit (SCBU), 714 cases notes were retrieved and analyzed giving a retrieval rate of 63%. There were 256 (35.9%) preterm babies as in-born, while 458 (64.1%) were out-born. Male preterm babies were 372 (52.1%), while female preterm babies were 342 (47.9%); with female to male ratio of 1.08:1. Extreme low birth weight (<1000grams) were 17 (2.3%), very low birth weight (1000-1499 grams) were 288 (40.3%) while low birth weight (1500-2499 grams) were 406 (56.9%). We also documented 3 preterm babies whose weights >2500 grams were large for gestational age weight. Duration of oxygen therapy (p = 0.620), duration of phototherapy (p = 0.474), and EBT (p = 0.466) showed no association with their survival while only duration of incubator care (p = 0.005) demonstrated significant association with outcome. CONCLUSION: The population of preterm babies studied is 32.70% and their survival has remarkably improved. However, this improved survival of preterm babies especially the extreme and very low birth weight categories has posed a big challenge due to limited access to incubator care, use of caffeine and surfactant which might influence the outcome.