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1.
Pan Afr Med J ; 41: 132, 2022.
Article in English | MEDLINE | ID: mdl-35519168

ABSTRACT

Stroke is a major cause of disability and mortality among the Nigerian general population and thought to be commoner after the fifth decade of life and usually driven by conventional risk factors which are mainly cardio metabolic. However, with the youthful population in a city such as Abuja, stroke could be a mode of presentation of HIV in young people who are also more sexually active. Methods. This is a case series, reporting four cases of HIV positive young Nigerians with stroke. Patients´ data were retrieved from ward admissions records. The patients here had their socio-demographic data taken. They had presented with documented varied clinical features including those suggestive of stroke, after which they had HIV screening done which returned positive. One thousand four hundred and eighty-seven (1487) patients, were admitted in the medical ward, over a three-year period. Female to male ratio of 1:1 in the HIV-positive group, with an age range of 32 to 42 years and an average age of 37.5 years. Stroke constituted 5.7% of all admissions, with stroke in the young accounting for 1.2%. Of all stroke cases, stroke in the young constituted 21.43%, with those who were HIV positive accounting for 4.8%. Young people with stroke should be offered an HIV screening test.


Subject(s)
HIV Infections , Stroke , Adolescent , Adult , Female , HIV Infections/complications , HIV Infections/diagnosis , HIV Infections/epidemiology , Hospitalization , Humans , Male , Nigeria/epidemiology , Risk Factors , Stroke/epidemiology , Stroke/etiology
2.
Drug Metab Dispos ; 50(5): 646-654, 2022 05.
Article in English | MEDLINE | ID: mdl-35221288

ABSTRACT

Drug-induced liver injury (DILI) remains one of the major concerns for healthcare providers and patients. Unfortunately, it is difficult to predict and prevent DILI in the clinic because detailed mechanisms of DILI are largely unknown. Many risk factors have been identified for both "intrinsic" and "idiosyncratic" DILI, suggesting that cofactors are an important aspect in understanding DILI. This review outlines the cofactors that potentiate DILI and categorizes them into two types: (1) the specific cofactors that target metabolic enzymes, transporters, antioxidation defense, immune response, and liver regeneration; and (2) the general cofactors that include inflammation, age, gender, comorbidity, gut microbiota, and lifestyle. The underlying mechanisms by which cofactors potentiate DILI are also discussed. SIGNIFICANCE STATEMENT: This review summarizes the risk factors for DILI, which can be used to predict and prevent DILI in the clinic. This work also highlights the gaps in the DILI field and provides future perspectives on the roles of cofactors in DILI.


Subject(s)
Chemical and Drug Induced Liver Injury , Chemical and Drug Induced Liver Injury/etiology , Humans , Inflammation , Liver , Risk Factors
3.
Toxicol Sci ; 181(1): 58-67, 2021 04 27.
Article in English | MEDLINE | ID: mdl-33629115

ABSTRACT

Liver-related diseases including drug-induced liver injury are becoming increasingly prominent in AIDS patients. Cobicistat (COBI) is the backbone of multiple regimens for antiretroviral therapy. The current work investigated the mechanisms of adverse drug-drug interactions associated with COBI that lead to liver damage. For individuals co-infected with HIV and tuberculosis (TB), the World Health Organization recommends the initiation of TB treatment followed by antiretroviral therapy. Rifampicin (RIF), a first line anti-TB drug, is a human specific activator of pregnane X receptor (PXR). Using PXR-humanized mice, we found that RIF-mediated PXR activation potentiates COBI hepatotoxicity. In contrast, rifabutin, a PXR-neutral analog of RIF, has no impact on COBI hepatotoxicity. Because of the crosstalk between PXR and the constitutive androstane receptor (CAR), the role of CAR in COBI hepatotoxicity was also investigated. Similar to PXR, ligand-dependent activation of CAR also potentiates COBI hepatotoxicity. Our further studies illustrated that PXR and CAR modulate COBI hepatotoxicity through the CYP3A4-dependent pathways. In summary, the current work determined PXR and CAR as key modulators of COBI hepatotoxicity. Given the fact that many prescription drugs and herbal supplements can activate PXR and CAR, these two receptors should be considered as targets to prevent COBI hepatotoxicity in the clinic.


Subject(s)
Chemical and Drug Induced Liver Injury , Receptors, Steroid , Animals , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/prevention & control , Cobicistat , Constitutive Androstane Receptor , Humans , Mice , Pregnane X Receptor , Receptors, Cytoplasmic and Nuclear , Xenobiotics/toxicity
4.
J Pharmacol Exp Ther ; 374(1): 38-43, 2020 07.
Article in English | MEDLINE | ID: mdl-32303561

ABSTRACT

Dolutegravir (DTG) is a potent integrase inhibitor of human immunodeficiency virus. Because DTG is a substrate of the efflux transporter ABCG2 and ABCG2 is highly polymorphic, we asked whether dose adjustment of DTG is needed for ABCG2-deficient individuals. Using Abcg2-null mice, the current work investigated the impact of ABCG2 deficiency on DTG metabolism and pharmacokinetics. Compared with wild-type mice, no statistically significant difference was found in the systemic and tissue-specific (liver, kidney, and brain) pharmacokinetics of DTG in Abcg2-null mice. In addition, ABCG2 deficiency had no statistically significant impact on the production and excretion of DTG metabolites. In summary, this study demonstrated that deficiency of ABCG2 does not alter DTG metabolism and pharmacokinetics, suggesting that dose adjustment of DTG is not needed for individuals with ABCG2 deficiency. SIGNIFICANCE STATEMENT: The current work demonstrated that deficiency of ATP-binding cassette subfamily G member 2 (ABCG2) does not alter Dolutegravir (DTG) metabolism and pharmacokinetics, suggesting that dose adjustment of DTG is not needed for individuals with ABCG2 deficiency.


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/deficiency , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Heterocyclic Compounds, 3-Ring/metabolism , Animals , Gene Deletion , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Mice , Organ Specificity , Oxazines , Piperazines , Pyridones , Tissue Distribution
5.
Sci Adv ; 5(9): eaaw6127, 2019 09.
Article in English | MEDLINE | ID: mdl-31555729

ABSTRACT

Erythropoietic protoporphyria (EPP) is an inherited disease caused by loss-of-function mutations of ferrochelatase, an enzyme in the heme biosynthesis pathway that converts protoporphyrin IX (PPIX) into heme. PPIX accumulation in patients with EPP leads to phototoxicity and hepatotoxicity, and there is no cure. Here, we demonstrated that the PPIX efflux transporter ABCG2 (also called BCRP) determines EPP-associated phototoxicity and hepatotoxicity. We found that ABCG2 deficiency decreases PPIX distribution to the skin and therefore prevents EPP-associated phototoxicity. We also found that ABCG2 deficiency protects against EPP-associated hepatotoxicity by modulating PPIX distribution, metabolism, and excretion. In summary, our work has uncovered an essential role of ABCG2 in the pathophysiology of EPP, which suggests the potential for novel strategies in the development of therapy for EPP.


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2 , Protoporphyria, Erythropoietic , Protoporphyrins , Skin , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Animals , Ferrochelatase/genetics , Ferrochelatase/metabolism , Liver/metabolism , Liver/pathology , Mice , Mice, Mutant Strains , Protoporphyria, Erythropoietic/genetics , Protoporphyria, Erythropoietic/metabolism , Protoporphyria, Erythropoietic/pathology , Protoporphyria, Erythropoietic/physiopathology , Protoporphyrins/genetics , Protoporphyrins/metabolism , Skin/metabolism , Skin/pathology
6.
Chem Res Toxicol ; 32(7): 1335-1342, 2019 07 15.
Article in English | MEDLINE | ID: mdl-31265262

ABSTRACT

Kavain is an active and major component in Piper methysticum Forst. (kava), which is a widely used dietary supplement for the treatment of anxiety, insomnia, and stress. However, kava-containing products can cause liver toxicity, and its underlying mechanisms are understudied. Cytochrome P450s (CYPs)-mediated bioactivation and biotransformation are highly associated with drug toxicity. In the current study, we profiled the metabolic pathways of kavain in mouse liver, urine, and feces. Overall, 28 kavain metabolites were identified including 17 new ones. The metabolic pathways of kavain include glutathione (GSH) conjugation, oxidation, dehydrogenation, O-demethylation, sulfation, and glucuronidation. The identification of kavain-GSH adducts suggests the formation of reactive metabolites of kavain in the liver. We further illustrated that CYP2C19, a highly polymorphic and inducible enzyme, was the major enzyme contributing to kavain biotransformation and bioactivation. Our data can be used to guide the safe use of kava products by preventing potential herb-drug interactions and hepatotoxicity.


Subject(s)
Pyrones/metabolism , Animals , Cytochrome P-450 CYP2C19/metabolism , Feces/chemistry , Humans , Liver/metabolism , Male , Metabolomics , Mice , Microsomes, Liver/metabolism , Urine/physiology
7.
J Clin Invest ; 129(7): 2898-2903, 2019 04 30.
Article in English | MEDLINE | ID: mdl-31039134

ABSTRACT

Ritonavir (RTV) is on the World Health Organization's List of Essential Medicines for antiretroviral therapy, but can cause hepatotoxicity by unknown mechanisms. Multiple clinical studies found that hepatotoxicity occurred in 100% of participants who were pretreated with rifampicin or efavirenz followed by RTV-containing regimens. Both rifampicin and efavirenz are activators of the pregnane X receptor (PXR), a transcription factor with significant inter-species differences in ligand-dependent activation. Using PXR-humanized mouse models, we recapitulated the RTV hepatotoxicity observed in the clinic. PXR was found to modulate RTV hepatotoxicity through CYP3A4-dependent pathways involved in RTV bioactivation, oxidative stress, and endoplasmic reticulum stress. In summary, the current work demonstrated the essential roles of human PXR and CYP3A4 in RTV hepatotoxicity, which can be applied to guide the safe use of RTV-containing regimens in the clinic.


Subject(s)
Chemical and Drug Induced Liver Injury/metabolism , Endoplasmic Reticulum Stress/drug effects , Oxidative Stress/drug effects , Pregnane X Receptor/metabolism , Ritonavir/adverse effects , Animals , Chemical and Drug Induced Liver Injury/genetics , Chemical and Drug Induced Liver Injury/pathology , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Disease Models, Animal , Endoplasmic Reticulum Stress/genetics , Humans , Mice , Oxidative Stress/genetics , Pregnane X Receptor/genetics , Ritonavir/pharmacology
8.
Biochem Pharmacol ; 158: 174-184, 2018 12.
Article in English | MEDLINE | ID: mdl-30342022

ABSTRACT

Dolutegravir (DTG), a potent integrase inhibitor, is part of a recommended initial regimen for the treatment of human immunodeficiency virus (HIV). Prior reports demonstrated that the clearance of DTG was higher in current smokers than non-smokers, but the mechanism remains unclear. Using a metabolomic approach, M4 (an aldehyde) was identified as a novel metabolite of DTG. In addition, the formation of M4 was found to be mediated by cytochrome P450 (CYP) 1A1 and 1B1, the enzymes that can be highly induced by cigarette smoking. CYP1A1 and 1B1 were also identified as the major enzymes contributing to the formation of M1 (an N-dealkylated metabolite of DTG) and M5 (an aldehyde). Furthermore, the production of M1 and M4 was significantly increased in the lung of mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin, an inducer of CYP1A1 and 1B1. In summary, the current study uncovered the CYP1A1 and 1B1-mediated metabolic pathways of DTG. These data suggest that persons with HIV infection receiving DTG should be cautious to cigarettes, and drugs, or exposure to environmental chemicals that induce CYP1A1 and 1B1.


Subject(s)
Cytochrome P-450 CYP1A1/metabolism , Cytochrome P-450 CYP1B1/metabolism , HIV Integrase Inhibitors/metabolism , Heterocyclic Compounds, 3-Ring/metabolism , Metabolic Networks and Pathways/drug effects , Animals , Dose-Response Relationship, Drug , HIV Integrase Inhibitors/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Male , Metabolic Networks and Pathways/physiology , Mice , Mice, Inbred C57BL , Oxazines , Piperazines , Pyridones
9.
Chem Res Toxicol ; 31(7): 548-555, 2018 07 16.
Article in English | MEDLINE | ID: mdl-29896955

ABSTRACT

Idelalisib (ILB) is a selective phosphatidylinositol-3-kinase delta inhibitor approved for the treatment of hematological malignancies. However, ILB frequently causes hepatotoxicity, and the exact mechanism remains unclear. The current study profiled the metabolites of ILB in mouse liver, urine, and feces. The major metabolites found in the liver were oxidized metabolite GS-563117 (M1) and ILB-glutathione (GSH) adduct (M2). These metabolic pathways were confirmed by analysis of urine and feces from mice treated with ILB. Identification of ILB-GSH adduct (M2) suggests the formation of reactive metabolites of ILB. We also found that M1 can produce reactive metabolites and form M1-GSH adducts. The GSH-conjugates identified in mouse liver were also found in the incubations of ILB and M1 with human liver microsomes. Furthermore, we illustrated that CYP3A4 and 2C9 are the key enzymes contributing to the bioactivation pathway of ILB and M1. In summary, our work revealed that both ILB and its major metabolite M1 can undergo bioactivation to produce reactive metabolites in the liver. Further studies are required to determine whether these metabolic pathways contribute to ILB hepatotoxicity.


Subject(s)
Enzyme Inhibitors/metabolism , Purines/metabolism , Quinazolinones/metabolism , Animals , Biotransformation , Chromatography, High Pressure Liquid , Cytochrome P-450 CYP2C9/genetics , Cytochrome P-450 CYP2C9/metabolism , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/urine , Feces/chemistry , Glutathione/chemistry , Humans , Male , Metabolomics , Mice , Mice, Inbred BALB C , Microsomes, Liver/metabolism , NAD/metabolism , Purines/chemistry , Purines/urine , Quinazolinones/chemistry , Quinazolinones/urine , Recombinant Proteins/biosynthesis , Recombinant Proteins/isolation & purification , Recombinant Proteins/metabolism , Spectrometry, Mass, Electrospray Ionization
10.
Biochem Pharmacol ; 154: 474-481, 2018 08.
Article in English | MEDLINE | ID: mdl-29906468

ABSTRACT

Erythropoietic protoporphyria (EPP) is a genetic disease that results from the defective mutation in the gene encoding ferrochelatase (FECH), the enzyme that converts protoporphyrin IX (PPIX) to heme. Liver injury and even liver failure can occur in EPP patients because of PPIX accumulation in the liver. The current study profiled the liver metabolome in an EPP mouse model caused by a Fech mutation (Fech-mut). As expected, we observed the accumulation of PPIX in the liver of Fech-mut mice. In addition, our metabolomic analysis revealed the accumulation of bile acids and ceramide (Cer) in the liver of Fech-mut mice. High levels of bile acids and Cer are toxic to the liver. Furthermore, we found that the major phosphatidylcholines (PC) in the liver and the ratio of total PC to PPIX in the bile were decreased in Fech-mut mice compared to wild type mice. A decrease of the ratio of PC to PPIX in the bile can potentiate the accumulation of PPIX in the liver because PC increases PPIX solubility and excretion. These metabolomic findings suggest that the accumulation of PPIX, together with the disruption of the homeostasis of bile acids, Cer, and PC, contributes to EPP-associated liver injury.


Subject(s)
Disease Models, Animal , Liver/metabolism , Metabolomics/methods , Protoporphyria, Erythropoietic/metabolism , Animals , Male , Mice , Mice, Transgenic , Protoporphyria, Erythropoietic/genetics
11.
Biochem Pharmacol ; 145: 218-225, 2017 12 01.
Article in English | MEDLINE | ID: mdl-28888949

ABSTRACT

Acetylation is the major metabolic pathway of isoniazid (INH) mediated by N-acetyltransferases (NATs). Previous reports suggest that slow acetylators have higher risks of INH hepatotoxicity than rapid acetylators, but the detailed mechanisms remain elusive. The current study used Nat1/2(-/-) mice to mimic NAT slow metabolizers and to investigate INH metabolism in the liver. We found that INH acetylation is abolished in the liver of Nat1/2(-/-) mice, suggesting that INH acetylation is fully dependent on NAT1/2. In addition to the acetylation pathway, INH can be hydrolyzed to form hydrazine (Hz) and isonicotinic acid (INA). We found that INA level was not altered in the liver of Nat1/2(-/-) mice, indicating that deficiency of NAT1/2 has no effect on INH hydrolysis. Because INH acetylation was abolished and INH hydrolysis was not altered in Nat1/2(-/-) mice, we expected an extremely high level of INH in the liver. However, we only observed a modest accumulation of INH in the liver of Nat1/2(-/-) mice, suggesting that there are alternative pathways in INH metabolism in NAT1/2 deficient condition. Our further studies revealed that the conjugated metabolites of INH with endobiotics, including fatty acids and vitamin B6, were significantly increased in the liver of Nat1/2(-/-) mice. In summary, this study illustrated that deficiency of NAT1/2 decreases INH acetylation, but increases the interactions of INH with endobiotics in the liver. These findings can be used to guide future studies on the mechanisms of INH hepatotoxicity in NAT slow metabolizers.


Subject(s)
Antitubercular Agents/pharmacokinetics , Arylamine N-Acetyltransferase/metabolism , Gene Expression Regulation, Enzymologic/drug effects , Isoenzymes/metabolism , Isoniazid/pharmacokinetics , Liver/enzymology , Animals , Arylamine N-Acetyltransferase/genetics , Drug Interactions , Isoenzymes/genetics , Mice , Mice, Knockout
12.
Curr Pharmacol Rep ; 3(1): 10-15, 2017 Feb.
Article in English | MEDLINE | ID: mdl-28758057

ABSTRACT

Although safety of drug candidates is carefully monitored in preclinical and clinical studies using a variety of approaches, drug toxicity may still occur in clinical practice. Therefore, novel approaches are needed to complement the current drug safety evaluation system. Metabolomics comprehensively analyzes the metabolites altered by drug exposure, which can therefore be used to profile drug metabolism, endobiotic metabolism, and drug-microbiota interactions. The information from metabolomic analysis can be used to determine the off-targets of a drug candidate, and thus provide a mechanistic understanding of drug toxicity. We herein discuss the opportunities of metabolomics in drug safety evaluation.

13.
Clin Liver Dis ; 21(1): 35-54, 2017 02.
Article in English | MEDLINE | ID: mdl-27842774

ABSTRACT

Drug-induced hepatotoxicity (DIH) is a significant cause of acute liver failure and liver transplantation. Diagnosis is challenging due to the idiosyncratic nature, its presentation in the form of other liver disease, and the lack of a definite diagnostic criteria. Generation of reactive metabolites, oxidative stress, and mitochondrial dysfunction are common mechanisms involved in DIH. Certain risk factors associated with a drug and within an individual further predispose patients to DIH.


Subject(s)
Chemical and Drug Induced Liver Injury/etiology , Liver Failure, Acute/chemically induced , Liver Failure, Acute/mortality , Liver/drug effects , Pharmaceutical Preparations/administration & dosage , Chemical and Drug Induced Liver Injury/physiopathology , Female , Humans , Liver Failure, Acute/physiopathology , Male , Needs Assessment , Oxidative Stress , Prognosis , Risk Assessment , Survival Rate
14.
Vaccine ; 34(42): 5125-5131, 2016 09 30.
Article in English | MEDLINE | ID: mdl-27591950

ABSTRACT

INTRODUCTION: In September 2015, Nigeria was removed from the list of polio-endemic countries after more than 12months had passed since the detection of last wild poliovirus case in the country on 24 July 2014. We are presenting here a report of two polio seroprevalence surveys conducted in September 2013 and October 2014, respectively, in the Kano state of northern Nigeria. METHODS: Health facility based seroprevalence surveys were undertaken at Murtala Mohammad Specialist Hospital, Kano. Parents or guardians of children aged 6-9months, 36-47months, 5-9years and 10-14years in 2013 and 6-9months and 19-22months (corresponding to 6-9months range at the time of 2013 survey) in 2014 presenting to the outpatient department, were approached for participation, screened for eligibility and asked to provide informed consent. A questionnaire was administered and a blood sample collected for polio neutralization assay. RESULTS: Among subjects aged 6-9months in the 2013 survey, seroprevalence was 58% (95% confidence interval [CI] 51-66%) to poliovirus type 1, 42% (95% CI 34-50%) to poliovirus type 2, and 52% (95% CI 44-60%) to poliovirus type 3. Among children 36-47months and older, seroprevalence was 85% or higher for all three serotypes. In 2014, seroprevalence in 6-9month infants was 72% (95% CI 65-79%) for type 1, 59% (95% CI 52-66%) for type 2, and 65% (95% CI 57-72%) for type 3 and in 19-22months, 80% (95% CI 74-85%), 57% (49-63%) and 78% (71-83%) respectively. Seroprevalence was positively associated with history of increasing oral poliovirus vaccine doses. CONCLUSIONS: There was significant improvement in seroprevalence in 2014 over the 2013 levels indicating a positive impact of recent programmatic interventions. However the continued low seroprevalence in 6-9month age is a concern and calls for improved immunization efforts to sustain the polio-free Nigeria.


Subject(s)
Poliomyelitis/epidemiology , Poliomyelitis/transmission , Poliovirus Vaccine, Oral/administration & dosage , Adolescent , Antibodies, Viral/blood , Child , Child, Preschool , Disease Eradication , Female , Humans , Infant , Male , Nigeria/epidemiology , Poliomyelitis/prevention & control , Poliomyelitis/virology , Poliovirus/immunology , Poliovirus/isolation & purification , Seroepidemiologic Studies , Serogroup , Surveys and Questionnaires
15.
Drug Metab Lett ; 10(2): 111-23, 2016.
Article in English | MEDLINE | ID: mdl-26935921

ABSTRACT

BACKGROUND: Cobicistat (COBI) is a pharmacoenhancer for antiretroviral therapy. OBJECTIVE: The current study was designed to profile the metabolic pathways of COBI and to determine the enzymes that contribute to COBI metabolism. METHOD: We screened COBI metabolites in mice and human liver microsomes. We also used cDNAexpressed human cytochromes P450 (CYPs) to explore the role of human enzymes in COBI metabolism. RESULTS: Twenty new and three known metabolites of COBI were identified in mouse urine and feces. These new metabolic pathways of COBI include glycine conjugation, N-acetyl cysteine conjugation, morpholine ring-opening, and thiazole ring-opening. Twelve of COBI metabolites were further confirmed in mouse and human liver microsomes, including nine new metabolites. Consistent with the previous report, CYP3A4 and CYP2D6 were determined as the major enzymes that contribute to COBI metabolism. CONCLUSION: This study provided a full map of COBI metabolism. These results can be used to manage CYP-mediated drug-drug interactions and adverse drug reactions that are associated with COBI-containing regimens in human.


Subject(s)
Cobicistat/pharmacokinetics , Cytochrome P-450 CYP2D6/metabolism , Cytochrome P-450 CYP3A/metabolism , Microsomes, Liver/metabolism , Animals , Anti-HIV Agents/pharmacokinetics , Humans , Male , Mice , Mice, Knockout
16.
J Infect Dis ; 213 Suppl 3: S124-30, 2016 May 01.
Article in English | MEDLINE | ID: mdl-26908720

ABSTRACT

BACKGROUND: Nigeria was one of 3 polio-endemic countries before it was de-listed in September 2015 by the World Health Organization, following interruption of transmission of the poliovirus. During 2011-2014, Nigeria conducted serial polio seroprevalence surveys (SPS) in Kano Metropolitan Area, comprising 8 local government areas (LGAs) in Kano that is considered very high risk (VHR) for polio, to monitor performance of the polio eradication program and guide the program in the adoption of innovative strategies. METHODS: Study subjects who resided in any of the 8 local government areas of Kano Metropolitan Area and satisfied age criteria were recruited from patients at Murtala Mohammed Specialist Hospital (Kano) for 3 seroprevalence surveys. The same methods were used to conduct each survey. RESULTS: The 2011 study showed seroprevalence values of 81%, 75%, and 73% for poliovirus types 1, 2, and 3, respectively, among infants aged 6-9 months age. Among children aged 36-47 months, seroprevalence values were greater (91%, 87%, and 85% for poliovirus types 1, 2, and 3, respectively).In 2013, the results showed that the seroprevalence was unexpectedly low among infants aged 6-9 months, remained high among children aged 36-47 months, and increased minimally among children aged 5-9 years and those aged 10-14 years. The baseline seroprevalence among infants aged 6-9 months in 2014 was better than that in 2013. CONCLUSIONS: The results from the polio seroprevalence surveys conducted in Kano Metropolitan Area in 2011, 2013, and 2014 served to assess the trends in immunity and program performance, as well as to guide the program, leading to various interventions being implemented with good effect, as evidenced by the reduction of poliovirus circulation in Kano.


Subject(s)
Disease Eradication , Health Plan Implementation , Immunization Programs , Poliomyelitis/epidemiology , Poliomyelitis/prevention & control , Adolescent , Child , Child, Preschool , History, 21st Century , Humans , Infant , Lot Quality Assurance Sampling , Nigeria/epidemiology , Poliomyelitis/history , Poliovirus/classification , Poliovirus/immunology , Poliovirus Vaccine, Oral/administration & dosage , Quality Assurance, Health Care , Seroepidemiologic Studies , Serogroup
17.
Expert Opin Drug Metab Toxicol ; 12(1): 21-30, 2016.
Article in English | MEDLINE | ID: mdl-26592418

ABSTRACT

INTRODUCTION: Among the infectious diseases, tuberculosis (TB) remains the second most common cause of death after HIV. TB treatment requires the combination of multiple drugs including the rifamycin class. However, rifamycins are activators of human pregnane X receptor (PXR), a transcription factor that regulates drug metabolism, drug resistance, energy metabolism and immune response. Rifamycin-mediated PXR activation may affect the outcome of TB therapy. AREAS COVERED: This review describes the role of PXR in modulating metabolism, efficacy, toxicity and resistance to anti-TB drugs; as well as polymorphisms of PXR that potentially affect TB susceptibility. EXPERT OPINION: The wide range of PXR functions that mediate drug metabolism and toxicity in TB therapy are often underappreciated and thus understudied. Further studies are needed to determine the overall impact of PXR activation on the outcome of TB therapy.


Subject(s)
Antitubercular Agents/administration & dosage , Receptors, Steroid/metabolism , Tuberculosis/drug therapy , Animals , Antitubercular Agents/adverse effects , Antitubercular Agents/pharmacology , Drug Resistance, Bacterial , Humans , Polymorphism, Genetic , Pregnane X Receptor , Receptors, Steroid/drug effects , Receptors, Steroid/genetics , Rifamycins/administration & dosage , Rifamycins/adverse effects , Rifamycins/pharmacology , Treatment Outcome
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