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1.  Direct and indirect effects of caregiver social support on adolescent psychological outcomes in two South African AIDS-affected communities 
Caregiver social support has been shown to be protective for caregiver mental health, parenting and child psychosocial outcomes. This is the first known analysis to quantitatively investigate the relationship between caregiver social support and adolescent psychosocial outcomes in HIV-endemic, resource-scarce Southern African communities. A cross-sectional household survey was conducted over 2009-2010 with 2477 South African adolescents aged 10-17 and their adult caregivers (18 years or older) in one urban and one rural community in South Africa’s KwaZulu-Natal province. Adolescent adjustment was assessed using adult caregiver reports of the Strengths and Difficulties questionnaire (SDQ), which measures peer problems, hyperactivity, conduct problems, emotional symptoms and child prosocial behavior. Hierarchical linear regressions and multiple mediation analyses, using bootstrapping procedures, were conducted to assess for: a) direct effects of more caregiver social support on better adolescent psychosocial wellbeing; and b) indirect effects mediated by better parenting and caregiver mental health. Direct associations (p<.001), and indirect associations mediated through better parenting, were found for all adolescent outcomes. Findings reinforce the importance of social support components within parenting interventions but also point to scope for positive intervention on adolescent psychosocial wellbeing through the broader family social network.
PMCID: PMC4414733  PMID: 25623784
caregiver social support; parenting; caregiver mental health; child mental health; child behavior; South Africa
2.  Electronic Cigarette and Traditional Cigarette Use among Middle and High School Students in Florida, 2011–2014 
PLoS ONE  2015;10(5):e0124385.
Recent youth trends in the prevalence of e-cigarette and traditional cigarette use in Florida were examined in a cross-sectional, representative state sample from 2011 to 2014. Traditional cigarette use among youth declined during the study period. Experimentation with and past 30-day use of e-cigarettes among Florida youth tripled over 4 years. Past 30-day e-cigarette use exceeded traditional cigarette use in 2014; 10.8% of high school and 4.0% of middle school students reported recent e-cigarette use, compared with 8.7% of high school and 2.9% of middle school students for traditional cigarettes (P<0.001). By 2014, 20.5% of high school and 8.5% of middle school students reported ever use of e-cigarettes. Among ever e-cigarette users in 2014, 30.3% of high school and 42.2% of middle school students had never smoked traditional cigarettes. Given the concern that significant rates of e-cigarette use by U.S. adolescents may have a negative effect on public health, further review of e-cigarette advertising, marketing, sales, and use among U.S. youth is warranted.
PMCID: PMC4430226  PMID: 25969979
3.  Double Disclosure Bind: Complexities of communicating an HIV diagnosis in the context of unintended pregnancy in Durban, South Africa 
AIDS and behavior  2014;18(0 1):10.1007/s10461-013-0521-1.
PMCID: PMC3823675  PMID: 23722975
PMTCT; HIV Disclosure; unintended pregnancy; South Africa
4.  A multi-center population-based case–control study of ovarian cancer in African-American women: the African American Cancer Epidemiology Study (AACES) 
BMC Cancer  2014;14:688.
Ovarian cancer (OVCA) is the leading cause of death from gynecological cancer, with poorer survival for African American (AA) women compared to whites. However, little is known about risk factors for OVCA in AA. To study the epidemiology of OVCA in this population, we started a collaborative effort in 10 sites in the US. Here we describe the study and highlight the challenges of conducting a study of a lethal disease in a minority population.
The African American Cancer Epidemiology Study (AACES) is an ongoing, population-based case–control study of OVCA in AA in 10 geographic locations, aiming to recruit 850 women with invasive epithelial OVCA and 850 controls age- and geographically-matched to cases. Rapid case ascertainment and random-digit-dialing systems are in place to ascertain cases and controls, respectively. A telephone survey focuses on risk factors as well as factors of particular relevance for AAs. Food-frequency questionnaires, follow-up surveys, biospecimens and medical records are also obtained.
Current accrual of 403 AA OVCA cases and 639 controls exceeds that of any existing study to date. We observed a high proportion (15%) of deceased non-responders among the cases that in part is explained by advanced stage at diagnosis. A logistic regression model did not support that socio-economic status was a factor in advanced stage at diagnosis. Most risk factor associations were in the expected direction and magnitude. High BMI was associated with ovarian cancer risk, with multivariable adjusted ORs and 95% CIs of 1.50 (0.99-2.27) for obese and 1.27 (0.85- 1.91) for morbidly obese women compared to normal/underweight women.
AACES targets a rare tumor in AAs and addresses issues most relevant to this population. The importance of the study is accentuated by the high proportion of OVCA cases ascertained as deceased. Our analyses indicated that obesity, highly prevalent in this population (>60% of the cases), was associated with increased OVCA risk. While these findings need to be replicated, they suggest the potential for an effective intervention on the risk in AAs. Upon completion of enrollment, AACES will be the largest epidemiologic study of OVCA in AA women.
PMCID: PMC4182887  PMID: 25242549
Epidemiology; Ovarian cancer; African American; Case–control study
5.  South Africans with recent pregnancy rarely know partner’s HIV serostatus: implications for serodiscordant couples interventions 
BMC Public Health  2014;14:843.
Implementation of safer conception strategies requires knowledge of partner HIV-serostatus. We recruited women and men in a high HIV-prevalence setting for a study to assess periconception risk behavior among individuals reporting HIV-serodiscordant partnerships. We report screening data from that study with the objective of estimating the proportion of individuals who are aware that they are in an HIV-serodiscordant relationship at the time of conception.
We screened women and men attending antenatal and antiretroviral clinics in Durban, South Africa for enrollment in a study of periconception risk behavior among individuals with serodiscordant partners. Screening questionnaires assessed for study eligibility including age 18–45 years (for women) or at least 18 years of age (for men), pregnancy in past year (women) or partner pregnancy in the past 3 years (men), HIV status of partner for recent pregnancy, participant’s HIV status, and infected partner’s HIV status having been known before the referent pregnancy.
Among 2620 women screened, 2344 (90%) met age and pregnancy criteria and knew who fathered the referent pregnancy. Among those women, 963 (41%) did not know the pregnancy partner’s HIV serostatus at time of screening. Only 92 (4%) reported knowing of a serodiscordant partnership prior to pregnancy. Among 1166 men screened, 225 (19%) met age and pregnancy criteria. Among those men, 71 (32%) did not know the pregnancy partner’s HIV status and only 30 (13%) reported knowing of a serodiscordant partnership prior to pregnancy.
In an HIV-endemic setting, awareness of partner HIV serostatus is rare. Innovative strategies to increase HIV testing and disclosure are required to facilitate HIV prevention interventions for serodiscordant couples.
PMCID: PMC4246447  PMID: 25124267
HIV prevention; HIV serodiscordant couples; Safer conception; HIV serostatus disclosure
6.  Challenges with couples, serodiscordance and HIV disclosure: healthcare provider perspectives on delivering safer conception services for HIV-affected couples, South Africa 
Introduction Safer conception interventions should ideally involve both members of an HIV-affected couple. With serodiscordant couples, healthcare providers will need to manage periconception risk behaviour as well tailor safer conception strategies according to available resources and the HIV status of each partner. Prior to widespread implementation of safer conception services, it is crucial to better understand provider perspectives regarding provision of care since they will be pivotal to the successful delivery of safer conception. This paper reports on findings from a qualitative study exploring the viewpoints and experiences of doctors, nurses, and lay counsellors on safer conception care in a rural and in an urban setting in Durban, South Africa.
We conducted six semistructured individual interviews per site (a total of 12 interviews) as well as a focus group discussion at each clinic site (a total of 13 additional participants). All interviews were coded in Atlas.ti using a grounded theory approach to develop codes and to identify core themes and subthemes in the data.
Managing the clinical and relationship complexities related to serodiscordant couples wishing to conceive was flagged as a concern by all categories of health providers. Providers added that, in the HIV clinical setting, they often found it difficult to balance their professional priorities, to maintain the health of their clients, and to ensure that partners were not exposed to unnecessary risk, while still supporting their clients’ desires to have a child. Many providers expressed concern over issues related to disclosure of HIV status between partners, particularly when managing couples where one partner was not aware of the other's status and expressed the desire for a child. Provider experiences were that female clients most often sought out care, and it was difficult to reach the male partner to include him in the consultation.
Providers require support in dealing with HIV disclosure issues and in becoming more confident in dealing with couples and serodiscordance. Prior to implementing safer conception programmes, focused training is needed for healthcare professionals to address some of the ethical and relationship issues that are critical in the context of safer conception care.
PMCID: PMC3956311  PMID: 24629843
safer conception; couples; serodiscordance; healthcare providers
7.  Cyanide Antidotes for Mass Casualties: Water-Soluble Salts of the Dithiane (Sulfanegen) from 3-Mercaptopyruvate for Intramuscular Administration 
Journal of medicinal chemistry  2013;56(3):1346-1349.
Current cyanide antidotes are administered by IV infusion which is suboptimal for mass casualties. Therefore, in a cyanide disaster intramuscular (IM) injectable antidotes would be more appropriate. We report the discovery of the highly water-soluble sulfanegen triethanolamine as a promising lead for development as an IM injectable cyanide antidote.
PMCID: PMC3575131  PMID: 23301495
8.  The Combination of Cobinamide and Sulfanegen Is Highly Effective in Mouse Models of Cyanide Poisoning 
Clinical toxicology (Philadelphia, Pa.)  2011;49(5):10.3109/15563650.2011.584879.
Cyanide poisoning is a major contributor to death in smoke inhalation victims and accidental exposure to cyanide occurs in a variety of industries. Moreover, cyanide has the potential to be used by terrorists, particularly in a closed space such as an airport or train station. Current therapies for cyanide poisoning must be given by intravenous administration, limiting their use in treating mass casualties.
We are developing two new cyanide antidotes—cobinamide, a vitamin B12 analog, and sulfanegen, a 3-mercaptopyruvate prodrug. Both drugs can be given by intramuscular administration, and therefore could be used to treat a large number of people quickly. We now asked if the two drugs would have an augmented effect when combined.
Materials and Methods
We used a non-lethal and two different lethal models of cyanide poisoning in mice. The non-lethal model assesses neurologic recovery by quantitatively evaluating the innate righting reflex time of a mouse. The two lethal models are a cyanide injection and a cyanide inhalation model.
We found that the two drugs are at least additive when used together in both the non-lethal and lethal models: at doses where all animals died with either drug alone, the combination yielded 80 and 40% survival in the injection and inhalation models, respectively. Similarly, drug doses that yielded 40% survival with either drug alone yielded 80 and 100% survival in the injection and inhalatiion models, respectively. As part of the inhalation model, we developed a new paradigm in which animals are exposed to cyanide gas, injected intramuscularly with antidote, and then re-exposed to cyanide gas. This simulates cyanide exposure of a large number of people in a closed space, because people would remain exposed to cyanide, even after receiving an antidote.
The combination of cobinamide and sulfanegen shows great promise as a new approach to treating cyanide poisoning.
PMCID: PMC3882312  PMID: 21740135
Inhalation exposure; intramuscular injection; lethal model; non-lethal model
9.  Pancreatic Islets and Insulinoma Cells Express a Novel Isoform of Group VIA Phospholipase A2 (iPLA2β) that Participates in Glucose-Stimulated Insulin Secretion and Is Not Produced by Alternate Splicing of the iPLA2β Transcript† 
Biochemistry  2003;42(47):13929-13940.
Many cells express a group VIA 84 kDa phospholipase A2 (iPLA2β) that is sensitive to inhibition by a bromoenol lactone (BEL) suicide substrate. Inhibition of iPLA2β in pancreatic islets and insulinoma cells suppresses, and overexpression of iPLA2β in INS-1 insulinoma cells amplifies, glucose-stimulated insulin secretion, suggesting that iPLA2β participates in secretion. Western blotting analyses reveal that glucose-responsive 832/13 INS-1 cells express essentially no 84 kDa iPLA2β-immunoreactive protein but predominantly express a previously unrecognized immunoreactive iPLA2β protein in the 70 kDa region that is not generated by a mechanism of alternate splicing of the iPLA2β transcript. To determine if the 70 kDa-immunoreactive protein is a short isoform of iPLA2β, protein from the 70 kDa region was digested with trypsin and analyzed by mass spectrometry. Such analyses reveal several peptides with masses and amino acid sequences that exactly match iPLA2β tryptic peptides. Peptide sequences identified in the 70 kDa tryptic digest include iPLA2β residues 7–53, suggesting that the N-terminus is preserved. We also report here that the 832/13 INS-1 cells express iPLA2β catalytic activity and that BEL inhibits secretagogue-stimulated insulin secretion from these cells but not the incorporation of arachidonic acid into membrane PC pools of these cells. These observations suggest that the catalytic iPLA2β activity expressed in 832/13 INS-1 cells is attributable to a short isoform of iPLA2β and that this isoform participates in insulin secretory but not in membrane phospholipid remodeling pathways. Further, the finding that pancreatic islets also express predominantly a 70 kDa iPLA2β-immunoreactive protein suggests that a signal transduction role of iPLA2β in the native β-cell might be attributable to a 70 kDa isoform of iPLA2β.
PMCID: PMC3716001  PMID: 14636061
10.  A conceptual framework for understanding HIV risk behavior in the context of supporting fertility goals among HIV-serodiscordant couples 
Reproductive health matters  2012;20(39 Suppl):50-60.
Integrated reproductive health services for people living with HIV must address their fertility intentions. For HIV-serodiscordant couples who want to conceive, attempted conception confers a substantial risk of HIV transmission to the uninfected partner. Behavioral and pharmacologic strategies may reduce HIV transmission risk among HIV-serodiscordant couples who seek to conceive. In order to develop effective pharmaco-behavioral programs, it is important to understand and address the contexts surrounding reproductive decision-making; perceived periconception HIV transmission risk; and periconception risk behaviors. We present a conceptual framework to describe the dynamics involved in periconception HIV risk behaviors in a South African setting. We adapt the Information-Motivation-Behavioral Skill Model of HIV Preventative Behavior to address the structural, individual and couple-level determinants of safer conception behavior. The framework is intended to identify factors that influence periconception HIV risk behavior among serodiscordant couples, and therefore to guide design and implementation of integrated and effective HIV, reproductive health and family planning services that support reproductive decision-making.
PMCID: PMC3608509  PMID: 23177680
conceptual framework; HIV; serodiscordant couples; pregnancy; safer conception
11.  Movie Smoking and Youth Initiation: Parsing Smoking Imagery and Other Adult Content 
PLoS ONE  2012;7(12):e51935.
To isolate the independent influence of exposure to smoking and other adult content in the movies on youth smoking uptake.
We used discrete time survival analysis to quantify the influence of exposure to smoking and other adult content in the movies on transitioning from (1) closed to open to smoking; (2) never to ever trying smoking; and (3) never to ever hitting, slapping, or shoving someone on two or more occasions in the past 30 days. The latter is a comparative outcome, hypothesized to have no correlation with exposure to smoking in the movies.
Assessed separately, both exposure to smoking imagery and exposure to adult content were associated with increased likelihood of youth becoming open to smoking (OR = 1.09, 95% CI: 1.04–1.15 and OR = 1.10, 95% CI: 1.04–1.17) and having tried smoking (OR = 1.06, 95% CI: 1.00–1.12 and OR = 1.06, 95% CI: 1.00–1.13). Both measures were also separately associated with aggressive behavior (OR = 1.09, 95% CI: 1.04–1.14 and OR = 1.09, 95% CI: 1.04–1.15). A very high correlation between the two measures (0.995, p<0.000) prevented an assessment of their independent effects on smoking initiation.
Although exposure to smoking in the movies is correlated with smoking susceptibility and initiation, the high correlation between exposure to smoking in the movies and other adult content suggests that more research is needed to disentangle their independent influence on smoking.
PMCID: PMC3522606  PMID: 23251654
12.  Activity of a Novel Combined Antiretroviral Therapy of Gemcitabine and Decitabine in a Mouse Model for HIV-1 
The emergence of drug resistance threatens to limit the use of current anti-HIV-1 drugs and highlights the need to expand the number of treatment options available for HIV-1-infected individuals. Our previous studies demonstrated that two clinically approved drugs, decitabine and gemcitabine, potently inhibited HIV-1 replication in cell culture through a mechanism that is distinct from the mechanisms for the drugs currently used to treat HIV-1 infection. We further demonstrated that gemcitabine inhibited replication of a related retrovirus, murine leukemia virus (MuLV), in vivo using the MuLV-based LP-BM5/murine AIDS (MAIDS) mouse model at doses that were not toxic. Since decitabine and gemcitabine inhibited MuLV and HIV-1 replication with similar potency in cell culture, the current study examined the efficacy and toxicity of the drug combination using the MAIDS model. The data demonstrate that the drug combination inhibited disease progression, as detected by histopathology, viral loads, and spleen weights, at doses lower than those that would be required if the drugs were used individually. The combination of decitabine and gemcitabine exerted antiviral activity at doses that were not toxic. These findings indicate that the combination of decitabine and gemcitabine shows potent antiretroviral activity at nontoxic doses and should be further investigated for clinical relevance.
PMCID: PMC3318345  PMID: 22271861
13.  A retrospective study of Human Immunodeficiency Virus transmission, mortality and loss to follow-up among infants in the first 18 months of life in a prevention of mother-to-child transmission programme in an urban hospital in KwaZulu-Natal, South Africa 
BMC Pediatrics  2012;12:146.
Follow up of Human Immunodeficiency Virus (HIV)-exposed infants is an important component of Prevention of Mother-to-Child Transmission (PMTCT) programmes in order to ascertain infant outcomes post delivery. We determined HIV transmission, mortality and loss to follow-up (LTFU) of HIV-exposed infants attending a postnatal clinic in an urban hospital in Durban, South Africa.
We conducted a retrospective cohort study of infants born to women in the PMTCT programme at McCord Hospital, where mothers paid a fee for service. Data were abstracted from patient records for live-born infants delivered between 1 May 2008 and 31 May 2009. The infants’ LTFU status and age was based on the date of the last visit. HIV transmission was calculated as a proportion of infants followed and tested at six weeks. Mortality rates were analyzed using Kaplan-Meier (K-M), with censoring on 15 January 2010, LTFU or death.
Of 260 infants, 155 (59.6%) remained in care at McCord beyond 28 weeks: one died at < 28 days, three died between one to six months; 34 were LTFU within seven days, 60 were LTFU by six months. K-M mortality rate: 1.7% at six months (95% confidence interval (CI): 0.6% to 4.3%). Of 220 (83%) infants tested for HIV at six weeks, six (2.7%, 95% CI: 1.1% to 5.8%) were HIV-infected. In Cox regression analysis, late antenatal attendance (≥ 28 weeks gestation) relative to attending in the first trimester was a predictor for infant LTFU (adjusted hazards ratio = 2.3; 95% CI: 1.0 to 5.1; p = 0.044).
This urban PMTCT programme achieved low transmission rates at six weeks, but LTFU in the first six months limited our ability to examine HIV transmission up to 18 months and determinants of mortality. The LTFU of infants born to women who attended antenatal care at 28 weeks gestation or later emphasizes the need to identify late antenatal attendees for follow up care to educate and support them regarding the importance of follow up care for themselves and their infants.
PMCID: PMC3468389  PMID: 22963527
HIV-exposed infants; LTFU; Prevention-of-Mother-to-Child Transmission; Postnatal clinic
14.  Reproductive Counseling by Clinic Healthcare Workers in Durban, South Africa: Perspectives from HIV-Infected Men and Women Reporting Serodiscordant Partners 
Background. Understanding HIV-infected patient experiences and perceptions of reproductive counseling in the health care context is critical to inform design of effective pharmaco-behavioral interventions that minimize periconception HIV risk and support HIV-affected couples to realize their fertility goals. Methods. We conducted semistructured, in-depth interviews with 30 HIV-infected women (with pregnancy in prior year) and 20 HIV-infected men, all reporting serodiscordant partners and accessing care in Durban, South Africa. We investigated patient-reported experiences with safer conception counseling from health care workers (HCWs). Interview transcripts were reviewed and coded using content analysis for conceptual categories and emergent themes. Results. The study findings indicate that HIV-infected patients recognize HCWs as a resource for periconception-related information and are receptive to speaking to a HCW prior to becoming pregnant, but seldom seek or receive conception advice in the clinic setting. HIV nondisclosure and unplanned pregnancy are important intervening factors. When advice is shared, patients reported receiving a range of information. Male participants showed particular interest in accessing safer conception information. Conclusions. HIV-infected men and women with serodiscordant partners are receptive to the idea of safer conception counseling. HCWs need to be supported to routinely initiate accurate safer conception counseling with HIV-infected patients of reproductive age.
PMCID: PMC3426202  PMID: 22927713
15.  Inhalant Use Initiation among U.S. Adolescents: Evidence from the National Survey of Parents and Youth Using Discrete-Time Survival Analysis 
Addictive behaviors  2011;36(8):878-881.
The purpose of this paper is to identify factors associated with initiation to inhalant use among adolescents ages 9 to 18. The data are from the National Survey of Parents and Youth, a longitudinal household survey. Baseline surveys for adolescents and parents were conducted between November 1999 and June 2001 and then annually for three subsequent rounds. The outcome measure is an indicator of a respondent’s first use of inhalants. Discrete-time survival analysis was used to model the hazard of initiation. The hazard of inhalant initiation peaks at about 14 years of age (slightly younger than smoking and marijuana initiation). African Americans were less likely than Whites to initiate inhalant use, and higher family income was protective against inhalant initiation. The findings suggest that parenting is associated with initiation of inhalant use: parental drug use was a risk factor for inhalant initiation, and a measure of parental monitoring was protective. The study results also suggest a strong relationship between inhalant use and other problem behaviors and sensation seeking. These results highlight the need to intervene early for youth at risk of or just beginning to engage in risky behaviors including inhalant use.
PMCID: PMC3104053  PMID: 21481544
inhalant use initiation; adolescence; discrete-time survival analysis
16.  Reproductive Decision-Making and Periconception Practices Among HIV-Positive Men and Women Attending HIV Services in Durban, South Africa 
AIDS and Behavior  2011;17(2):461-470.
Understanding reproductive decisions and periconception behavior among HIV-discordant couples is important for designing risk reduction interventions for couples who choose to conceive. In-depth interviews were conducted to explore reproductive decision-making and periconception practices among HIV-positive women with recent pregnancy (n = 30), and HIV-positive men (n = 20), all reporting partners of negative or unknown HIV-status, and attending HIV services in Durban, South Africa. Transcripts were coded for categories and emergent themes. Participants expressed strong reasons for having children, but rarely knew how to reduce periconception HIV transmission. Pregnancy planning occurred on a spectrum ranging from explicitly intended to explicitly unintended, with many falling in between the two extremes. Male fertility desire and misunderstanding serodiscordance contributed to HIV risk behavior. Participants expressed openness to healthcare worker advice for safer conception and modified risk behavior post-conception, suggesting the feasibility of safer conception interventions which may target both men and women and include serodiscordance counseling and promotion of contraception.
PMCID: PMC3560938  PMID: 22038045
HIV-serodiscordant couples; HIV prevention; Safer conception; Family planning; South Africa
17.  A polymorphism in the VKORC1-regulator calumenin predicts higher warfarin doses in African-Americans 
Warfarin demonstrates wide interindividual variability that is partly mediated by variants in CYP2C9 and VKORC1. Whether variants in CALU (vitamin K reductase regulator) influence warfarin dose is unknown.
Methods and Results
We resequenced CALU regions in a discovery cohort of dose-outliers: patients with high(>90th percentile, n=55) or low(<10th percentile, n=53) dose requirements(after accounting for known genetic and nongenetic variables). One CALU variant, rs339097, was associated with high-doses(p=0.01). We validated this variant as a predictor of higher warfarin doses in two replication cohorts: 1)496 patients of mixed ethnicity, 2)194 African-American patients. The G allele of rs339097(African-American and Caucasian allele frequency 0.14 and 0.002, respectively), was associated with a 14.5%(SD±7%) greater therapeutic dose(p=0.03) in the first replication cohort and a higher than predicted dose in the second replication cohort(allele frequency=0.14, one-sided p=0.03).
CALU rs339097 A>G is associated with higher warfarin dose requirements independent of known genetic and nongenetic predictors of warfarin dose in African-Americans.
PMCID: PMC2928561  PMID: 20200517
anticoagulants; calumenin; genetic polymorphism; pharmacogenetics; warfarin/administration & dosage
18.  Analysis of the Ex Vivo and In Vivo Antiretroviral Activity of Gemcitabine 
PLoS ONE  2011;6(1):e15840.
Replication of retroviral and host genomes requires ribonucleotide reductase to convert rNTPs to dNTPs, which are then used as substrates for DNA synthesis. Inhibition of ribonucleotide reductase by hydroxyurea (HU) has been previously used to treat cancers as well as HIV. However, the use of HU as an antiretroviral is limited by its associated toxicities such as myelosuppression and hepatotoxicity. In this study, we examined the ribonucleotide reductase inhibitor, gemcitabine, both in cell culture and in C57Bl/6 mice infected with LP-BM5 murine leukemia virus (LP-BM5 MuLV, a murine AIDS model). Gemcitabine decreased infectivity of MuLV in cell culture with an EC50 in the low nanomolar range with no detectable cytotoxicity. Similarly, gemcitabine significantly decreased disease progression in mice infected with LP-BM5. Specifically, gemcitabine treatment decreased spleen size, plasma IgM, and provirus levels compared to LP-BM5 MuLV infected, untreated mice. Gemcitabine efficacy was observed at doses as low as 1 mg/kg/day in the absence of toxicity. Higher doses of gemcitabine (3 mg/kg/day and higher) were associated with toxicity as determined by a loss in body mass. In summary, our findings demonstrate that gemcitabine has antiretroviral activity ex vivo and in vivo in the LP-BM5 MuLV model. These observations together with a recent ex vivo study with HIV-1[1], suggest that gemcitabine has broad antiretroviral activity and could be particularly useful in vivo when used in combination drug therapy.
PMCID: PMC3021508  PMID: 21264291
19.  A Novel Paradigm for Assessing Efficacies of Potential Antidotes against Neurotoxins in Mice 
Toxicology letters  2007;175(1-3):111-117.
Historically, antidotal potencies of cyanide antagonists were measured as increases in the experimental LD50 for cyanide elicited by the antidotes. This required the use of high doses of cyanide following pretreatment with the putative antidote. Since IACUC guidelines at our institutions strongly discourage LD50 determinations: we developed a new test paradigm that allowed for maximal survival of cyanide-treated animals with greatly reduced numbers of animals. Symptoms of cyanide toxicity include disruption of neuromuscular coordination, i.e., the righting reflex. Therefore, to establish a dose-response curve, the times required for recovery of this righting reflex with increasing doses of cyanide were measured. A cyanide dose that disrupted this righting reflex for approximately one h with minimal deaths was then selected. Using this paradigm, the current cyanide antidotes, viz., nitrite plus thiosulfate and hydroxocobalamin, as well as some potential cyanide antidotes that we developed, were evaluated pre- and post-cyanide. This allowed, for the first time, the assessment of the post-cyanide effectiveness of the current antidotes against cyanide poisoning in a live animal. In addition, some prototype compounds were found to exhibit antidotal efficacy not only when injected i.p. following cyanide, but also when administered orally 30 min before cyanide. Pre-cyanide oral efficacy suggests that such compounds have the potential of being administered prophylactically before exposure to cyanide. This new test paradigm was found to be a powerful tool for assessing the efficacies of some novel antidotes against cyanide and should be equally applicable for evaluating putative antidotes for other neurotoxins.
PMCID: PMC2171362  PMID: 18024011
Cyanide; animal model; recovery; righting reflex; post-cyanide; pre-cyanide; oral efficacy; antidote
20.  Novel, Orally Effective Cyanide Antidotes 
Journal of medicinal chemistry  2007;50(26):6462-6464.
A series of prodrugs of 3-mercaptopyruvate (3-MP), the substrate for the enzyme 3-mercaptopyruvate/cyanide sulfurtransferase (3-MPST) that converts cyanide to the nontoxic thiocyanate, which are highly effective cyanide antidotes, have been developed. These prodrugs of 3-MP are unique in being not only orally bioavailable, but may be administered up to an hour prior to cyanide as a prophylactic agent and are both rapid- or slow-acting when given parenterally.
PMCID: PMC2274902  PMID: 18038966
21.  Heteroactivation of cytochrome P450 1A1 by teas and tea polyphenols 
British Journal of Pharmacology  2005;145(7):926-933.
We studied 7-ethoxyresorufin deethylase as an index of cytochrome P4501A1 (CYP1A1) activity in liver microsomes from rats pretreated with 3-methylcholanthrene. The enzyme had complex kinetics compatible with a multisite model.At 1 μM substrate, brewed black, green and white teas had complex effects on enzyme activity consisting of activation at low concentrations and inhibition at higher concentrations.Data fit well to a two-site model that allowed us to determine maximal activation (% increase above control), pEC50 for activation (g ml−1) and pIC50 for inhibition (g ml−1). These parameters were 190±40, 5.9±0.1 and 4.51±0.09 for green tea, 350±40, 5.43±0.05 and 5.43±0.05 for black tea and 230±80, 5.3±0.3 and 4.7±0.2 for white tea, respectively.The effects of the brewed teas were mimicked to different degrees by the green tea polyphenols. Maximal activation, pEC50 (M) and pIC50 (M) were: (−)-epicatechin, 55±9, 5.4±0.3, 2±1; (−)-epicatechin gallate, 160±60, 6.2±0.3, 5.28±0.06; (−)-epigallocatechin 30±10, 6.5±0.5, 3.37±0.08; and (−)-epigallocatechin gallate 130±40, 6.7±0.3, 5.0±0.1. A crude extract of black tea polyphenols inhibited 7-ethoxyresorufin deethylase, but did not cause enzyme activation consistently.Enzyme activation was dependent upon substrate concentration.Heteroactivation of CYP1A1 may partially explain the lack of agreement between biological and epidemiological evidence of a role for tea in cancer prevention.
PMCID: PMC1576212  PMID: 15895106
CYP1A1; tea; polyphenols; EROD; catechins; activation; (−)-epigallocatechin gallate
22.  Effects of some isoprostanes on the human umbilical artery in vitro 
British Journal of Pharmacology  2000;129(3):509-514.
Cumulative concentration-effect curves for the selective prostanoid TP receptor agonist U46619 and six isoprostanes were constructed in the human isolated umbilical artery.All compounds except 8-iso-PGF3α produced concentration-dependent contractions. The contractile response to the isoprostanes increased with each cumulative addition up to a point, after which subsequent addition reduced the contraction below the previous level. This [downturn] in the concentration-effect curve did not occur with U46619.The potencies of the compounds tested were as follows (pEC50±s.e.mean): U46619, 6.7±0.2; 8-iso-PGE2, 6.5±0.1; 8-iso-PGF2α, 5.8±0.2; 8-iso-PGE1, 5.4±0.1; 8-iso-PGF1α, 5.0±0.1; 8-iso-PGF2β> 4.8; 8-iso-PGF3α>> 4.8 (n=4–17). Neither 8-iso-PGF2β nor 8-iso-PGF3α at 44 μM had a significant effect on cumulative concentration-effect curves to U46619.The selective TP receptor antagonist GR32191 (0.1 μM) caused rightward shifts in the concentration-effect curves to all the active compounds. pA2 values for GR32191 against U46619, 8-iso-PGE2, 8-iso-PGF2α, 8-iso-PGE1 were 7.6±0.2, 9±1, 8.2±0.3 and 7.7±0.3, respectively (n=4).Neither Nω-nitro-L-arginine methyl ester (100 μM) nor the selective DP receptor antagonist BW A868C (50 nM) affected the complex concentration-effect curve to 8-iso-PGE2 (n=3).Stable contractions to U46619 (1–3 μM) were unaffected by anandamide at concentrations up to 60 μM.
PMCID: PMC1571866  PMID: 10711349
Human umbilical artery; contraction; isoprostanes; TP receptors; U46619
23.  Operational correlates of prostanoid TP receptor expression in human non-pregnant myometrium are unaffected by excision site or menstrual cycle status of the donor 
British Journal of Pharmacology  1999;128(7):1524-1528.
Cumulative concentration-effect curves for the selective prostanoid TP receptor agonist, U46619, were constructed in strips of human non-pregnant myometrium grouped according to tissue excision site (top, lateral wall, lower uterine segment, sub-serosal or sub-endometrial), tissue orientation (strips cut either parallel or perpendicular to the serosa) and donor menstrual status (proliferative or secretory phase).U46619 was excitatory in all tissues. There was no significant difference in either pEC50 or maximum response between groups (P<0.05). The range of pEC50 values was 6.8±0.1 (lateral wall, proliferative phase, n=5) to 7.1±0.3 (lateral wall, secretory phase, n=5). The range of maximum response values was 0.9±0.8 N cm−2 (lateral wall, proliferative phase, n=5) to 3.1±1.0 N cm−2 (lateral wall, secretory phase, n=5).Saturation binding analyses were conducted using the radiolabelled TP receptor agonist, [125I]-BOP. Binding parameters were estimated for membranes prepared from human non-pregnant myometrium excised from the lateral wall and grouped according to donor menstrual status.There were no significant differences in the mean pKd and [R]tot values for [125I]-BOP binding between the two groups (proliferative phase: pKd=8.3±0.3, [R]tot=412±319 fmol mg protein−1, n=5; secretory phase: pKd=8.5±0.4, [R]tot=369±192 fmol mg protein−1, n=6; P<0.05).These data indicate that U46619-mediated responses in human non-pregnant myometrium are not influenced by tissue excision site, tissue orientation or donor menstrual status and that [125I]-BOP binding is not influenced by donor menstrual status. This suggests that the TP receptor population is homogeneous throughout the human non-pregnant myometrium, and not subject to hormonal regulation.
PMCID: PMC1571797  PMID: 10602332
Myometrium (human); TP receptor; [125I]-BOP; U46619; response variability; menstrual cycle
24.  Characterization of excitatory prostanoid receptors in the human umbilical artery in vitro 
British Journal of Pharmacology  1999;128(7):1505-1512.
5-HT and the prostanoid TP receptor agonists, U46619 and I-BOP, constricted the human umbilical artery with pEC50 values of 7.3±0.2, 6.7±0.1, and 7.3±0.2, respectively. The selective TP receptor antagonist, GR32191 (0.1 μM), shifted the concentration-effect curves to U46619 and I-BOP to the right, but had no effect on the response to 5-HT.The natural prostaglandins, PGF2α and PGE2, caused concentration-dependent contraction with pEC50 values of 5.2±0.2 and 4.9±0.2, respectively. PGD2 was a partial agonist with a pEC50 of 5.24±0.03. GR32191 (0.1 μM) inhibited the responses to all of these compounds suggesting that they produce contraction by acting at TP receptors.Sulprostone failed to elicit contraction in the human umbilical artery at concentrations up to 4.4 μM suggesting the absence of EP1 and EP3 receptors. Despite this, 17-phenyltrinor PGE2 and GR63799 both induced contraction at concentrations above 1 μM, but the effects were sensitive to GR32191 (0.1 μM).Fluprostenol had no effect on the human umbilical artery at concentrations up to 17 μM suggesting the absence of FP receptors. Cloprostenol was ineffective in two tissues, but caused contraction in one tissue at the highest concentration tested (1.7 μM). However, this response was abolished in the presence of GR32191 (0.1 μM).The effects of four TP receptor antagonists were assessed by global non-linear regression analysis. GR32191, SQ29548, SQ30741, and ICI192605 competitively inhibited responses to U46619 with pKb values of 8.0±0.1, 7.6±0.1, 7.0±0.2 and 8.1±0.1, respectively.These results suggest that the human umbilical artery functionally expresses TP receptors, but not EP1, EP2 or FP receptors.
PMCID: PMC1571798  PMID: 10602330
Human umbilical artery; contraction; competitive antagonism; TP receptors; U46619
25.  Pharmacokinetics of propofol when given by intravenous infusion. 
We have previously shown with i.v. bolus studies that the elimination of propofol is much slower than previously reported. Now we have studied the implications of this for prolonged i.v. infusion of propofol in seven patients who received continuous infusions of propofol for up to 9 h. Values of elimination half-life ranged from 13.1 to 44.7 h, systemic clearance from 1.02 to 1.63 l h-1 and volume of distribution from 1390 to 3940 l and these were similar to those obtained with bolus administration. The large volume of distribution is consistent with the high octanol/blood partition coefficient, which was found to be 72.0. Despite the very long elimination half-life, blood propofol concentrations appeared to approach steady state within 20 min rather than the 4-5 half-lives normally expected. This is because for this drug, which displays multicompartment pharmacokinetics, the rate of initial rise of blood concentrations is governed primarily by the very short distribution half-life of the drug. Therefore, the long elimination half-life of propofol is probably of little significance in designing infusions regimens, but the lower systemic clearance should be taken into account to avoid unwanted accumulation.
PMCID: PMC1368287  PMID: 2390424

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