Annika C. Montag

Liver-Targeted Drug Delivery Using HepDirect Prodrugs

Targeting drugs to specific organs, tissues, or cells is an attractive strategy for enhancing drug efficacy and reducing side effects. Drug carriers such as antibodies, natural and manmade polymers, and labeled liposomes are capable of targeting drugs to blood vessels of individual tissues but often fail to deliver drugs to extravascular sites. An alternative strategy is to use low molecular weight prodrugs that distribute throughout the body but cleave intracellularly to the active drug by an organ-specific enzyme. Here we show that a series of phosphate and phosphonate prodrugs, called HepDirect prodrugs, results in liver-targeted drug delivery following a cytochrome P450-catalyzed oxidative cleavage reaction inside hepatocytes. Liver targeting was demonstrated in rodents for MB06866 [(2R,4S)-9-[2-[4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methoxyethyl]adenine (remofovir)], a Hep-Direct prodrug of the nucleotide analog adefovir (PMEA), and MB07133 [(2R,4S)-4-amino-1-[5-O-[2-oxo-4-(4-pyridyl)-1,3,2-dioxaphosphorinan-2-yl]-β-d-arabinofuranosyl]-2(1H)-pyrimidinone], a HepDirect prodrug of cytarabine (araC) 5′-monophosphate. Liver targeting led to higher levels of the biologically active form of PMEA and araC in the liver and to lower levels in the most toxicologically sensitive organs. Liver targeting also confined production of the prodrug byproduct, an aryl vinyl ketone, to hepatocytes. Glutathione within the hepatocytes rapidly reacted with the byproduct to form a glutathione conjugate. No byproduct-related toxicity was observed in hepatocytes or animals treated with HepDirect prodrugs. A 5-day safety study in mice demonstrated the toxicological benefits of liver targeting. These findings suggest that HepDirect prodrugs represent a potential strategy for targeting drugs to the liver and achieving more effective therapies against chronic liver diseases such as hepatitis B, hepatitis C, and hepatocellular carcinoma.

Modulation of cardiac remodeling by adenosine: In vitro and in vivo effects

The increasing incidence of congestive heart failure has stimulated efforts to develop pharmacologic strategies to prevent or reverse the associated process of adverse cardiac remodeling. The possibility of utilizing endogenously generated factors that are capable of inhibiting this process is beginning to be explored. Adenosine, has been described as a retaliatory autacoid with homeostatic activities in the regulation of myocardial blood flow, catecholamine release, and reduction of injury resulting from periods of ischemia. Adenosine exerts a variety of actions that are consistent with the concept that it can reduce or inhibit the process of cardiac remodeling. In this manuscript, the basics of adenosine metabolism, its cell surface receptors and beneficial actions on the cardiovascular system are reviewed. In addition new, in vitro and in vivo data will be presented supporting the concept that adenosine exerts actions that may ameliorate adverse cardiac remodeling.

A Review of Evidence-Based Approaches for Reduction of Alcohol Consumption in Native Women Who Are Pregnant or of Reproductive Age

Background: Fetal alcohol spectrum disorders (FASDs) are the leading preventable cause of developmental disabilities in the United States and likely throughout the world. FASDs can be prevented by avoiding alcohol use during pregnancy; however, efforts to prevent risky alcohol consumption in women of childbearing potential have not been universally successful. Objectives: Data suggest that successful interventions may require tailoring methods to meet the needs of specific populations and cultures. Key findings of interventions previously tested among American Indian and Alaskan Native (AI/AN) women who are or may become pregnant, data gaps, and promising ongoing interventions are reviewed. Methods: A systematic review of the current literature on empirically based interventions among AI/AN women was conducted. Selected alternative approaches currently being tested in AI/AN settings are also described. Results: Similar to findings among other populations of women in the United States, a number of interventions have been implemented; however, only a small number have measured results. Approaches have included standard interventions involving hospitalization, inpatient, or outpatient care; wellness education; traditional approaches; and case management for high-risk women. An ongoing Screening, Brief Intervention, and Referral to Treatment (SBIRT) protocol comparing the effectiveness of a web-based culturally adapted tool, or a peer health educator model to standard clinical practice is described. Conclusion: Translation of successful interventions from other settings to AI/AN populations holds promise. Scientific Significance: FASDs represent a significant health issue with high personal and societal costs. Improvement of interventions to prevent prenatal alcohol consumption in specific populations, including AI/AN women, is a critical public health need.

Fetal alcohol-spectrum disorders: identifying at-risk mothers

Fetal alcohol-spectrum disorders (FASDs) are a collection of physical and neurobehavioral disabilities caused by prenatal exposure to alcohol. To prevent or mitigate the costly effects of FASD, we must identify mothers at risk for having a child with FASD, so that we may reach them with interventions. Identifying mothers at risk is beneficial at all time points, whether prior to pregnancy, during pregnancy, or following the birth of the child. In this review, three approaches to identifying mothers at risk are explored: using characteristics of the mother and her pregnancy, using laboratory biomarkers, and using self-report assessment of alcohol-consumption risk. At present, all approaches have serious limitations. Research is needed to improve the sensitivity and specificity of biomarkers and screening instruments, and to link them to outcomes as opposed to exposure. Universal self-report screening of all women of childbearing potential should ideally be incorporated into routine obstetric and gynecologic care, followed by brief interventions, including education and personalized feedback for all who consume alcohol, and referral to treatment as indicated. Effective biomarkers or combinations of biomarkers may be used during pregnancy and at birth to determine maternal and fetal alcohol exposure. The combination of self-report and biomarker screening may help identify a greater proportion of women at risk for having a child with FASD, allowing them to access information and treatment, and empowering them to make decisions that benefit their children.

Effect of Depression on Risky Drinking and Response to a Screening, Brief Intervention, and Referral to Treatment Intervention

We assessed alcohol consumption and depression in 234 American Indian/Alaska Native women (aged 18-45 years) in Southern California. Women were randomized to intervention or assessment alone and followed for 6 months (2011-2013). Depression was associated with risk factors for alcohol-exposed pregnancy (AEP). Both treatment groups reduced drinking (P < .001). Depressed, but not nondepressed, women reduced drinking in response to SBIRT above the reduction in response to assessment alone. Screening for depression may assist in allocating women to specific AEP prevention interventions.

Delivery of high levels of anti-proliferative nucleoside triphosphates to CYP3A-expressing cells as a potential treatment for hepatocellular carcinoma

PurposeHepatocellular carcinoma (HCC) is a life-threatening condition with only one drug treatment regimen approved for use. Oncolytic nucleosides are minimally effective against HCC putatively because of their inability to achieve cytotoxic levels of the active metabolite [nucleoside triphosphate (NTP)] in tumor cells at doses that are well tolerated. The aim of our studies was to explore the utility of CYP3A-activated prodrugs of cytarabine and fludarabine monophosphate for the treatment of HCC.MethodsProdrugs of cytarabine and fludarabine monophosphates were evaluated for their ability to safely achieve NTP levels in the liver of normal mice that are cytotoxic to hepatoma cells.ResultsWhile therapeutic levels of NTPs are achieved in the livers of normal rodents after administration of the prodrugs, only MB07133 achieved these levels whithout exhibiting signs of liver toxicity or myelosuppression.ConclusionsAs the levels of araCTP achieved in the liver at therapeutic doses are only toxic to proliferating cells (such as those in HCC tumors), but not the non-proliferative adjacent tissue, MB07133 treatment has the potential to be both efficacious and well tolerated in HCC patients.

Tailoring an Alcohol Intervention for American Indian Alaska Native Women of Childbearing Age: Listening to the Community

BACKGROUND Reduction of risky drinking in women of childbearing age is 1 strategy that may be employed to prevent fetal alcohol spectrum disorder, a sequela of prenatal alcohol exposure. Communities differ in risk and protective factors, necessitating culturally informed interventions for maximal efficacy. This article describes the modification of an existing web-based screening, brief intervention, and referral to treatment intervention to reduce risky drinking among American Indian Alaska Native (AIAN) women of childbearing age in Southern California into a peer-to-peer-based intervention using motivational interviewing (MI). METHODS The modification process was iterative and included various community focus groups, interviews, and a final review. RESULTS Intervention modification was required for cultural congruence. Components of the peer-to-peer intervention designed by this project included a flip chart used to guide the motivational interviewing, charts of the financial and physical costs of alcohol consumption, revised baseline and follow-up questionnaires, and guidance regarding the application of MI techniques. CONCLUSIONS This study may inform the modification of future interventions among AIAN communities.