Constant oxygen supply is essential for proper tissue development, homeostasis and function of all eukaryotic organisms. Cellular response to reduced oxygen levels is mediated by the transcriptional regulator hypoxia-inducible factor-1 (HIF-1). It is a heterodimeric complex protein consisting of an oxygen dependent subunit (HIF-1α) and a constitutively expressed nuclear subunit (HIF-1β). In normoxic conditions, de novo synthesized cytoplasmic HIF-1α is degraded by 26S proteasome. Under hypoxic conditions, HIF-1α is stabilized, binds with HIF-1β and activates transcription of various target genes. These genes play a key role in regulating angiogenesis, cell survival, proliferation, chemotherapy, radiation resistance, invasion, metastasis, genetic instability, immortalization, immune evasion, metabolism and stem cell maintenance. This review highlights the importance of hypoxia signaling in development and progression of various vision threatening pathologies such as diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration and glaucoma. Further, various inhibitors of HIF-1 pathway that may have a viable potential in the treatment of oxygen-dependent ocular diseases are also discussed.

Cancer remains one of the major leading causes of death worldwide. Acquisition of multidrug resistance (MDR) remains a major impediment to successful chemotherapy. As the name implies, MDR is not limited only to one drug but often associated to structurally and functionally unrelated chemotherapeutics. Extensive research and investigations have identified several mechanisms underlying the development of MDR. This process of drug resistance is considered to be multifactorial including decreased drug accumulation, increased efflux, increased biotransformation, drug compartmentalization, modification of drug targets and defects in cellular pathways. In the first part of the review, these pharmacokinetic and pharmacodynamic mechanisms have been described in brief. Although the pathways can act independently, they are more often intertwined. Of the various mechanisms involved, up-regulation of efflux transporters and metabolizing enzymes constitute a major resistance phenotype. This review also provides a general biological overview of important efflux transporters and metabolizing enzymes involved in MDR. Further, synergistic action between efflux transporters and metabolizing enzymes leading to MDR could possibly arise due to two different factors; overlapping substrate specificity and coordinated regulation of their expression. The expression of efflux transporters and metabolizing enzymes is governed by nuclear receptors, mainly pregnane X receptor (PXR). The pharmacological role of PXR and advances in the development of PXR antagonists to overcome MDR are outlined.

Sodium dependent multivitamin transporter (SMVT; product of the SLC5A6 gene) is an important transmembrane protein responsible for translocation of vitamins and other essential cofactors such as biotin, pantothenic acid and lipoic acid. Hydropathy plot (Kyte-Dolittle algorithm) revealed that human SMVT protein consists of 635 amino acids and 12 transmembrane domains with both amino and carboxyl termini oriented towards the cytoplasm. SMVT is expressed in various tissues such as placenta, intestine, brain, liver, lung, kidney, cornea, retina and heart. This transporter displays broad substrate specificity and excellent capacity for utilization in drug delivery. Drug absorption is often limited by the presence of physiological (epithelial tight junctions), biochemical (efflux transporters and enzymatic degradation) and chemical (size, lipophilicity, molecular weight, charge, etc.) barriers. These barriers may cause many potential therapeutics to be dropped from the preliminary screening portfolio and subsequent entry into the market. Transporter targeted delivery has become a powerful approach to deliver drugs to target tissues because of the ability of the transporter to translocate the drug to intracellular organelles at a higher rate. This review highlights studies employing SMVT transporter as a target for drug delivery to improve bioavailability and investigate the feasibility of developing SMVT targeted drug delivery systems.

Introduction Complete delineation of the HIV-1 life cycle has resulted in the development of several antiretroviral drugs. Twenty-five therapeutic agents belonging to five different classes are currently available for the treatment of HIV-1 infections. Advent of triple combination antiretroviral therapy has significantly lowered the mortality rate in HIV patients. However, fungal infections still represent major opportunistic diseases in immunocompromised patients worldwide. Areas covered Antiretroviral drugs that target enzymes and/or proteins indispensable for viral replication are discussed in this article. Fungal infections, causative organisms, epidemiology and preferred treatment modalities are also outlined. Finally, observed/predicted drug-drug interactions between antiretrovirals and antifungals are summarized along with clinical recommendations. Expert opinion Concomitant use of amphotericin B and tenofovir must be closely monitored for renal functioning. Due to relatively weak interactive potential with the CYP450 system, fluconazole is the preferred antifungal drug. High itraconazole doses (> 200 mg/day) are not advised in patients receiving booster protease inhibitor (PI) regimen. Posaconazole is contraindicated in combination with either efavirenz or fosamprenavir. Moreover, voriconazole is contraindicated with high-dose ritonavir-boosted PI. Echino-candins may aid in overcoming the limitations of existing antifungal therapy. An increasing number of documented or predicted drug-drug interactions and therapeutic drug monitoring may aid in the management of HIV-associated opportunistic fungal infections.

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