Uracil Hydroxybenzamides as Potential Antidiabetic Prodrugs

Pharmaceutical Chemistry Journal - A series of N1, N3-bis-hydroxybenzoyl, -acetoxybenzoyl, and -methoxybenzoyl uracil derivatives were synthesized. All compounds were screened for the ability to...     

Targeted Transport as a Promising Method of Drug Delivery to the Central Nervous System (Review)

Pharmaceutical Chemistry Journal - Targeted transport systems for drug delivery to the central nervous system (CNS) are reviewed. A modern classification of dosage forms according to generation and...     

On Secondary Patenting of Organic Compounds Suitable for use as Active Pharmaceutical Ingredients

Pharmaceutical Chemistry Journal - Secondary patenting of organic compounds that can undoubtedly be used as active pharmaceutical ingredients (APIs) is discussed. As a rule, such compounds, their...     

Application of Near-IR Spectroscopy to Analysis of Kemantane Drug Substance

Pharmaceutical Chemistry Journal - Near-IR spectroscopy is a promising analytical method in pharmacy. It was shown that it can be used as a rapid method for confirming the identity and analyzing...     

Chemoprevention of Radiation-Induced Carcinogenesis Using Decoction of Meadowsweet (Filipendula Ulmaria) Flowers

Pharmaceutical Chemistry Journal - The ability of the decoction of meadowsweet flowers (Filipendula ulmaria, FU) to inhibit tumor development in female LIO rats was demonstrated using a...     

Synthesis and Antiarrhythmic Activity of N-[2-(Adamantan-2-YL)Aminocarbonyl-Methyl-N′-(Dialkylamino)Alkylnitrobenzamides

Pharmaceutical Chemistry Journal - Novel 2-aminoadamantane derivatives, specifically N-[2-(adamant-2-yl)-aminocarbonylmethyl]-N′-(dialkylamino) alkylnitrobenzamides and their physiologically...     

Dissolution of Ketoprofen from Poly(Ethylene Glycol) Solid Dispersions

Pharmaceutical Chemistry Journal - The effect of solid dispersions (SDs) on the solubility of the nonsteroidal anti-inflammatory drug ketoprofen was determined. Ketoprofen and its SDs with...     

Liver-directed gene therapy corrects cardiovascular lesions in feline mucopolysaccharidosis type I

Patients with mucopolysaccharidosis type I (MPS I), a genetic deficiency of the lysosomal enzyme α-l-iduronidase (IDUA), exhibit accumulation of glycosaminoglycans in tissues, with resulting diverse clinical manifestations including neurological, ocular, skeletal, and cardiac disease. MPS I is currently treated with hematopoietic stem cell transplantation or weekly enzyme infusions, but these therapies have significant drawbacks for patient safety and quality of life and do not effectively address some of the most critical clinical sequelae, such as life-threatening cardiac valve involvement. Using the naturally occurring feline model of MPS I, we tested liver-directed gene therapy as a means of achieving long-term systemic IDUA reconstitution. We treated four MPS I cats at 3–5 mo of age with an adeno-associated virus serotype 8 vector expressing feline IDUA from a liver-specific promoter. We observed sustained serum enzyme activity for 6 mo at ∼30% of normal levels in one animal, and in excess of normal levels in three animals. Remarkably, treated animals not only demonstrated reductions in glycosaminoglycan storage in most tissues, but most also exhibited complete resolution of aortic valve lesions, an effect that has not been previously observed in this animal model or in MPS I patients treated with current therapies. These data point to clinically meaningful benefits of the robust enzyme expression achieved with hepatic gene transfer that extend beyond the economic and quality of life advantages over lifelong enzyme infusions.Mucopolysaccharidosis type I (MPS I) is a recessive genetic disorder caused by deficiency of the lysosomal enzyme α-l-iduronidase (IDUA). In the absence of IDUA, cells are unable to catabolize the ubiquitous glycosaminoglycans (GAGs) heparan and dermatan sulfates. The resulting lysosomal GAG storage causes multisystem organ pathology and diverse clinical manifestations, including bone and joint deformity, upper airway obstruction, hepatosplenomegaly, corneal clouding, and cognitive impairment (1). Most patients also develop cardiac disease, which arises from the combined effects of GAG deposition in the myocardium, coronary arteries, and left-sided heart valves (2). Without treatment, median survival in patients with the severe form of the disease is less than 7 y (3).Care of MPS I patients has been vastly improved by the introduction of two disease-modifying therapies—hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). Both treatments are based on the principle of cross-correction: that cells can efficiently endocytose extracellular lysosomal enzymes bearing a mannose-6-phosphate residue, allowing IDUA secreted from donor-derived cells after HSCT or recombinant enzyme delivered i.v. to correct the metabolic defect in many tissues (4, 5). The introduction of HSCT has increased the survival of MPS I patients and has demonstrated improvements in growth, mobility, hepatosplenomegaly, and some aspects of cardiac disease such as left ventricular hypertrophy (2, 6–9). ERT has shown a similar capacity to improve many of the clinical features of MPS I (7, 10, 11). ERT is favored in patients with an attenuated disease phenotype because of the high mortality associated with HSCT, although HSCT remains the first-line intervention for patients less than 2 y of age owing to the beneficial effect of early transplantation on cognitive outcomes (7).Despite the enormous advances that have been made in the treatment of MPS I, significant shortcomings remain. Neurological symptoms do not improve with ERT and are highly variable after HSCT (7, 9). Skeletal disease is incompletely treated by both therapies. ERT and HSCT may improve heart disease but do not reverse valvular GAG deposition, often leaving treated patients with persistent aortic and mitral valve insufficiency or stenosis (2, 12). Additionally, the current treatment options are fundamentally limited by the morbidity and mortality associated with HSCT and the need for lifelong, expensive, weekly enzyme infusions in ERT.For diseases such as MPS I that require lifelong systemic enzyme replacement, liver-directed gene therapy has emerged as a potential therapeutic option. The high synthetic capacity of the liver, coupled with the discovery of adeno-associated virus (AAV) vectors capable of safe and efficient hepatic targeting, make this a feasible alternative to exogenous enzyme infusion (13, 14). The first clinical success of AAV-mediated liver gene therapy was recently demonstrated in a trial for hemophilia B, in which some patients were able to discontinue prophylactic factor IX injections (15). Apart from the potential safety and quality of life benefits over HSCT and ERT, respectively, we hypothesized that liver-directed gene therapy could have three potential benefits specific to MPS I. First, the liver is a therapeutic target in MPS I, making the high local concentrations of enzyme potentially useful for efficiently treating hepatomegaly due to GAG storage. Second, liver-mediated expression could theoretically result in circulating concentrations of IDUA higher than those achieved with HSCT, and more stable than those achieved with i.v. infusion of the enzyme, which has a serum half-life of less than 4 h (11). Maintaining high levels of serum IDUA could drive greater enzyme uptake and improve efficacy in difficult-to-treat tissues. Finally, antibody responses to IDUA, which develop in the vast majority of patients receiving ERT, seem to limit treatment efficacy (16, 17). Evidence from mouse models suggests that AAV-mediated hepatic expression of an enzyme is less immunogenic than i.v. delivery of the recombinant protein, indicating that this approach could exhibit improved efficacy by eliciting less-robust immune responses to IDUA (18).In the present study we tested liver-directed gene therapy in the naturally occurring feline model of MPS I, which recapitulates many of the clinical and pathological features of the disease, including progressive cardiac valve involvement (19–23). Four animals were treated at 3–5 mo of age with an i.v. injection of an AAV serotype 8 vector expressing feline IDUA from a liver-specific promoter. Three of the animals exhibited sustained supraphysiologic IDUA expression, with subsequent GAG clearance from all tissues examined. Remarkably, aortic valve lesions were reversed in these three animals, indicating the potential utility of this approach for targeting treatment refractory tissues in MPS I.