Characterization and Systemic Delivery of Dibenzoylmethane via the Intranasal Route.

Intranasal (IN) administration is known to be noninvasive with the potential to carry a drug or vaccine directly to the blood, bypassing first-pass metabolism in the liver and the harsh environment of the gastrointestinal system. Orally administered dibenzoylmethane (DBM) has been shown experimentally to be neuroprotective in animal models of tauopathy and prion disease and effective in the treatment of certain forms of cancers. The purpose of this study was to prepare, characterize, and test formulations of DBM designed for IN administration. DBM was formulated in brain homogenate (BH) and hypromellose and as nanoparticles (NPs). These formulations were detected using UPLC and characterized in solid and suspension states; NPs were also characterized by in vitro cell culture-based studies. Particle size for DBM NP was 163.8 ± 3.2 nm, and in vitro release studies showed 95.80% of DBM was released from the NPs within 8 days. In vitro cell, culture studies suggested no drug uptake until 6 h. A histological analysis of nasal cavity (NC) sections and blood detection studies were carried out 30 min after inhalation. DBM amounting to 40.77 ± 4.93 and 44.45 ± 5.36 ng/mL was detected in the blood of animals administered DBM in polymeric and NP formulation, respectively. Histological studies on NCs confirmed the presence of BH within lymphatic vessels in the lamina propria of each animal; BH was identified traversing the mucosa in 2 animals. Thus, formulations for DBM administered via IN route were successfully designed and characterized and able to cross the nasal mucosa following inhalation.

Evaluation of triazole-chelated lanthanides as chemically stabile bioimaging agents.

Europium (Eu), dysprosium (Dy), samarium (Sm), and terbium (Tb) complexes were prepared using the neutral tridentate chelator 2,6-bis(1-benzyl-1,2,3-triazol-4-yl)pyridine and one equivalent of each lanthanide salt. The physicochemical, aerodynamic, and in vitro cellular properties of each lanthanide metal complex were studied to determine their viability as cell surface fluorescent probes. Each compound was characterized by electrospray ionization mass spectroscopy (ESI-MS), ultraperformance liquid chromatography (UPLC), differential scanning calorimetry (DSC), and thermogravimetic analysis (TGA). Upon excitation at 320 nm each complex displayed characteristic lanthanide-based fluorescence emission in the visible wavelength range with stokes shifts greater than 200 nm. Each complex was found to be chemically stable when exposed to pH range of 1-11 for 72 h and resistant to photobleaching. To simulate pulmonary administration of these fluorophores, the aerodynamic properties of the Eu and Tb complexes were determined using a next generation impactor (NGI). This measurement confirmed that the complexes retain their fluorescence emission properties after nebulization. Cellular cytotoxicity was determined on A-549 lung cancer cell line using methylthiazol tetrazolium (MTT) cytotoxicity assay at 24, 48, and 72 h postexposure to the complexes. The complexes showed a dose and time-dependent effect on the percent viability of the cells.

Treatment options for refractory and difficult to treat seizures: focus on vigabatrin.

Complex partial seizures are often refractory to current pharmacological therapies. These difficult to treat seizures are typically managed using multiple antiepileptic drugs (AEDs). AEDs as a group are frequently associated with significant adverse drug effects, multiple drug interactions, and numerous potential clinical complications due to their individual pharmacokinetic profiles and unique drug properties. Recently, the approval of vigabatrin by the US Food and Drug Administration has necessitated that clinicians re-evaluate these risk-benefit relationships and determine where the drug fits within the treatment scheme for the management of complex partial seizures. This review will facilitate that re-evaluation through a brief review of AEDs used in the treatment of complex partial seizures, followed by a focused discussion on vigabatrin.

Safety and efficacy of vigabatrin for the treatment of infantile spasms.

In 2009, vigabatrin became the first FDA approved medication for the treatment of infantile spasms in the United States. There are few well-designed prospective studies comparing the drug to placebo or other modalities used in the treatment of infantile spasms. The available data have demonstrated that vigabatrin is efficacious in the treatment of infantile spasms regardless of underlying etiology, but that it is particularly beneficial in patients with a diagnosis of tuberous sclerosis. Adrenocorticotropic hormone (ACTH), the only other medication with robust efficacy data, has been used as first line therapy for infantile spasms associated with other etiologies, and in general controls spasms sooner than vigabatrin, though relapse is common with both therapies. Vigabatrin is generally well tolerated. However, use has been associated with permanent loss of peripheral vision in some patients. In children with tuberous sclerosis, vigabatrin should be considered as initial therapy for infantile spasms. It is a viable alternative for patients with suboptimal response, contraindications or intolerance to ACTH.

Advances in the pulmonary delivery of poorly water-soluble drugs: influence of solubilization on pharmacokinetic properties.

BACKGROUND: Pulmonary drug delivery is an accepted route of drug administration for the management of lung conditions and diseases as well as an evolving route of administration for the systemic delivery of agents. Many inhaled drugs pose formulation and delivery challenges in part because of poor aqueous solubility. The influence of poor aqueous solubility and formulation-based solubility enhancements on the pharmacokinetic profile of inhaled agents was reviewed. METHOD: A systematic review was performed to identify literature that reported pharmacokinetic findings following the pulmonary delivery of a poorly water-soluble agent. RESULTS: The influence of solubility and formulation-based solubility enhancements on pharmacokinetic parameters following inhalation of corticosteroids, antifungals, oligopeptides, and opioids, was compiled. CONCLUSION: Poor aqueous solubility did not uniformly affect the pharmacokinetic profile for inhaled agents. Physicochemical and formulation-based solubility enhancement did affect drug absorption from the lungs. Numerous drug- and formulation-dependant pharmacokinetic effects were identified.

Vigabatrin: a comprehensive review of drug properties including clinical updates following recent FDA approval.

BACKGROUND: Vigabatrin (Sabril) was approved in the USA in mid-2009 for the adjunctive treatment of refractory complex partial seizures and as treatment of infantile spasms. Vigabatrin's more than 30-year history of research and development is condensed into a clinically relevant review pertaining to this 2009 approval. METHODS/DISCUSSION: A review of the scientific literature was conducted with special focus given to the drug molecule, its mechanism of action, its effects on living systems (e.g., pharmacokinetic, pharmacologic and toxicologic), and its anticipated role among antiepileptic drugs in the USA. CONCLUSIONS: The recent approval of vigabatrin makes a significant addition to antiepileptic drug options. The FDA implemented a Risk Evaluation and Mitigation Strategy to control for the possibility of severe adverse drug events.

Dose tolerability of chronically inhaled voriconazole solution in rodents.

Invasive pulmonary aspergillosis (IPA) is a fungal disease of the lung associated with high mortality rates in immunosuppressed patients despite treatment. Targeted drug delivery of aqueous voriconazole solutions has been shown in previous studies to produce high tissue and plasma drug concentrations as well as improved survival in a murine model of IPA. In the present study, rats were exposed to 20 min nebulizations of normal saline (control group) or aerosolized aqueous solutions of voriconazole at 15.625 mg (low dose group) or 31.25mg (high dose group). Peak voriconazole concentrations in rat lung tissue and plasma after 3 days of twice daily dosing in the high dose group were 0.85+/-0.63 microg/g wet lung weight and 0.58+/-0.30 microg/mL, with low dose group lung and plasma concentrations of 0.38+/-0.01 microg/g wet lung weight and 0.09+/-0.06 microg/mL, respectively. Trough plasma concentrations were low but demonstrated some drug accumulation over 21 days of inhaled voriconazole administered twice daily. Following multiple inhaled doses, statistically significant but clinically irrelevant abnormalities in laboratory values were observed. Histopathology also revealed an increase in the number of alveolar macrophages but without inflammation or ulceration of the airway, interstitial changes, or edema. Inhaled voriconazole was well tolerated in a rat model of drug inhalation.

Characterization and pharmacokinetic analysis of aerosolized aqueous voriconazole solution.

Invasive fungal infections in immunocompromised patients have high mortality rates despite current treatment modalities. This study was designed to evaluate the suitability of an aqueous solution of voriconazole solubilized with sulfobutyl ether-beta-cyclodextrin for targeted drug delivery to the lungs via nebulization. A solution was prepared such that the inspired aerosol dose was isotonic with an acceptable mass median aerodynamic diameter of 2.98 microm and a fine particle fraction of 71.7%. Following single and multiple inhaled doses, high voriconazole concentrations were observed within 30 min in the lung tissue and plasma. Drug solubilization with sulfobutyl ether-beta-cyclodextrin contributed to the rapid and high drug concentrations in plasma following inhalation. Maximal concentrations in the lung and plasma were 11.0 +/- 1.6 microg/g wet lung weight and 7.9 +/- 0.68 microg/mL, respectively, following a single inhaled dose with a corresponding tissue/plasma concentration ratio of 1.4 to 1. Following multiple inhaled doses, peak concentrations in lung tissue and plasma were 6.73 +/- 3.64 microg/g wet lung weight and 2.32 +/- 1.52 microg/mL, respectively. AUC values in lung tissue and plasma were also high. The clinically relevant observed pharmacokinetic parameters of inhaled aqueous solutions of voriconazole suggest that therapeutic outcomes could be benefitted through the use of inhaled voriconazole.

Inhaled voriconazole for prevention of invasive pulmonary aspergillosis.

Targeted airway delivery of antifungals as prophylaxis against invasive aspergillosis may lead to high lung drug concentrations while avoiding toxicities associated with systemically administered agents. We evaluated the effectiveness of aerosolizing the intravenous formulation of voriconazole as prophylaxis against invasive pulmonary aspergillosis caused by Aspergillus fumigatus in an established murine model. Inhaled voriconazole significantly improved survival and limited the extent of invasive disease, as assessed by histopathology, compared to control and amphotericin B treatments.