A new oral testosterone (TLANDO) treatment regimen without dose titration requirement for male hypogonadism.

BACKGROUND: Male hypogonadism (testosterone level < 300 ng/dl) is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone. Most marketed testosterone replacement therapy products often require multiple dose adjustment clinic visits to achieve the desired, eugonadal testosterone levels. OBJECTIVE: To evaluate the efficacy and safety of a novel oral testosterone undecanoate therapy for the treatment of hypogonadism. MATERIAL AND METHODS: Ninety-five (N = 95) hypogonadal men were enrolled in this open-label, single-arm, multicenter study in the United States (NCT03242590). Subjects received 225 mg of oral testosterone undecanoate (TLANDO) twice a day for 24 days without dose adjustment. Primary efficacy was percentages of subjects who achieved mean 24-h testosterone levels within the eugonadal range and secondary efficacies were evaluated based on the upper limit of lab normal range of testosterone concentration. RESULTS: Subjects enrolled were on average age of 56 years, with about 17% of subjects older than 65 years. The mean body mass index was 32.8 kg/m2 . The baseline mean total testosterone values were below the normal range (202 ± 74 ng/dl). Post-treatment with 450 mg testosterone undecanoate daily dose without dose adjustment, 80% of subjects (95% confidence interval of 72%-88%) achieved a testosterone Cavg in the normal range and restored testosterone levels to mean testosterone Cavg of 476 ± 184 ng/dl at steady state. Testosterone restoration was comparable to other approved testosterone replacement therapy products. TLANDO was well tolerated with no deaths, no drug-related serious adverse events, and no hepatic adverse events. DISCUSSION AND CONCLUSIONS: TLANDO restored testosterone levels to the normal range in the majority of hypogonadal males. This new oral testosterone replacement therapy can provide an option for no-titration oral testosterone replacement therapy. This therapy has the potential to improve patient compliance in testosterone replacement therapy.

Transscleral Iontophoresis for Noninvasive Ocular Drug Delivery of Macromolecules.

Purpose: The objectives were to investigate the effect of transscleral iontophoresis of macromolecules in vitro and in vivo, to study the importance of electroosmosis on macromolecules of low charge to mass ratio, and to evaluate transscleral iontophoresis efficacy in a choroidal neovascularization (CNV) animal model. Methods: Through in vitro transport experiments, the permeability coefficients of macromolecules [eg, immunoglobulin G (IgG), dextran 70 kDa] were determined under different conditions. The effect of ionic strength formulations and iontophoretic conditions was studied on the distribution of IgG and bevacizumab into the eye in vivo. Magnetic resonance imaging (MRI) was utilized to evaluate in vivo real time distribution of gadolinium-labeled albumin (Galbumin) following iontophoresis. The efficacy between no treatment, intravitreal injection (IVT), and iontophoresis of bevacizumab on a CNV model of subretinal injection of adeno-associated virus encoding human VEGF-165 was investigated. Results: The permeability data suggested a significant effect of ionic strength on the iontophoretic transport of macromolecules. Transscleral iontophoresis of IgG at 4 mA with a low ionic strength formulation was about 600 times greater than passive diffusion and 14-fold over a conventional formulation in vitro. Approximately 0.6 mg of bevacizumab can be delivered into the rabbit eye in vivo with a 20-min treatment of iontophoresis. MRI showed that Galbumin was in the posterior tissues after iontophoresis. In the CNV model, the iontophoresis and IVT methods of bevacizumab delayed retinal neovascularization by 4 and 8 weeks, respectively. Conclusions: Transscleral iontophoresis is capable of delivering macromolecule drugs through the conjunctiva and sclera, eventually exposing the retina/choroid to the drugs.

Characterization and evaluation of fluoridated apatites for the development of infection-free percutaneous devices.

The wound healing process in the soft tissues adjacent to percutaneous implants induces "epithelial downgrowth", and subsequently, a sinus tract around the device. This provides an optimal environment for bacterial colonization and proliferation. In an attempt to arrest downgrowth and achieve epithelial attachment to a device surface, we have sought to mimic the most common and successful percutaneous organ, the tooth. Since teeth are composed of partially and fully fluoridated forms of hydroxyapatite (HA), it was hypothesized that the surface properties of fluoridated apatites, fluorohydroxyapatite (FHA) and fluorapatite (FA), would improve epithelial cellular adhesion and differentiation when compared to HA and titanium (Ti) surfaces. In this study, the apatites (HA, FHA, and FA) were synthesized and characterized. Following a high-temperature sintering treatment of these apatites, keratinocyte and fibroblast adhesion and differentiation properties were analyzed in vitro, revealing a statistically significant increase in keratinocyte adhesion and terminal differentiation on FA surfaces sintered at 1050-1150 °C as compared to Ti or HA. Moreover, fibroblasts displayed enhanced adhesion on FHA surfaces. This data suggests that percutaneous devices coated with, or fabricated from, fluoridated apatites may induce improved epithelial cellular adhesion and differentiation, potentially limiting deeply penetrating epithelial downgrowth and resultant bacterial ingress.

Novel Dexamethasone Sodium Phosphate Treatment (DSP-Visulex) for Noninfectious Anterior Uveitis: A Randomized Phase I/II Clinical Trial.

PURPOSE: Frequent steroid drops represent a challenge in patient compliance. This study evaluated the safety and efficacy of 5 minute topical dexamethasone sodium phosphate-Visulex (DSP-Visulex) treatment regimen (two applications on the first week then weekly after) compared to daily prednisolone acetate 1% (PA) for noninfectious anterior uveitis. MATERIALS AND METHODS: Forty-four patients were randomized to 8% DSP-Visulex with placebo eye drops (8% group, n = 14), 15% DSP-Visulex with placebo eye drops (15% group, n = 15), or Vehicle-Visulex with PA eye drops (PA group, n = 15). Patients received daily eye drops and Visulex treatments on days 1, 3, 8, and 15 with an optional treatment on day 22. Efficacy measures were change in anterior chamber cell (ACC) count from baseline and proportion of patients with zero ACC count at days 8, 15, and 29. Safety measures were adverse events (AEs), visual acuity, ocular symptoms, and intraocular pressure (IOP). RESULTS: ACC resolution over time was similar among the three groups. The percentage of patients with clear ACC was 18%, 22%, and 15% on day 8; 27%, 56%, and 54% on day 15; and 90%, 88%, and 77% on day 29 for the 8%, 15%, and PA groups, respectively. The numbers of reported AEs were 10, 36, and 12 for the 8%, 15%, and PA groups, respectively. Ten patients among all groups experienced treatment-related AEs, which included headache, eye pain, corneal abrasion, conjunctival/corneal staining, conjunctivitis, visual acuity reduction, and keratitis all of which were resolved during the timeframe of patients' participation in the study. IOP elevation was noted in the PA group throughout the study, whereas IOP elevation in the DSP-Visulex groups was observed at day 3 but not thereafter. CONCLUSIONS: The efficacy of the DSP-Visulex applications was comparable to the daily PA drops in the treatment of noninfectious anterior uveitis. Both 8% and 15% DSP-Visulex treatments were safe and well tolerated.

Ocular Drug Distribution and Safety of a Noninvasive Ocular Drug Delivery System of Dexamethasone Sodium Phosphate in Rabbit.

PURPOSE: To determine the ocular toxicity, systemic exposure, and amounts of dexamethasone sodium phosphate (DSP) in ocular tissues after administration of DSP with the Visulex system (DSP-Visulex). METHODS: DSP-Visulex was applied onto healthy rabbit eyes. DSP concentrations (4%, 8%, 15%, and 25%) and treatment durations (5, 10, and 20 min) were evaluated for the amounts of DSP in the ocular tissues and in plasma after single administrations of DSP-Visulex. The drug in eye tissues and plasma was analyzed by high-performance liquid chromatography-UV/VIS and by liquid chromatography-mass spectrometry, respectively. The safety and tolerability were ascertained based on clinical observations and histopathological examinations from repeat weekly DSP-Visulex treatments (4%, 8%, 15%, and 25% for 20 min) for 12 weeks. RESULTS: Significant amounts of DSP (ie, higher than 1 µg/g) were found in the anterior chamber, retina-choroid, cornea, vitreous, conjunctiva, and sclera after single applications of DSP-Visulex. The DSP concentrations in the ocular tissues and in plasma increased with increased DSP concentrations in the Visulex applicator and with increased application times. Systemic DSP was rapidly detected. The plasma half-life was 2-3 h. Cmax was 148 and 1,844 ng/mL, and the area under the plasma drug concentration versus time curve (AUC) was 418 and 3,779 ng · h/mL for the low dose (4% DSP-Visulex for 5 min) and the high dose (15% DSP-Visulex for 20 min), respectively. Ocular findings over 12 weeks were mostly conjunctival injection and eye discharge. These were transient and mild. Histopathological examinations indicated the eyes to be normal. CONCLUSIONS: DSP can be administered safely and effectively into the rabbit eye with the Visulex system. Treatment duration and DSP concentration are important factors in achieving therapeutic levels. Repeat applications of DSP-Visulex are safe and well tolerated for weekly administrations over 4-12 weeks. DSP-Visulex has clinical potential for the noninvasive treatment of ocular diseases.

Noninvasive Ocular Drug Delivery System of Dexamethasone Sodium Phosphate in the Treatment of Experimental Uveitis Rabbit.

PURPOSE: To investigate the efficacy and safety of dexamethasone sodium phosphate administered through Visulex system (DSP-Visulex) in treating experimental uveitis. METHODS: Uveitis was induced in rabbits by subcutaneous injections of complete Freund's adjuvant and an intravitreal injection of H37RA antigen. After induction, the animals of the control group received no treatment and the others received various treatment regimens of DSP-Visulex. Each regimen was different in DSP strength (4%, 8%, and 15%), application time, or treatment frequency. Efficacy and safety of DSP-Visulex were evaluated by ophthalmic observations and histopathological examinations for ocular inflammations and pathology. RESULTS: The control group exhibited panuveitis with significant inflammation in the vitreous, choroid, and retina, but less in the conjunctiva, cornea, and anterior chamber. The uveitis occurred within 24 h after induction and persisted throughout the study in the control group. All treatments showed some reduction in inflammation in the vitreous, choroid, and retina. The higher dose regimens generally showed more rapid and higher degree of resolution than the lower dose regimens. The posterior eye tissues of the 15% and 8% DSP-Visulex appeared normal with minimal or no inflammation, whereas the untreated eye and the 4% DSP-Visulex eyes showed minimal response. CONCLUSIONS: All DSP-Visulex regimens suppressed the signs of inflammation and were well tolerated over the course of a 29-day study. The 8% and 15% DSP-Visulex treatment regimens were safe and efficacious for anterior, intermediate, and posterior uveitis. On the other hand, the 4% DSP-Visulex regimen may only be considered for anterior and intermediate uveitis.

Chemometric evaluation of physicochemical properties of carbonated-apatitic preparations by Fourier transform infrared spectroscopy.

The purpose of this study was to develop a simple and quick method of evaluating the physicochemical properties of carbonated apatite preparations (CAP) as an index of the bioaffinity of implantable materials based on Fourier-transformed-infrared (IR) spectra by chemometrics. The wet-synthesized CAPs contained various levels of carbonate content (CO(3)), and were analyzed microstrain parameter (MS), crystallite size parameter (CP), specific surface area (Sw), CO(3), and solubility parameter (pK(HAP)) using by X-ray powder diffraction, nitrogen gas adsorption, IR, and UV absorption. The IR spectral results of CAPs suggested that the peak intensities of CAP reflected the physicochemical properties of the samples. The IR data sets were calculated to obtain calibration models evaluating the physicochemical properties of CAPs by a partial least squares regression analysis (PLS). As validation of the calibration model, physicochemical properties of CAP could be evaluated based on validation IR data sets of independent samples, and those values had sufficient accuracy. The regression vector of each calibration model suggested that the physicochemical properties of CAP, such as CO(3), Sw, MS, CP, and pK(HAP), were affected by phosphate, hydroxyl, and carbonate groups.

Passive and oxymetazoline-enhanced delivery with a lens device: pharmacokinetics and efficacy studies with rabbits.

PURPOSE: The aims of this study were to assess the trans-scleral delivery of dexamethasone phosphate (DexP) with a prototype lens device and a formulation comprising a vasoconstrictor and to determine the efficacy of this delivery system in treating experimentally induced uveitis in a rabbit model. METHODS: Passive trans-scleral delivery was performed on New Zealand white rabbits in vivo, using the lens device and a formulation of 0.034 M oxymetazoline (OMZ, the vasoconstrictor) and 0.5 M of dexamethasone sodium phosphate (DexNaP). Trans-scleral delivery of DexP without OMZ was the control. The amounts of DexP delivered into the eye and its distributions in the eye were determined by dissection of the eye and high-performance liquid chromatography assay in the pharmacokinetics study. The efficacy of the DexP delivery system in treating lipopolysaccharide-induced uveitis was also evaluated in the rabbit model in vivo. The effect of OMZ upon DexP delivery and its treatment efficacy was studied by comparing the DexP results with and without OMZ. RESULTS: In the pharmacokinetics study, the amounts of DexP delivered into the eye using the lens system with OMZ were significantly higher than those without OMZ. The results in the efficacy study showed a better treatment outcome with OMZ to relieve the symptoms of endotoxin-induced uveitis in rabbits. CONCLUSIONS: The potential of vasoconstrictors to enhance eye disease treatments in passive trans-scleral drug delivery was demonstrated. The higher DexP level in the eye and the improvement of the outcome in the efficacy study in the presence of the vasoconstrictor are consistent with the hypothesis that the vasoconstrictor enhances drug delivery by decreasing clearance.

Influence of crystallite microstrain on surface complexes governing the metastable equilibrium solubility behavior of carbonated apatites.

This study was on the influence of the mineral phase crystallite microstrain (CM) on the nature of the surface complex (SC) governing the metastable equilibrium solubility (MES) behavior of carbonated apatites (CAPs) in aqueous acidic media (0.10 M acetate buffers, with and without fluoride, 0.50 M ionic strength maintained with NaCl). The MES behavior of a set of four CAPs (synthesized at 85 degrees C by a precipitation method) of increasing CM and therefore of increasing MES (CAP4 > CAP3 > CAP2 > CAP1) was quantified. The following were the findings. For CAP1 and CAP2, the SCs deduced were Ca10(PO4)6(OH)2 and Ca10(PO4)6F2 for the nonfluoride and the fluoride cases, respectively. For CAP3 and CAP4, the SCs deduced were Ca9.5(PO4)6OH or Ca9.5(HPO4)(PO4)5(OH)2 and NaCa9.5(PO4)6F2 for the nonfluoride and the fluoride cases, respectively. These results together with that from an earlier limited study show that the Ca/P ratio of the SC decreases from 1.67 to 1.58 to 1.50 with increasing CM of the CAPs; this relationship inversely correlates with the chemistry of maturation of aqueously precipitated defective apatites. Also the SCs do not appear to exist as a continuous series and only a few SCs may account for the MES behavior over a wide range of CAP preparations.

Osteotropic Peptide that differentiates functional domains of the skeleton.

HPMA copolymer-d-aspartic acid octapeptide (D-Asp8) conjugates have been found to target the entire skeleton after systemic administration. In a recent study using the ovariectomized rat model of osteoporosis, we surprisingly discovered that D-Asp8 would favorably recognize resorption sites in skeletal tissues, while another bone-targeting moiety, alendronate (ALN), directs the delivery system to both formation and resorption sites. Atomic force microscopy (AFM) analyses reveal that ALN has a stronger binding force to hydroxyapatite (HA) than D-Asp8. In vitro HA binding studies indicate that D-Asp8 is more sensitive to change of HA crystallinity than ALN. Because the bone apatite in the newly formed bone (formation sites) usually has lower crystallinity than the resorption sites (mainly mature bone), we believe that the favorable recognition of D-Asp8 to the bone resorption sites could be attributed to its relatively weak binding to apatite, when compared to bisphosphonates, and the different levels of crystallinity of bone apatite at different functional domains of the skeleton.

How well can an idiotope peptide mimic replace its parent idiotype in a synthetic peptide vaccine?

PURPOSE: To determine whether a vaccine consisting of an idiotope peptide mimic of the third complementarity-determining region of the immunoglobulin heavy chain (CDR-H3) is an effective substitute for its parent idiotype. Such peptide vaccines could ultimately be used for targeting pathological B lymphocytes. METHODS: Hen egg lysozyme (HEL) conjugates of the Fab' fragment of monoclonal anti-fluorescein antibody 9-40 (Fab'-HEL) or a peptide mimic of the 9-40 CDR-H3 (referred to as the "B epitope" or "Bep," the conjugate is referred to as "Bep-HEL") were injected into separate cohorts of B10.A mice. Two additional control cohorts were injected with either the Bep peptide alone or a noncovalent mixture of Bep and HEL. Sera were assayed for both anti-idiotope and anti-idiotype activity by enzyme-linked immunosorbant assay (ELISA). Primary, secondary, and tertiary immune responses were examined. RESULTS: Both the Bep-HEL idiotope and the Fab-HEL idiotype immunogens elicited homologous, allogenic immune responses. No cross-reactivity was observed between anti-idiotope and anti-idiotype responses after primary immunization. With secondary immunization, 50% of mice immunized with the Bep-HEL conjugate exhibited a cross-reactive anti-idiotype response. Conversely, 100% of mice immunized with the Fab'-HEL conjugate exhibited a marginal, but statistically significant cross-reactive anti-idiotope response. Upon tertiary immunization, 100% of mice immunized with Bep-HEL exhibited a cross-reactive anti-idiotype response, and 55.6% of mice immunized with the Fab'-HEL conjugate exhibited a cross-reactive anti-idiotope response. CONCLUSIONS: Covalent coupling of a xenogenic carrier protein to an idiotype immunogen or its peptide mimic significantly enhances the intensity of homologous, allogenic anti-idiotype or anti-idiotope immune responses. Multiple immunizations are necessary to induce cross-reactivity between the peptide mimic and its parent idiotype.