The Intraocular Pressure Lowering Effect of a Dual Kinase Inhibitor (ITRI-E-(S)4046) in Ocular Hypertensive Animal Models.

Purpose: The purpose of this study was to develop a preclinical compound, ITRI-E-(S)4046, a dual synergistic inhibitor of myosin light chain kinase 4 (MYLK4) and Rho-related protein kinase (ROCK), for reducing intraocular pressure (IOP). Methods: ITRI-E-(S)4046 is an amino-pyrazole derivative with physical and chemical properties suitable for ophthalmic formulation. In vitro kinase inhibition was evaluated using the Kinase-Glo Luminescent Kinase Assays. A comprehensive kinase selectivity analysis of ITRI-E-(S)4046 was performed using the KINOMEscan assay from DiscoverRx. The IOP reduction and tolerability of ITRI-E-(S)4046 were assessed in ocular normotensive rabbits, ocular normotensive non-human primates, and ocular hypertensive rabbits. In vivo studies were conducted to assess drug concentrations in ocular tissue. The adverse ocular effects of rabbit eyes were evaluated following the OECD405 guidelines. Results: ITRI-E-(S)4046 showed highly selective kinase inhibitory activity against ROCK1/2, MYLK4, and mitogen-activated protein kinase kinase kinase 19 (MAP3K19), with high specificity against protein kinase A, G, and C families. In ocular normotensive rabbits and non-human primates, the mean IOP reductions of 0.1% ITRI-E-(S)4046 eye drops were 29.8% and 28.5%, respectively. In hypertonic saline-induced and magnetic beads-induced ocular hypertensive rabbits, the mean IOP reductions of ITRI-E-(S)4046 0.1% eye drops were 46.9% and 22.0%, respectively. ITRI-E-(S)4046 was well tolerated with only temporary and minor signs of hyperemia. Conclusions: ITRI-E-(S)4046 is a novel type of highly specific ROCK1/2 and MYLK4 inhibitor that can reduce IOP in normotensive and hypertensive animal models. It has the potential to become an effective and well-tolerated treatment for glaucoma.

A Proposed Complete Methodology to Predict Gravity Flow Obstruction of Pharmaceutical Powders in Drug Product Manufacturing.

We present herein a comprehensive methodology to evaluate the risks involved in gravity-driven flow of pharmaceutical powders, including mass flow/funnel flow pattern, arch formation under active stress state (initial discharging) and passive stress state (following initial discharging), and rathole formation. Built on original theories underpinning the hopper design procedure, the methodology was modified to accommodate practices of pharmaceutical powder handling. All data required are generated from conventional ring shear tester. We applied the methodology to evaluate the powder flow risks during drug product manufacturing campaigns, where two powder blends with distinct flow behavior were discharged from a 200-L bin. The predicted results are in agreement with experiments where visual observations were possible, including the flow pattern, arch formation under active stress state, and rathole formation. One notable discovery is that pharmaceutical powders exhibit high risk of arch formation under active stress state, because of the exceeding major principal stress than the passive state. This phenomenon has been so far overlooked and the existing flow function-based classification cannot capture this risk. We propose, through this methodology, that reliable powder flow assessment should consider factors preventing flow (i.e., flow function), as well as factors facilitating flow (i.e., external stress).

A mechanistic study on tablet ejection force and its sensitivity to lubrication for pharmaceutical powders.

Pharmaceutical powders can exhibit markedly different tablet ejection forces. The purpose of this study is to understand the factors leading to the variability of the tablet ejection force and its sensitivity to lubrication. The study showed that the tablet ejection force is mainly governed by 1) tablet diameter and thickness, 2) compact-die wall friction coefficient, and 3) residual die wall stress upon ejection; the latter was further controlled by the maximum compression pressure, as well as the degree of non-elastic deformation during compression. Brittle powders, such as lactose or dicalcium phosphate, often exhibit exceeding ejection force because of their significant contribution from the non-elastic deformation during loading. These conclusions were verified through compaction experiments of five pharmaceutical powders with diverse compaction properties. Additionally, we found that boundary lubrication was highly effective in reducing tablet ejection force, achievable through decreasing the compact-die wall friction coefficient, but not through altering the intrinsic consolidation behavior of powders. High ejection force is indicative of the sub-optimal stress condition of the tablet post-unloading. Therefore learnings from this study are beneficial for practitioners to harness the ejection force as an effective metric to identify and mitigate risks of tablet defects.

Flow Function of Pharmaceutical Powders Is Predominantly Governed by Cohesion, Not by Friction Coefficients.

The purpose of this study was to demonstrate that the flow function (FFc) of pharmaceutical powders, as measured by rotational shear cell, is predominantly governed by cohesion but not friction coefficients. Driven by an earlier report showing an inverse correlation between FFc and the cohesion divided by the corresponding pre-consolidation stress (Wang et al. 2016. Powder Tech. 294:105-112), we performed analysis on a large data set containing 1130 measurements from a ring shear tester and identified a near-perfect inverse correlation between the FFc and cohesion. Conversely, no correlation was found between FFc and friction angles. We also conducted theoretical analysis and estimated such correlations based on Mohr-Coulomb failure model. We discovered that the correlation between FFc and cohesion can sustain as long as the angle of internal friction at incipient flow is not significantly larger than the angle of internal friction at steady-state flow, a condition covering almost all pharmaceutical powders. The outcome of this study bears significance in pharmaceutical development. Because the cohesion value is strongly influenced by the interparticle cohesive forces, this study effectively shows that it is more efficient to improve the pharmaceutical powder flow by lowering the interparticle cohesive forces than by lowering the interparticle frictions.

Solubility Advantage (and Disadvantage) of Pharmaceutical Amorphous Solid Dispersions.

The solubility of a drug is ultimately governed by its chemical potential as it is present in the undissolved solute. For a pharmaceutical amorphous solid dispersion (ASD), its solubility depends on the state and composition of the undissolved solute when the ASD is equilibrated with water. Concerning the undissolved solute phase that can contain up to 3 components (drug, polymer, and water), we developed a complete thermodynamic model to calculate the chemical potential of a drug in the multicomponent, amorphous system. This approach enables the estimation of the true solubility advantage of ASD from calorimetric measurements and moisture sorption isotherms. Both theoretical estimation and experimental studies, using indomethacin (IMC)/Eudragit E ASD systems, show that the solubility advantage of the amorphous IMC is significantly reduced through ASD formation and water partitioning. For the ASD with 70% drug loading, the solubility of IMC is lower than its crystalline counterpart. Our results show that stabilization through the ASD formation and water sorption can be manifested by the lowering of drug solubility; they demonstrate that the core property in ASD development is the drug chemical potential, which is essentially the thermodynamic driving force and can be quantitated using the model presented in this work.

Presenile diffuse familial sebaceous hyperplasia successfully treated with low-dose isotretinoin: A report of two cases and review of the published work.

Presenile diffuse familial sebaceous hyperplasia (PDFSH) presents as extensive yellowish papules with central umbilication on the face without involvement of periorificial regions and occurs in adolescents or young adults with a positive family history. Thirteen cases of PDFSH have been reported in the English-language published work, 10 of which responded to oral isotretinoin from 0.5 to 1 mg/kg per day but recurrences were often observed. Herein, we report two cases of PDFSH, which were successfully managed without recurrence with prolonged low-dose isotretinoin (0.2 mg/kg per day, a cumulative dose of 41 and 64 mg/kg, respectively). Treatment protocols among different published works were reviewed to verify the efficacy of isotretinoin.

Sebaceous carcinoma associated with seborrheic keratosis.

BACKGROUND: The association of a seborrheic keratosis with other common cutaneous neoplasms such as basal cell carcinoma and Bowen disease has been reported, but the association between a seborrheic keratotis and a malignant neoplasm with sebaceous differentiation is very unusual. OBJECTIVE: We present a case of two contiguous neoplasms, a seborrheic keratosis and a sebaceous carcinoma, and discuss the possibility of malignant change in a seborrheic keratosis as an explanation for the findings. METHODS AND RESULTS: A 57-year-old man presented with an asymptomatic tumor on the skin of his abdomen that was composed of two separate but contiguous lesions. The central lesion, about 0.9 cm in diameter, was nodular, irregular, and reddish and was surrounded by a blackish lesion about 3 cm in greatest dimension. Histopathologic examination revealed that the plaque was composed of two different adjacent tumors, including a central portion showing findings consistent with a sebaceous carcinoma and a peripheral part showing a seborrheic keratosis. CONCLUSION: Although the association is likely to be a coincidence and probably represents a collision tumor, the possibility that the sebaceous carcinoma represents malignant degeneration of the seborrheic keratosis cannot be entirely excluded.

Colorimetry provides a rapid objective measurement of de novo hair growth rate in mice.

BACKGROUND: Depilated mice have been used as a test platform for hair growth-regulating agents. However, currently available assessment tools for hair growth in mice are less than ideal. METHODS: Tristimulus colorimetry of the fur color of depilated agouti, albino, and black mice with L*, a*, and b* values were performed daily until the full growth of pelage. Using light-emitting diode (LED) irradiation (650 and 890 nm) with a daily dose of 3.5 J/cm(2) as hair growth regulators, the hair growth rates observed by the global assessment were compared with those derived from colorimetry. RESULTS: In contrast to a* and b* values, L* values changed more drastically over time in the anagen phase regardless of fur color. Unlike the inhibitory effect of 650 nm irradiation, LED of 890 nm promoted de novo hair regrowth in mice. The difference in hair growth rates detected by colorimetry paralleled the observation made by the global assessment. CONCLUSION: The L* value of fur color obtained by tristimulus colorimetry was a sensitive yet quantitative indicator of de novo hair growth, and could be used to project the hair growth rate in mice.

Biosorption of chromium, copper and zinc by wine-processing waste sludge: single and multi-component system study.

Wine-processing waste sludge (WPWS) has been shown to have powerful potential for sorption of some heavy metals (i.e., chromium, lead and nickel) in single-component aqueous solutions. But although most industrial wastewater contains two or more toxic metals, there are few sorption studies on multicomponent metals by WPWS. This study has two goals: (i) conduct competitive adsorption using Cr, Cu and Zn as sorbates and examine their interaction in binary or ternary systems; and (ii) determine the effects of temperature on the kinetic sorption reaction. The sludge tested contained a high amount of organic matter (38%) and had a high cation exchange capacity (CEC, 255 cmol(c)kg(-1)). Infrared analysis reveals that carboxyl is the main functional group in this WPWS. The (13)C NMR determination indicates alkyl-C and carboxyl-C are major organic functional groups. At steady state, there are about 40.4% (Cr), 35.0% (Cu) and 21.9% (Zn) sorbed in the initial 6.12 mM of single-component solutions. Only pseudo-second-order sorption kinetic model successfully describes the kinetics of sorption for all experimental metals. The rate constants, k(2), of Cr, Cu and Zn in single-component solutions are 0.016, 0.030 and 0.154 g mg(-1)min(-1), respectively. The sorption of metals by WPWS in this competitive system shows the trend: Cr>Cu>Zn. Ions of charge, hydrated radius and electronic configuration are main factors affecting sorption capacity. The least sorption for Zn in this competitive system can be attributed to its full orbital and largest hydrated radius. Though the effect of temperature on Zn sorption is insignificant, high temperature favors the other metallic sorptions, in particular for Cr. However, the Cr sorption is lower than Cu at 10 degrees C. The Cr sorption by WPWS can be higher than that of Cu at 30 degrees and 50 degrees C.

Bipolar cellular morphology of malignant melanoma in unstained human melanoma skin tissue.

Microstructures of unstained human melanoma skin tissues have been examined by multimodal nonlinear optical microscopy. The polarized shape of the individual melanoma cell can be readily recognized-a phenotype that has been identified in laboratory cultures as characteristic of proliferating melanocytes but has not been demonstrated in clinical instances. The results thus provide snapshots of invading melanoma cells in their native environment and suggest a practical means of connecting in vitro laboratory studies to in vivo processes.

Crystal structure, crystal morphology, and surface properties of an investigational drug.

In this study we investigated the correlations between the single crystal structure, the crystal habit and morphology, and surface energetics of an investigational pharmaceutical compound. Crystal structures of both the anhydrous form (Form A) and monohydrate form (Form B) have been solved from single crystal X-ray analysis. The external morphology of Form A solid was predicted by molecular modeling using attachment energies to be thick plate-like with two dominant faces (100) and (002). The external morphology of Form B was predicted to be needle-like with a dominant face (101 ). The predicted morphologies were confirmed by optical micrographs and the Miller indices of the dominant faces were complemented by X-ray powder diffraction (XRPD) method. Contact angle measurements showed that the anhydrous form has better wettability as predicted from crystal structure and morphology.

Decision factors and the recognition of medical specialty in patients receiving cosmetic laser and intense pulsed light treatment.

BACKGROUND: In addition to dermatologists and plastic surgeons, physicians of other medical specialties also provide cosmetic laser and light treatment. OBJECTIVE: This study aimed to determine the major decision factors in patients who received cosmetic laser or intense pulsed light treatment and how they perceived different medical specialties in providing such services. METHODS: The method of factor analysis was adopted to extract the common characteristics (major decision factors) from a list of 17 items patients would regard as important when they planned to receive laser and intense pulsed light treatment. In addition, the level of recognition of different medical specialties in cosmetic patients was indirectly forecast using an analytic hierarchy process. RESULTS: Medical competence (0.3296) was the most important decision factor, followed by recommendation (0.2198), friendliness (0.1350), cost (0.1307), complete service (0.0984), and the physical attributes of the physician (0.0865). Dermatologists and plastic surgeons outscored cosmetic practitioners in five factors except for cost, in which the plastic surgeons were weakest. CONCLUSION: Medical competence and recommendation are the core issues for cosmetic patients. Dermatologists and plastic surgeons gain better overall recognition than physicians of other medical specialties in cosmetic patients.

Pimecrolimus and narrowband UVB as monotherapy or combination therapy in children and adolescents with atopic dermatitis.

Topical pimecrolimus and narrowband ultraviolet B (UVB) are both known to be effective in treating atopic dermatitis. We compared the clinical efficacy of monotherapy with either twice daily topical 1% pimecrolimus cream or twice weekly narrowband UVB, and combination therapy in 26 children and adolescents with moderate to severe atopic dermatitis in a half-side manner for 6 weeks. Twenty-four patients completed the study. Monotherapy and combination therapy notably reduced the scores of the Eczema Area and Severity Index ( p = 0.002) and the severity of pruritus ( p < or = 0.004). There was no significant difference in therapeutic efficacy among the treatment regimens at week 6. In conclusion, because of the lack of short-term additive therapeutic efficacy, concomitant use of pimecrolimus and narrowband UVB is inadvisable in treating moderate to severe atopic dermatitis in children and adolescents.

Cutaneous manifestations of human immunodeficiency virus infection in Taiwan.

Cutaneous manifestations are common and often the presenting feature of human immunodeficiency virus (HIV) infection, but a comprehensive study of HIV-associated skin lesions is not available in Taiwan. We reviewed all skin lesions in all HIV patients diagnosed in our department between 1990 and 1998 to document the spectrum of skin manifestations, the frequency of each disorder, and their relationship with CD4 counts. A total of 64 HIV patients were studied, including 38 with acquired immunodeficiency syndrome (AIDS) (CD4 < 200 x 10(6) cells/L) and 26 who had not developed AIDS (non-AIDS). There were 142 episodes of skin conditions representing 25 different skin diseases, including oral candidiasis (15% in non-AIDS vs 71% in AIDS patients), drug eruptions, herpes simplex, seborrheic dermatitis, dermatophytosis, herpes zoster, secondary syphilis, condyloma acuminatum, Kaposi's sarcoma (16% among AIDS patients), hairy leukoplakia, and molluscum contagiosum (13% among AIDS patients), in decreasing order. Several unusual cases are briefly described, including verrucous herpes infection, condyloma-like molluscum contagiosum, and AIDS-associated pigmented erythroderma. In our study, 70% of all HIV patients had skin diseases, with an average of 2.2 conditions per patient (3.2 in AIDS patients vs 0.7 in non-AIDS patients; p < 0.001). A broad spectrum of HIV-associated skin diseases was observed in our series. The frequency of HIV-associated skin disease was 92% in AIDS patients and 39% in non-AIDS patients; 78% of skin lesions in AIDS patients were diagnosed when CD4 counts were below 100 x 10(6) cells/L.

Identification of oxidative degradates of the TRIS salt of a 5,6,7,8-tetrahydro-1,8-naphthyridine derivative by LC/MS/MS and NMR spectroscopy--interactions between the active pharmaceutical ingredient and its counterion.

The Tris(hydroxymethyl)aminomethane (TRIS) salt of a substituted 5,6,7,8-tetrahydro-1,8-naphthyridine compound (I) in a mannitol-based formulation was stressed at various conditions. Liquid chromatography/mass spectrometry (LC/MS) and liquid chromatography/tandem mass spectrometry (LC/MS/MS) analyses of the stressed samples revealed that oxidation and dimerization were the primary degradation pathways for this compound. 1H- and 13C-nuclear magnetic resonance (NMR) spectroscopy were used to characterize the isolated dimers. The aromatized degradate, N-oxide, amide, and three dimeric products were all confirmed by either LC/MS using authentic standards or NMR spectroscopy. In general, the aromatized product was always the primary degradate produced under all stress conditions. When stressed at 80 degrees C, the TRIS counterion also underwent thermal degradation to yield formaldehyde in situ which reacted with the parent compound to form a unique methylene-bridged dimeric product and an N-formyl degradate. A minor condensation product between the compound I and the TRIS counterion was also detected in the 80 degrees C stressed samples. Under 40 degrees C/75% RH stress conditions, TRIS derived degradates were insignificant, while dimers formed by compound I became predominant. In addition, two hydroxylated products (7-OH and 5-OH) were also detected. Mechanisms for the formation of the oxidative and dimeric degradates were proposed.