Associations between Drug Use and Sexual Risk Behaviours among Men Who Have Sex with Men in Japan: Results from the Cross-Sectional LASH Study.

This study assessed drug use patterns among men who have sex with men (MSM) in Japan, and evaluated their potential associations with sexual risk behaviours. Between September and October 2016, study subjects were recruited through a cross-sectional survey (LASH: Love Life and Sexual Health) using a geosocial networking application for MSM. Of the participants, 25.4% (1756/6921) reported ever having used drugs, and 11.3% (780/6921) reported having done so in the past six months. Those who used drugs were more likely to have greater knowledge of HIV/sexually transmitted infections (STIs). Drug use in the past six months was independently associated with each of the following sexual risk behaviours in the same period: (i) six or more sexual partners (adjusted odds ratio [aOR] = 2.70, 95% confidence interval [CI]: 2.30-3.17); (ii) condomless anal intercourse (aOR = 2.88, 95% CI: 2.43-3.42); (iii) group sex (aOR = 2.60, 95% CI: 2.22-3.05); and (iv) sex work (aOR = 2.30, 95% CI: 1.67-3.16). These results suggest that MSM in Japan who use drugs are more likely to report sexual risk behaviours, while also having greater knowledge of HIV/STIs. Supporting MSM to minimise the harm from drug use may be helpful in reducing HIV transmission among this priority population.

Effect of textured eye drop bottles on the photostability of pranoprofen 0.1% ophthalmic solution.

CONTEXT: Ophthalmic solutions are usually filled in a plastic bottle due to its durability and disposability. In Japan, photostability is one of the concerns for the quality control because an eye drop bottle must be a transparent container. OBJECTIVE: The present work studied the effect of textured eye drop bottles on its light blocking to improve the photostability of ophthalmic solutions. MATERIALS AND METHODS: We investigated the photostability of Pranoprofen ophthalmic solution filled in a variety of textured eye drop bottles. Pranoprofen content was analyzed by high-performance liquid chromatography and surface structure of textured eye drop bottles was evaluated by transmittance, calculated average roughness (Ra) and haze intensity. RESULTS: We observed that eye drop bottle which had greater than Ra value of 1.0 µm and haze intensity 62% clearly showed photostability improvement. CONCLUSIONS: This report is the first one which shows that photostability of ophthalmic solution is improved by using textured eye drop bottle. Moreover, this approach is a simple and effective method to improve the photostability. This method is available for not only various ophthalmic applications but also other liquid pharmaceuticals or food products.

Mucoadhesive properties of chitosan-coated ophthalmic lipid emulsion containing indomethacin in tear fluid.

To evaluate the residence of chitosan-coated emulsion (CE) containing indomethacin in tears, the drug retention of CE in tear fluid was compared with non-coated emulsion (NE) after instillation in rabbit eyes. CE had mean concentrations 3.6-fold and 3.8-fold higher than NE at 0.5 h and 0.75 h after instillation, respectively. Mean residence time and half-life of CE were lengthened to 1.5-fold and 1.8-fold those of NE, respectively. Volume of distribution of CE in tear fluid was also 1.6-fold greater than that of NE. These findings indicated that retention of the drug in tears was appreciably prolonged by chitosan-coated emulsion, and that CE had higher distribution on the ocular surface than NE. The drug levels in cornea, conjunctiva, and aqueous humor at 1 h after instillation were clearly higher than those of NE. In a generalized ocular pharmacokinetic model, the ratio of CE to NE for peak concentration values (C(max)) and the area under the concentration/time curve (AUC) nearly corresponded to aqueous humor levels in vivo. Additionally, tensile testing showed that the force of detachment between CE and mucin was significantly larger than that of emulsion containing hydroxypropylmethyl cellulose (HPMCE) with a viscosity similar to CE; the forces of detachment of CE and HPMCE measured using phosphate-buffered saline (PBS) were almost the same since these formulations have similar viscosity. Mucoadhesive strength of CE was confirmed by measurements of force of detachment between formulations and mucin. The residence time of the emulsion in tear fluid was prolonged by chitosan coating because of its mucoadhesive properties.

Molecular design to enhance the penetration into the retina via ocular instillation.

To investigate the molecular design of drugs that have good penetration into the retina from anterior segment of the eye via ocular instillation, we optimized the length of methoxyethylene glycol chain (mEG) in the P3 region of an oral bioavailable calpain inhibitor SNJ-1945 (2) as a model compound. Modulation of the mEG length led to the optimal balance between hydrophilicity and lipophilicity and provided the compound with higher retinal exposure via ocular instillation. Incorporation of a mEG moiety would be a useful and convenient approach to attain high intraocular penetration.

Corneal critical barrier against the penetration of dexamethasone and lomefloxacin hydrochloride: evaluation by the activation energy for drug partition and diffusion in cornea.

The cornea is a solid barrier against drug permeation. We searched the critical barrier of corneal drug permeation using a hydrophobic drug, dexamethasone (DM), and a hydrophilic drug, lomefloxacin hydrochloride (LFLX). The activation energies for permeability of DM and LFLX across the intact cornea were 88.0 and 42.1 kJ/mol, respectively. Their activation energies for permeability across the cornea without epithelium decreased to 33.1 and 16.6 kJ/mol, respectively. The results show that epithelium is the critical barrier on the cornea against the permeation of a hydrophobic drug of DM as well as a hydrophilic drug of LFLX. The activation energy of partition for DM (66.8 kJ/mol) was approximately 3-fold larger than that of diffusion (21.2 kJ/mol). The results indicate that the partition for the hydrophobic drug of DM to the corneal epithelium is the primary barrier. Thermodynamic evaluation of activation energy for the drug permeation parameters is a good approach to investigate the mechanism of drug permeability.

Exploration of orally available calpain inhibitors 2: peptidyl hemiacetal derivatives.

We previously reported a potent calpain inhibitor 1 (SJA6017, N-(4-fluorophenyl)-l-valyl-l-leucinal), which displayed relatively low oral bioavailability (BA). Replacing the metabolically labile aldehyde moiety of 1with more chemically stable warheads, such as a cyclic hemiacetal, hydrazone, and alpha-ketoamide, provided the inhibitors with improved in vitro metabolic stability. Cyclic hemiacetal 2 was the most stable of these compounds. The optimization of 2 led to hemiacetal 8 (SNJ-1715) which exhibited high potency, good aqueous solubility, excellent oral BA, and prolonged plasma half-life in rats. Furthermore, 8 showed neuroprotective efficacy via oral administration in a rat retinal ischemia model.

Exploration of orally available calpain inhibitors. Part 3: Dipeptidyl alpha-ketoamide derivatives containing pyridine moiety.

Calpain-mediated proteolysis has been implicated as a major process in neuronal cell death including retinal neurological degeneration. The previously reported calpain inhibitor SJA6017 (1) showed oral efficacy in a retinal pharmacological model, but its oral bioavailability was low due to the metabolic lability and low water-solubility. The purpose of present study was to identify good orally bioavailable calpain inhibitors. A series of water-soluble dipeptidyl alpha-ketoamides containing a pyridine moiety at P3 were designed, synthesized, and evaluated for their oral bioavailability and retinal penetration. Introduction of a pyridineethanol moiety provided the potent alpha-ketoamide inhibitor 8 with good oral bioavailability. Compound 8 showed about 12-fold higher retinal AUC than 1.

Retinal penetration of calpain inhibitors in rats after oral administration.

Calpain-mediated proteolysis has been involved in neuronal cell death of retinal neurological degeneration. An aldehyde-based calpain inhibitor, SJA6017 (1), was effective following oral administration in a rat retinal ischemia model but had low oral bioavailability. The aim of this study was to identify calpain inhibitors with good retinal penetration after oral dosing. The orally bioavailable inhibitors, hemiacetal 3 (SNJ-1715), amphipathic ketoamide 5 (SNJ-1945), and pyridine ketoamide 6 (SNJ-2008), were evaluated for their retinal pharmacokinetic (PK) profiles. The retinal drug exposure of these inhibitors was more than tenfold higher than 1. Among these compounds, 5 exhibited the most favorable retinal PK properties, such as good penetration and long half-life. Comparisons of 5 and the structurally related ketoamide 6 suggested that the presence of a methoxy diethylene glycol moiety resulted in the inhibitor with high penetration into the retina and the sustained high retinal levels. Ketoamide 5 was selected as the development candidate for the treatment of retinal diseases.

Calpain may contribute to hereditary cataract formation in sheep.

PURPOSE: To determine the involvement of calpain in ovine cataractogenesis by measuring calcium, calpain activity, proteolysis, and the effect of calpain inhibition. METHODS: Sheep with genetic cataracts were examined for cataract severity. Calcium in normal and cataract lenses was measured. The presence of calpain was detected by casein zymography and immunoblotting. Calpain activity was assayed using BODIPY-casein as a substrate. Degradation of calpain substrates spectrin and vimentin was assessed by immunoblotting. The calpain inhibitor SJA6017 was applied to the left eye of cataract lambs, leaving the right eye as an untreated control. Both eyes were monitored by slit-lamp microscopy for cataract progression. RESULTS: Cortical cataracts were first observed in lambs at 1 to 2 months of age. Lens calcium concentration increased in the early stages of cataract formation and was >10-fold higher in mature cataract than normal lenses. Three calpain isoforms were detected in young lamb lenses. Calpain activity decreased as cataracts progressed. Both spectrin and vimentin were degraded with cataract maturity, which could indicate calpain proteolysis. Cataract lambs treated with SJA6017 eyedrops over a period of 4 months showed significantly smaller cataracts in the left treated eye over the right untreated eye. CONCLUSIONS: The presence of calpains and calcium elevation during cataract formation suggests that proteolysis may play a role in opacification in ovine lens. This hypothesis is supported by the delay in opacification with SJA6017 treatment. The results also suggested that the ovine hereditary cataract is a useful nonrodent model to test the role of calpains in cataractogenesis.

Formulation of an ophthalmic lipid emulsion containing an anti-inflammatory steroidal drug, difluprednate.

Preparation of oil-in-water (o/w) type lipid emulsion is one of the approaches to formulate drugs that are poorly water-soluble but can be dissolved in the oil phase of the emulsions. A synthetic glucocorticoid medicine, difluprednate (DFBA), is a water-insoluble compound. We formulated DFBA (0.05%, w/v) ophthalmic lipid emulsion containing 5.0% (w/v) caster oil and 4.0% (w/v) polysorbate 80. The appearance of the emulsion was blue and translucent lipid emulsion, and the median particle size of the lipid emulsion was 104.4 nm. Neither separation nor change in particle size was observed after 6 months at 40 degrees C. Furthermore, when compared with DFBA (0.05%, w/v) ophthalmic suspension, the lipid emulsion showed 5.7-fold higher concentration of DFB that was an active metabolite of DFBA in aqueous humor at 1h after instillation. Ophthalmic lipid emulsion enhances the intraocular penetration of drugs, and it is useful as a delivery system for the ophthalmic preparations of lipophilic drugs.

Exploration of orally available calpain inhibitors: peptidyl alpha-ketoamides containing an amphiphile at P3 site.

A novel series of dipeptidyl alpha-ketoamide derivatives with amphiphile was designed and synthesized as water-soluble calpain inhibitors. The introduction of amphiphiles at the P3 site increased water solubility without loss of membrane permeability and provided the oral available inhibitors. Extension of the ethylene glycol chain at the P3 site led to an improvement in persistence of plasma levels. In particular, introduction of a combination of a diethylene glycol methyl ether moiety at the P3 site, a phenylalanine residue at the P1 site and a cyclopropyl moiety at the P' site was the most effective modification for an increase in plasma drug exposure.

Novel 6-hydroxy-3-morpholinones as cornea permeable calpain inhibitors.

A novel series of 6-hydroxy-3-morpholinones, in which the functional aldehyde and the hydroxy group of P(2) site form a cyclic hemiacetal, was identified as calpain inhibitors. The placement of isobutyl group at the 2-position of the 3-morpholinone was the most effective modification for inhibiting micro- and m-calpains. Substitutions of benzyl at the 5-position in the S-configuration had virtually no effect on inhibitory activity. Several compounds showed appreciable selectivity for calpains over cathepsin B. NMR experiments demonstrated that the representative 6-hydroxy-3-morpholinone 10a (SNJ-1757) was more stable to nucleophilic attack than the corresponding aldehyde inhibitor 24. Furthermore, 6-hydroxy-3-morpholinone 10a proved to have better corneal permeability than aldehyde inhibitor 24 in an in vitro experiment.

Exploration of cornea permeable calpain inhibitors as anticataract agents.

To explore cornea permeable calpain inhibitors, four compounds displaying different characteristics were designed and synthesized based on the known potent calpain inhibitor, peptidyl aldehyde SJA6017. Two approaches were adopted; an improvement in the physicochemical properties, and conversion of the active aldehyde. The water-soluble peptidyl aldehyde 1 containing a pyridine ring at the P3 site showed a modest inhibition against calpains and an improvement of corneal permeability in comparison with SJA6017. Replacement of the aldehyde of SJA6017 by an alpha-ketoamide provided compound 2 that was approximately equipotent with SJA6017, but it was extremely water-insoluble. However, compound 3, in which the aldehyde was converted into a cyclic hemiacetal, proved to be a less potent calpain inhibitor than SJA6017, but demonstrated excellent transcorneal permeability. Further modification generating the cyclic hemiacetal 4 containing a thiourea linker between the P3 and P2 sites exhibited potent inhibitory activities, high cornea permeability and excellent efficacy in the rat lens culture cataract model.