Protective effect of different doses of trimethoprim-sulfamethoxazole prophylaxis for early severe infections among patients with antineutrophil cytoplasmic autoantibody-associated vasculitis.

OBJECTIVES: To analyse the protective effect of different doses of trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis for early severe infections in antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV), considering time-varying changes. METHODS: In this retrospective observational study, we assessed the protective effect of TMP/SMX within the first 6 months of diagnosis among Japanese patients with AAV. We included 250 consecutive patients with AAV who were admitted to our hospital. The protective effect of TMP/SMX against early severe infections was verified using Cox regression analysis along with potential confounding factors. Cox regression with inverse probability treatment weights for early severe infections was also performed as a sensitivity analysis. RESULTS: Cox regression analysis showed that the reduced TMP/SMX exposure group had a significant protective effect against early severe infections (standard-dose group versus no TMP/SMX group: hazard ratio [HR] 0.393, 95% confidence interval [CI]: 0.139-1.11, p=0.077; reduced-dose group versus no TMP/SMX group: HR 0.418, 95%CI: 0.216-0.807, p=0.009), even when considering time-dependent changes. In the sensitivity analysis, the reduced-dose group still had a significantly lower risk of early severe infections than the no TMP/SMX group (HR = 0.393, 95%CI: 0.177-0.873, p=0.022). During follow-up, 18.0% of the patients discontinued TMP/SMX due to side effects. CONCLUSIONS: TMP/SMX is highly effective in preventing severe infections among patients with AAV despite the high incidence of side effects. Further studies are needed to determine the optimal dose of TMP/SMX for preventing severe infections, especially considering renal impairment.

Phase separation of supersaturated solution created from amorphous solid dispersions: Relevance to oral absorption.

Dissolution of amorphous solid dispersions (ASDs) is a complicated process, which may involve phase separation from the supersaturated state and formation of a colloidal phase. However, relevance of the phase separation behavior to oral absorption from ASDs is still not well understood. We investigated phase separation of a supersaturated fenofibrate (FEN) solution in the presence of polymers, in vitro dissolution of FEN ASDs, and their in vivo absorption. The supersaturation behavior was assessed based on turbidity measurement in an artificial supersaturation system, where FEN ethanol solutions were added to aqueous polymer solutions. The phase separation concentration of FEN was ca. 1 µg/mL regardless of the presence/absence of the polymer, which was approximately 10-fold the equilibrium solubility. In the presence of 0.1% Tween 80 in the media, the phase separation concentration depended on the polymer species, presumably due to differences in their inhibitory effect of crystallization. The degrees of supersaturation achieved by the ASDs were similar to those found in the artificial system, suggesting that the artificial system works for comprehending the effect of polymer species on supersaturation ability for designing ASDs. A robust in vitro-in vivo correlation was achieved using the paddle and the flow-through cell methods by employing non-sink and pH-shift conditions. However, the phase separation concentration may rather be a good and simple indicator to estimate the absorption-enhancing ability of the polymeric excipients for ASDs, if the absorption is limited by solubility.

Physical Stabilization of Pharmaceutical Glasses Based on Hydrogen Bond Reorganization under Sub-Tg Temperature.

Amorphous solid dispersions (ASDs) play a key role in the pharmaceutical industry through the use of high-energy amorphous state to improve solubility of pharmaceutical agents. Understanding the physical stability of pharmaceutical glasses is of great importance for their successful development. We focused on the anti-HIV agent, ritonavir (RTV), and investigated the influence of annealing at temperatures below the glass transition temperature (sub-Tg) on physical stability, and found that the sub-Tg annealing effectively stabilized RTV glasses. Through the atomic structure analyses using X-ray pair distribution functions and infrared spectroscopy, we ascertained that this fascinating effect of the sub-Tg annealing originated from strengthened hydrogen bonding between molecules and probably from a better local packing associated with the stronger hydrogen bonds. The sub-Tg annealing is effective as a physical stabilization strategy for some pharmaceutical molecules, which have relatively large energy barrier for nucleation.

Physicochemical Properties of Solid Phospholipid Particles as a Drug Delivery Platform for Improving Oral Absorption of Poorly Soluble Drugs.

PURPOSE: A novel drug delivery platform, mesoporous phospholipid particle (MPP), is introduced. Its physicochemical properties and ability as a carrier for enhancing oral absorption of poorly soluble drugs are discussed. METHODS: MPP was prepared through freeze-drying a cyclohexane/t-butyl alcohol solution of phosphatidylcholine. Its basic properties were revealed using scanning electron microscopy, x-ray diffraction, thermal analysis, hygroscopicity measurement, and so on. Fenofibrate was loaded to MPP as a poorly soluble model drug, and effect of MPP on the oral absorption behavior was observed. RESULTS: MPP is spherical in shape with a diameter typically in the range of 10-15 µm and a wide surface area that exceeds 10 m2/g. It has a bilayer structure that may accommodate hydrophobic drugs in the acyl chain region. When fenofibrate was loaded in MPP as a model drug, it existed partially in a crystalline state and improvement in the dissolution behavior was achieved in the presence of a surfactant, because of the formation of mixed micelles composed of phospholipids and surfactants in the dissolution media. MPP greatly improved the oral absorption of fenofibrate compared to that of the crystalline drug and its efficacy was almost equivalent to that of an amorphous drug dispersion. CONCLUSION: MPP is a promising option for improving the oral absorption of poorly soluble drugs based on the novel mechanism of dissolution improvement.

Enhanced Boosting of Oral Absorption of Lopinavir Through Electrospray Coencapsulation with Ritonavir.

In vivo activities of absorption enhancers coencapsulated with poorly absorptive drugs in the same enteric-coated particles were evaluated. Lopinavir [a substrate of cytochrome P450 3A (CYP3A)] and ritonavir (an inhibitor of CYP3A-mediatd metabolism) were used as a model drug and a model absorption enhancer, respectively. Lopinavir and ritonavir were encapsulated into enteric-coated particles as amorphous forms using coaxial electrospray deposition. The electrospray treatment resulted in dramatic improvement of dissolution profiles of both compounds, probably because of complete amorphization and superior dispersion efficiency of the particles. Poor absorption of lopinavir in rats was observed after oral administration of enteric-coated particles containing lopinavir alone. When the particles were coadministered with enteric-coated particles containing ritonavir alone, lopinavir absorption was boosted. The boosting effect was further enhanced when ritonavir was coencapsulated with lopinavir into the same enteric-coated particles. A significant increase in area under the plasma concentration-time curve reflected an extension of mean residence time rather than an elevation of Cmax . Lopinavir absorption was improved presumably because lopinavir was always accompanied by a practical amount of ritonavir required for the boosting during the gastrointestinal transit of the particles. Not only did the electrospray coencapsulation technique improve drug absorption, but also increased trough concentration that might result in the reduction of the number of doses.

TEX101, a germ cell-marker glycoprotein, is associated with lymphocyte antigen 6 complex locus k within the mouse testis.

In adult male mice, the glycosylphosphatidyl inositol-anchored glycoprotein TEX101 is expressed only in germ cells and is thought to be involved in spermatogenesis. However, the details regarding the function of TEX101 remain to be clarified. We previously identified Ly6k as a candidate TEX101-associated protein, but as molecular probes are not currently available to detect Ly6k, we do not have conclusive evidence of the association between TEX101 and Ly6k. In this study, we confirmed the biological interaction between TEX101 and Ly6k using an established anti-mouse Ly6k polyclonal antibody (pAb). A combination of immunoprecipitation, Western blot, and immunohistochemical analyses using the pAb revealed that TEX101 is physically associated with Ly6k within the testis. In addition, these proteins simultaneously co-migrate into the detergent-resistant membrane fractions, suggesting that TEX101 collaborates with Ly6k on the cell membrane and may play a role in spermatogenesis.