A Novel Amphotericin B Hydrogel Composed of Poly(Vinyl Alcohol)/Borate Complex for Ophthalmic Formulation.

In this study, we developed a water-soluble complex-hydrogel viscosity-controlled formulation of amphotericin B (AmB). AmB is insoluble in water, but borax makes it soluble by forming a complex with AmB. Borax also forms complexes with poly(vinyl alcohol) (PVA) to produce viscous hydrogels. Furthermore, boric acid interacts with mucin expressed in corneal epithelial cells. Accordingly, by utilizing these properties of borax simultaneously, we prepared a water-soluble AmB complex-hydrogel with poly(vinyl alcohol)/borate (PVA-B-AmB), which is suitable for eye drops. PVA-B-AmB was easily prepared by simply mixing aqueous AmB solution dissolved in borax, PVA solution, and water. The 11B-NMR results suggested that PVA-B-AmB existed by bonding PVA and AmB via boronic acid. PVA-B-AmB (gel ratio = 0.55) has a viscosity of 18.3 ± 0.5 mPa·s and is suitable for ophthalmic formulations. This formulation exhibited sustained release of AmB of approximately 45% at 24 h. It was also shown that this formulation interacts with mucin. These results suggest that PVA-B-AmB can be used as a water-soluble AmB preparation suitable for ophthalmic use.

Amphotericin B nanohydrogel ocular formulation using alkyl glyceryl hyaluronic acid: Formulation, characterization, and in vitro evaluation.

The present study focused on the development of an amphotericin B (AmB) nanoformulation for ophthalmic applications. Accordingly, AmB nanohydrogels (AHA/AmB) using alkyl glyceryl hyaluronic acid (Hyalorepair®, AHA), a hydrophobized hyaluronic acid, were prepared by employing the dialysis method, followed by assessments of physical properties, drug efficacy, and toxicity. In the AHA/AmB formulation, AmB existed in a self-aggregated and amorphous state in the hydrophobic environment of the AHA moiety. AHA/AmB was shown in vitro to interact with mucin, which is known to be expressed in the corneal epithelium and was expected to improve its corneal retention. Compared with the conventional AmB formulation, amphotericin B sodium deoxycholate, AHA/AmB had the same in vitro antifungal activity but significantly lower in vitro toxicity. These findings indicate that nanohydrogels prepared with AHA possess high fungal selectivity and serve as a promising system for ophthalmic AmB delivery.

Pharmacist's Intervention Considering the Prognosis for a Terminal Cancer Patient: A Case Report.

Prognostic prediction has been reported to affect the decision of doctors and non-physician health care providers such as nurses, social workers, pastors, and hospice volunteers on the selection of appropriate medical interventions. This was a case of a 65-year-old woman who presented with a poor oral intake. The patient had a history of sigmoid colon cancer with abdominal wall metastasis and peritoneal dissemination. On the day of admission, nausea, anorexia, and malaise were noted, requiring immediate intervention. The patient's prognosis was predicted using the Palliative Prognostic Index. The pharmacist suggested the use of dexamethasone tablets in order to alleviate the patient's symptoms. Indeed, the administration of dexamethasone alleviated the symptoms of nausea, loss of appetite, and malaise. To the best of our knowledge, this is the first case report to demonstrate that prognosis prediction is important not only for other medical staff but also for pharmacists when deciding the need to initiate a treatment and continue such treatment, and when providing pharmacist interventions.

Development of an amphotericin B micellar formulation using cholesterol-conjugated styrene-maleic acid copolymer for enhancement of blood circulation and antifungal selectivity.

Amphotericin B (AmB) is an effective antifungal agent for life-threatening systemic fungal infections. However, its poor solubility in water and organic solvents makes it difficult to formulate. We previously reported AmB-encapsulated micellar formations using styrene-maleic acid copolymer (SMA) and butylated SMA. These micelles make AmB water-soluble; however, the blood circulation of AmB by these intravenous administrations was as low as that of Fungizone®, a conventional micellar formulation of AmB. The destabilization of SMA micelles by salt in the blood has been suggested to be a cause of low blood circulation. Therefore, in this study, to reduce salt-induced instability and increase blood circulation of the micelles, we covalently attached cholesterol molecules to the SMA backbone because AmB interacts with sterols. This AmB nanoparticle micellar formulation (Cho-SMA/AmB micelles) was water-soluble, stable in the presence of salts, and formed a complex with albumin. Compared with Fungizone®, this formulation had equal antifungal activity and markedly improved blood circulation and lower toxicity. Its toxicity was further reduced in the presence of albumin. Taken together, our results indicate that Cho-SMA/AmB micelles could be an intravenous formulation with high antifungal selectivity, and drug interactants-conjugated SMA system could be applied to a variety of drug-loaded nanomicellar systems.

Coenzyme Q10-Polyethylene Glycol Monostearate Nanoparticles: An Injectable Water-Soluble Formulation.

Therapeutic applications of coenzyme Q10 (CoQ10) are greatly limited by its lack of solubility in aqueous media. In this study, polyethylene glycol monostearate (stPEG) was used to construct micelles containing CoQ10 as a new formulation. The micellar formulations (stPEG/CoQ10) were prepared using five types of stPEG with 10, 25, 40, 55, and 140 PEG repeat units, respectively. The micellar preparation was simple, consisting of only stPEG and CoQ10. Next, we compared the physical properties and blood circulation of these micelles. The CoQ10 load of this formulation was approximately 15 w/w%. Based on the dynamic light scattering method, the average molecular size of the stPEG/CoQ10 micelles was approximately 15 to 60 nm. The zeta potentials of these micelles were approximately -10 to -25 mV. The micelles using stPEG25, 40, and 55 demonstrated high solubility in water. Furthermore, these micelles had in vitro antioxidant activity. On comparing the blood circulation of micelles using stPEG25, 40, 55, and 140, micelles using stPEG55 had a significantly higher circulation in blood. The stPEG55/CoQ10 micelle demonstrated a protective effect against acetaminophen-induced liver injury in mice. In conclusion, these data indicate that the intravenous administration of the stPEG/CoQ10 micellar aqueous formulation is of great value against oxidant stress.

Synthesis and evaluation of styrene-maleic acid copolymer conjugated amphotericin B.

Amphotericin B (AmB), which plays a central role in the treatment of systemic fungal infections, is difficult to formulate because it's sparingly soluble in water and organic solvents. We previously prepared AmB-loaded micelles using styrene-maleic acid copolymer (SMA). Although solubilization was achieved by this formulation, stability in the blood circulation was as insufficient as that of Fungizone®, which is a conventional formulation of AmB. Meanwhile, it is well known that polymer-drug conjugates are more stable in circulation than drug-loaded micelles. Therefore, in this study, we developed covalently conjugated SMA-AmB (SMA-AmB conjugate). The SMA-AmB conjugate was found to be soluble and present as micelles in aqueous solution. Furthermore, it was revealed that this micelle behaves as a larger molecule by forming a complex with albumin. The circulation in the blood increased significantly compared to that of Fungizone®, which was suggested to be due to this complex-forming ability. Although in vitro and in vivo antifungal activity of the SMA-AmB conjugate against Saccharomyces cerevisiae was reduced by 1/3 compared to that of Fungizone®, hemolysis decreased to 1/40 or less, and the LD50 decreased to 1/10. In conclusion, it is expected that the SMA-AmB conjugate can be a polymer-therapeutic agent with high antifungal selectivity.

A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies.

Mitochondrial disorders have the highest incidence among congenital metabolic disorders characterized by biochemical respiratory chain complex deficiencies. It occurs at a rate of 1 in 5,000 births, and has phenotypic and genetic heterogeneity. Mutations in about 1,500 nuclear encoded mitochondrial proteins may cause mitochondrial dysfunction of energy production and mitochondrial disorders. More than 250 genes that cause mitochondrial disorders have been reported to date. However exact genetic diagnosis for patients still remained largely unknown. To reveal this heterogeneity, we performed comprehensive genomic analyses for 142 patients with childhood-onset mitochondrial respiratory chain complex deficiencies. The approach includes whole mtDNA and exome analyses using high-throughput sequencing, and chromosomal aberration analyses using high-density oligonucleotide arrays. We identified 37 novel mutations in known mitochondrial disease genes and 3 mitochondria-related genes (MRPS23, QRSL1, and PNPLA4) as novel causative genes. We also identified 2 genes known to cause monogenic diseases (MECP2 and TNNI3) and 3 chromosomal aberrations (6q24.3-q25.1, 17p12, and 22q11.21) as causes in this cohort. Our approaches enhance the ability to identify pathogenic gene mutations in patients with biochemically defined mitochondrial respiratory chain complex deficiencies in clinical settings. They also underscore clinical and genetic heterogeneity and will improve patient care of this complex disorder.