Direct costs of glaucoma: Relationship between cost and severity of the disease.

OBJECTIVES: To estimate the direct medical costs associated with the management of patients with primary open-angle glaucoma and to compare the costs of patients according to the degree of severity. METHODS: A longitudinal retrospective study was carried out using all patients with primary open-angle glaucoma that recorded follow-up from May 2010 to June 2013 at the Hospital Privado de Córdoba. We estimated the cost of the disease from the perspectives of the institution, with a bottom-up approach. RESULTS: The three-year follow-up after treatment of 104 patients revealed that the average cost of care for a patient with primary open-angle glaucoma was US$2746 ± 1560. The first year of treatment was significantly more expensive than subsequent ones (US$1100-$810-$827). Cost was related to the degree of severity of glaucoma; patients in "Stage 0" had significantly lower costs than those in other groups (Kruskal-Wallis test, p < 0.01). This was a consequence of lower costs associated with medication and a lower percentage of patients undergoing surgery. DISCUSSION: The direct medical costs of a patient with primary open-angle glaucoma vary according to the severity of their disease and the year of treatment. We found that costs increased with disease severity, but decreased over time.

Triamcinolone acetonide-loaded lipid nanocapsules for ophthalmic applications.

Triamcinolone acetonide (TA) is an effective drug widely (off-label) used in the treatment of several ocular diseases involving inflammation and angiogenic processes. However, the use of TA ocular presents some limitations mainly related to its excipient composition, as in the case of benzyl alcohol. Thus, the aim of this work was to obtain an alternative TA formulation based on lipid nanocapsules (LNCs). Triamcinolone acetonide-loaded lipid nanocapsules (TA-LNCs) were obtained by the phase inversion temperature process without the use of irritating excipients, by combining lipids and surfactants generally recognized as safe. Pre-formulation studies were carried out to evaluate the TA solubility in different co-surfactants and to optimize the lipid core composition in order to enhance the drug loading and encapsulation rate in the LNCs. A stable final TA-LNC formulation was obtained with a mean particle size (MPS) of below 50 nm, a narrow size distribution (PDI < 0.2), a negative zeta potential (ZP) and a high encapsulation efficiency (%EE > 98%). In vitro cellular viability assays revealed that blank LNCs and TA-LNCs at 0.1 µg/mL did not affect the viability of the human corneal epithelial (HCE) cells. TA-LNCs showed a high anti-inflammatory activity below the toxicity level, with a reduction of 30% in interleukin (IL)-6 secretion observed in an in vitro model using the same cell line. More importantly, the TA-LNCs revealed a therapeutic efficacy in the endotoxin-induced uveitis (EIU) rabbit model with a significant attenuation of clinical signs of an inflammatory response. These findings make the TA-LNCs a safer and more efficient alternative for the treatment of eye disorders.

The reactivation time in the treatment of AMD: a forgotten key parameter?

OBJECTIVE: Summarize and compare the available evidence on the reactivation times in patients with age-related macular degeneration treated with Ranibizumab (RNB). METHOD: Systematic review of studies that reported the reactivation time of patients (direct method) or the number of injections received in a certain period of follow-up (indirect method). RESULTS: Only 18 of 89 selected studies reported the average reactivation time of patients in a manifest form, without the need of any calculation. The average calculated, weighted reactivation time was 101.8 days with the direct method and 99.8 days in the indirect method (84 studies included). With both methods, it was found that the average reactivation time of the RCTs was between 2 and 3 weeks less than the average time identified in the observational studies. These differences are also reflected in the clinical results, there being a correlation between the number of doses received and the change in BCVA. The analysis of 11 comparative studies showed a difference in reactivation times between patients treated with RNB or Bevacizumab (BVZ). CONCLUSION: There are few direct studies of reactivation time, but calculation from the PRN dose number turns out to be a good approximation for retrospective study of the variable. The use of the PRN, with criteria not based on optical coherence tomography scans, delays the application of doses between 2 or 3 weeks, and patients suffer loss of clinical benefits. RNB enables patients to receive less injections than BVZ throughout treatment.

Ophthalmic administration of a 10-fold-lower dose of conventional nanoliposome formulations caused levels of intraocular pressure similar to those induced by marketed eye drops.

The purpose of this study was to compare the in vivo efficacy of several timolol (TM)-loaded liposomal formulations with current TM antiglaucoma treatment (aqueous 0.5% w/v eye drops). In this study, conventional liposomes (CL) and deformable liposomes, without (DL1) and with ethanol (DL2) were prepared and characterized. In addition, in vitro release and permeation studies, as well as in vivo lowering intraocular pressure (IOP) and biocompatibility studies were performed. It was found that the quali and quantitative lipid bilayer composition played a significant role in modifying the physical properties of vesicles. The deformability study and electronic microscopy images revealed that membrane elasticity of DL1 and DL2 was much higher than CL. However, in vitro permeation results showed that the flux and permeability coefficient were significantly higher in CL compared to DL. The IOP study revealed that TM-loaded CL showed the best pharmacological activity, in comparison to deformable vesicles. Compared to the eye drops, CL formulation could equally reduce the IOP but using a concentration 10-fold lower, whereas the effective time was significantly longer. In addition, the formulations showed no irritant effects after instillation on the ocular surface.

Acanthamoeba in the eye, can the parasite hide even more? Latest developments on the disease.

Acanthamoeba spp. is a free living protozoan in the environment, but can cause serious diseases. Acanthamoeba keratitis (AK), a severe and painful eye infection, must be treated as soon as possible to prevent ulceration of the cornea, loss of visual acuity, and eventually blindness or enucleation. Although the disease affects principally contact lens (CLs) wearers, it is recognized nowadays as a cause of keratitis also in non-CLs wearers. Although the number of infections caused by these amoebae is low, AK is an emerging disease presenting an extended number of cases each year worldwide mostly due to the increasing use of CLs, but also to better diagnostic methods and awareness. There are two principal causes that lead to severe outcomes: misdiagnosis or late diagnosis of the causal agent, and lack of a fully effective therapy due to the existence of a highly resistant cyst stage of Acanthamoeba. Recent studies have reported different genotypes that have not been previously associated with this disease. In addition, Acanthamoeba can act as a reservoir for phylogenetically diverse microorganisms. In this regard, recently giant viruses called Pandoravirus have been found within genotypes producing keratitis. What potential risk this poses is not yet known. This review focuses on an overview of the present status and future prospects of this re-emerging pathology, including features of the parasite, epidemiology, clinical aspects, diagnosis, and treatment.

The role of hyaluronan as a drug carrier to enhance the bioavailability of extended release ophthalmic formulations. Hyaluronan-timolol ionic complexes as a model case.

The aim of this work was to obtain information concerning the properties of ophthalmic formulations based on hyaluronic-drug ionic complexes, to identify the factors that determine the onset, intensity and duration of the pharmacotherapeutic effect. Dispersions of a complex of 0.5% w/v of sodium hyaluronate (HyNa) loaded with 0.5% w/v of timolol maleate (TM) were obtained and presented a counterionic condensation higher than 75%. For comparison a similar complex obtained with hyaluronic acid (HyH) was also prepared. Although the viscosity of HyNa-TM was significantly higher than that of HyH-TM, in vitro release of TM from both complexes showed a similar extended drug release profile (20-31% over 5h) controlled by diffusion and ionic exchange. Ocular pharmacokinetic study performed in normotensive rabbits showed that HyNa-TM complex exhibited attractive bioavailability properties in the aqueous humor (AUC and Cmax significantly higher and later Tmax) compared to commercial TM eye-drops. Moreover, a more prolonged period of lowered intra-ocular pressure (10h) and a more intense hypotensive activity was observed after instillation of a drop of HyNa-TM as compared to the eye-drops. Such behavior was related to the longer pre-corneal residence times (400%) observed with HyNa-TM complex. No significant changes in rabbit transcorneal permeation were detected upon complexation. These results demonstrate that the ability of HyNa to modulate TM release, together with its mucoadhesiveness related to the viscosity, affected both the pharmacokinetic and pharmacodynamic parameters. The HyNa-TM complex is a potentially useful carrier for ocular drug delivery, which could improve the TM efficacy and reduce the frequency of administration to improve patient compliance.

Preliminary characterization of dexamethasone-loaded cross-linked hyaluronic acid films for topical ocular therapy.

The aim of this work was to design and characterize cross-linked hyaluronic acid (HA)-itaconic acid (IT) films loaded with dexamethasone sodium phosphate salt (DEX) for topical therapy of inflammatory ocular surface diseases. Films were chemically cross-linked with polyethylene glycol diglycidyl ether (PEGDE), then physical and mechanical characterization by stress-strain, X-ray diffraction, X-ray fluorescence spectrometry and swelling assays was conducted. A sequential in vitro therapeutic efficacy model was designed to assess changes in interleukin (IL)-6 production in an inflamed human corneal epithelial (HCE) cell line after film exposure. Changes in cell proliferation after film exposure were assessed using the alamarBlue(®) proliferation assay. Experimental findings showed desirable mechanical properties and in vitro efficacy to reduce cell inflammation. A moderately decreased proliferation rate was induced in HCE cells by DEX-loaded films, compared to commercial DEX eye drops. These results suggest that DEX and HA have opposite effects. The sequential in vitro therapeutic efficacy model arises as an efficient tool to study drug release from delivery systems by indirect measurement of a biological response.

Ivermectin-loaded lipid nanocapsules: toward the development of a new antiparasitic delivery system for veterinary applications.

Ivermectin (IVM) is probably one of the most widely used antiparasitic drugs worldwide, and its efficacy is well established. However, slight differences in formulation may change the plasma kinetics, the biodistribution, and in consequence, the efficacy of this compound. The present study focuses on the development of a novel nanocarrier for the delivery of lipophilic drugs such as IVM and its potential application in antiparasitic control. Lipid nanocapsules (LNC) were prepared by a new phase inversion procedure and characterized in terms of size, surface potential, encapsulation efficiency, and physical stability. A complement activation assay (CH50) and uptake experiments by THP-1 macrophage cells were used to assess the stealth properties of this nanocarrier in vitro. Finally, a pharmacokinetics and biodistribution study was carried out as a proof of concept after subcutaneous (SC) injection in a rat model. The final IVM-LNC suspension displayed a narrow size distribution and an encapsulation rate higher than 90 % constant over the evaluated time (60 days). Through flow cytometry and blood permanence measurements, it was possible to confirm the ability of these particles to avoid the macrophage uptake. Moreover, the systemic disposition of IVM in the LNC administered by the SC route was higher (p < 0.05) (1367 ng h/ml) compared to treatment with a commercial formulation (CF) (1193 ng.h/ml), but no significant differences in the biodistribution pattern were found. In conclusion, this new carrier seems to be a promising therapeutic approach in antiparasitic control and to delay the appearance of resistance.

Novel bioadhesive hyaluronan-itaconic acid crosslinked films for ocular therapy.

New hyaluronic acid (HA)-itaconic acid (IT) films have been previously synthesized and used as potential topical drug delivery systems (DDS) for ocular administration. In this study we explored homogeneous and heterogeneous crosslinking reactions of HA using glutaraldehyde (GTA) and polyethylene glycol diglycidyl ether (PEGDE) in the presence of IT, a naturally occurring compound that is non-toxic and readily biodegradable. We have studied the morphology, mechanical properties and in vitro biocompatibility between these new materials and ocular surface cells (human corneal epithelial cell line) and evaluated the biopharmaceutical performance of the designed formulations. Although all the synthesized materials exhibited good mechanical properties, the PEGDE modified films exhibited the best biocompatibility, with in vivo assays showing good adhesive performance and minimal irritation. PEGDE films were also tested for their effects in the treatment of intraocular pressure (IOP) in rabbits using timolol maleate (TM) as the model drug. These results may be useful for further design of novel bioadhesive matrix containing drugs by topical application in ophthalmology.

Design of novel antifungal mucoadhesive films. Part II. Formulation and in vitro biopharmaceutical evaluation.

This paper deals with the formulation of the mucoadhesive films containing nystatin. The design and formulation of the films were based on the mucoadhesive properties of carbomer 934P (CB) and carboxymethycellulose (NaCMC), and also on the plasticizer properties of polyethyleneglycol 400 (PEG400). A surfactant (ascorbyl palmitate, ASC16) was added to the system to aid in nystatin dispersion. Addition of these last two components produced a significant improvement in physical-mechanical properties (flexibility and strength) as well as an increase in the nystatin release rate. X-ray powder diffraction (XRPD) and scanning electronic microscopy (SEM) were used to evaluate the morphological changes in the films while PEG400 and ASC16 were added to the formulations. Furthermore, the in vitro nystatin profile release was determined.

Design of novel antifungal mucoadhesive films Part I. Pre-formulation studies.

In this work, pre-formulation studies concerning the design of novel mucoadhesive films have been carried out. The rationality of the design is based on the utilization of mucoadhesive polymers (carbomer and carboxymethylcellulose), a plasticizer (polyethyleneglycol 400, PEG400) and a surfactant (ascorbyl palmitate, ASC16). In the gel preparation, the casting method using water as a solvent was employed. To provide a better understanding of the structural arrangements produced during the casting process, the changes in morphology (Cryo-TEM) and rheology (viscosity) of the film forming gel were evaluated. When PEG400 was included as a plasticizer, a disorder was produced in the network, reflected in the globular structure adopted by the gel and the consequent decrease in viscosity. The addition of ASC16 improved the solubilization of nystatin and provoked a decrease in gel viscosity. However, as water was removed during casting, ASC16 produced a significant increase in the viscosity at the point in which the polymer concentrations were sufficient to strengthen the inter-polymeric interactions, giving rise to a more rigid tri-dimensional network.

Potential use of ascorbic acid-based surfactants as skin penetration enhancers.

6-O-Ascorbic acid alkanoates (ASCn) are amphiphilic molecules having physical-chemical properties that depend on the alkyl chain length. The derivatives of low molecular weight (n < 11) have enough aqueous solubility to produce self-assemblies at room temperature ( approximately 25 degrees C), while those with longer alkyl chains possess a critical micellar temperature (CMT) higher than 30 degrees C. At higher temperatures (T degrees > CMT), ASCn aqueous suspensions turn into either micellar solutions or gel phases, depending on the length of the hydrophobic chain. On cooling, coagels are produced, which possess a lamellar structure that exhibit sharp X-ray diffraction patterns and optical birefringence. The semisolid consistency of such coagels is an interesting property to formulate dermatological pharmaceutical dosage forms able to solubilize and stabilize different drugs. The objective of the present study was the evaluation of the enhancing permeation effect of ASCn with different chain lengths and to correlate permeability changes with histological effects. With this purpose, ASCn coagels containing anthralin (antipsoriasic drug) or fluorescein isothiocyanate (FITC, hydrophobic fluorescent marker) were assayed on rat skin (ex vivo) and mice skin (in vivo), respectively. Also, histological studies were performed aimed at detecting some possible side effects of ASCn. No inflammatory cellular response was observed in the skin when ASCn coagels were applied, suggesting non-irritating properties. Light microscopy indicated slight disruption and fragmentation of stratum corneum. The penetration of ASCn through rat skin epidermis was very fast and quantitatively significant. The permeation of anthralin was significantly increased when the drug was vehiculized in ASCn coagels, compared to other pharmaceutical systems. The results indicated that ASC12 seems to have the highest enhancing effect on FITC permeation. ASC12 appears to be the compound that possesses the highest capacity to enhance the penetration of the drugs. Furthermore, it has the highest permeation of the serie.

Dry plant extracts loaded on fumed silica for direct compression: preparation and preformulation.

This paper describes the development of a method to load fumed silica with vegetal material (solid residue) from a liquid extract to obtain a solid loaded silica product (LSP) with satisfactory flow properties and compressibility to be processed by direct-compression technology. Extracts of Melissa officinalis L. (M.o.), Cardus marianus L. (C.m.), and Peumus boldus L. (P.b.) were used to load silica support. The release of boldine from LSP (P.b.) reached 100% in HCl 0.1 N solution and only approximately 70% in water. Some physical-mechanical properties of LSP (M.o. and C.m.) alone and LSP-excipient mixtures were determined. The densities (bulk and tap) of LSP were higher than those of fumed silica alone. Consequently, good flow properties of LSP products were observed. On the other hand, flowability, densities, and compactibility of directly compressible excipients (lactose, dicalcium phosphate dihydrate, and microcrystalline cellulose) were not adversely affected when mixed with LSP.

Cisplatin, doxorubicin and cyclophosphamide in advanced salivary gland carcinoma. A phase II trial of 22 patients.

BACKGROUND: To evaluate the activity of CAP regimen in advanced salivary gland carcinomas. PATIENTS AND METHODS: Twenty-two patients with advanced salivary gland carcinomas were treated according to the CAP regimen. All patients were previously treated with surgery and/or radiotherapy and/or chemotherapy. Seven patients had local or locoregional disease, nine patients had local and metastatic disease, six patients had metastatic disease only. The most common histologies were included. RESULTS: Of 22 patients, six achieved a partial response (27%, 95% CI: 11%-50%): no complete response was observed. Response duration ranged between 3 and 13 months (median seven months). The median survival time for the entire series was 21 months. CONCLUSIONS: In this investigation, on 22 consecutive patients, CAP combination provided an overall response rate of 27%. This study confirms that, at present, available drugs yield poor results, either as single agents or as combination therapy.