BACKGROUND: Successful delivery of compounds to the brain and retina is a challenge in the development of therapeutic drugs and imaging agents. This challenge arises because internalization of compounds into the brain and retina is restricted by the blood–brain barrier (BBB) and blood-retinal barrier (BRB), respectively. Simple and reliable in vivo assays are necessary to identify compounds that can easily cross the BBB and BRB. METHODS: We developed six fluorescent indoline derivatives (IDs) and examined their ability to cross the BBB and BRB in zebrafish by in vivo fluorescence imaging. These fluorescent IDs were administered to live zebrafish by immersing the zebrafish larvae at 7–8 days post fertilization in medium containing the ID, or by intracardiac injection. We also examined the effect of multidrug resistance proteins (MRPs) on the permeability of the BBB and BRB to the ID using MK571, a selective inhibitor of MRPs. RESULTS: The permeability of these barriers to fluorescent IDs administered by simple immersion was comparable to when administered by intracardiac injection. Thus, this finding supports the validity of drug administration by simple immersion for the assessment of BBB and BRB permeability to fluorescent IDs. Using this zebrafish model, we demonstrated that the length of the methylene chain in these fluorescent IDs significantly affected their ability to cross the BBB and BRB via MRPs. CONCLUSIONS: We demonstrated that in vivo assessment of the permeability of the BBB and BRB to fluorescent IDs could be simply and reliably performed using zebrafish. The structure of fluorescent IDs can be flexibly modified and, thus, the permeability of the BBB and BRB to a large number of IDs can be assessed using this zebrafish-based assay. The large amount of data acquired might be useful for in silico analysis to elucidate the precise mechanisms underlying the interactions between chemical structure and the efflux transporters at the BBB and BRB. In turn, understanding these mechanisms may lead to the efficient design of compounds targeting the brain and retina.
- Journal of the European Academy of Dermatology and Venereology : JEADV
- Published over 8 years ago
Background Patient preferences for psoriasis treatments can impact treatment satisfaction and adherence and may therefore influence clinical outcome. Objective To assess the impact of treatment experience (satisfaction with current treatment, number of prior visits, disease duration, number of preceding therapies and currently prescribed treatment modalities) on treatment preferences. Methods A computer-based conjoint analysis experiment was conducted to analyse preferences of patients with moderate or severe psoriasis (n = 163) treated at a German University Medical Center for outcome (probability, magnitude and duration of benefit; probability, severity and reversibility of side effects) and process attributes (location, frequency, duration, delivery method, individual cost) of psoriasis treatments. Relative importance scores (RIS) were calculated for each attribute and compared using anova, post hoc test and multivariate regression analysis. Results Participants with longer disease duration attached significantly greater importance to duration of benefit (β = 0.206, P = 0.018), whereas participants on oral therapy were more concerned about magnitude of benefit by trend (β = 0.218, P = 0.058). Participants receiving injectables not only set higher value to probability of benefit (RIS = 32.80 vs. 21.89, P = 0.025) but also to treatment location (RIS = 44.74 vs. 23.03, P = 0.011), delivery method (RIS = 43.75 vs. 19.29, P = 0.019), treatment frequency (RIS = 31.24 vs. 16.89, P = 0.005) and duration (RIS = 32.54 vs. 16.57, P = 0.003) when compared with others. Treatment satisfaction was significantly higher in participants on infusions or injections compared with those on phototherapy and mere topical therapy. Conclusions Treatment preferences may change over time course and with treatment experience. Participants on injectables attach great importance to efficiency and convenience of therapies, and are highly satisfied with their treatment.
The objective of this study was to develop a controlled delivery system for PEGylated octreotide using a Poloxamer based in situ gel forming polymer. PEGylated octreotide kept its full biological activity and higher serum half-life compared to the original octreotide. The designed drug delivery system contained low concentration of Poloxamer 407 (P407) (<0.16%) with polyvinyl alcohol (PVA) as a polymeric additive. Rheological measurements of gel vehicle formulations indicated that the in situ gel forming system with optimum sol-gel transition temperature of 28.7°C could be formed using a combination of P407 and PVA at ratio of 15-10% (w/v). The effect of formulation additives such as buffering agents on rheological behavior demonstrated that sodium bicarbonate and lactic acid have opposite effect on sol-gel transition temperature of the system. Using buffering agents, it was possible to shift the sol-gel transition to lower or higher temperatures. The in vitro release profiles of octreotide and PEGylated octreotide from the selected P407/PVA formulations were measured using a membrane-less device. PEGylated octreotide showed slower release rate from the gel system with different release kinetic compared to octreotide. In animal studies, a sustained release rate was achieved with both PEGylated and non-PEGylated octreotide, but longer delivery was observed for PEGylated octreotide. Tissue histopathological studies confirmed the biocompatibility of the delivery system for PEGylated octreotide, supporting the suitability of P407/PVA mixture as an injectable drug delivery system. The total effects of increasing PEGylated peptide half-life and prolonged release from thermoresponsive gel system offer the potential for sustained delivery of PEGylated octreotide.
Nanostructured lipid carrier (NLC) is second generation smarter drug carrier system having solid matrix at room temperature. This carrier system is made up of physiological, biodegradable and biocompatible lipid materials and surfactants and is accepted by regulatory authorities for application in different drug delivery systems. The availability of many products in the market in short span of time reveals the success story of this delivery system. Since the introduction of the first product, around 30 NLC preparations are commercially available. NLC exhibit superior advantages over other colloidal carriers viz., nanoemulsions, polymeric nanoparticles, liposomes, SLN etc. and thus, have been explored to more extent in pharmaceutical technology. The whole set of unique advantages such as enhanced drug loading capacity, prevention of drug expulsion, leads to more flexibility for modulation of drug release and makes NLC versatile delivery system for various routes of administration. The present review gives insights on the definitions and characterization of NLC as colloidal carriers including the production techniques and suitable formulations. This review paper also highlights the importance of NLC in pharmaceutical applications for the various routes of drug delivery viz., topical, oral, pulmonary, ocular and parenteral administration and its future perspective as a pharmaceutical carrier.
Intravitreal injection is widely used for easy control of drug levels in posterior segment of the eye by injecting the drug directly with hypodermic needles. Patients, however, often experience complications from intravitreal injection due to repeated injections, increased intraocular pressure, and infection. In addition, injected drug reflux after intravitreal injection makes it challenging to maintain predetermined drug dose due to the drug loss through backward effusions. Here, we described that the Tower Microneedle can reduce initial reflux and bleb formation due to its smaller outer diameter compared to a traditional hypodermic needle. Furthermore, we use phenylephrine hydrochloride for pupil expansion and demonstrated that Tower Microneedle induced similar pupil expansions using only half the drug volume, in the same period of time, compared to the 31 Gauge hypodermic needle. Consequently, Tower Microneedle achieves the same therapeutic effect in the vitreous body using fewer drugs than a traditional hypodermic needle due to the decreased backward drug effusion. Tower Microneedle described herein holds great promise for intravitreal injection with less reflux and lower drug dosage.
Efficacy, Safety, and Patient Satisfaction of a Monophasic Cohesive Polydensified Matrix Versus a Biphasic Nonanimal Stabilized Hyaluronic Acid Filler After Single Injection in Nasolabial Folds
- Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]
- Published over 7 years ago
BACKGROUND: Intradermal injection of hyaluronic acid (HA) is currently the criterion standard to reduce the appearance of nasolabial folds (NLF). OBJECTIVE: Effects of a monophasic HA filler using cohesive polydensified matrix (CPM) technology were compared with those of nonanimal stabilized HA (NASHA). MATERIALS AND METHODS: In a double-blind, half-side comparison, 20 subjects (ages 35-65, mean 52 ± 5.6) with symmetric NLF grade 3 to 4 were randomized to contralateral treatment with a monophasic polydensified filler (CPM) and a biphasic HA filler (NASHA). Efficacy was assessed at baseline and after 2, 24, and 48 weeks using a wrinkle severity rating scale (WSRS) for NLF, subject questionnaire, and biophysical in vivo methods. RESULTS: All subjects showed significant improvements with both fillers up to day 365. Subject questionnaires confirmed significantly less injection pain for the CPMHA, significantly greater patient satisfaction after 2 weeks with both fillers, and after 24 and 48 weeks significantly greater improvement with the CPMHA compared to baseline. WSRS and skin surface topography parameters improved significantly up to 48 weeks with both fillers. CONCLUSION: A single intradermal injection of a monophasic CPMHA and a biphasic NASHA filler showed significant improvements in WSRS and measured wrinkle depth up to 48 weeks for both fillers and significant differences in injection comfort and patient satisfaction in favor of CPMHA.
- Biomedicine & pharmacotherapy = Biomédecine & pharmacothérapie
- Published over 5 years ago
Inhibiting or circumventing drug resistance by using drug delivery systems (DDSs) such as micelles has attracted significant attention recently. In this present study, a polyvinyl caprolactam-polyvinyl acetate-polyethylene (Soluplus(®)) micelle was developed as the delivery system for doxorubicin (DOX) and evaluated both in vitro and in vivo. In vitro, Soluplus(®) micelles could significantly enhance the cellular accumulation of DOX in MCF-7/DOX cells, meanwhile, P-glycoprotein (P-gp)-mediated drug efflux was inhibited which was also verified in the membrane fluidity study. And MCF-7/DOX cells were found to be more susceptible to the cytotoxic effects of DOX-M. In vivo, both the P-gp inhibitors verapamil and Soluplus(®) could improve the cytotoxicity of DOX·HCl in MCF-7/DOX tumor-bearing mice, which were further certified by the effect of Soluplus(®) on P-gp inhibition. Furthermore, the excellent antitumor efficacy of DOX-M by intravenous injection was also observed, which indicated that the P-gp inhibition effect of Soluplus(®) could enhance the susceptibility of resistant tumor to DOX in vivo. In conclusion, our study suggested that Soluplus(®) micelles might be an applicable drug delivery system for enhancing the antitumor efficacy of P-gp substrates.
Recently, injectable dermal fillers have become important alternatives to surgical procedures for the correction of facial wrinkles. Bovine collagen is the first approved material for filler injection, and several studies have shown its efficacy. However, the risk of developing an allergic reaction and xenogenic transmission of bovine spongiform encephalopathy remain among its disadvantages. In this randomized, double-blinded, split-face study, we compared the efficacy and safety of a porcine collagen filler (TheraFill®) with that of a bovine collagen filler (KOKEN®) for nasolabial fold correction. A total of sixty one patients with mild to severe nasolabial fold were randomized to receive TheraFill® and KOKEN® on contralateral sides of the face. During the 12-month follow-up period, improvement in the Wrinkle-Severity Rating Scale score was slightly higher in TheraFill® group than KOKEN® group, although the difference was not statistically significant. No serious adverse reactions were observed and both materials were tolerable in most cases. In conclusion, the long-term effect of TheraFill® on nasolabial fold correction was comparable to that of KOKEN®, and it may be a good alternative to bovine collagen filler.
This third article of a three-part series addresses techniques and recommendations for aesthetic treatment of the lower face. The lower face is considered an advanced area for facial aesthetic treatment. In this region, soft-tissue fillers play a more important role than neuromodulators and should be used first to provide structure and support before neuromodulators are considered for treatment of dynamic lines. Treatment of the lip, perioral region, and chin, in addition to maintaining balance of the lower face with the face overall, is challenging. Procedures on the lip should avoid overcorrection while respecting the projection of the lips on the profile view and the ratio of lip size to chin. The chin is often neglected, but reshaping the jawline can provide dramatic improvement in facial aesthetics. Both profile and anterior views are critical in assessment and treatment of the lower face. Finally, rejuvenation of the neck region requires fillers for structural support of the chin and jawline and neuromodulators for treatment of the masseter and platysma.
At times, the Food and Drug Administration (FDA) must grapple with safety concerns related to off-label uses of FDA-approved medications. Over the past several years, we have sought to understand the risk of serious neurologic events that occur after the epidural injection of glucocorticoids (corticosteroids) - a procedure that is commonly performed in the United States in an effort to manage radicular neck and back pain. The FDA has not approved any injectable glucocorticoid product for epidural administration, so any such use is considered off-label - part of the practice of medicine and not regulated by the FDA. In 2009, . . .