Beyond Traditional Sunscreens: A Review of Liposomal-Based Systems for Photoprotection.

Sunscreen products are essential for shielding the skin from ultraviolet (UV) radiation, a leading cause of skin cancer. While existing products serve this purpose, there is a growing need to enhance their efficacy while minimizing potential systemic absorption of UV filters and associated toxicological risks. Liposomal-based formulations have emerged as a promising approach to address these challenges and develop advanced photoprotective products. These vesicular systems offer versatility in carrying both hydrophilic and lipophilic UV filters, enabling the creation of broad-spectrum sunscreens. Moreover, their composition based on phospholipids, resembling that of the stratum corneum, facilitates adherence to the skin's surface layers, thereby improving photoprotective efficacy. The research discussed in this review underscores the significant advantages of liposomes in photoprotection, including their ability to limit the systemic absorption of UV filters, enhance formulation stability, and augment photoprotective effects. However, despite these benefits, there remains a notable gap between the potential of liposomal systems and their utilization in sunscreen development. Consequently, this review emphasizes the importance of leveraging liposomes and related vesicular systems as innovative tools for crafting novel and more efficient photoprotective formulations.

Exploring the permeability of Amphotericin B trough serum albumin dispersions and lipid nanocarriers for oral delivery.

Amphotericin B (AmB) is a potent polyenic antifungal agent with leishmanicidal activity. Due to its low solubility and permeability in the gastrointestinal tract, AmB is usually administered intravenously. In this context, various approaches have been used to try to improve these properties. Some of the systems developed have shown proven successful, but there is still a lack of knowledge about the pathways AmB takes after oral administration. Therefore, the aim of this work was not only to obtain aqueous dispersions containing AmB at different aggregation states, but also to entrap this molecule in nanocarriers, and evaluate the influence of these conditions on the jejunal permeability of AmB. To observe the aggregation states of AmB, physicochemical characterization of AmB-albumin complexes and AmB-loaded formulations was performed. Different degrees of AmB aggregation states were obtained. Thus, permeability tests were performed in the Ussing chamber and a decrease in AmB concentration in the donor compartment was observed. Electrophysiological measurements showed different responses depending on the AmB formulation. In conclusion, although control of the AmB aggregation state was observed by physicochemical characterization, this approach does not seem to have a sufficient effect on AmB permeability, but on its toxicity. For a complete understanding of AmB-loaded nanocarriers, other pathways, such as lymphatic absorption, should also be investigated.

Treatment of colitis by oral negatively charged nanostructured curcumin in rats.

PURPOSE: To examine the effects of a negatively charged nanostructured curcumin microemulsion in experimental ulcerative colitis (UC) in rats. METHODS: Four percent acetic acid was used to induce UC. The animals were treated for seven days and randomly assigned to four groups: normal control (NC), colitis/normal saline (COL/NS), colitis/curcumin (COL/CUR), and colitis/mesalazine (COL/MES). The nanostructured curcumin was formulated with a negative zeta potential (-16.70 ± 1.66 mV). Dosage of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin 1-ß (IL-1ß), interleukin 6 (IL-6), and antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase), macro and microscopic evaluation of the colon tissue were analyzed. RESULTS: The COL/CUR group had a higher level of antioxidant enzymes compared to the COL/MESgroup. The levels of TNF-α, IL-1ß and IL-6 were significantly lower in the colonic tissue of the COL/CUR group rats, when compared to the COL/NS and COL/MES groups (p < 0.001). The presence of ulcers in the colonic mucosa in rats of the COL/NSgroup was significantly higher than in the COL/MES group (p < 0.001). In the NC and COL/CUR groups, there were no ulcers in the colonic mucosa. CONCLUSIONS: The nanostructured microemulsion of curcumin, used orally, positively influenced the results of the treatment of UC in rats. The data also suggests that nanostructured curcumin with negative zeta potential is a promising phytopharmaceutical oral delivery system for UC therapy. Further research needs to be done to better understand the mechanisms of the negatively charged nanostructured curcumin microemulsion in UC therapy.

Pharmaceutical Care Practice and Consequences on Quality of Life and Satisfaction of Diabetic Patients: A Randomized Clinical Trial

Abstract The pursuit of quality of life, which has become marked in recent years, has translated into important population health benefits. This study assessed the quality of life of patients with type 2 diabetes (T2DM) who received pharmaceutical care, and their satisfaction with the service provided in community pharmacies. This single blind, randomized controlled clinical trial included 100 patients. The intervention group (N=47) received pharmaceutical care by a clinical pharmacist and the control group (N=42) received standard care. The Quality of Life Diabetes Questionnaire (DQOL) was used to measure all participants´ quality of life at study enrollment and six months later. Satisfaction of the participants in the intervention group was measured using a validated 14-items questionnaire. At the end of the study, participants in the intervention group had a statistically significant improvement in DQOL scores ( -0.62 x 1.57, p < 0.001) and were highly satisfied with the intervention (96% excellent satisfaction scores). Pharmaceutical care practice was associated with high satisfaction and increased quality of life scores in T2DM patients. These results underscore the important role of pharmacists to improve the health of diabetic patients.

Anti-Inflammatory Activity of Bullfrog Oil Polymeric Nanocapsules: From the Design to Preclinical Trials.

BACKGROUND: Although bullfrog oil (BFO) exerts anti-inflammatory effects, it has undesirable properties limiting its use. METHODOLOGY: BFO nanocapsules (BFONc) were produced through nanoprecipitation, and their physicochemical and morphological properties were characterized. To evaluate the biocompatibility of the formulation, a mitochondrial activity evaluation assay was conducted, and cell uptake was assessed. The in vitro anti-inflammatory activity was evaluated by measuring reactive oxygen species (ROS), nitric oxide (NO), type-6 interleukin (IL-6), and tumor necrosis factor (TNF) levels. The in vivo anti-inflammatory effect was assessed by quantifying myeloperoxidase (MPO) levels using the carrageenan-induced paw edema model. RESULTS: BFONc showed a particle size of 233 ± 22 nm, a polydispersity index of 0.17 ± 0.03, and a zeta potential of -34 ± 2.6mV. BFONc revealed remarkable biocompatibility and did not induce changes in cell morphology. Furthermore, BFONc decreased ROS levels by 81 ± 4%; however, NO level increased by 72 ± 18%. TNF and IL-6 levels were reduced by approximately 10% and 90%, respectively. Significant in vivo anti-inflammatory activity was observed compared to dexamethasone. MPO levels were reduced up to 2 MPOs/mg. CONCLUSION: Taken together, the results pointed out the remarkable biocompatibility and anti-inflammatory effects of BFONc.

Current trends on cannabidiol delivery systems: where are we and where are we going?

INTRODUCTION: Cannabidiol (CBD), a phytocannabinoid from Cannabis sativa, has several therapeutic properties. However, its high lipophilicity, metabolization, and instability impair its bioavailability and translational use in clinical settings. Several advanced drug delivery systems (ADDSs) have been evaluated as CBD carriers to overcome these drawbacks. These systems can improve the CBD dissolution profile, protect it against metabolization, and produce a site-specific release, increasing its bioavailability and making CBD administration clinically effective. AREAS COVERED: This review summarizes scientific reports on cannabidiol advanced delivery systems (CBD-ADSs) that have been (i) developed, and (ii) applied therapeutically; reports published in the main scientific databases until January 2020 were included. Studies without experimental data and/or published in languages other than English were excluded. Moreover, pharmaceutical technology tools in CBD therapeutic use have been discussed, emphasizing the clinical translation of CBD carrier use. EXPERT OPINION: Studies reporting CBD-ADS use for medicinal applications were reviewed and revealed multifaceted systems that can overcome the physicochemical drawbacks of CBD and improve its biological activities. Therefore, researchers concluded that the developed CBD-ADS can be used as an alternative to traditional formulations because they show comparable or superior effectiveness in treatment protocols. Although several criteria remain to be met, our findings emphasize the potential of CBD-ADSs for translational therapeutics, particularly for neurological-disorders.

Ferri-Liposomes: Preformulation and Selective Cytotoxicity against A549 Lung Cancer Cells.

Liposomes have become successful nanostructured systems used in clinical practices. These vesicles are able to carry important drug loadings with noteworthy stability. The aim of this work was to develop iron oxide-loaded stealth liposomes as a prospective alternative for the treatment of lung cancer. In this study, citric acid iron oxide nanoparticles (IONPs-Ac) were synthesized and encapsulated in stealth liposomes. Their cytotoxicity and selectivity against lung tumor cells were assessed. Stealth liposomal vesicles, with relevant content of IONPs-Ac, named ferri-liposomes (SL-IONPs-Ac), were produced with an average size of 200 nm. They displayed important cytotoxicity in a human lung cancer cells model (A549 cells), even at low concentrations, whereas free IONPs-Ac displayed adequate biocompatibility. Nevertheless, the treatment at the same concentration of ferri-liposomes against HEK-293 cells, a normal human cell lineage, was not significantly cytotoxic, revealing a probable lung tumor selectiveness of the fabricated formulation. Furthermore, from the flow cytometry studies, it was possible to infer that ferri-liposomes were able to induce A549 tumor cells death through apoptosis/ferroptosis processes, evidenced by a significant reduction of the mitochondrial membrane potential.

Effect of the Ileum and Colon on Liver Regeneration.

PURPOSE: The colon and ileum play significant roles on liver physiology. Studies about simultaneous hepatectomy and colectomy or enterectomy are scarce and controversial. We investigated and compared the effects of ileum and colon resection on liver regeneration. MATERIALS AND METHODS: Twenty four Wistar rats were allocated in group I-(sham), group II-70% hepatectomy; group III-70% hepatectomy + ileal resection, and group IV-70% hepatectomy + partial colectomy. On the sixth day, serum hepatic enzymes, albumin, hepatocyte growth-factor (HGF) and transforming growth factor-alpha (TGF-α) were measured. The hepatic regeneration rate was estimated. Ki-67 immunohistochemical analysis was done in remnant liver. RESULTS: Hepatic enzymes levels were significantly higher in group III rats comparing to the other groups (p < 0.001). In group IV, the levels were significantly lower than in groups II and III (p < 0.001). Albuminemia was significantly lower in group III rats comparing with the other groups (p < 0.001). Albuminemia was not different comparing groups I and IV (p > 0.05). Cytokines HGF and TGF-α levels in group IV were significantly higher than in the other groups (p < 0.001). Liver regeneration rate was higher group IV than in groups II and III, and the difference was statistically significant (p = 0.002). The hepatocytes expression of Ki-67 was significantly higher in the remnant liver of group IV than in group III (p = 0.002). There was no difference in Ki-67 expression between groups II and IV (p > 0.05). CONCLUSION: Ileum and colon resection have different effects on liver regeneration. Colon resection positively influences liver regeneration, while ileum resection negatively influences the regenerative process, in a rat model.

Self-Assembled Cationic-Covered Nanoemulsion as A Novel Biocompatible Immunoadjuvant for Antiserum Production Against Tityus serrulatus Scorpion Venom.

This study assesses the efficacy of different nanoemulsion formulations as new and innovative adjuvants for improving the in vivo immunization against the Tityus serrulatus scorpion venom. Nanoemulsions were designed testing key-variables such as surfactants, co-solvents, and the influence of the temperature, which would be able to induce the phase transition from a liquid crystal to a stable nanoemulsion, assessed for four months. Additionally, cationic-covered nanoemulsion with hyper-branched poly(ethyleneimine) was prepared and its performance was compared to the non-cationic ones. The physicochemical properties of the selected nanoemulsions and the interactions among their involved formulation compounds were carefully monitored. The cytotoxicity studies in murine macrophages (RAW 264.7) and red blood cells were used to compare different formulations. Moreover, the performance of the nanoemulsion systems as biocompatible adjuvants was evaluated using mice immunization protocol. The FTIR shifts and the zeta potential changes (from -18.3 ± 1.0 to + 8.4 ± 1.4) corroborated with the expected supramolecular anchoring of venom proteins on the surface of the nanoemulsion droplets. Cell culture assays demonstrated the non-toxicity of the formulations at concentrations less than 1.0 mg/mL, which were able to inhibit the hemolytic effect of the scorpion venom. The cationic-covered nanoemulsion has shown superior adjuvant activity, revealing the highest IgG titer in the immunized animals compared to both the non-cationic counterpart and the traditional aluminum adjuvant. In this approach, we demonstrate the incredible potential application of nanoemulsions as adjuvants, using a nanotechnology platform for antigen delivery system on immune cells. Additionally, the functionalization with hyper-branched poly(ethyleneimine) enhances this recognition and improves its action in immunization.

Xylan microparticles for controlled release of mesalamine: Production and physicochemical characterization.

Xylan extracted from corn cobs was used to produce mesalamine-loaded xylan microparticles (XMP5-ASA) by cross-linking polymerization using a non-hazardous cross-linking agent. The microparticles were characterized by thermal analysis (DSC/TG), X-ray diffraction (XRD), Infrared spectroscopy (FTIR-ATR) and scanning electron microscopy (SEM). A comparative study of the in vitro drug release from XMP5-ASA and from gastro-resistant capsules filled with XMP5-ASA (XMPCAP5-ASA) or 5-ASA was also performed. NMR, FTIR-ATR, XRD and DSC/TG studies indicated molecularly dispersed drug in the microparticles with increment on drug stability. The release studies showed that XMPCAP5-ASA allowed more efficient drug retention in the simulated gastric fluid and a prolonged drug release lasting up to 24 h. XMPCAP5-ASA retained approximately 48 % of its drug content after 6 h on the drug release assay. Thus, the encapsulation of 5-ASA into xylan microparticles together with gastro-resistant capsules allowed a better release control of the drug during different simulated gastrointestinal medium.

Self-assembled cationic-covered nanoemulsion as a novel biocompatible immunoadjuvant for antiserum production against Tityus serrulatus scorpion venom

This study assesses the efficacy of different nanoemulsion formulations as new and innovative adjuvants for improving the in vivo immunization against the Tityus serrulatus scorpion venom. Nanoemulsions were designed testing key-variables such as surfactants, co-solvents, and the influence of the temperature, which would be able to induce the phase transition from a liquid crystal to a stable nanoemulsion, assessed for four months. Additionally, cationic-covered nanoemulsion with hyper-branched poly(ethyleneimine) was prepared and its performance was compared to the non-cationic ones. The physicochemical properties of the selected nanoemulsions and the interactions among their involved formulation compounds were carefully monitored. The cytotoxicity studies in murine macrophages (RAW 264.7) and red blood cells were used to compare different formulations. Moreover, the performance of the nanoemulsion systems as biocompatible adjuvants was evaluated using mice immunization protocol. The FTIR shifts and the zeta potential changes (from −18.3 ± 1.0 to + 8.4 ± 1.4) corroborated with the expected supramolecular anchoring of venom proteins on the surface of the nanoemulsion droplets. Cell culture assays demonstrated the non-toxicity of the formulations at concentrations less than 1.0 mg/mL, which were able to inhibit the hemolytic effect of the scorpion venom. The cationic-covered nanoemulsion has shown superior adjuvant activity, revealing the highest IgG titer in the immunized animals compared to both the non-cationic counterpart and the traditional aluminum adjuvant. In this approach, we demonstrate the incredible potential application of nanoemulsions as adjuvants, using a nanotechnology platform for antigen delivery system on immune cells. Additionally, the functionalization with hyper-branched poly(ethyleneimine) enhances this recognition and improves its action in immunization

Therapeutic bullfrog oil-based nanoemulsion for oral application: Development, characterization and stability.

The aim of this study was to develop, optimize, and characterize a stable therapeutic bullfrog oil based nanoemulsion for oral application using a rational experimental design approach. The optimized oral nanoemulsion contained 0.2 % sodium benzoate and 0.02 % propyl-paraben as preservatives; 0.1 % sucralose and 0.4 % acesulfam K as sweeteners and 0.1 % tutti-frutti as flavoring to mask the unpleasant organoleptic characteristics of bullfrog oil. The oral O/W-nanoemulsion showed the droplet size, PDI, zeta potential, and pH of 410 ± 8 nm, 0.20 ± 0.02, -38 ± 2.5 mV, and 6.43 ± 0.05, respectively. The optimized oral nanoemulsion showed a milky single-phase and optimal physical stability at 25 °C for 90 days. Indeed, higher oxidation induction time and lower formation of peroxides in the oral nanoemulsion were responsible for improving its stability. A therapeutic delivery system containing bullfrog oil for oral application was successfully developed and optimized with ideal thermo-oxidative stability.

A Functional Wound Dressing as a Potential Treatment for Cutaneous Leishmaniasis.

Cutaneous leishmaniasis (CL) is a parasitic disease characterized by progressive skin sores. Currently, treatments for CL are limited to parenteral administration of the drug, which presents severe adverse effects and low cure rates. Therefore, this study aimed to develop poly(vinyl-alcohol) (PVA) hydrogels containing Amphotericin B (AmB) intended for topical treatment of CL. Hydrogels were evaluated in vitro for their potential to eliminate promastigote forms of Leishmania spp., to prevent secondary infections, to maintain appropriate healing conditions, and to offer suitable biocompatibility. AmB was incorporated into the system in its non-crystalline state, allowing it to swell more and faster than the system without the drug. Furthermore, the AmB release profile showed a continuous and controlled behavior following Higuchi´s kinetic model. AmB-loaded-PVA-hydrogels (PVA-AmB) also showed efficient antifungal and leishmanicidal activity, no cytotoxic potential for VERO cells, microbial impermeability and water vapor permeability compatible with the healthy skin's physiological needs. Indeed, these results revealed the potential of PVA-AmB to prevent secondary infections and to maintain a favorable environment for the healing process. Hence, these results suggest that PVA-AmB could be a suitable and efficient new therapeutic approach for the topical treatment of CL.

Protective effect of aqueous extract, fractions and phenolic compounds of Hancornia speciosa fruits on the inflammatory damage in the lungs of mice induced by Tityus serrulatus envenomation.

Scorpion envenomation has been considered a public health issue around the world. Tityus serrulatus represents a specie of major medical importance in Brazil due to mortality rates of approximately 1% among children and elderly populations. The aim of this work was to evaluate the in vivo anti-inflammatory potential of aqueous extract from Hancornia speciosa fruits, its fractions and its phenolic compounds against T. serrulatus envenomation. After receiving the T. serrulatus venom (TsV, 0.8 mg/kg) intraperitoneally, the animals were treated intravenously with the aqueous extract (20, 30 and 40 mg/kg), the arachnid antivenom (50 µL/animal), the dichloromethane, ethyl acetate and n-butanol fractions (20 mg/kg) as well as rutin and chlorogenic acid (2, 2.5 and 5 mg/kg). The treatment with the aqueous extract, fractions and phenolic compounds decreased the migration of leukocytes to the peritoneal cavity and reduced the levels of IL-1ß, IL-6 and IL-12. Moreover, the pulmonary histopathologic analysis showed a reduction in both interstitial and alveolar edema, as well as in the leukocytes infiltration and vascular ectasia in the mice's lungs, which evidences a protective effect attributed to H. speciosa. This is the first study that demonstrates the inhibitory potential of the aqueous extract from H. speciosa fruits against inflammation induced by TsV. These findings suggest that the bioactive compounds from the aqueous extract, especially chlorogenic acid and rutin, are responsible for the reported anti-inflammatory activity of H. speciosa.

Improving Encapsulation of Hydrophilic Chloroquine Diphosphate into Biodegradable Nanoparticles: A Promising Approach against Herpes Virus Simplex-1 Infection.

Chloroquine diphosphate (CQ) is a hydrophilic drug with low entrapment efficiency in hydrophobic nanoparticles (NP). Herpes simplex virus type 1 (HSV-1) is an enveloped double-stranded DNA virus worldwide known as a common human pathogen. This study aims to develop chloroquine-loaded poly(lactic acid) (PLA) nanoparticles (CQ-NP) to improve the chloroquine anti- HSV-1 efficacy. CQ-NP were successfully prepared using a modified emulsification-solvent evaporation method. Physicochemical properties of the NP were monitored using dynamic light scattering, atomic force microscopy, drug loading efficiency, and drug release studies. Spherical nanoparticles were produced with modal diameter of <300 nm, zeta potential of -20 mv and encapsulation efficiency of 64.1%. In vitro assays of CQ-NP performed in Vero E6 cells, using the MTT-assay, revealed different cytotoxicity levels. Blank nanoparticles (B-NP) were biocompatible. Finally, the antiviral activity tested by the plaque reduction assay revealed greater efficacy for CQ-NP compared to CQ at concentrations equal to or lower than 20 µg mL-1 (p < 0.001). On the other hand, the B-NP had no antiviral activity. The CQ-NP has shown feasible properties and great potential to improve the antiviral activity of drugs.

In-vitro and in-vivo antileishmanial activity of inexpensive Amphotericin B formulations: Heated Amphotericin B and Amphotericin B-loaded microemulsion.

Amphotericin B (AmB) is effective against visceral leishmaniasis (VL), but the renal toxicity of the conventional form, mixed micelles with deoxycholate (M-AmB), is often dose-limiting, while the less toxic lipid-based formulations such as AmBisome® are very expensive. Two different strategies to improve the therapeutic index of AmB with inexpensive ingredients were evaluated on this work: (i) the heat treatment of the commercial formulation (H-AmB) and (ii) the preparation of an AmB-loaded microemulsion (ME-AmB). M-AmB was heated to 70 °C for 20 min. The resulting product was characterized by UV spectrophotometry and circular dichroism, showing super-aggregates formation. ME-AmB was prepared from phosphate buffer pH 7.4, Tween 80®, Lipoid S100® and Mygliol 812® with AmB at 5 mg/mL. The droplet size, measured by dynamic light scattering, was about 40 nm and transmission electron microscopy confirmed a spherical shape. Rheological analysis showed low viscosity and Newtonian behavior. All the formulations were active in vitro and in vivo against Leishmania donovani (LV9). A selectivity index (CC50 on RAW/IC50 on LV9) higher than 10 was observed for ME-AmB, H-AmB and AmBisome®. Furthermore, no important in vivo toxicity was observed for all the samples. The in-vivo efficacy of the formulations after IV administration was evaluated in Balb/C mice infected with LV9 (three doses of 1 mg/kg AmB) and no significant difference was observed between H-AmB, M-AmB, ME-AmB and AmBisome®. In conclusion, these two inexpensive alternative formulations for AmB showing good efficacy and selectivity for Leishmania donovani merit further investigation.

An analytical GC-MS method to quantify methyl dihydrojasmonate in biocompatible oil-in-water microemulsions: physicochemical characterization and in vitro release studies.

Microemulsions (MEs) loaded with methyl dihydrojasmonate (MJ) were developed to improve the aqueous solubility of this drug. The composition of the formulations ranged according to the oil/surfactant ratio (O/S). The MEs were characterized according to diameter of droplets, X-ray diffraction and polarized light microscopy. The MJ identification and quantification was performed by gas chromatography-mass spectrometry (GC-MS). The MJ showed a retention time of ∼16.7 min for all samples. The obtained correlation coefficient from the calibration graph was 0.991. The developed analytical method was effective enough to quantify low and high concentrations of MJ. The increase of the O/S ME ratio led to a reduction of the droplet diameter. All formulations showed an amorphous structure and the behavior varied between isotropic and anisotropic systems. A decrease in the release of MJ with the increase of the O/S ratio in the formulations was observed. The analytical method developed for the quantitative determination of MJ is suitable to detect and quantify the drug compound from different compositions of MEs in the in vitro release test, and by analogy in other prolonged effects related to the drug reservoir effect of these systems was observed, revealing that ME can be a promising nanocarrier for MJ delivery to tumor cells.

Understanding Drug Release Data through Thermodynamic Analysis.

Understanding the factors that can modify the drug release profile of a drug from a Drug-Delivery-System (DDS) is a mandatory step to determine the effectiveness of new therapies. The aim of this study was to assess the Amphotericin-B (AmB) kinetic release profiles from polymeric systems with different compositions and geometries and to correlate these profiles with the thermodynamic parameters through mathematical modeling. Film casting and electrospinning techniques were used to compare behavior of films and fibers, respectively. Release profiles from the DDSs were performed, and the mathematical modeling of the data was carried out. Activation energy, enthalpy, entropy and Gibbs free energy of the drug release process were determined. AmB release profiles showed that the relationship to overcome the enthalpic barrier was PVA-fiber > PVA-film > PLA-fiber > PLA-film. Drug release kinetics from the fibers and the films were better fitted on the Peppas-Sahlin and Higuchi models, respectively. The thermodynamic parameters corroborate these findings, revealing that the AmB release from the evaluated systems was an endothermic and non-spontaneous process. Thermodynamic parameters can be used to explain the drug kinetic release profiles. Such an approach is of utmost importance for DDS containing insoluble compounds, such as AmB, which is associated with an erratic bioavailability.