Targeted Drug Delivery and Treatment of Endoparasites with Biocompatible Particles of pH-Responsive Structure.

Biomaterials conceived for vectorization of bioactives are currently considered for biomedical, biological, and environmental applications. We have produced a pH-sensitive biomaterial composed of natural source alginate and chitosan polysaccharides for application as a drug delivery system via oral administration. The composite particle preparation was in situ monitored by means of isothermal titration calorimetry. The strong interaction established between the macromolecules during particle assembly led to 0.60 alginate/chitosan effective binding sites with an intense exothermic effect and negative enthalpy variation on the order of a thousand kcal/mol. In the presence of model drugs mebendazole and ivermectin, with relatively small and large structures, respectively, mebendazole reduced the amount of chitosan monomers available to interact with alginate by 27%, which was not observed for ivermectin. Nevertheless, a state of intense negative Gibbs energy and large entropic decrease was achieved, providing evidence that formation of particles is thermodynamically driven and favored. Small-angle X-ray scattering provided further evidence of similar surface aspects independent of the presence of drug. The physical responses of the particles to pH variation comprise partial hydration, swelling, and the predominance of positive surface charge in strong acid medium, whereas ionization followed by deprotonation leads to compaction and charge reversal rather than new swelling in mild and slightly acidic mediums, respectively. In vivo performance was evaluated in the treatment of endoparasites in Corydoras fish. Systematically with a daily base oral administration, particles significantly reduced the infections over 15 days of treatment. The experiments provide evidence that utilizing particles granted and boosted the action of the antiparasitic drugs, leading to substantial reduction or elimination of infection. Hence, the pH-responsive particles represent a biomaterial with prominent characteristics that is promising for the development of targeted oral drug delivery.

Effect of matrix composition, sphere size and hormone concentration on diffusion coefficient of insulin for controlled gastrointestinal delivery for diabetes treatment.

Oral insulin administration is limited due to its degradation by proteases. The hormone was encapsulated in spheres made of either pure calcium alginate (ALG) or its association with whey protein isolate (WPI-ALG) in order to minimise loss in the stomach region while allowing liberation in the maximum absorption area, located in the intestine. Diffusion coefficients for both matrix compositions were determined in vitro for gastric pH (5.88 and 10.26 × 10-12 m2 s-1) and intestinal pH (21.11 and 79.29 × 10-12 m2 s-1). Higher initial insulin concentrations and lower diameters accelerated its release, confirming Fickian behaviour. The analytic model exhibited a good fit in most cases. Computer simulations revealed that ALG spheres are more convenient for oral administration because they release more insulin in the intestine than the WPI-ALG ones, thus supporting its therapeutic viability for the purpose of reducing stress in those who depend on insulin.

In Situ Gelation-Induced Death of Cancer Cells Based on Proteinosomes.

Hydrogels are an excellent type of material that can be utilized as a platform for cell culture. However, when a bulky hydrogel forms on the inside of cancer cells, the result would be different. In this study, we demonstrate a method for in situ gelation inside cancer cells that can efficiently induce cell death. Glutathione-responsive proteinosomes with good biocompatibility were prepared as carriers for sodium alginate to be endocytosed by cancer cells, where the chelation between sodium alginate and free calcium ions in the culture medium occurs during the diffusion process. The uptake of the hydrogel-loaded proteinosomes into the cancer cells, and then the triggered release of hydrogel with concomitant aggregation, was well-confirmed by monitoring the change of the Young's modulus of the cells based on AFM force measurements. Accordingly, when a large amount of hydrogel formed in cells, the cell viability would be inhibited by ∼90% by MTT assay at a concentration of 5.0 µM of hydrogel-loaded proteinosomes after 48 h incubation, which clearly proves the feasibility of the demonstrated method for killing cancer cells. Although more details regarding the mechanism of cell death should be conducted in the near future, such a demonstrated method of in situ gelation inside cells provides another choice for killing cancer cells.

Experimental and simulation studies on focused ultrasound triggered drug delivery.

To improve drug delivery efficiency in cancer therapy, many researchers have recently concentrated on drug delivery systems that use anticancer drug loaded micro- or nanoparticles. In addition, induction methods, such as ultrasound, magnetic field, and infrared light, have been considered as active induction methods for drug delivery. Among these, focused ultrasound has been regarded as a promising candidate for the active induction method of drug delivery system because it can penetrate a deep site in soft tissue, and its energy can be focused on the targeted lesion. In this research, we employed focused ultrasound as an active induction method. For an anticancer drug loaded microparticles, we fabricated poly-lactic-co-glycolic acid docetaxel (PLGA-DTX) nanoparticle encapsulated alginate microbeads using the single-emulsion technique and the aeration method. To select the appropriate operating parameter for the focused ultrasound, we measured the pressure and temperature induced by the focused ultrasound at the focal area using a needle-type hydrophone and a digital thermal detector, respectively. Additionally, we conducted a simulation of focused ultrasound using COMSOL Multiphysics 4.3a. The experimental measurement results were compared with the simulation results. In addition, the drug release rates of the PLGA-DTX-encapsulated alginate microbeads induced by the focused ultrasound were tested. Through these experiments, we determined that the appropriate focused ultrasound parameter was peak pressure of 1 MPa, 10 cycle/burst, and burst period of 20 µSec. Finally, we performed the cell cytotoxicity and drug uptake test with focused ultrasound induction and found that the antitumor effect and drug uptake efficiency were significantly enhanced by the focused ultrasound induction. Thus, we confirmed that focused ultrasound can be an effective induction method for an anticancer drug delivery system.

Refilling drug delivery depots through the blood.

Local drug delivery depots have significant clinical utility, but there is currently no noninvasive technique to refill these systems once their payload is exhausted. Inspired by the ability of nanotherapeutics to target specific tissues, we hypothesized that blood-borne drug payloads could be modified to home to and refill hydrogel drug delivery systems. To address this possibility, hydrogels were modified with oligodeoxynucleotides (ODNs) that provide a target for drug payloads in the form of free alginate strands carrying complementary ODNs. Coupling ODNs to alginate strands led to specific binding to complementary-ODN-carrying alginate gels in vitro and to injected gels in vivo. When coupled to a drug payload, sequence-targeted refilling of a delivery depot consisting of intratumor hydrogels completely abrogated tumor growth. These results suggest a new paradigm for nanotherapeutic drug delivery, and this concept is expected to have applications in refilling drug depots in cancer therapy, wound healing, and drug-eluting vascular grafts and stents.

Preclinical and pharmacotoxicology evaluation of α-l-guluronic acid (G2013) as a non-steroidal anti-inflammatory drug with immunomodulatory property.

CONTEXT: Therapeutic effects of α-l-guluronic acid with the greatest tolerability and efficacy (G2013) have been shown in experimental model of multiple sclerosis and other in vitro and in vivo examinations regarding α-l-guluronic acid; there are no toxicological researches on its safety although the pharmacological impacts have been recorded. OBJECTIVE: This study was designed to determine the acute and sub chronic toxicity of α-l-guluronic acid in healthy male and female BALB/c mice. MATERIALS AND METHODS: For the acute toxicity study, the animals orally received five different single doses of α-l-guluronic acid and were kept under observation for 14 d. In the sub-chronic study, 24 male and female BALB/c mice were divided into four groups and treated daily with test substance preparation at dose levels of 0, 50, 250, and 1250 mg/kg body weight for at least 90 consecutive days. The mortality, body weight changes, clinical signs, hematological and biochemical parameters, gross findings, histopathological, and organs weight determinants were monitored during this study. RESULTS: The results of acute toxicity indicated that the LD50 of α-l-guluronic acid is 4.8 g/kg. We found no mortality or abnormality in clinical signs, body weight, relative organs weight, or necropsy in any of the animals in the subchronic study. Additionally, the results showed no significant difference in hematological, biochemical, and histopathological parameters in rats. CONCLUSIONS: Our results suggest that α-l-guluronic acid has high safety when administered orally in animals.

Development and evaluation of alginate-chitosan gastric floating beads loading with oxymatrine solid dispersion.

Oxymatrine (OM) can be metabolized to matrine in gastrointestinal ileocecal valve after oral administration, which affects pharmacological activity and reduce bioavailability of OM. A type of multiple-unit alginate-chitosan (Alg-Cs) floating beads was prepared by the ionotropic gelation method for gastroretention delivery of OM. A solid dispersion technique was applied and incorporated into beads to enhance the OM encapsulation efficiency (EE) and sustain the drug release. The surface morphology and internal hollow structure of beads were evaluated using optical microscopy and scanning electron microscopy (SEM). The developed Alg-Cs beads were spherical in shape with hollow internal structure and had particle size of 3.49 ± 0.09 mm and 1.33 ± 0.09 mm for wet and dried beads. Over 84% of the optimized OM solid dispersion-loaded Alg-Cs beads were able to continuously float over the simulated gastric fluid for 12 h in vitro. The OM solid dispersion-loaded Alg-Cs beads showed drug EE of 67.07%, which was much higher than that of beads loading with pure OM. Compared with the immediate release of OM capsules and pure OM-loaded beads, the release of OM from solid dispersion-loaded Alg-Cs beads was in a sustained-release manner for 12 h. Prolonged gastric retention time of over 8.5 h was achieved for OM solid dispersion-loaded Alg-Cs floating beads in healthy rabbit in in vivo floating ability evaluated by X-ray imaging. The developed Alg-Cs beads loading with OM solid dispersion displayed excellent performance features characterized by excellent gastric floating ability, high drug EE and sustained-release pattern. The study illustrated the potential use of Alg-Cs floating beads combined with the solid dispersion technique for prolonging gastric retention and sustaining release of OM, which could provide a promising drug delivery system for gastric-specific delivery of OM for bioavailability enhancement.

Novel in situ gelling ocular inserts for voriconazole-loaded niosomes: design, in vitro characterisation and in vivo evaluation of the ocular irritation and drug pharmacokinetics.

This work aimed to develop voriconazole in situ gelling ocular inserts loaded with niosomal suspension. Niosomes and mixed niosomes were prepared using span 40 and span 60 with pluronic L64 and pluronic F127. The entrapment efficiency percentages (EE%), mean vesicle size, polydispersity index (PI), zeta potential and in vitro drug release of these niosomes were evaluated. F3-mixed niosomes prepared with span 60 and pluronic L64 was selected, due to its highest EE; optimum vesicle size with smallest PdI and suitable release pattern of the drug (63% after 8 h). In situ ocular inserts were prepared using sodium carboxymethylcellulose (CMC Na) and sodium alginate (ALG) and characterised for surface morphology, surface pH, water uptake, mucoadhesion and in vitro release. ALG in situ ocular insert (S2) was selected for further in vivo evaluation of the ocular irritation and drug pharmacokinetics in the aqueous humour of rabbit's eyes. S2 in situ gelling ocular insert was non-irritant and showed significantly (p < 0.01) higher Cmax, delayed Tmax and increased bioavailability.

X-ray visible and uniform alginate microspheres loaded with in situ synthesized BaSO4 nanoparticles for in vivo transcatheter arterial embolization.

The lack of noninvasive tracking and mapping the fate of embolic agents has restricted the development and further applications of the transcatheter arterial embolization (TAE) therapy. In this work, inherent radiopaque embolic material, barium alginate (ALG) microspheres loaded with in situ synthesized BaSO4 (denoted as BaSO4/ALG microspheres), have been synthesized by a one-step droplet microfluidic technique. One of the advantages of our microfluidic approach is that radiopaque BaSO4 is in the form of nanoparticles and well dispersed inside ALG microspheres, thereby greatly enhancing the imaging quality. The crystal structure of in situ synthesized BaSO4 nanoparticles in ALG microspheres is confirmed by X-ray diffraction analysis. Results of in vitro and in vivo assays from digital subtraction angiography and computed tomography scans demonstrate that BaSO4/ALG microspheres possess excellent visibility under X-ray. Histopathological analysis verifies that the embolic efficacy of BaSO4/ALG microspheres is similar to that of commercially available alginate microsphere embolic agents. Furthermore, the visibility of radiopaque BaSO4/ALG microspheres under X-ray promises the direct detection of the embolic efficiency and position of embolic microspheres after embolism, which offers great promises in direct real-time in vivo investigations for TAE.

Release and swelling studies of an innovative antidiabetic-bile acid microencapsulated formulation, as a novel targeted therapy for diabetes treatment.

In previous studies carried out in our laboratory, a bile acid formulation exerted a hypoglycaemic effect in a rat model of type 1 diabetes (T1D). When the antidiabetic drug gliclazide was added to the bile acid, it augmented the hypoglycaemic effect. In a recent study, we designed a new formulation of gliclazide-deoxycholic acid (G-DCA), with good structural properties, excipient compatibility and which exhibited pseudoplastic-thixotropic characteristics. The aim of this study is to test the slow release and pH controlled properties of this new formulation. The aim is also to examine the effect of DCA on G release kinetics at various pH values and different temperatures. Microencapsulation was carried out using our Buchi-based microencapsulating system developed in our laboratory. Using sodium alginate (SA) polymer, both formulations were prepared including: G-SA (control) and G-DCA-SA (test) at a constant ratio (1:3:30), respectively. Microcapsules were examined for efficiency, size, release kinetics, stability and swelling studies at pH 1.5, 3, 7.4 and 7.8 and temperatures of 25 °C and 37 °C. The new formulation is further optimised by the addition of DCA. DCA reduced bead-swelling of the microcapsules at pH 7.8 and 3 at 25 °C and 37 °C, and even though bead size remains similar after DCA addition, the percentage of G release was enhanced at high pH values (pH 7.4 and 7.8, p < 0.01). The new formulation exhibits colon-targeted delivery and the addition of DCA prolonged G release suggesting its suitability for the sustained and targeted delivery of G and DCA to the lower intestine.

Multifunctional interpenetrating polymer network hydrogels based on methacrylated alginate for the delivery of small molecule drugs and sustained release of protein.

Multifunctional injectable thermo-/pH-responsive hydrogels as release systems for the oral delivery of small molecule drugs and the local delivery of protein are presented. The injectable interpenetrating polymer network (IPN) hydrogels based on poly(ethylene glycol) methacrylate, N-isopropylacrylamide, and methacrylated alginate were prepared by using ammonium persulfate (APS) and N,N,N',N'-tetramethylethylenediamine (TEMED) as a redox initiator system at body temperature, and the obtained hydrogels overcame the instability of calcium cross-linked alginate hydrogels under physiological conditions. The hydrogels showed good mechanical strength by rheometer and exhibited temperature and pH sensitivity by a swelling test. Diclofenac sodium (DCS) as a model for small molecule water-soluble anti-inflammatory drugs and bovine serum albumin (BSA) as a model for protein drugs were encapsulated in situ in the hydrogel. The DCS and BSA release results indicated that these hydrogels, as carriers, have great potential for use in the oral delivery of small molecule drugs and for long-term localized protein release. Furthermore, the cytotoxicity of these hydrogels was studied via live/dead viability and alamarBlue assays using adipose tissue-derived mesenchymal stem cells.

Development of a novel drug delivery system: chitosan nanoparticles entrapped in alginate microparticles.

A novel carrier using chitosan nanoparticles entrapped into alginate microparticles is proposed for protecting molecules of interest from degradation in the digestive tract. The effects of polymer concentration, sonication, stirring, pH, and processing conditions on the physical characteristics of the carrier were studied. FITC and RBITC were used to localise the polymers within particles using CLSM. Diffusion of amaranth red (AR) from nanoparticles was quantified during dissolution under gastric and intestinal conditions. Under optimal preparation conditions, the size distribution of nanoparticles loaded with AR was uniform (690 nm) with an encapsulation efficacy of 21.9%. Alginate microparticles (285 µm) containing a homogenous distribution of nanoparticles and polymers were obtained. At gastric pH, the carrier released less than 5% of the loaded AR and, at intestinal pH, the release was rapid and complete. The drug carriers developed shows a promising use as a vehicle suitable to protect molecules of interest after oral administration.

Fast-dissolving sublingual films of terbutaline sulfate: formulation and in vitro/in vivo evaluation.

Terbutaline sulfate fast dissolving sublingual films were prepared using seven drug compatible film formers in different combinations and proportions. The film polymers are maltodextrin, Na alginate, Carpabol 430, xanthan gum, HPMC E5, PVP K-25, and Na CMC. Propylene glycol and sorbitol were used as plasticizers and mannitol as filler. The optimum polymer concentrations and the plasticizer amount were selected on the basis of flexibility, tensile strength, and stickiness of the films. The prepared films were evaluated for their tensile strength, thickness uniformity, disintegration time (in vitro and in vivo), in vitro dissolution, and moisture content. Polymer type rather than total polymer concentration or plasticizer amount showed a significant effect on the tested film properties. A randomized, single dose, crossover study was conducted in four healthy volunteers to compare the pharmacokinetic profile of terbutaline sulfate from the prepared films and the conventional oral tablets. The film formula of choice gave a significantly faster drug absorption rate and recorded a relative bioavailability of 204.08%. Sublingual films could be promising as a convenient delivery system for terbutaline sulfate in patients with swallowing problems. The improved extent of absorption (higher AUC(0-24)) indicates success in improving drug bioavailability, and the faster absorption rate could be promising for the management of acute episodes of asthma.

Mechanisms for eliminating monoterpenes of sagebrush by specialist and generalist rabbits.

Pygmy rabbits (Brachylagus idahoensis) are one of only three vertebrates that subsist virtually exclusively on sagebrush (Artemisia spp.), which contains high levels of monoterpenes that can be toxic. We examined the mechanisms used by specialist pygmy rabbits to eliminate 1,8-cineole, a monoterpene of sagebrush, and compared them with those of cottontail rabbits (Sylvilagus nuttalli), a generalist herbivore. Rabbits were offered food pellets with increasing concentrations of cineole, and we measured voluntary intake and excretion of cineole metabolites in feces and urine. We expected pygmy rabbits to consume more, but excrete cineole more rapidly by using less-energetically expensive methods of detoxification than cottontails. Pygmy rabbits consumed 3-5 times more cineole than cottontails relative to their metabolic body mass, and excreted up to 2 times more cineole metabolites in their urine than did cottontails. Urinary metabolites excreted by pygmy rabbits were 20 % more highly-oxidized and 6 times less-conjugated than those of cottontails. Twenty percent of all cineole metabolites recovered from pygmy rabbits were in feces, whereas cottontails did not excrete fecal metabolites. When compared to other mammals that consume cineole, pygmy rabbits voluntarily consumed more, and excreted more cineole metabolites in feces, but they excreted less oxidized and more conjugated cineole metabolites in urine. Pygmy rabbits seem to have a greater capacity to minimize systemic exposure to cineole than do cottontails, and other cineole-consumers, by minimizing absorption and maximizing detoxification of ingested cineole. However, mechanisms that lower systemic exposure to cineole may come with a higher energetic cost in pygmy rabbits than in other mammalian herbivores.

Preparation and characterization of nicotine-magnesium aluminum silicate complex-loaded sodium alginate matrix tablets for buccal delivery.

Nicotine (NCT) buccal tablets consisting of sodium alginate (SA) and nicotine-magnesium aluminum silicate (NCT-MAS) complexes acting as drug carriers were prepared using the direct compression method. The effects of the preparation pH levels of the NCT-MAS complexes and the complex/SA ratios on NCT release, permeation across mucosa, and mucoadhesive properties of the tablets were investigated. The NCT-MAS complex-loaded SA tablets had good physical properties and zero-order release kinetics of NCT, which indicate a swelling/erosion-controlled release mechanism. Measurement of unidirectional NCT release and permeation across porcine esophageal mucosa using a modified USP dissolution apparatus 2 showed that NCT delivery was controlled by the swollen gel matrix of the tablets. This matrix, which controlled drug diffusion, resulted from the molecular interactions of SA and MAS. Tablets containing the NCT-MAS complexes prepared at pH 9 showed remarkably higher NCT permeation rates than those containing the complexes prepared at acidic and neutral pH levels. Larger amounts of SA in the tablets decreased NCT release and permeation rates. Additionally, the presence of SA could enhance the mucoadhesive properties of the tablets. These findings suggest that SA plays the important role not only in controlling release and permeation of NCT but also for enhancing the mucoadhesive properties of the NCT-MAS complex-loaded SA tablets, and these tablets demonstrate a promising buccal delivery system for NCT.

Bioactive long-term release from biodegradable microspheres preserves implanted ALG-PLO-ALG microcapsules from in vivo response to purified alginate.

PURPOSE: To assess whether prevention of unexpected in vivo adverse inflammatory and immune responses to biohybrid organ grafts for the treatment of Type I Diabetes Mellitus (T1DM) is possible by superoxide dismutase and ketoprofen controlled release. METHODS: Superoxide dismutase and ketoprofen-loaded polyester microspheres were prepared by W/O/W and O/W methods, embodied into purified alginate-poly-L-ornithine-alginate microcapsules and intraperitoneally implanted into CD1 mice. The microspheres were characterized for morphology, size, encapsulation efficiency, enzyme activity and in vitro release. Purified alginate contaminants were assayed, and the obtained microcapsules were investigated for size and morphology before and after implantation over 30 days. Cell pericapsular overgrowth and expression were evaluated by optical microscopy and flow cytometry. RESULTS: Superoxide dismutase and ketoprofen sustained release reduced cell pericapsular overgrowth in comparison to the control. Superoxide dismutase release allowed preserving the microcapsules over 30 days. Ketoprofen-loaded microspheres showed some effect in the immediate post-grafting period. A higher macrophage and T-cell expression was observed for the control group. CONCLUSIONS: Microspheres containing superoxide dismutase and ketoprofen may represent novel tools to limit or prevent unpredictable adverse in vivo response to alginate, thus contributing to improve cell transplantation success rates in T1DM treatment.

Sustained release of multiple growth factors from injectable polymeric system as a novel therapeutic approach towards angiogenesis.

PURPOSE: The aim was to investigate that a bio-degradable alginate and poly lactide-co-glycolide (PLG) system capable of delivering growth factors sequentially would be superior to single growth factor delivery in promoting neovascularization and improving perfusion. METHODS: Three groups of apoE null mice underwent unilateral hindlimb ischemia surgery and received ischemic limb intramuscular injections of alginate (Blank), alginate containing VEGF(165) (VEGF), or alginate containing VEGF(165) combined with PLG microspheres containing PDGF-BB (VEGF/PDGF). Vascularity in the ischemic hindlimb was assessed by morphologic and immunohistochemical end-points, while changes in blood flow were assessed by Laser Doppler Perfusion Index. Muscle VEGF and PDGF content was assessed at multiple time points. RESULTS: In the VEGF/PDGF group, local tissue VEGF and PDGF levels peaked at week 2 and 4, respectively, with detectable PDGF levels at week 6. At week 6, mean vessel mean diameter was significantly greater in the VEGF/PDGF group compared to the VEGF or Blank groups with evidence of well-formed smooth muscle-lined arterioles. CONCLUSIONS: Sequential delivery of VEGF and PDGF using an injectable, biodegradable platform resulted in stable and sustained improvements in perfusion. This sustained, control-released, injectable alginate polymer system is a promising approach for multiple growth factor delivery in clinical application.

Alginate-antacid combinations: raft formation and gastric retention studies.

BACKGROUND: Alginate-based gastroesophageal reflux disease treatments have been used extensively and fall into two main categories. Those containing alginate as the principle active agent and those containing alginate in combination with a significant amount of antacid. METHOD: The effectiveness of the raft formed by a new alginate/antacid suspension (Gaviscon Double Action Liquid, GDAL), in which calcium carbonate was the main antacid ingredient, was compared with those of existing alginate/antacid suspensions. RESULT: GDAL had similar raft strength and improved raft resilience than Gaviscon Liquid (GL), and both were significantly greater than five other products tested. Gastric retention of GDAL was similar to that of GL. CONCLUSION: the in vitro and in vivo performance is maintained in the new GDAL formulation even with higher antacid levels and the product is as good as, or better than, previous formulations.

[Antihypertensive effect and pharmacokinetics of low molecular mass potassium alginate].

OBJECTIVE: To investigate the effect of low molecular weight potassium alginate (L-PA) on blood pressures in spontaneously hypertensive rats (SHRs) and its pharmacokinetics characteristics in mice. METHODS: The systolic blood pressure (SBP) was measured by tail-cuff method in conscious SHRs. Forty rats were randomly assigned to the following five groups: control, hydrochlorothiazide (HCT, 6.25 mg/kg), L-PA in low, middle or high dose groups (100, 250, 500 mg/kg). SHRs were intragastrically (i. g.) administrated once daily for 28 days. The SBP was measured once weekly during drug treatment, and 3 and 6 days after drug with drawal. KM mice were i. g. administered with 100 mg/kg (74 MBq/kg) of 3H-L-PA. Ten microl blood samples were obtained from the tail vein at 2, 5, 10, 20, 30 min and 1, 2, 4, 6, 12, 24, 48, 72, 96, 120 or 144 h after drug administration for measuring radioactivities. Pharmacokinetics parameters of the oral administration of L-PA were analysed with DAS 2.0 software. RESULTS: Twenty-one or 28 days after administration, the rats in the groups treated with HCT or L-PA at 100, 250 or 500 mg/kg had a significant decrease in SBP (P<0.01 vs control group). Three or 6 days after drug withdrawal, the antihypertensive effect of HCT disappeared (P>0.05), whereas the rats treated with 250 or 500 mg/kg L-PA still had lower SBP than the controls (P<0.01). The L-PA at a dose of 100 mg/kg also led to a significant decrease in SBP 3 days after drug withdrawal (P<0.05). The pharmacokinetics of L-PA (i. g.) was consistent with a two-compartment model, with 2.76 h of absorption half-life (t1/2, Ka), 42. 30 h of distributional half-life (t1/2alpha), 42. 31 h of elimination half-life (t1/2beta), and 36.28 h of terminal phase elimination half-life (t1/2z). CONCLUSION: Oral administration of L-PA has significant anti-hypertensive effect, which can be maintained to 6 days after drug withdrawal. The sustaining anti-hypertensive effect of L-PA is probably associated with its slow elimination in vivo.

In-vivo evaluation in rats of colon-specific microspheres containing 5-fluorouracil.

The aims of this investigation were to determine the distribution in the gastrointestinal (GI) tract of Eudragit S-100 encapsulated colon-specific sodium alginate microspheres containing 5-fluorouracil (5-FU) in rats, and to perform pharmacokinetic and pharmacodynamic studies. Comparisons were with a control immediate-release (IR) formulation of 5-FU. 5-FU was distributed predominantly in the upper GI tract from the IR formulation but was distributed primarily to the lower part of the GI tract from the microsphere formulation. No drug was released in the stomach and intestinal regions from the colon-specific microspheres. Significantly, a high concentration of the active drug was achieved in colonic tissues from the colon-specific microspheres (P < 0.001), which was higher than the IC50 required to halt the growth of and/or kill colon cancer cells. Colon cancer was induced in rats by subcutaneous injection of 1,2-dimethylhydrazine (40 mg kg (-1)) for 10 weeks. The tumours induced were non-invasive adenocarcinomas and were in Duke's stage A. The 5-FU formulations were administered for 4 weeks after tumour induction. Non-significant reductions in tumour volume and multiplicity were observed in animals given the colon-specific microspheres. Enhanced levels of liver enzymes (SGOT, SGPT and alkaline phosphatase) were found in animals given the IR formulation of 5-FU, and values differed significantly (P < 0.001) from those in animals treated with the colon-specific microspheres. Elevated levels of serum albumin and creatinine, and leucocytopenia and thrombocytopenia were observed in the animals given the IR formulation. In summary, Eudragit S-100 coated alginate microspheres delivered 5-FU to colonic tissues, with reduced systemic side-effects. A long-term dosing study is required to ascertain the therapeutic benefits.