A phase I/II randomized, controlled, clinical trial for assessment of the efficacy and safety of ß-D-mannuronic acid in rheumatoid arthritis patients.

BACKGROUND: Following the potent efficacy of ß-D-mannuronic acid (M2000) in phase I/II trial in ankylosing spondylitis patients, the present clinical trial was conducted to evaluate the efficacy, safety, and tolerability of this novel drug in rheumatoid arthritis (RA) patients who had inadequate response to conventional therapy. METHOD: The study was a 12-week randomized, controlled, phase I/II clinical trial with two treatment arms: M2000 and conventional treatment. Patients who had RA according to the modified American College of Rheumatology (ACR) criteria, with active disease at baseline also inadequate response to conventional therapy, were enrolled in this study. M2000 was administrated at a dose of two capsules (500 mg) per day orally during a period of 12 weeks. The primary endpoint was the proportion of patients fulfilling the ACR 20% improvement criteria after 12 weeks of M2000 therapy. Moreover, the patients were also followed up for safety. RESULTS: There were no statistically significant differences between treatment and conventional groups at baseline characteristics. The ACR20 response rate was significantly higher among M2000-treated patients than conventional-treated control, so that 74% of patients in treatment group showed an ACR20 response after 12 weeks of M2000 therapy (74 versus 16%; P = 0.011). 10% of M2000-treated patients and 57.1% of conventional-treated patient's adverse events occurred during this study. CONCLUSION: Treatment with M2000 in combination with conventional therapy showed a significantly superior efficacy along with a high safety profile compared to conventional-treated patients. Thereby, M2000 might be suggested as a suitable option in the treatment of RA.

In vitro and in vivo toxicity assessment of alginate/eudragit S 100-enclosed chitosan-calcium phosphate-loaded iron saturated bovine lactoferrin nanocapsules (Fe-bLf NCs).

Lactoferrin has been known to have antimicrobial properties. This research was conducted to investigate the toxicity of Alginate/EUDRAGIT® S 100-enclosed chitosan-calcium phosphate-loaded Fe-bLf nanocapsules (NCs) by in vitro and in vivo assays. Brine shrimp lethality assay showed that the LC50 value of NCs was more than 1mg/mL which indicated that NCs was not toxic to Brine shrimp. However, the LC50 values for the positive control potassium dichromate at 24h is 64.15µg/mL, which was demostrated the toxic effect against the brine shrimp. MTT cytotoxicity assay also revealed that NCs was not toxic against non-cancerous Vero cell line with IC50 values of 536µg/mL. Genotoxicity studies by comet assay on Vero cells revealed that NCs exerted no significant genotoxic at 100µg/mL without tail or shorter comet tail. Allium cepa root assay carried out at 125, 250, 500 and 1000µg/mL for 24h revealed that the NCs was destitute of significant genotoxic effect under experimental conditions. The results show that there is no significant difference (p>0.05) in mitotic index between the deionized water and NCs treated Allium cepa root tip cells. In conclusion, no toxicity was observed in NCs in this study. Therefore, nontoxic NCs has the good potential to develop as a therapeutic agent.

Reactogenicity and safety assessment of an attenuated nanovaccine against scorpion envenomation: Preclinical study.

An attenuated nanovaccine (Nps - V∗) has been developed to protect humans from fatal scorpion envenomation in at-risk regions. This study was conducted to evaluate the toxicity and the local reactogenicity of the Nps - V∗ nanovaccine developed against Androctonus australis hector (Aah) venom. Assessment of the systemic inflammatory response and serum cytokine levels were evaluated in vaccinated mice with 100µg of irradiated Aah venom (V∗) encapsulated or not into polymeric calcium-alginate nanoparticles (Nps) and injected by subcutaneous (s.c) route. The local reactogenicity was evaluated by dermal Draize observations and skin tissue analysis at the injection site of vaccinated rabbits with 250 or 500µg of V∗-loaded into Nps. All animals gained weight and had normal food consumption during the study. Additionally, results showed that the nanoformulation Nps - V∗ did not cause clinical evidence of systemic toxicity in mice or rabbits, a transient edema/erythema at the injection site was only recorded as treatment-related reactogenicity. These results indicated a favorable safety profile for Nps - V∗ and supported its use in superior animal tests, then in a Phase 1 clinical trial.

A Randomized Controlled Trial on the Outcome in Comparing an Alginate Silver Dressing With a Conventional Treatment of a Necrotizing Fasciitis Wound.

Necrotizing fasciitis (NF) is a high morbidity and mortality disease and also demands high economic resources. The standard treatment of NF is surgical debridement and proper dressing for wound bed preparation. The efficacy of silver alginate dressing can inhibit the growth of microorganisms and keep the environment clean for wound bed preparation. However an optimal dressing to manage such wounds has yet to emerge. NF patients who were admitted between April 2013 and May 2016 were randomized to have wound dressing using either silver dressing (Ag group) or normal saline solution gauze (NSS group). The 4 main outcomes for comparison between the 2 groups were the duration of wound bed preparation, total cost during hospital stay, the duration of hospital stay, and the pain score. Thirty-nine patients were included in the study: 19 patients in the NSS group and 20 patients in the Ag group. The mean duration of wound bed preparation in the NSS group was 31.87 days, and in Ag group it was 21.39 days, but this trend was not statistically significant ( P = .057). The mean cost of treatment in the NSS and Ag groups was not significantly different ( P = .434; US$3308.83 and US$2647.82, respectively). The duration of hospital days in the 2 groups was not significantly different either (29.19 days [NSS group] and 20.99 days [Ag group]; P = .222). The pain score was significantly lower in the Ag group than those in the NSS group. Although silver dressing seems to be expensive, the cost of total treatment during hospital stay and the duration of hospital stay were not significantly different between groups. However, the mean duration of wound bed preparation seems to trend favoring toward the silver dressing group.

Medical and Economic Evaluation of FOREseal Bioabsorbable Reinforcement Sleeves Compared With Current Standard of Care for Reducing Air Leakage Duration After Lung Resection for Malignancy: A Randomized Trial.

OBJECTIVE: The objective of this study was to determine the efficacy of alginate staple-line reinforcement of fissure openings as compared with stapling alone, with or without tissue sealant or glue, in reducing the incidence and duration of air leakage after pulmonary lobectomy for malignancy. SUMMARY BACKGROUND DATA: No randomized trial evaluating alginate staple-line reinforcement has been performed to date. METHODS: The Staple-line Reinforcement for Prevention of Pulmonary Air Leakage study was a multicenter randomized trial, with blinded evaluation of endpoints. Patients over 18 years of age scheduled for elective open lobectomy or bilobectomy for malignancy were eligible for enrollment. At thoracotomy, patients were deemed ineligible if an unanticipated pneumonectomy was indicated, or if air leakage occurred after the liberation of pleural adhesions. Otherwise, if the fissure was incomplete or the lung had an emphysematous appearance, patients were randomized to either standard management or interventional procedure consisting of fissure opening with linear cutting staplers buttressed with paired alginate sleeves (FOREseal). The number of eligible patients necessary in each randomization arm was estimated to be 190, and an outcomes analysis was performed on an intention-to-treat basis. RESULTS: Of the 611 patients consented to study enrollment, 380 met the inclusion criteria and were randomized. Based on an intention-to-treat analysis, the primary endpoint of air leak duration was not different between the 2 groups: 1 day (range: 0-2 d) in the FOREseal group and 1 day (range: 0-3 d) in the control group (P = 0.8357). In addition, the 2 groups were similar in terms of the proportion of patients presenting with prolonged air leakage (7.8% in the FOREseal group vs 11.3% in the control group, P = 0.264) and the average duration of chest drainage (P = 0.107). Procedure costs were comparable for both groups. CONCLUSIONS: FOREseal did not demonstrate a significant advantage over standard treatment alone.

Thiolated alginate-based multiple layer mucoadhesive films of metformin forintra-pocket local delivery: in vitro characterization and clinical assessment.

INTRODUCTION: Periodontal disease broadly defines group of conditions in which the supportive structure of the tooth (periodontium) is destroyed. Recent studies suggested that the anti-diabetic drug metformin hydrochloride (MF) has an osteogenic effect and is beneficial for the management of periodontitis. OBJECTIVE: Development of strong mucoadhesive multiple layer film loading small dose of MF for intra-pocket application. METHODOLOGY: Multiple layer film was developed by double casting followed by compression method. Either 6% carboxy methyl cellulose sodium (CMC) or sodium alginate (ALG) constituted the inner drug (0.6%) loaded layer. Thiolated sodium alginate (TSA; 2 or 4%) constituted the outer drug free layers to enhance mucoadhesion and achieve controlled drug release. Optimized formulation was assessed clinically on 20 subjects. RESULTS: Films were uniform, thin and hard enough for easy insertion into periodontal pockets. Based on water uptake and in vitro drug release, CMC based film with 4% TSA as an outer layer was the optimized formulation with enhanced mucoadhesion and controlled drug release (83.73% over 12 h). SEM showed the effective fabrication of the triple layer film in which connective lines between the layers could be observed. FTIR examination suggests possibility of hydrogen bonding between the -NH groups of metformin and -OH groups of CMC. DSC revealed the presence of MF mainly in the amorphous form. Clinical results indicated improvement of all clinical parameters six months post treatment. CONCLUSION: The results suggested that local application of the mucoadhesive multiple layer films loaded with metformin hydrochloride was able to manage moderate chronic periodontitis.

MR-guided portal vein delivery and monitoring of magnetocapsules: assessment of physiologic effects on the liver.

PURPOSE: The authors previously developed magnetic resonance (MR)-trackable magnetocapsules (MCs) that can simultaneously immunoprotect human islet cells and noninvasively monitor portal delivery and engraftment in real time with MR imaging. This study was designed to assess the physiologic effects of the delivery of a clinical dose of MCs (140,000 capsules) into the portal vein (PV) in swine over a 1-month period. MATERIALS AND METHODS: MCs were formed by using clinical-grade alginate mixed with a clinically applicable dosage of ferumoxide. Percutaneous access into the PV was obtained by using a custom-built, MR-trackable needle, and 140,000 MCs were delivered under MR guidance in five swine. Portal pressures and liver function data were obtained over a 4-week period. RESULTS: A transient increase in portal pressure occurred immediately after MC delivery that returned to normal levels by 4 weeks after MC delivery. Liver function test results were normal during the entire period, and the appearance of the MCs on MR imaging did not change. CONCLUSIONS: A clinically applicable dose of 140,000 MCs has no adverse effects on portal pressures or liver function in this normal swine model during the first month after delivery.

Randomized controlled trial of pelvic calcium alginate following rectal cancer surgery.

BACKGROUND: The aim of this randomized controlled trial was to assess the possible benefit of using a new haemostatic agent (Hémoionic) in the pelvic cavity in sphincter-saving surgery for rectal cancer. METHODS: Eighty-five patients undergoing elective sphincter-saving rectal resection for cancer were randomized into Hémoionic (41 patients) and control (44) groups. In both groups, a pelvic suction drain was left in place for as long as the daily output exceeded 20 ml. The primary endpoint was volume of fluid collected by the suction drain; secondary endpoints were duration of drainage, and postoperative mortality and morbidity rates. RESULTS: The mean total drainage volume was significantly lower in the Hémoionic group (453 ml versus 758 ml in control group; P = 0.031). There was no significant difference between groups in duration of drainage and morbidity. The mortality rate was four of 41 in the Hémoioni group and one of 44 in the control group (P = 0.192). CONCLUSION: Hémoionic may reduce the drainage volume after sphincter-saving surgery for rectal cancer, but offers no clinical advantage. REGISTRATION NUMBER: ISRCTN79721331 (http://www.isrctn.org).

Targeted delivery of chemotherapeutic agents using improved radiosensitive liquid core microcapsules and assessment of their antitumor effect.

PURPOSE: Radiation-sensitive microcapsules composed of alginate and hyaluronic acid are being developed. We report the development of improved microcapsules that were prepared using calcium- and yttrium-induced polymerization. We previously reported on the combined antitumor effect of carboplatin-containing microcapsules and radiotherapy. METHODS AND MATERIALS: We mixed a 0.1% (wt/vol) solution of hyaluronic acid with a 0.2% alginate solution. Carboplatin (l mg) and indocyanine green (12.5 microg) were added to this mixture, and the resultant material was used for capsule preparation. The capsules were prepared by spraying the material into a mixture containing a 4.34% CaCl(2) solution supplemented with 0-0.01% yttrium. These capsules were irradiated with single doses of 0.5, 1.0, 1.5, or 2 Gy (60)Co gamma-rays. Immediately after irradiation, the frequency of microcapsule decomposition was determined using a microparticle-induced X-ray emission camera. The amount of core content released was estimated by particle-induced X-ray emission and colorimetric analysis with 0.25% indocyanine green. The antitumor effect of the combined therapy was determined by monitoring its effects on the diameter of an inoculated Meth A fibrosarcoma. RESULTS: Microcapsules that had been polymerized using a 4.34% CaCl(2) solution supplemented with 5.0 x 10(-3)% (10(-3)% meant or 10%(-3)) yttrium exhibited the maximal decomposition, and the optimal release of core content occurred after 2-Gy irradiation. The microcapsules exhibited a synergistic antitumor effect combined with 2-Gy irradiation and were associated with reduced adverse effects. CONCLUSION: The results of our study have shown that our liquid core microcapsules can be used in radiotherapy for targeted delivery of chemotherapeutic agents.