Recent progress in drug delivery of pluronic P123: pharmaceutical perspectives.

This review focuses on recent investigations that used Pluronic P123 (P123) as pharmaceutical ingredients in vesicle, micelle, mixed micelle, in situ gel, tablet and emulsion. The main results from these studies show that P123 can significantly increase the stability of incorporated hydrophobic drugs with enhanced in vitro cytotoxicity and cellular uptake of anticancer drugs. Moreover, modified forms of P123 with RGD, folate or other targeted marker have shown its therapeutic potentials in various types of tumors and cancers. Furthermore, modified forms of P123 alone and/or mixed with other copolymers have less toxic effects and more tumor-specific delivery of anticancer drugs. They are promising materials as a nanoplatform for the drug delivery. Finally, the future perspectives of the field are briefly discussed.

[Evaluation of the efficiency and reactogenicity of emulsion-based adjuvant systems in the manufacture of polyclonal enteroviral diagnostic sera].

Whether various adjuvants might be used in the manufacture of commercial enteroviral diagnostic sera (EDS) was studied. The following adjuvants: Ribi, SAF-1, and TiterMax were compared; vaseline-lanoline emulsion used to prepare EDSs, as well as modified Freund's complete adjuvant served as controls. Chinchilla rabbits were intramuscularly injected enterovirus antigens (enterovirus 70 and ECHO 2) together with the adjuvant emulsions. TiterMax showed the highest efficiency comparable with the activity of Freund's adjuvant. The activities of Ribi, SAF-1, and vaseline-lanoline emulsion were 3-4 times lower. The neutralizing activity of the sera obtained after 2-3 (TiterMax) or 4-5 (Ribi, SAF-1) immunizations was maximal. Further immunizations resulted in a reduction in the titers of neutralizing antibodies. TiterMax and vaseline-lanoline emulsion caused minimal complications at the site of inoculation whereas SAF-1 and Ribi gave rise to severer inflammatory responses.

A randomized, double-blind, placebo-controlled safety and acceptability study of two Invisible Condom formulations in women from Cameroon.

BACKGROUND: The objectives of this clinical trial were to evaluate the safety, tolerance and acceptability of two gel formulations of the Invisible Condom: (i) the polymer alone and (ii) the polymer-containing sodium lauryl sulfate (SLS) compared to placebo when applied intravaginally with our unique applicator in sexually abstinent and active woman volunteers. STUDY DESIGN: A randomized, doubled-blind, placebo-controlled study in healthy women from Yaoundé, Cameroon. Two hundred sixty women were randomized into three gel arms: (a) gel alone, (b) gel plus SLS and (c) placebo gel. Thirty-seven sexually abstinent women applied gel intravaginally once a day for 14 days, while 75, 74 and 74 sexually active women applied gel intravaginally once, twice or three times daily for 14 days, respectively. RESULTS: Retention rate was high at 85% and 221 women applied the two products and the placebo for a total of 6005 times. Nugent score, H(2)O(2)-producing lactobacilli and vaginal pH were stable throughout the study and were not affected by the study products. Colposcopy showed neither genital ulceration nor mucosal lesions. No study product-related serious adverse events were reported. The majority of reported adverse events were mild or moderate and largely similar in all 3 arms. Satisfaction questionnaire showed that the gel formulations and applicator were generally comfortable and acceptable. CONCLUSION: The Invisible Condom formulations and applicator were found to be comfortable, well tolerated and acceptable when applied intravaginally once, twice or thrice daily for 14 days. Thus, expanded safety evaluation is warranted.

EMLA y púrpura cutánea / Purpura After Application of a Eutectic Mixture of Local Anesthetic

No disponible

No disponible

Effects of three pharmaceutical and personal care products on natural freshwater algal assemblages.

Treated wastewaters in the United States contain detectable quantities of surfactants, antibiotics, and other types of antimicrobial chemicals contained in pharmaceutical and personal-care products (PPCPs) that are released into stream ecosystems. The degradation characteristics of many of these chemicals are not yet known, nor are the chemical properties of their byproducts. They also are not currently mandated for removal under the U.S. Clean Water Act. Three representative PPCPs were individually tested in this study using a series of laboratory dilution bioassays: Ciprofloxacin (an antibiotic), Triclosan (an antimicrobial agent), and Tergitol NP 10 (a surfactant), to determine their effects on natural algal communities sampled both upstream and downstream of the Olathe, KS wastewater treatment plant (WWTP). There were no significant treatment effects on algal community growth rates during the exponential phase of growth, but significant differences were observed in the final biomass yields (p < 0.001). All three compounds caused marked shifts in the community structure of suspended and attached algae at both the upstream and downstream sites (p < 0.05). Increasing the concentrations of all three compounds over a 3 orders of magnitude range also caused a consistent decline in final algal genus richness in the bioassays. Our results suggest that these three PPCPs may potentially influence both the structure and the function of algal communities in stream ecosystems receiving WWTP effluents. These changes could result in shifts in both the nutrient processing capacity and the natural food web structure of these streams.

CpG DNA induces stronger immune responses with less toxicity than other adjuvants.

The ability to augment protective immune responses with minimal side effects is quintessential for a good adjuvant. This study has compared various adjuvants that are used in animal research (Freund's complete and incomplete adjuvants, Titermax Gold), are licensed for human use (alum), or are in clinical testing for humans (monophosphoryl lipid, CpG DNA), for their ability to augment humoral responses to a model antigen (hepatitis B surface antigen) and for the degree of damage they caused in the injected muscle. According to the data, the adjuvant combination CpG DNA+alum had the greatest potential to augment immune responses with minimal side effects at the injection site. Evaluation of antibody isotypes indicated Th2 responses (no IgG2a) with all adjuvants except monophosphoryl lipid and CpG DNA, which gave mixed Th1/Th2 responses (IgG1 and IgG2a). Strong Th1 responses (predominantly IgG2a) were obtained with combinations of CpG DNA with other adjuvants.

Randomized, controlled trial of RheothRx (poloxamer 188) in patients with suspected acute myocardial infarction. RheothRx in Myocardial Infarction Study Group.

BACKGROUND: Patients with acute myocardial infarction (AMI) who are not eligible for thrombolytic therapy or primary coronary angioplasty are distinguished by advanced age, complicated medical histories, relatively frequent use of prior revascularization procedures, and worse outcomes than their counterparts who are eligible for reperfusion therapy. METHODS AND RESULTS: The purpose of this randomized, controlled trial was to determine whether RheothRx, a hemorheologic agent, reduced myocardial infarct size and improved left ventricular function in patients who had suspected AMI at the time of hospital admission and were not eligible for reperfusion therapy. Patients were randomly assigned to RheothRx (n = 97) or placebo (n = 99). Patients in the two groups were similar with respect to age, sex, medical history, and clinical presentation. Enzyme evidence of AMI was present in 69% of the treatment group and 70% of the placebo group. Infarct size measured before hospital discharge was similar in the two groups (14.1% +/- 18.5% vs 11.7% +/- 14.1%, p = 0.60), although left ventricular ejection fraction was lower in the treatment group (47 +/- 14 vs 52 +/- 11, p = 0.026). Hospital mortality rate was 11.3% and 7.1% in patients receiving RheothRx and patients receiving placebo, respectively (p = 0.30). There was a higher occurrence of acute renal dysfunction in the RheothRx group (12% vs 2%, p = 0.005). Because of changes in drug dosage necessitated by the occurrence of acute renal dysfunction, the trial was stopped. CONCLUSIONS: In this study of patients who had suspected AMI and were not eligible for thrombolytic therapy, RheothRx did not decrease infarct size or favorably alter outcome. The need for effective treatment for this large patient population remains largely unmet.

Beneficial effects of RheothRx injection in patients receiving thrombolytic therapy for acute myocardial infarction. Results of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: RheothRx (poloxamer 188) is a surfactant with hemorheological and antithrombotic properties that reduces myocardial reperfusion injury in animal models of myocardial infarction. The purpose of the present study was to evaluate the safety and efficacy of adjunctive therapy with poloxamer 188 in patients receiving thrombolytic therapy for acute myocardial infarction. METHODS AND RESULTS: In this multicenter trial, we randomized 114 patients to a 48-hour infusion of poloxamer 188 or vehicle placebo beginning immediately after the initiation of thrombolytic therapy. Tomographic imaging with 99mTc sestamibi before reperfusion and again 5 to 7 days after the infarction was used to determine myocardium at risk for infarction, infarct size, and myocardial salvage. Radionuclide angiography at 5 to 7 days after infarction was used to measure left ventricular ejection fraction. The treated and control groups had comparable baseline characteristics, time to thrombolytic administration, and time to treatment with poloxamer 188 or placebo. Poloxamer 188-treated patients demonstrated a 38% reduction in median myocardial infarct size (25th and 75th percentile) compared with placebo (16% [7, 30] versus 26% [9, 43]; P = .031), greater median myocardial salvage (13% [7, 20] versus 4% [1, 15]; P = .033), and a 13% relative improvement in median ejection fraction (52% [43, 60] versus 46% [35, 60]; P = .020). Poloxamer 188 treatment also resulted in a reduced incidence of reinfarction (1% versus 13%; P = .016). Poloxamer 188 was well tolerated without adverse hemodynamic effects or significant organ toxicity. CONCLUSIONS: Adjunctive therapy with poloxamer 188 resulted in substantial benefit in this randomized trial, including significantly smaller infarcts, greater myocardial salvage, better left ventricular function, and a lower incidence of in-hospital reinfarction. Although the mechanisms are unproven, poloxamer 188 treatment may accelerate thrombolysis, reduce reocclusion, and ameliorate reperfusion injury.

Comparison of the effects of five adjuvants on the antibody response to influenza virus antigen in guinea pigs.

Five adjuvants were tested for their effect on the immune response in guinea pigs to the hemagglutinin antigen of influenza virus strain B/Panama. Vaccines containing 924 micrograms of hemagglutinin antigen/ml were prepared at high and low doses of Freund's complete and incomplete adjuvants, Syntex adjuvant, RIBI's adjuvant, TiterMax adjuvant, and aluminum phosphate adjuvant. Responses to these vaccines were compared with those to a control vaccine containing influenza virus B/Panama hemagglutinin antigen and saline. On day 28, vaccines containing the following adjuvant doses had significantly higher titers than the titer for the control: Freund adjuvants at high and low doses, RIBI at high dose, TiterMax at high and low doses, and aluminum phosphate at high dose. On day 42, vaccines containing the following adjuvant doses had significantly higher titers than that for the control: Freund adjuvants at high and low doses, RIBI at high dose, TiterMax at high dose, and aluminum phosphate at high dose. Freund adjuvants at high and low doses, RIBI adjuvant at high dose, and aluminum phosphate at high dose caused significantly greater swelling at the inoculation site than did the control vaccine. TiterMax adjuvant at high and low doses, and aluminum phosphate at low dose caused minor swelling at the inoculation site, but it was not significantly different from the swelling caused by the control vaccine. Syntex adjuvant at high and low doses, RIBI at low dose, and control (saline/antigen) at high and low doses caused no swelling after inoculation. Overall, the high dose of adjuvants caused greater tissue swelling than did the low dose of adjuvants.(ABSTRACT TRUNCATED AT 250 WORDS)

Haemolytic properties of pluronic surfactants and effects of purification.

The effects of incubating blood from mice, rats, rabbits or hamsters with either a commercial grade or a silica-purified fraction of Pluronic F-68 or Pluronic F-38 have been studied. Incubation of blood with up to 4.0% (w/v) of commercial or purified Pluronic F-68 produced no detectable haemolysis (< 0.1%). Haemolysis did occur with concentrations of commercial Pluronic F-68 above 4.0% (w/v). This was maximal with rat blood incubated with 10.0% (w/v) Pluronic F-68, where the mean haemolysis was 4.7 +/- 1.5%; the mean haemolysis in rat blood was reduced to 0.5 +/- 0.3% (P < 0.05) following incubation with the purified Pluronic F-68 fraction. Neither commercial grade or purified Pluronic F-38 produced any significant haemolysis when incubated with rat or hamster blood. Incubation of rabbit blood with 10.0% (w/v) commercial Pluronic F-38 produced only 0.5% haemolysis.

Pluronic polyol: a potential alloplastic keratorefractive material.

Pluronic polyol possesses a negative temperature coefficient of gelation; it is liquid at low temperatures and gelatinous at high temperatures. Pluronic F108 was evaluated as a potential material for alloplastic keratorefractive surgery: 0.3 ml of the material in a liquid state was injected into a surgically prepared axial 7 mm mid-stromal corneal bed in 17 rabbits; fellow eyes in the rabbits were sham-operated but not injected. Postoperatively, rabbits were clinically evaluated with biomicroscopy, keratometry, and pachymetry at regular intervals up to three months following surgery. Animals were periodically sacrificed and corneas were studied by light and electron microscopy. The material appeared to be well tolerated by the cornea. Both control and pluronic eyes showed an initial increase in corneal thickness peaking at one week postoperatively, with return to near normal levels by the end of the third week. Refractive flattening of approximately three diopters was noted in the experimental group, while no change was seen in the control group.

Limitation of complement activation by perfluorocarbon emulsions: superiority of lecithin-emulsified preparations.

A considerable body of evidence suggests that complement and granulocyte activation may be important in the occasional adverse reactions which occur on the administration of perfluorocarbon emulsions to patients. In an attempt to develop an emulsion which was less prone to activate complement than was the first product clinically tested, we devised an in-vitro protocol for the testing of an emulsion's ability to activate complement: emulsions were serially diluted, and were incubated with minimally-heparinized plasmas from each of several donors; the generation of C3a was assessed by commercial immunoassay. In such a system, F-Adamantane emulsions prepared with highly-purified lecithin as the emulsifier were consistently less complement-activating than comparable emulsions prepared with Pluronic F-68 as the emulsifier. Emulsification technique seemed unimportant, and HPLC fractionation of the Pluronics identified no innocuous subfraction. Application of these findings to an animal model is underway, to see if the superiority of lecithin-based emulsions is also evident in vivo.

Poloxamer 188 as vehicle for injectable diazepam.

The significant occurrence of thrombophlebitis in patients administered diazepam intravenously was described recently. This side effect has been attributed to the crystallization of diazepam and its subsequent precipitation upon contact with blood or intravenous fluids. The current study was designed to reveal whether the solubilizing capability of poloxamer 188 reduces the incidence of thrombotic and inflammatory effects of diazepam in rabbits. The incidence of early (3-hr) ear vein necrosis was 72% in the diazepam-treated ears, while the incidence of necrosis in the ears that received poloxamer 188 as a vehicle for diazepam was 25%. The occurrence of thrombosis and loss of vessel integrity also was higher in diazepam-treated ears than in those treated with diazepam plus poloxamer 188. Solubilization of diazepam with poloxamer 188 may decrease the incidence of the tested side effects.

Study of the comparative effectiveness of Dulcolax, Laxadine, Dorbanex, Normacen and Senokot laxatives in the bowel preparation of patients for radiological examinations.

The effectiveness of five laxatives - Dulcolax, Normacen, Laxadine, Dorbanex and Senokot in the bowel preparation of adult patients for radiological examinations has been compared. The value of using suppositories in addition to the tablets in those preparations that have tablet and suppository forms has also been assessed. The use of Dulcolax tablets plus suppository was most effective. Dulcolax, especially its suppository, was however very expensive and more frequently attended by side effects when compared with the other preparations. Normacen tablet was the second most effective and it is cheap and quite free of side effects. It is therefore given the position of first choice. Laxadine tablet plus its suppository was third best. It is cheap and free of side effects. Dorbanex was fourth best but it is rather expensive. Senokot tablet was the least effective but it is cheap and relatively free from side effects. In those laxatives with tablet and suppository forms, the use of both tablet and suppository is much more effective than the use of the tablet form alone.