Preparation, characterization, and sonodynamic antitumor effect of the folate receptor targeted FA-EN-ß-CD containing hematoporphyrin in vitro.

To improve water solubility, reduce phototoxicity and increase the tumor-targeting ability of hematoporphyrin (Hp) as a sonosensitizer for sonodynamic therapy under ultrasonic conditions, a novel folate receptor (FR)-targeted, folate-conjugated ethylenediamine-ß-cyclodextrin (FA-EN-ß-CD) containing Hp (FA-EN-ß-CD-Hp) was constructed. ß-Cyclodextrin containing Hp (ß-CD-Hp) was also established as a nontargeted control. The inclusion efficiencies of Hp in FA-EN-ß-CD-Hp and ß-CD-Hp were determined to be 90.4 ± 2.7% (wt/wt) and 92.5 ± 3.4% (wt/wt), respectively. Growth inhibition rates in HepG-2 cells in vitro were assessed upon ultrasound exposure. The results indicated that the growth inhibition rates of FA-EN-ß-CD-Hp, ß-CD-Hp, and F-Hp (Hp: 150 µg/ml) reached 96.4 ± 3.6%, 53.4 ± 3.4%, and 48.2 ± 2.8%, respectively. These results indicated that FA-EN-ß-CD-Hp is a promising drug delivery system in the field of sonodynamic cancer therapy.

Lessons to be learned: Using National Immunisation strategies to improve adherence to acute rheumatic fever secondary prophylaxis.

Rheumatic heart disease, as a result of a single or recurrent episode of acute rheumatic fever (ARF), remains a significant cause of morbidity and mortality in northern and remote Australia; ARF has a peak incidence among 5-14-year-old Aboriginal and Torres Strait Islander children. Long-term regular benzathine penicillin G injections are the only currently successful secondary prevention strategy; however, rates of adherence remain critically low. In contrast, rates of adherence to immunisations on the National Immunisation Program (NIP) Schedule are high, even among this target population. This article compares strategies used to implement and improve ARF secondary prophylaxis with those used in the NIP. Some successful NIP strategies, such as Service Incentive Payment for health providers, home-visiting delivery models and integration into the National Immunisation Register, if applied to ARF secondary prophylaxis have the potential to improve benzathine penicillin G adherence.

Bacterial zincophore [S,S]-ethylenediamine-N,N'-disuccinic acid is an effective inhibitor of MBLs.

Objectives: Carbapenemases such as MBLs are spreading among Gram-negative bacterial pathogens. Infections due to these MDR bacteria constitute a major global health challenge. Therapeutic strategies against carbapenemase-producing bacteria include ß-lactamase inhibitor combinations. [S,S]-ethylenediamine-N,N'-disuccinic acid (EDDS) is a chelator and potential inhibitor of MBLs. We investigated the activity of EDDS in combination with imipenem against MBL-producing bacteria in vitro as well as in vivo. Methods: The inhibitory activity of EDDS was analysed by means of a fluorescence-based assay using purified recombinant MBLs, i.e. NDM-1, VIM-1, SIM-1 and IMP-1. The in vitro activity of imipenem ± EDDS against mutants as well as clinical isolates expressing MBLs was evaluated by broth microdilution assay. The in vivo activity of imipenem ± EDDS was analysed in a Galleria mellonella infection model. Results: EDDS revealed potent MBL inhibitory activity against purified NDM-1, weaker activity against VIM-1 and SIM-1, and marginal activity against IMP-1. EDDS did not exhibit any intrinsic antibacterial activity, but enabled a concentration-dependent potentiation of imipenem against mutants as well as clinical isolates expressing various MBLs. The in vivo model showed a significantly better survival rate for imipenem + EDDS-treated G. mellonella larvae infected with NDM-1-producing Klebsiella pneumoniae compared with monotherapy with imipenem. Conclusions: The bacterial natural zincophore EDDS is a potent MBL inhibitor and in combination with imipenem overcomes MBL-mediated carbapenem resistance in vitro and in vivo.

Role of sigma 1 receptor in high fat diet-induced peripheral neuropathy.

The neurobiological mechanisms of obesity-induced peripheral neuropathy are poorly understood. We evaluated the role of Sigma-1 receptor (Sig-1R) and NMDA receptor (NMDARs) in the spinal cord in peripheral neuropathy using an animal model of high fat diet-induced diabetes. We examined the expression of Sig-1R and NMDAR subunits GluN2A and GluN2B along with postsynaptic density protein 95 (PSD-95) in the spinal cord after 24-week HFD treatment in both wild-type and Sig-1R-/- mice. Finally, we examined the effects of repeated intrathecal administrations of selective Sig-1R antagonists BD1047 in HFD-fed wild-type mice on peripheral neuropathy. Wild-type mice developed tactile allodynia and thermal hypoalgesia after 24-week HFD treatment. HFD-induced peripheral neuropathy correlated with increased expression of GluN2A and GluN2B subunits of NMDARs, PDS-95, and Sig-1R, as well as increased Sig-1R-NMDAR interaction in the spinal cord. In contrast, Sig-1R-/- mice did not develop thermal hypoalgesia or tactile allodynia after 24-week HFD treatment, and the levels of GluN2A, GluN2B, and PSD-95 were not altered in the spinal cord of HFD-fed Sig-1R-/- mice. Finally, repeated intrathecal administrations of selective Sig-1R antagonists BD1047 in HFD-fed wild-type mice attenuated peripheral neuropathy. Our results suggest that obesity-associated peripheral neuropathy may involve Sig-1R-mediated enhancement of NMDAR expression in the spinal cord.

The iron chelating agent, deferoxamine detoxifies Fe(Salen)-induced cytotoxicity.

Iron-salen, i.e., µ-oxo-N,N'-bis(salicylidene)ethylenediamine iron (Fe(Salen)) was a recently identified as a new anti-cancer compound with intrinsic magnetic properties. Chelation therapy has been widely used in management of metallic poisoning, because an administration of agents that bind metals can prevent potential lethal effects of particular metal. In this study, we confirmed the therapeutic effect of deferoxamine mesylate (DFO) chelation against Fe(Salen) as part of the chelator antidote efficacy. DFO administration resulted in reduced cytotoxicity and ROS generation by Fe(Salen) in cancer cells. DFO (25 mg/kg) reduced the onset of Fe(Salen) (25 mg/kg)-induced acute liver and renal dysfunction. DFO (300 mg/kg) improves survival rate after systematic injection of a fatal dose of Fe(Salen) (200 mg/kg) in mice. DFO enables the use of higher Fe(Salen) doses to treat progressive states of cancer, and it also appears to decrease the acute side effects of Fe(Salen). This makes DFO a potential antidote candidate for Fe(Salen)-based cancer treatments, and this novel strategy could be widely used in minimally-invasive clinical settings.

Metal chelator TPEN selectively induces apoptosis in K562 cells through reactive oxygen species signaling mechanism: implications for chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a hematologic disorder characterized by the constitutive expression of BCR-ABL tyrosine kinase. Although successful implementation of tyrosine kinase inhibitors for the treatment of CML remain a traditional choice for molecularly targeted therapy, some patients present primary or secondary resistance to such therapy. Therefore, alternative therapeutic strategies are required to treat resistant CML cells. Accordingly, new anti-proliferative and/or pro-apoptotic compounds would be needed for clinical treatment. In the present investigation, we demonstrate that TPEN (e.g. 3 µM), a lipid-soluble metal chelator, induces apoptosis in K562 cells via a molecular cascade involving H2O2 â‰« JNK, NF-κB > c-JUN, P73 > PUMA, BAX > loss of ΔΨm > CASPASE-3 > nuclei/DNA fragmentation. Fragmentation of the nuclei and DNA are indicative of cell death by apoptosis. Remarkably, the antioxidant N-acetyl-cysteine, and inhibitors of the transcription factors CASPASE 3 and (JNK) kinase, decreased oxidative stress (OS) and cell death in these cells. This is evidenced by fluorescence microscopy, flow cytometry and immunocytochemistry for OS markers (e.g. generation of H2O2 and DJ 1 oxidation) and nuclear expression of apoptotic markers (e.g. activated caspase 3 and JNK kinase). In addition, TPEN causes no detectable damage in human peripheral blood lymphocyte cells (hPBLCs). We conclude that TPEN selectively induces apoptosis in K562 cells via an OS-mechanism. Our findings may provide insight into more effective CML anticancer therapies.

Inhibition of FAK and VEGFR-3 binding decreases tumorigenicity in neuroblastoma.

Neuroblastoma is the most common extracranial solid tumor of childhood and is responsible for over 15% of pediatric cancer deaths. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumor development and progression. Vascular endothelial growth factor receptor-3 (VEGFR-3), another tyrosine kinase, has also been found to be important in the development of many human tumors including neuroblastoma. Recent reports have found that FAK and VEGFR-3 interact, and we have previously shown that both of these kinases interact in neuroblastoma. We have hypothesized that interruption of the FAK-VEGFR-3 interaction would lead to decreased neuroblastoma cell survival. In the current study, we examined the effects of a small molecule, chloropyramine hydrochloride (C4), designed to disrupt the FAK-VEGFR-3 interaction, upon cellular attachment, migration, and survival in two human neuroblastoma cell lines. We also utilized a murine xenograft model to study the impact of C4 upon tumor growth. In these studies, we showed that disruption of the FAK-VEGFR-3 interaction led to decreased cellular attachment, migration, and survival in vitro. In addition, treatment of murine xenografts with chloropyramine hydrochloride decreased neuroblastoma xenograft growth. Further, this molecule acted synergistically with standard chemotherapy to further decrease neuroblastoma xenograft growth. The findings from this current study help to further our understanding of the regulation of neuroblastoma tumorigenesis, and may provide novel therapeutic strategies and targets for neuroblastoma and other solid tumors of childhood.

Early phase evaluation of SQ109 alone and in combination with rifampicin in pulmonary TB patients.

OBJECTIVES: SQ109, an asymmetrical diamine, is a novel anti-TB drug candidate. This first study in patients was done to determine safety, tolerability, pharmacokinetics and bacteriological effect of different doses of SQ109 alone and in combination with rifampicin when administered over 14 days. PATIENTS AND METHODS: Smear-positive pulmonary TB patients were randomized into six groups of 15 to receive once-daily oral treatment with 75, 150 or 300 mg of SQ109, rifampicin (10 mg/kg body weight), rifampicin plus 150 mg of SQ109, or rifampicin plus 300 mg of SQ109 for 14 days. Patients were hospitalized for supervised treatment, regular clinical, biochemical and electrocardiographic safety assessments, pharmacokinetic profiling and daily overnight sputum collection. RESULTS: SQ109 was safe and generally well tolerated. Mild to moderate dose-dependent gastrointestinal complaints were the most frequent adverse events. No relevant QT prolongation was noted. Maximum SQ109 plasma concentrations were lower than MICs. Exposure to SQ109 (AUC0-24) increased by drug accumulation upon repeated administration in the SQ109 monotherapy groups. Co-administration of SQ109 150 mg with rifampicin resulted in decreasing SQ109 exposures from day 1 to day 14. A higher (300 mg) dose of SQ109 largely outweighed the evolving inductive effect of rifampicin. The daily fall in log cfu/mL of sputum (95% CI) was 0.093 (0.126-0.059) with rifampicin, 0.133 (0.166-0.100) with rifampicin plus 150 mg of SQ109 and 0.089 (0.121-0.057) with rifampicin plus 300 mg of SQ109. Treatments with SQ109 alone showed no significant activity. CONCLUSIONS: SQ109 alone or with rifampicin was safe over 14 days. Upon co-administration with rifampicin, 300 mg of SQ109 yielded a higher exposure than the 150 mg dose. SQ109 did not appear to be active alone or to enhance the activity of rifampicin during the 14 days of treatment.

Combined Inhibition of Histamine H1 Receptors and Leukotrienes Reduces Compound 48/80-Induced Contraction of the Human Bronchus in vitro.

BACKGROUND/AIMS: Bronchial asthma continues to be a big challenge to therapy. Mast cells play an important role in allergic asthma. Histamine and leukotrienes are established mast cell mediators, but antihistamines currently play no role in asthma therapy. METHODS: Human bronchial strips were exposed to the mast cell activator compound 48/80 (200 µg/ml) in isolated organ experiments. RESULTS: The contractile response was not inhibited by the H1 receptor antagonist antihistamine chloropyramine (0.3 µmol/l), the leukotriene cys-LT1 receptor antagonist MK 571 (3 µmol/l), the 5-lipoxygenase inhibitor MK 886 (5 µmol/l), the cyclo-oxygenase inhibitor indomethacin (5 µmol/l), tetrodotoxin, or atropine. Chloropyramine, combined with either MK 571 or MK 886 significantly reduced the response. CONCLUSION: A supra-additive effect is proposed for the antihistamine and the anti-leukotrienes, which might have relevance to human asthma therapy as well; such a combination deserves a large-scale clinical study. These data also indicate that substances like compound 48/80 should be denoted as mast cell activators rather than 'histamine liberators'.

Single dose acute toxicity testing for N,N-bis(2-mercaptoethyl)-N',N' diethylethylenediamine in beagles.

N,N-Bis(2-mercaptoethyl)-N',N'-diethylenediamine (BMEDA) is used in the preparation of the (188)Re-BMEDA-liposome as a chelator to deliver rhenium 188 into liposomes. Although the safety of the (188)Re-BMEDA-liposome had been established, the use of BMEDA in preparing the liposome is of interest; however, an assessment of its safety is warranted. In this present work, we report on the acute toxicity study of BMEDA in beagles to identify doses causing no adverse effect and doses causing life-threatening toxicity. In a single dose 14-day systemic toxicity study conducted in beagles, BMEDA was without compound-related adverse effects at doses of up to 2mg/kg in a series of clinical observations and clinical pathology examinations. The results of these studies could aid in choosing doses for repeat-dose studies and in the selection of starting doses for Phase 1 human studies.

Pharmacokinetics of BMEDA after intravenous administration in beagle dogs.

The pharmacokinetics of N,N-bis(2-mercapatoethly)-N',N'-diethylenediamine (BMEDA), a molecule that can form a chelate with rhenium-188 (188Re) to produce the 188Re-BMEDA-liposomes, was studied. In this work, beagles received a single injection of BMEDA, at doses of 1, 2, or 5 mg/kg; the concentration of BMEDA in the beagles' plasma was then analyzed and determined by liquid chromatography-mass spectrometry/mass spectrometry. Based on the pharmacokinetic parameters of BMEDA, we found that male and female animals shared similar patterns indicating that the pharmacokinetics of BMEDA is independent of gender differences. In addition, the pharmacokinetics of BMEDA was seen to be non-linear because the increase of mean AUC0-t and AUC0-∞ values tend to be greater than dose proportional while the mean Vss and CL values of BMEDA appeared to be dose dependent. The information on the pharmacokinetics of BMEDA generated from this study will serve as a basis to design appropriate pharmacology and toxicology studies for future human use.

Therapeutic efficacy of 188Re-liposome in a C26 murine colon carcinoma solid tumor model.

Nanoliposomes are good drug delivery systems that allow the encapsulation of drugs into vesicles for their delivery. The objective of this study is to investigate the therapeutic efficacy of a new radio-therapeutics of (188)Re-labeled pegylated liposome in a C26 murine colon carcinoma solid tumor model. The safety of (188)Re-liposome was evaluated before radiotherapy treatment. The anti-tumor effect of (188)Re-liposome was assessed by tumor growth inhibition, survival ratio and ultrasound imaging. Apoptotic marker in tumor was also evaluated by the TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling) method after injection of (188)Re-liposome. The group treated with (188)Re-liposome displayed slight loss in body weight and decrease in white blood cell (WBC) count 7 to 14 days post-injection. With respect to therapeutic efficacy, the tumor-bearing mice treated with (188)Re-liposome showed better mean tumor growth inhibition rate (MGI) and longer median survival time (MGI = 0.140; 80 day) than those treated with anti-cancer drug 5-FU (MGI = 0.195; 69 day) and untreated control mice (MGI = 0.413; 48 day). The ultrasound imaging showed a decrease in both tumor volume and number of blood vessels. There were significantly more apoptotic nuclei (TUNEL-positive) in (188)Re-liposome-treated mice at 8 h after treatment than in control mice. These results evidenced the potential benefits achieved by oncological application of the radio-therapeutics (188)Re-liposome for adjuvant cancer treatment.

Amelioration of diet-induced nonalcoholic steatohepatitis in rats by Mn-salen complexes via reduction of oxidative stress.

BACKGROUND: Nonalcoholic steatohepatitis (NASH), a progressive stage of nonalcoholic fatty liver disease (NAFLD), is characterized by steatosis (accumulation of triacylglycerols within hepatocytes) along with inflammation and ballooning degeneration. It has been suggested that oxidative stress may play an important role in the progress of NAFLD to NASH. The aim of present study was to determine whether antioxidant supplementations using EUK-8, EUK-134 and vitamin C could improve the biochemical and histological abnormalities associated with diet-induced NASH in rats. METHODS: NASH was induced in male N-Mary rats by feeding a methionine - choline deficient (MCD) diet. The rats were fed either normal chow or MCD diet for 10 weeks. After NASH development, the MCD-fed rats were randomly divided into four groups of six: the NASH group that received MCD diet, the EUK-8 group which was fed MCD diet plus EUK-8, the EUK-134 group which was fed MCD diet plus EUK-134 and the vitamin C group which received MCD diet plus vitamin C. EUK-8, EUK-134 and vitamin C (30 mg/kg body weight/day) were administered by gavage for eight weeks. RESULTS: Treatment of MCD-fed rats with salens reduced the sera aminotransferases, cholesterol, low density lipoprotein contents, the extent of lipid peroxidation and protein carbonylation whereas the HDL-C cholesterol levels were significantly increased. In addition, EUK-8 and EUK-134 improved steatosis, ballooning degeneration and inflammation in liver of MCD-fed rats. CONCLUSION: Antioxidant (EUK-8, EUK-134 and vitamin C) supplementation reduces NASH-induced biochemical and histological abnormalities, pointing out that antioxidant strategy could be beneficial in treatment of NASH.

Efficiency of a new strategy involving a new class of natural hetero-ligand iron(III) chelates (Fe(III)-NHL) to improve fruit tree growth in alkaline/calcareous soils.

BACKGROUND: Iron (Fe) chlorosis is a serious problem affecting the yield and quality of numerous crops and fruit trees cultivated in alkaline/calcareous soils. This paper describes the efficiency of a new class of natural hetero-ligand Fe(III) chelates (Fe-NHL) to provide available Fe for chlorotic lemon trees grown in alkaline/calcareous soils. These chelates involve the participation in the reaction system of a partially humified lignin-based natural polymer and citric acid. RESULTS: First results showed that Fe-NHL was adsorbed on the soil matrix while maintaining available Fe for plants in alkaline/calcareous solution. The effects of using three different sources as Fe fertilisers were also compared: two Fe-NHL formulations (NHL1, containing 100% of Fe as Fe-NHL, and NHL2, containing 80% of Fe as Fe-NHL and 20% of Fe as Fe-ethylenediamine-N,N'-bis-(o-hydroxyphenylacetic) acid (Fe-EDDHA)) and Fe-EDDHA. Both Fe-NHL formulations increased fruit yield without negative effects on fruit quality in comparison with Fe-EDDHA. In the absence of the Fe-starter fraction (NHL1), trees seemed to optimise Fe assimilation and translocation from Fe-NHL, directing it to those parts of the plant more involved in development. CONCLUSION: The field assays confirmed that Fe-NHL-based fertilisers are able to provide Fe to chlorotic trees, with results comparable to Fe-EDDHA. Besides, this would imply a more sustainable and less expensive remediation than synthetic chelates.

Evaluation of an automated dental unit water system's contamination control protocol.

BACKGROUND: This study addresses the efficacy of an automated decontamination protocol using the germicide 'tetra acetyl ethylene diamine (TAED) perborate' (Farmec SpA, Italy). The germicide TAED perborate protocol is used in the Castellini Dental Units fitted with an Autosteril unit (an automated device that can cycle 0.26% TAED perborate solution and sterile water for cleaning the water system between patients and overnight). Prior to testing the Autosteril and the 0.26% TAED perborate protocol on the Logos Jr Dental Unit (Castellini SpA, Italy), TAED perborate was used on a dental unit water system simulation device. METHODS: A dental unit water system simulation device equipped with four dental unit water systems and with naturally grown and mature biofilm contamination was used in this study (three treatment units and one control). One treatment group used a simulated 5 minutes contact with TAED perborate and sterile water for irrigation; the second used a simulated 5 minutes contact with TAED perborate and 2 ppm ClO2 for irrigation; the third used a simulated 5 minutes contact with TAED perborate and municipal water for irrigation. The control group used municipal water for irrigation with no cleaning/disinfection protocols. This protocol was repeated for 30 cycles. Laser scanning confocal microscopy (LSCM) was used to study the effects on natural and mature biofilms, and R2A agar used to quantify heterotrophic plate counts in the effluent irrigant. Antimicrobial efficacy was evaluated by challenging TAED perborate with microbes and spores (M. smegmatis and B. subtilis). Deleterious effects of the germicide were evaluated on metal and nonmetal parts of dental unit water systems. Heterotrophic plate counts using R2A agar and LSCM of the lines were conducted to assess biofilm and microbial control. RESULTS: Baseline water samples showed mean contamination >5.6 log10 cfu/ml. After initial cleaning, all three groups maintained mean contamination levels of less than 1.1 (SD <0.3) log10 cfu/ml. LSCM of baseline samples was positive for live biofilm in all groups. At the end of the study, viable biofilm was only present in the control. In the microbial challenge test, all vegetative organisms were killed within 30 seconds of contact, while spores were killed within 5 minutes. Corrosion was seen in metals used in US-manufactured dental unit materials, while not observed in those used in the Castellini Logos Jr dental unit. CONCLUSION: In this study, the TAED perborate protocol was effective in biofilm control and control of dental treatment water contamination. Use of sterile water or 2 ppm ClO2 along with TAED treatment also controlled planktonic contamination effectively. CLINICAL SIGNIFICANCE: Environmental biofilms contaminate dental unit water systems over time and affect the quality of dental treatment water. Contaminants include environmental biofilms, microbes, including gram-negative rods and endotoxins in high doses that are not of acceptable quality for treating patients. There are many germicidal protocols for treating this contamination and one such is the prescribed use of TAED perborate used in conjunction with sterile water for irrigation in the autosteril device, an integral component of the Castellini dental units for between patient decontamination of dental unit water systems. This study was conducted on an automated simulation dental unit water system to test the TAED perborate protocol's efficacy on naturally grown, mature environmental biofilms, it's efficacy on microbes and spores and it's effects on materials used in dental unit water systems. This translational research addresses both microbial control and material effects of TAED perborate in studying efficacy and possible deleterious effects and simulated use in dentistry. Currently, this antimicrobial use protocol is followed worldwide in the Castellini dental units that are used in day-to-day dental patient care.

Polyaminated pullulan, a new biodegradable and cationic pullulan derivative for mucosal drug delivery.

AIM: To prepare new polycationic pullulan derivatives exhibiting highly mucoadhesive and sustained drug release properties. METHODS: Hydroxy groups of pullulan were activated with mesyl chloride followed by conjugation with low-molecular weight polyamines. Pullulan-tris(2-aminoethyl)amine (Pul-TAEA) and pullulan-polyethyleneimine (Pul-PEI) were evaluated regarding swelling behaviour, mucoadhesive properties and potential to control drug release. RESULTS: Pul-TAEA and Pul-PEI exhibited excellent swelling properties at pH 6.8 showing 240- and 370-fold increase in weight. Compared to unmodified pullulan, Pul-TAEA and Pul-PEI displayed 5- and 13.3-fold increased dynamic viscosity in mucus. Mucoadhesion studies of Pul-TAEA and Pul-PEI on intestinal mucosa showed a 6- and 37.8-fold increase in tensile strength, and a 72- and 120-fold increase in mucoadhesion time compared to unmodified pullulan, respectively. Due to additional ionic interactions between cationic groups on polyaminated pullulans and an anionic model drug, a sustained drug release was achieved. CONCLUSIONS: Polyaminated pullulans are promising novel mucoadhesive excipients for mucosal drug delivery.

Clinical evidence for the activity of tetrahydroxypropyl ethylenediamine (THPE), a new anti-aging active cosmetic.

UNLABELLED: BACKGROUND/ OBJECTIVES: The cellular surface modification of superficial epidermal keratinocytes can induce immediate skin tensioning effects and may improve signs of skin aging. Tetrahydroxypropyl ethylenediamine (THPE) is an active that has been described to induce keratinocytes' morphological changes in vitro. We conducted an in vivo study to assess anti-aging clinical benefits of a THPE-containing product. METHODS: An eight-week double-blind, randomized intra-individual placebo controlled clinical study was performed to evaluate the clinical benefits of a 2.5% THPE-containing cream. This study included 41 Caucasian women who received the THPE cream product on one side of the face and a placebo cream on the other side daily. Evaluations were performed at baseline, 45 minutes after first application, week 4 and week 8 and included clinical examination and digital photography. RESULTS: The study demonstrated the immediate lifting effect of a 2.5% THPE-containing cream. Forty-five minutes after a single application on the face, as the skin surface smoothed out, light reflection was modified: healthy glow and radiance of the skin were significantly improved (respectively 22.9% and 40% of improvement) and skin yellowishness was reduced (7.1%). Notably, the THPE-treated side was significantly lifted, both immediately after product application (8.1%) and after 8 weeks of application (14%), compared to the placebo-treated side. CONCLUSION: This clinical study demonstrated that the effect of a 2.5% THPE-containing cream on the keratinocytes cells leads to an immediate and long-term clinical improvement of the skin appearance (radiance and skin firmness, skin lifting) and can therefore be considered as a new anti-aging cosmetic active.

Acute intravenous injection toxicity of BMEDA in mice.

(188)Re/(186)Re-N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine-labeled pegylated liposome ((188)Re-BMEDA-liposome) has been proven as a promising candidate for cancer therapy in tumor-rodent models. (188)Re-BMEDA complexes should be prepared for the radiolabeling of liposomes. This article describes the acute toxicity of BMEDA in Imprinting Control Region (ICR) mice. Treated mice were administered with BMEDA at dose levels of 3, 6, 9, and 12 mg/kg, with a dose volume of 10 mL/kg. The control mice were administered 10 mL/kg of vehicle control. The mice were observed for 14 days. Observations included mortality, clinical signs, total body-weight gains, food consumption, and gross necropsy findings. BMEDA exerted no adverse toxic effects in ICR mice at dose levels 3 mg/kg, which are up to 360,000 times higher than the intended human dose. The lethal-dose (LD(50)) value of BMEDA was 8.13 and 8.68 mg/kg in male and female mice, respectively.

Evaluation of the efficacy of a topical cosmetic slimming product combining tetrahydroxypropyl ethylenediamine, caffeine, carnitine, forskolin and retinol, In vitro, ex vivo and in vivo studies.

Three studies were performed to investigate the mechanism of action and evaluate the efficacy of a topical cosmetic slimming product combining tetrahydroxypropyl ethylenediamine, caffeine, carnitine, forskolin and retinol. The Ex vivo study on skin explants showed that caffeine and forskolin both stimulated glycerol release and demonstrates for the first time that retinol and carnitine in combination synergistically stimulated keratinocyte proliferation, which leads to an increase epidermal thickness. The double-blind, randomized, placebo-controlled clinical study associating circumference measurements on five selected parts of the body, cutaneous hydration measurements as well as blinded expert grading of skin aspect was conducted on 78 women who applied the product or placebo twice daily for 12 consecutive weeks. After 4 weeks of twice-daily application of the product, significant reductions in circumference of abdomen, hips-buttocks and waist were already observed. Improvements concerned all the measured body parts after 12 weeks. Orange peel and stubborn cellulite decreased significantly from 4 weeks of treatment and tonicity improved from 8 weeks, demonstrating that the product improved skin aspect. At the end of the study, eight parameters of the thirteen evaluated were significantly improved in the active group and compared with placebo.

A phase I study of samarium lexidronam/bortezomib combination therapy for the treatment of relapsed or refractory multiple myeloma.

PURPOSE: This open-label, phase I dose-escalation study assessed the safety, tolerability, and initial efficacy of Samariam 153 (153Sm)-lexidronam/bortezomib combination therapy for patients with relapsed/refractory multiple myeloma. EXPERIMENTAL DESIGN: Patients were enrolled in six cohorts and given bortezomib (1.0 or 1.3 mg/m2) on days 1, 4, 8, and 11 and 153Sm-lexidronam (0.25, 0.5, or 1.0 mCi/kg) on day 3 of a 56-day cycle (maximum of four cycles). The primary endpoints were safety and tolerability of the 153Sm-lexidronam/bortezomib regimen. RESULTS: Twenty-four patients were enrolled. Median values for age, time since diagnosis, and number of prior treatments were 63 years, 29 months, and three regimens, respectively. The most common toxicities were hematologic; during the first cycle, median neutrophil and platelet nadirs were 1,000/mm3 and 98,500/mm3, respectively, and observed generally 3 to 4 weeks post-treatment. The incidences of grade 4 neutropenia and thrombocytopenia were 12.5% and 8.3%, respectively, during treatment cycle 1. Dose-limiting toxicity, reached in cohort 6 as a result of hematologic toxicity, defined the maximum tolerated dose as 0.5 mCi/kg 153Sm-lexidronam in combination with 1.3 mg/m2 bortezomib. The maximum tolerated dose for 153Sm-lexidronam in combination with the 1.0 mg/m2 bortezomib was not reached. No nonhematologic dose-limiting toxicities were observed; both the incidence and the severity of peripheral neuropathy were low. Responses occurred in 5 (21%) patients, including 3 (12.5%) complete and 2 (8.3%) minimal responses. CONCLUSIONS: Bortezomib combined with 153Sm-lexidronam appears to be a well-tolerated regimen, which showed clinical activity in this phase I trial for patients with relapsed or refractory multiple myeloma.