Effect of postoperative proton pump inhibitor therapy on voice outcomes following phonomicrosurgery for vocal fold polyp: a randomized controlled study.

OBJECTIVE: To determine the effect of a postoperative proton pump inhibitor (PPI) on voice outcomes after phonomicrosurgery in patients with vocal fold polyp. STUDY DESIGN: This is a prospective, randomized controlled study. SETTINGS: This study was carried out in a tertiary care referral medical centre. PARTICIPANTS: A total of 48 patients underwent phonomicrosurgery for vocal fold polyps. After surgery, patients were randomized to the PPI group (lansoprazole 15 mg twice daily for 2 months) and the non-PPI group. MAIN OUTCOME MEASURES: Voice handicap index (VHI) and perceptual and acoustic voice analysis were evaluated at baseline and 2 months after surgery. RESULTS: Among 48 enrolled patients, a total of 42 patients [non-PPI group (n = 23), PPI group (n = 19)] completed the study. The VHI, perceptual and most acoustic parameters significantly improved in both groups after surgery. However, there was no significant difference in the per cent of change in those parameters. CONCLUSION: Postoperative PPI treatment did not significantly influence voice outcomes after phonomicrosurgery in patients with vocal fold polyp.

Pandemic influenza virus, pH1N1, induces asthmatic symptoms via activation of innate lymphoid cells.

BACKGROUND: The pandemic strain of the influenza A virus (pH1N1) in 2009 caused many complications in patients. In this study, we introduce asthmatic symptoms as a complication of pH1N1 infection in children, not having a relationship with asthma history. The aim of this study was to quantify asthmatic symptoms in pH1N1-infected children and elucidate the underlying mechanisms of airway hyper-responsiveness (AHR) induced in a murine model of pH1N1 infection. METHODS: As a retrospective study, pH1N1-infected children who were hospitalized with moderate to severe acute asthmatic symptoms were enrolled and administered a methacholine challenge test (MCT) at 3 months post-discharge. Additionally, the induction of AHR by pH1N1 infection was measured by MCT in wild-type and Rag1(-/-) mice. The effect of the innate immune response on the development of AHR following pH1N1 infection was investigated. RESULTS: More than 70% of the pH1N1-infected children without a pre-infection diagnosis of asthma had a negative response on the MCT. None of these children had recurrent wheezing or asthma during the 3 years following pH1N1 infection. The development of AHR in pH1N1-infected mice was associated with an elevation in IL-33 and innate lymphoid cells 2 (ILC2). CONCLUSIONS: This study demonstrates that pH1N1 infection directly induces transient asthmatic symptoms in patients regardless of their medical history. pH1N1 infection was shown to stimulate the rapid development of AHR and Th2-type cytokine secretion in mice via the activation of ILC2; it may be activated independently of adaptive immunity.

Food hypersensitivity in adult patients with atopic dermatitis in Korea.

BACKGROUND: It is known that atopic dermatitis (AD) is associated with food or environmental allergens and increased levels of serum IgE. However, the role of hypersensitivity to food antigens in adult patients remains controversial. AIM: To evaluate the association between food hypersensitivity and AD in 126 adult Korean participants. METHODS: Patients with AD were assessed for a previous history of food hypersensitivity that aggravated the symptoms of AD. Blood samples were taken from the patients to measure food allergen-specific IgE. Based on history and laboratory results, open oral food challenge (OFC) tests were performed. RESULTS: Of 126 participants, 33 (26.2%) claimed to have experienced previous food hypersensitivity. Both pork and wheat (n = 5 each) were the main foods mentioned, followed by beef (n = 4) and shellfish (n = 3). We found that 20 participants (15.9%) had raised levels of food-specific IgE, with beef (n = 7), pork (n = 6), milk (n = 5) and wheat (n = 5) being the most common (some patients had more than one). However, when the open OFC tests were conducted in 48 participants with self-reported food hypersensitivity or raised levels of food-specific IgE, only one showed a positive reaction; this participant had a previous history of pork consumption exacerbating AD. CONCLUSIONS: Although some participants claimed to have a history of AD aggravation related to food intake, when an open OFC test was conducted, few of them had positive results. Our study result indicates that there is a positive reaction rate of only 0.79% for adults. We therefore conclude that adults are less sensitive than children with regard to the association between AD and food hypersensitivity.

Optimal formation of genetically modified and functional pancreatic islet spheroids by using hanging-drop strategy.

BACKGROUND: Rejection and hypoxia are important factors causing islet loss at an early stage after pancreatic islet transplantation. Recently, islets have been dissociated into single cells for reaggregation into so-called islet spheroids. Herein, we used a hanging-drop strategy to form islet spheroids to achieve functional equivalence to intact islets. METHODS: To obtain single islet cells, we dissociated islets with trypsin-EDTA digestion for 10 minutes. To obtain spheroids, we dropped various numbers of single cells (125, 250, or 500 cells/30 µL drop) onto a Petri dish, that was inverted for incubation in humidified air containing 5% CO(2) at 37 °C for 7 days. The aggregated spheroids in the droplets were harvested for further culture. RESULTS: The size of the aggregated islet spheroids depended on the number of single cells (125-500 cells/30 µL droplet). Their morphology was similar to that of intact islets without any cellular damage. When treated with various concentrations of glucose to evaluate responsiveness, their glucose-mediated stimulation index value was similar to that of intact islets, an observation that was attributed to strong cell-to-cell interactions in islet spheroids. However, islet spheroids aggregated in general culture dishes showed abnormal glucose responsiveness owing to weak cell-to-cell interactions. Cell-to-cell interactions in islet spheroids were confirmed with an anti-connexin-36 monoclonal antibody. Finally, nonviral poly(ethylene imine)-mediated interleukin-10 cytokine gene delivered beforehand into dissociated single cells before formation of islet spheroids increased the gene transfection efficacy and interleukin-10 secretion from islet spheroids >4-fold compared with intact islets. CONCLUSION: These results demonstrated the potential application of genetically modified, functional islet spheroids with of controlled size and morphology using an hanging-drop technique.

Synergistic effect of surface modification with poly(ethylene glycol) and immunosuppressants on repetitive pancreatic islet transplantation into antecedently sensitized rat.

BACKGROUND: Polymeric modification of islet surface is highly effective in preventing transplanted islets against host immune reactions. However, grafted islets are eventually rejected by the host immune reaction. Thus, repetitive islet transplantation is needed to treat type 1 diabetic patients experiencing graft rejection. We explored whether using poly(ethylene glycol) (PEG) as surface camouflage of islets (PEGylation) can be an affordable immunoprotective remedy for repeated islet transplantation. METHODS: The surface coverage of PEG was evaluated in vitro. The viability of PEGylated islets cocultured with sensitized or nonsensitized splenocytes was evaluated using lactate dehydrogenase assay. In addition, the effect of surface modification on immunoprotection for repetitively transplanted islets was evaluated in a sensitized rat model. RESULTS: Unmodified islets transplanted in combination with Cyclosporine (CsA) and anti-CD4 monoclonal antibody (OX-38) into the sensitized recipients did not maintain a normal level of blood glucose over 20 days. Interestingly, however, three of the five recipients became normoglycemic up to 30 days when PEGylated islets were transplanted in combination with CsA and OX-38. CONCLUSION: These results demonstrated that PEGylation alone was not an affordable immunoprotective method, but the combination of CsA and OX-38 along with PEGylation showed a highly improved a synergic effects on the inhibition of sensitized host immune reactions.

Plating of humeral shaft fractures: comparison of standard conventional plating versus minimally invasive plating.

PURPOSE: This study compared clinical outcomes and complications in patients with humeral shaft fractures treated using two methods of fixation by plating. METHODS: Minimally invasive plate osteosynthesis (MIPO, n=29) was prospectively performed from around the middle of the study period, while open reduction and plate osteosynthesis (ORPO, n=30) had been the original standard method. Locking compression plate was used in these two groups. Major characteristics of the two groups were similar in terms of fracture type, fracture location, age, associated injuries and numbers of open fractures. RESULTS: Primary union was achieved in 28 of 29 in the MIPO and in 27 of 30 in the ORPO. Mean time to union was similar in the two groups. Mean operation time in the MIPO (110min) was shorter than in the ORPO (169min) (P<0.05). Bone grafting was performed in five patients of in the ORPO, but in no patient in the MIPO (P<0.0001). There was one case of deep infection in the ORPO. Functional outcome was satisfactory in both groups. CONCLUSIONS: Minimally invasive plate osteosynthesis may achieve comparable results with the open plate osteosynthesis method in simple as well as complex fractures of humeral shaft. Although MIPO potentially has the radiation hazard, it may reduce the perioperative complications with a shortened operation time. LEVEL OF EVIDENCE: Level III. Case-control study.

The humoral immune response to the inactivated influenza A (H1N1) 2009 monovalent vaccine in patients with Type 2 diabetes mellitus in Korea.

AIMS: We evaluated the antibody response to a single-dose adjuvanted, inactivated, pandemic H1N1 influenza vaccination in patients with diabetes and assessed factors associated with the failure to induce antibody responses. METHODS: Eighty-two patients with Type 2 diabetes were vaccinated and antibody responses were determined with haemagglutination inhibition assay and anti-haemagglutinin antibody ELISA. RESULTS: Among 70 antibody-negative patients at baseline, 34 (48.6%) achieved seroconversion; 28 (60.9%) in the young adults group and six (25%) in the elderly group acquired H1N1-specific antibodies. Patients in the older age range or with longer duration of diabetes had a lower seroconversion rate. CONCLUSIONS: Our data show low cross-reactive antibody carrying rate and low seroconversion rate in patients with diabetes. Until larger-scale, case-controlled trials become available, older patients and patients with a longer duration of diabetes should be considered for the two-dose vaccination or have antibody titres measured after the first vaccination.

Pharmacokinetic evaluation of an oral tablet form of low-molecular-weight heparin and deoxycholic acid conjugate as a novel oral anticoagulant.

This study was designed to develop a solid oral dosage form of deoxycholic acid (DOCA)-conjugated low-molecular-weight heparin (LMWH) and to evaluate its oral absorption, distribution, and metabolic stability for the prospect of providing an orally bioavailable LMWH. The LMWH derivative (LHD) was synthesised and then formulated with solubilisers and other pharmaceutical excipients to form a solid tablet. Its absorption and distribution after oral administration were evaluated in mice, rats, and monkeys. The in vitro metabolic stability of LHD was examined by liver microsome assays. More than 80% of LHD was released from the tablet within 60 minutes, guaranteeing rapid tablet disintegration after oral administration. Oral bioavailability of LHD in mice, rats and monkeys were 16.1 ± 3.0, 15.6 ± 6.1, and 15.8 ± 2.5%, respectively. After the oral administration of 131I-tyramine-LHD, most of the absorbed drug remained in the blood circulation and was eliminated mainly through the kidneys. LHD was hardly metabolised by the liver microsomes and showed a stable metabolic pattern similar to that of LMWH. In a rat thrombosis model, 10 mg/kg of orally administered LHD reduced thrombus formation by 60.8%, which was comparable to the anti-thrombotic effect of the subcutaneously injected LMWH (100 IU/kg). Solid tablets of LHD exhibited high oral absorption and statistically significant therapeutic effects in preventing venous thromboembolism. Accordingly, LHD tablets are expected to satisfy the unmet medical need for an oral heparin-based anticoagulant as an alternative to injectable heparin and oral warfarin.

Objective and subjective assessment of masticatory function for patients with temporomandibular disorder in Korea.

This study examined the differences in the masticatory function of patients with temporomandibular disorder (TMD) in Korea. The experimental groups were as follows: 23 patients with painful arthralgia classified as pain group according to the research diagnostic criteria for temporomandibular disorder (RDC/TMC) and 28 patients with pain-free disc displacement and reduction classified as clicking group. The subjects were obtained from those who had visited Yonsei University Dental Hospital from 2007 to 2008. Twenty dental students without TMD symptoms were enroled as the normal control group. The Mixing Ability Index (MAI) was used as the objective index, and the Food Intake Ability (FIA) Index, Visual Analogue Scale (VAS) and oral health impact profile (OHIP) were used as the subjective indices. The MAI, FIA and VAS were significantly lower in the pain group than in the normal and clicking groups (P<0·05). The pain group showed a MAI, FIA and VAS of 16%, 81% and 67%, respectively, compared to that of the normal group. However, there were no significant differences in the MAI, FIA and VAS between the clicking and normal groups. The pain and clicking groups showed a 1·7 and 1·4 times higher OHIP value than the normal group (P<0·05). The MAI and subjective indices, such as the FIA (r=0·40) and VAS (r=0·48), showed a moderate correlation (P<0·01). In conclusion, pain is the main factor for the reduced masticatory function in patients with TMD in Korea, and the joint sound, not the masticatory function, affects the declining OHIP.

Evidence for viscoelastic effects in surface capillary waves of molten polymer films.

The surface dynamics of supported ultrathin polystyrene films with thickness comparable to the radius of gyration were investigated by surface sensitive x-ray photon correlation spectroscopy. We show for the first time that the conventional model of capillary waves on a viscous liquid has to be modified to include the effects of a shear modulus in order to explain both static and dynamic scattering data from ultrathin molten polymer films.

Minimization of immunosuppressive therapy after islet transplantation: combined action of heme oxygenase-1 and PEGylation to islet.

We previously established a type of PEGylated islets to attenuate cellular immune reactions by immobilizing polyethylene glycol (PEG) molecules on islet surfaces, thereby synergistically reducing the dose of immunosuppressant cyclosporine A (CsA; 3 mg/kg/day) to protect transplanted islets. However, higher doses of immunosuppressants should be administered after islet transplantation due to nonspecific inflammation. This study documents that PEGylated islets can be cooperatively protected by the systemic overexpression of heme oxygenase-1 (HO-1), which has a potent cytoprotective function in preventing nonspecific inflammation during an early stage following islet transplantation. Under this scheme, the viability of PEGylated islets was improved; that is, PEG molecules could block cellular immunity and HO-1 could exert its cytoprotective property against inflammation. Interestingly, when employed with a low dose of CsA (1 mg/kg/day), a cooperative action of PEG molecules and HO-1 in immune reactions could result in the complete survival of transplanted islets for 100 days without islet function impairment. However, unmodified islets (control) were completely rejected within 2 weeks despite cotreatment with HO-1 expression and CsA. These results demonstrated that the combinatorial protocol of initial induction of HO-1 expression, followed by the daily administration of a low dose CsA after transplantation of PEGylated islets can be employed as a successful cell therapy in clinical islet transplantation.

PEGylated glucagon-like peptide-1 displays preserved effects on insulin release in isolated pancreatic islets and improved biological activity in db/db mice.

AIMS/HYPOTHESIS: The rapid degradation and clearance of glucagon-like peptide-1 (GLP-1) by the enzymes dipeptidyl peptidase-IV and neutral endopeptidase 24.11 are the main impediments to the development of GLP-1 as a potential glucose-lowering agent. In this study, new enzyme-resistant polyethylene glycol (PEG)-conjugated GLP-1 analogues were designed and examined for metabolic stability and biological potency. MATERIALS AND METHODS: Two mono-PEGylated GLP-1 analogues, N-terminally modified N-PEG/GLP-1 and Lys-modified Lys-PEG/GLP-1, were prepared. Stability was tested in plasma and tissue extracts. In vitro insulin release studies were performed using isolated rat pancreatic islets, while in vivo glycaemic responses were measured in db/db mice. RESULTS: The half-life of Lys-PEG/GLP-1 was 40-, 10- and 28-fold longer than that of GLP-1 in plasma, liver and kidney homogenates, respectively. Lys-PEG/GLP-1 stimulated insulin secretion in the islets in a dose- and glucose-dependent manner, and was as potent as GLP-1. In contrast, N-PEG/GLP-1 showed extended metabolic stability but had significantly lower biological activity. The administration of Lys-PEG/GLP-1 (9 nmol/kg i.p.) to non-fasted db/db mice stabilised glycaemia (p<0.001), whereas GLP-1 (9 nmol/kg) only caused small changes in glucose level. During OGTT in fasted db/db mice, Lys-PEG/GLP-1 administered at 1, 3 and 9 nmol/kg (i.p.) reduced the glucose AUC(0-3h) by 48.7+/-9.4, 55.0+/-2.9 and 63.4+/-2.5%, respectively, compared with placebo (p<0.01), whereas GLP-1 (9 nmol/kg) lowered the glucose level by 39.5+/-12.9% (p<0.01). CONCLUSIONS/INTERPRETATION: This study demonstrates that site-specific PEGylated GLP-1 analogues are resistant to degradation. The enhanced biological potencies of these analogues highlight their potential as new, GLP-1-like glucose-lowering agents.

Treadmill running promotes functional recovery and decreases brain-derived neurotrophic factor mRNA expression following sciatic crushed nerve injury in rats.

AIM: Peripheral nerve injuries are commonly encountered clinical problems and often result in severe functional deficits. In the present study, the effects of treadmill running on the recovery rate of locomotor function and the expression of brain-derived neurotrophic factor (BDNF) mRNA following sciatic crushed nerve injury in rats were investigated. EXPERIMENTAL DESIGN: Comparative investigation was performed over 14 days. SETTING: Experimental animal laboratory. PARTICIPANTS: 24 male Sprague-Dawley rats weighing 200+/-10 g. Animals were randomly assigned into 3 groups: the sham-operation group, the sciatic nerve injury group, and the sciatic nerve injury and running group. INTERVENTIONS: The right sciatic nerve was crushed for 30 s using a surgical clip. Rats of the running group were made to run on a treadmill for 30 min once a day for 12 consecutive days. MEASURES: Functional recovery was analyzed using a walking track analysis which can be quantified with the sciatic function index (SFI) and BDNF mRNA expression was analyzed using reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Sciatic crushed nerve injury showed characteristic gait changes showing decrease of SFI value and treadmill running significantly enhanced the SFI value. The level of BDNF mRNA expression was increased following sciatic crushed nerve injury and treadmill running significantly suppressed the sciatic nerve injury-induced increment of BDNF mRNA expression. CONCLUSIONS: It can be suggested that treadmill running after peripheral nerve injury is effective in the functional recovery by inhibition on the over-expression of BDNF mRNA.

A new drug carrier, Nalpha-deoxycholyl-L: -lysyl-methylester, for enhancing insulin absorption in the intestine.

AIMS/HYPOTHESIS: The development of an orally active insulin formulation will offer great advantages over conventional injectable insulin therapy in the treatment of patients with diabetes mellitus. Since insulin absorption in the intestine is restricted by the natural physiological characteristics of insulin, we developed a small synthetic compound, Nalpha-deoxycholyl-L: -lysyl-methylester (DCK), as an insulin carrier to enhance oral delivery. METHODS: Streptozotocin-induced diabetic rats orally received single doses of insulin (42 U/kg) or insulin/DCK formulation (10, 21, 30 and 42 U/kg) under fasting conditions. Blood glucose levels and plasma insulin concentrations were measured for 6 h following the administration of the agents. An OGTT was also performed immediately after the administration of the oral insulin/DCK formulation. RESULTS: The administration of 21, 30 and 42 U/kg (based on insulin activity) of insulin/DCK formulation reduced plasma glucose levels by up to 33.0% (median; range 30.6-70.2%), 78.5% (39.4-86.8%) and 75.2% (67.0-87.4%), respectively, compared with baseline levels. Furthermore, plasma insulin concentrations were observed to rapidly increase. In the OGTT, the insulin/DCK formulation reduced the AUC0-240 for glucose by 30.8% (22.3-54.9%) (p<0.01), and stabilized glycaemia for up to 4 h. CONCLUSIONS/INTERPRETATION: The results of this study demonstrate that the insulin/DCK formulation can be absorbed in the intestine and that it is biologically efficacious. We therefore suggest that this oral formulation could be used as an alternative to injectable insulin with enhanced clinical effects.

Separate vertical wiring for the fixation of comminuted fractures of the inferior pole of the patella.

Comminuted and displaced fractures of the inferiorole of the patella are not easy to reduce and it is difficult to fix the fragments soundly enough to allow early movement of the knee. We have evaluated the clinical effectiveness of the separate vertical wiring technique in acute comminuted fractures of the inferior pole of the patella. A biomechanical study was also performed using ten pairs of embalmed cadaver knees. A four-part fracture was made on the inferior pole of the patella and fixed by two separate vertical wires on one side and two pull-out sutures after partial patellectomy on the other. The ultimate load to failure in the first group was significantly higher than in the second (250.1+/- 109.7 N v 69.7 +/- 18.9 N, p < 0.002), as was the stiffness (279.9 +/- 76.4 N/mm v 23.2 +/- 11.4 N/mm, p < 0.001). The separate wire technique was used in 25 patients with comminuted fractures of the inferior pole of the patella who were followed up for a mean period of 22 months (10 to 50). All the fractures healed at a mean of seven weeks (6 to 10). No breakage of a wire or infection occurred. The mean grading at the final follow-up was 29.5 points (27 to 30) using the Böstman method. This technique preserved the length of the patella, fixed the comminuted fragments of the inferior pole and avoided long-term immobilisation of the knee.

Metalloprotease-specific poly(ethylene glycol) methyl ether-peptide-doxorubicin conjugate for targeting anticancer drug delivery based on angiogenesis.

This article proposes a novel cancer-targeting drug-delivery system based on angiogenesis, in which the enzymatic activity of type IV collagenases is used to cleave the inactive drug conjugate, thereby activating drug fragments. In this study, the amount and distribution of metalloprotease (MMP)-2 and MMP-9 secreted from Lewis lung carcinoma (LCC) cells and the formation of blood vessels were evaluated by gelatin zymography, in situ film zymography and immunostaining. LLC cells secreted MMP-2 and MMP-9, thereby distributing large amounts of MMPs around a solid tumor. The newly developed blood vessels were also found in a solid LLC tumor. The anticancer drug conjugate (mPEG-GPLGV-DOX) was synthesized by conjugating doxorubicin with Gly-Pro-Leu-Gly-Val (GPLGV) peptide and poly(ethylene glycol) methyl ether (mPEG). GPLGV pentapeptide was used as a substrate for MMP-2 and MMP-9, where the cleavage of Gly-Val bond by MMP was expected. In addition, mPEG was grafted to peptide-doxorubicin conjugate to increase the circulation time in the body and to reduce the cytotoxicity of the anticancer drug. The mPEG-GPLGV-DOX conjugate formed a micelle structure in aqueous solution, with a critical micelle concentration (CMC) of about 0.25 mg/ml and a diameter of 73.1 +/- 12.7 nm at 1 mg/ml. In an in vivo experiment, mPEG-GPLGV-DOX showed 20% chemotherapeutic activity compared with free doxorubicin. Although a 50 mg/kg dose of mPEG-GPLGV-DOX showed similar therapeutic effects to a 10 mg/kg dose of doxorubicin, the life span of mice in the conjugate group was significantly increased. Therefore, an efficient anticancer drug-delivery system could be created by increasing therapeutic efficiency and decreasing drug-toxicity by optimizing the degradation rate of the peptide link by MMP and circulation time in the body.

Conjugation of low-molecular-weight heparin and deoxycholic acid for the development of a new oral anticoagulant agent.

BACKGROUND: Heparin administration is usually limited to intravenous or subcutaneous injection. Oral delivery of heparin is an alternative to this and has been in great demand for treating patients who are at a high risk of deep vein thrombosis or pulmonary embolism. In this study, new heparin derivatives were synthesized to enhance the oral absorption of heparin in the gastrointestinal tract. Methods and Results- By using heparin of 3000 Da [LMWH(3 kDa)], heparin of 6000 Da [LMWH(6 kDa)], and unfractionated heparin (UFH), we synthesized 3 kinds of conjugates of heparin and deoxycholic acid (DOCA): LMWH(3 kDa)-DOCA, LMWH(6 kDa)-DOCA, and UFH-DOCA. After oral administration of 100 mg/kg of heparin-DOCA, the maximum activated partial thromboplastin times of the LMWH(3 kDa)-DOCA, LMWH(6 kDa)-DOCA, and UFH-DOCA were 31.0+/-6.0, 87.8+/-11.1, and 51.0+/-8.7 seconds, respectively. The peak plasma concentrations of LMWH(3 kDa)-DOCA, LMWH(6 kDa)-DOCA, and UFH-DOCA were 0.06+/-0.02, 0.76+/-0.15, and 0.41+/-0.13 IU/mL, respectively. The bioavailability of LMWH(6 kDa)-DOCA at the 20-mg/kg dosage was calculated to be 7.8%. CONCLUSIONS: LMWH(6 kDa)-DOCA was found to have a high anticoagulant effect when administered orally and could be used as a new oral anticoagulant agent. Furthermore, the present work proposed a new method for oral delivery of macromolecules and polysaccharide drugs.

Inhibition effect of new farnesol derivatives on all-trans-retinoic acid metabolism.

All-trans-retinoic acid (atRA) is a promising anticancer and antiwrinkle drug. However, its clinical application is limited because it is rapidly metabolized by the induced cytochrome P450 (P450). In this study, farnesol derivatives are proposed as new inhibitors to prevent P450-mediated metabolism. The farnesol derivatives were suc-farnesol and mal-farnesol, which were synthesized by the chemical conjugation of farnesol with succinic anhydride and maleic anhydride, respectively. The inhibition effects of farnesol, farnesoic acid, and farnesol derivatives on the atRA metabolism were evaluated in microsome and in AMC-HN-6 cells. In the microsome experiment, suc-farnesol and mal-farnesol strongly inhibited atRA metabolism at 10(minus;4) mol/L concentration by as much as 61% and 77%, respectively. In the cell experiment, the inhibition effects of farnesol derivatives on the atRA metabolism showed similar tendency as the results in the microsome experiment, even if the effect was somewhat decreased. Effects of farnesoic acid and farnesol, however, were not significant. This research suggests that carboxylic end groups, such as atRA and hydrophobicity, might be important factors causing the higher inhibition effect, and that derivatization of farnesol can be 1 method to develop new inhibitors of atRA metabolism.

Noble 2-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-isoindolinone derivatives. part I: synthesis and SAR studies for the inhibition of TNF-alpha production.

This study describes the synthesis and in vitro evaluation of noble 2-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-isoindolinone derivatives for the inhibition of TNF-alpha production. Among these compounds, 2-[3-(cyclopentyloxy)-4-methoxyphenyll-3-methyl-1-isoindolinone (5) was the most potent in inhibitory activity of TNF-alpha production in LPS-stimulated RAW264.7 cells.

Effects of ethylene oxide gas sterilization on physical properties of poly(L-lactide)-poly(ethylene glycol)-poly(L-lactide) microspheres.

The aggregation of poly(alpha-hydroxy acid) microspheres during ethylene oxide (EO) gas sterilization makes it difficult for the microspheres to be used in clinical applications. In this study, six kinds of PLLA-PEG-PLLA triblock copolymers (TriPLE) were synthesized with various composition ratios of PEG/PLLA in the range of 0.012 to 0.103. TriPLE microspheres were prepared by the oil-in-water emulsion method. TriPLE microspheres were characterized by using 1H-NMR, gel permeation chromatography (GPC), and differential scanning calorimetry (DSC). After sterilization by EO gas at 55 degrees C, the microspheres were analyzed by scanning electron microscope (SEM), laser diffractometry, standard sieves, X-ray diffraction (XRD), GPC, and DSC. When the composition ratio of PEG/PLLA was above 0.02, the initial crystallinity of TriPLE in microspheres was as high as 50%, and the microspheres were suitable to be sterilized by EO gas. On the other hand, TriPLE microspheres, which had composition ratios of PEG/PLLA below 0.02, had low initial crystallinities of about 30%, and aggregated during EO gas sterilization. For these microspheres, crystallinity increased up to 50% during the sterilization, whereas other TriPLE microspheres did not show any changes in crystallinity. Therefore, the aggregation of TriPLE microspheres during EO gas sterilization was markedly reduced as the initial crystallinity of TriPLE in the microspheres was increased.