Efficient entrapment of poorly water-soluble pharmaceuticals in hybrid nanoparticles

Polymeric micelles consisting of amphiphilic block copolymers have emerged as a promising carrier of various drugs, but unfortunately show a limited potential for encapsulating (solubilizing) such drugs. In this study, hybrid nanoparticles consisting of monomethoxypolyethyleneglycol-polylactide block copolymer (PEG-PLA) and oleic acid calcium salt were prepared to enhance the solubilization of poorly water-soluble drugs. Micelles made of a mixture of sodium oleate and PEG-PLA at various ratios were used as the template for preparation of the nanoparticles. These mixed micelles could efficiently solubilize poorly water-soluble drugs in aqueous media, when compared with polymeric micelles made of PEG-PLA alone. Addition of calcium to the mixed micelles induced the formation of oleic acid calcium salt, resulting in hybrid nanoparticles. These hybrid nanoparticles had a high colloidal stability, neutral zeta potential, and high drug entrapment efficiency. Drugs entrapped in nanoparticles made at a high PEG-PLA ratio were protected from enzymatic degradation in serum, while drugs entrapped in the mixed micelles were not, indicating that the hybrid nanoparticles show good drug retention. These results suggested that such hybrid nanoparticles may be used to expand the availability of poorly water-soluble drugs for various therapeutic applications.     

Regular exercise reduces 8-oxodG in the nuclear and mitochondrial DNA and modulates the DNA repair activity in the liver of old rats

Exercise is often said to increase the generation of reactive oxygen species that are potentially harmful. On the other hand, regular exercise has various health benefits even late in life. The specific aim of this study was to explore effects of regular exercise on oxidative status of DNA in aged animals. We report that 2 months of regular treadmill running of aged rats (21 month old) significantly reduced 8-oxodG content to the level of young adult animals (11 month old) in both nuclear and mitochondrial DNA of the liver. The mitochondrial DNA showed 10-fold higher content of the oxidative lesion than the nuclear DNA. The levels in old animals were 2- and 1.5-fold higher than that in young adults for the nucleus and mitochondria, respectively. The activity of the repair enzyme OGG1 was upregulated significantly in the nucleus but not in mitochondria by the exercise. To our knowledge, this is the first report demonstrating that regular exercise can reduce significantly oxidative damage to both the nuclear and mitochondrial DNA. We suggest that the apparent beneficial outcomes in reducing the DNA damage by regular exercise can be interpreted in terms of hormetic effect by moderate oxidative stress and potential adaptation to stronger stresses.     

High-frequency oscillation (HFO) prevents activation of NF-kappaB found with conventional mechanical ventilation (CMV) in surfactant-depleted rabbit lung

High-frequency oscillation (HFO) has been recognized as an effective ventilatory strategy to minimize lung injury during respiratory support. Conventional mechanical ventilation (CMV) compared with HFO was shown to result in an increased number of PMNs and inflammatory cytokines in the lung lavage fluid. However how mechanical forces can be sensed by cells and converted into biochemical signals for intracellular signal transduction is still unknown. In this current study, we sought to determine whether the activation of Nuclear factor-kappa B (NF-kappaB) might be involved in the lung injury caused by CMV. Surfactant-depleted Japanese white rabbits received 1- or 4-hr CMV or 1- or 4-hr HFO. Then, activation of NF-kappaB in the lungs was assessed by conducting electrophoretic mobility shift assays (EMSA). In the experiment with whole lungs, NF-kappaB activity was much higher in the 4-hr CMV lungs than in the 4-hr HFO lungs. To clarify the origin of the cells in which NF-kappaB was activated, we did a second lung lavage at the end of ventilation and washed out the cells that had infiltrated the alveoli. The levels of NF-kappaB activity were the similar in the lungs of 4-hr HFO rabbits and in those of 4-hr CMV ones. On the other hand, NF-kappaB activity was much higher in the 4-hr CMV lungs than in the 4-hr HFO lungs in the experiment with the lung lavage fluid cells. These results show that the increase in NF-kappaB activity in the lungs of 4-hr CMV rabbits was due mainly to the cells that had infiltrated the alveoli.     

Effects of topical application of clonidine cream on pain behaviors and spinal Fos protein expression in rat models of neuropathic pain, postoperative pain, and inflammatory pain

BACKGROUND: Clonidine can effectively reduce pain and/or hypersensitivity. However, the antihypersensitivity effects of clonidine topically applied in cream (CC) have not been investigated. The authors evaluated effects of topical application of CC on pain behaviors and spinal Fos-like immunoreactivity in rats with hypersensitivity. METHODS: Clonidine (30, 100, and 300 microg/g) was prepared in a cream base. In rat models of neuropathic pain, inflammatory pain, and postoperative pain, the authors evaluated effects of CC (0.1 g), topically applied onto the plantar surface of the injured or uninjured paw, on thermal hyperalgesia and mechanical allodynia to von Frey filaments. The authors also evaluated effects of CC on lumbar spinal Fos-like immunoreactivity. RESULTS: In neuropathic rats, CC applied onto the injured paw reduced thermal hyperalgesia and mechanical allodynia dose dependently, whereas CC applied onto the uninjured paw had no effect. The antihypersensitivity effects of CC were antagonized by intraperitoneal yohimbine (10 mg/kg). Further, CC reduced Fos-like immunoreactivity in neuropathic rats. In contrast, CC in a single dose had no effects on hyperalgesia, allodynia, or Fos-like immunoreactivity in rats with inflammatory or postoperative pain. In rats with postoperative pain, CC repeatedly applied for 6 days reduced thermal hyperalgesia, but not mechanical allodynia, in the postoperative days, whereas it had no effects on hyperalgesia or allodynia in those with inflammatory pain. CONCLUSIONS: Topical CC in concentrations examined significantly reduced hypersensitivity and lumbar spinal Fos-like immunoreactivity in rats with neuropathic pain, probably through activation of peripherally located alpha2 adrenoceptors. However, CC was only partially effective and totally ineffective in rats with postoperative pain and inflammatory pain, respectively.     

Significance of monitoring Bio-Intact PTH (1-84) during parathyroidectomy for secondary hyperparathyroidism

BACKGROUND: The Bio-Intact PTH (1-84) assay has recently been developed to specifically measure the intact PTH (1-84) molecule, and in this study we used it to investigate sequential changes in serum Bio-Intact PTH (1-84) levels during parathyroidectomy for secondary HPT. MATERIAL AND METHODS: The subjects of this study were 70 patients (41 women, 29 men) who underwent parathyroidectomy between April 2002 and March 2005. Ethylene diamine tetraacetic acid serum samples were drawn via a peripheral venous catheter after induction of anesthesia (basal), and at 5, 10, and 30 min after diseased glands excision. Serum active PTH (1-84) was measured by the Bio-Intact PTH (1-84) assay, which is a two-site chemiluminometric assay. RESULTS: When 4 or more diseased parathyroid glands were removed, the basal of Bio-Intact PTH (1-84) level in patients without persistent HPT (52 cases) was 539 +/- 355 pg/mL. The level of the Bio-Intact PTH (1-84) at 30 min after sufficient parathyroidectomy had decreased to less than 45 pg/mL, whereas the Bio-Intact PTH (1-84) level in patients with persistent HPT at 30 min was greater than 45 pg/mL (3 cases). After removal of three or fewer diseased parathyroid glands (15 cases), the Bio-Intact PTH (1-84) at 30 min in patients without persistent HPT (13 cases) was less than 45 pg/mL. The 2 patients whose the Bio-Intact PTH (1-84) at 30 min was greater than 45 pg/mL underwent reoperation, and residual enlarged parathyroid gland in the neck was removed. CONCLUSIONS: The Bio-Intact PTH (1-84) level at 30 min after parathyroidectomy seems to be useful for judging whether the parathyroidectomy is complete irrespective of the number of glands removed from patients with secondary HPT. When only three diseased parathyroid glands are removed, the surgeon can decide whether to continue or stop neck exploration according to the level of Bio-Intact PTH (1-84) at 30 min.     

Pathophysiological response to hypoxia - from the molecular mechanisms of malady to drug discovery: drug discovery for targeting the tumor microenvironment

The tumor microenvironment, characterized by regions of hypoxia, low nutrition, and acidosis due to incomplete blood vessel networks, has been recognized as a major factor that influences not only the response to conventional anti-cancer therapies but also malignant progression and metastasis. However, exploiting such a cumbersome tumor microenvironment for cancer treatment could provide tumor-specific therapeutic approaches. In particular, hypoxia is now considered a fundamentally important characteristic of the tumor microenvironment in which hypoxia inducible factor (HIF)-1-mediated gene regulation is considered essential for angiogenesis and tumor development. Additional oxygen sensitive signaling pathways including mammalian target of rapamycin (mTOR) signaling and signaling through activation of the unfolded protein response (UPR) also contribute to the adaptation in the tumor microenvironment. This in turn has led to the current extensive interest in the signal molecules related to adaptive responses in the tumor microenvironment as potential molecular targets for cancer therapy against refractory cancer and recurrence in preparation for the aging society. Therefore, we should focus on the drug discovery for targeting the tumor microenvironment to develop tumor-specific cytostatic agents including angiogenesis inhibitors. In this paper, the development of hypoxia-selective prodrugs, HIF-1 inhibitors, and modulators of the tumor microenvironment will be discussed.     

Current strategy for triple-negative breast cancer: appropriate combination of surgery,radiation, and chemotherapy

Triple-negative breast cancer (TNBC) often grows rapidly and has poor outcomes, with a high recurrence rate and a short interval between recurrence and death. New molecular-targeted therapies are being developed, but cannot be used at present. Other strategies for the management of TNBC are needed. TNBC is characterized by an expanding growth pattern without extensive intraductal spread and is a good candidate for breast-conserving therapy (BCT) with sufficient margins. The local recurrence rate after BCT is not high as those of other subtypes of breast cancer. In contrast, the regional recurrence rate is higher in TNBC than in other subtypes. Sentinel node biopsy and axillary resection should therefore be performed with the upmost caution. Radiation therapy has been shown to be useful for the management of TNBC. Radiation therapy of the chest wall after mastectomy and the regional area as well as the breast after breast-conserving surgery should be considered. Chemotherapy is the only systemic treatment available for TNBC. In our hospital, a combination of cyclophosphamide, epirubicin, and 5-fluorouracil (FEC) followed by docetaxel (DTX) or DTX followed by FEC has been used to treat tumors more than 2 cm in diameter or node-positive breast cancer. Neoadjuvant chemotherapy with these regimens has produced pathological complete response (pCR) rates higher than 20% in patients with TNBC, regardless of the specific order of agents. Tumors tend to shrink towards their center and can be a good indication for BCT. After 3 years, a pCR is associated with good outcomes, whereas a non-pCR sometimes results in distant recurrence, even when residual tumor is minimal. Patients should be closely observed during neoadjuvant chemotherapy. If there is any evidence of tumor progression, the chemotherapeutic regimen should be modified or surgery performed, without losing the opportunity to administer potentially effective treatment. Several studies indicate that neoadjuvant chemotherapy with platinum-based regimens is effective for TNBC and is thus an important treatment option. We have used regimens combining epirubicin and cyclophosphamide (EC) to treat tumors 1–2 cm in diameter without node metastasis, and 2 of 21 patients presented with distant metastases (disease-free interval, 2 and 5 years). We have not used systemic therapy to treat tumors 1 cm or less in diameter without node metastasis, and all 8 patients are alive without recurrence for more than 4 years. After distant recurrence in patients with TNBC, the same chemotherapeutic agents as those used for other subtypes of breast cancer are recommended, but the response is often disappointing, leading to poor outcomes. TNBC presents with different clinical features from other subtypes. The treatment strategy should be selected according to the characteristics of the specific subtype of breast cancer.     

Assessment of health-related quality of life after radiofrequency ablation or laparoscopic surgery for small renal cell carcinoma: a prospective study with medical outcomes Study 36-Item Health Survey (SF-36)

OBJECTIVE: The purpose of this study was to assess the changes in health-related quality of life (HRQoL) during follow-up period in patients treated with percutaneous radiofrequency ablation (RFA) or laparoscopic surgery for small renal cell carcinoma. METHODS: From December 2004 through September 2006, for 37 consecutive patients, who were diagnosed with renal cell carcinoma and underwent percutaneous RFA (n = 20) or laparoscopic radical nephrectomy (n = 17) at our institution. HRQoL was evaluated prospectively using SF-36 Health survey pre- and post-operatively (1, 4, 12 and 24 weeks after surgery). RESULTS: Four of the eight scale scores of SF-36 were significantly lower pre-operatively in the RFA group than in the laparoscopic surgery group. The QoL scores in physical functioning, role-physical functioning and role-emotional functioning were significantly reduced one week after laparoscopic surgery. However, there was no reduction of the SF-36 QoL scores one week after operation in the RFA group. Furthermore, HRQoL scores in the RFA group showed a tendency to improve during follow-up periods. CONCLUSIONS: This is the first study to evaluate HRQoL changes (up to 24 weeks) in patients who have undergone RFA or laparoscopic radical nephrectomy for small renal cell carcinoma. No reduction, but rather an improvement, in HRQoL was seen in the RFA group during follow-up periods. From the point of view of QoL, RFA could be a viable alternative treatment for selected patients with small renal cell carcinoma. RFA could be a viable alternative treatment for the selected patients with small renal cell carcinoma.     

Age and sex-related differences in dose-dependent hemodynamic response to landiolol hydrochloride during general anesthesia

Objective Landiolol hydrochloride is a new ultra-short-acting β₁-adrenergic receptor blocking agent that is used for patients with tachycardia during general anesthesia. The hemodynamic response to a β-adrenergic receptor blocking agent is generally dependent on the subject. In the present investigation we investigated the effects of age and sex on the hemodynamic response to different doses of landiolol. Methods Following a persistence of tachycardia for more than 1 min, landiolol was infused at 0.03125, 0.0625 and 0.125 mg kg⁻¹ min⁻¹ for 1 min followed by 0.01, 0.02 and 0.04 mg kg⁻¹min⁻¹ for 10 min in groups L, M and H, respectively. Heart rate (HR), systolic (sBP) and diastolic blood pressure (dBP) were recorded each minute during the procedure. The respective changes were evaluated using logistic analysis with the equation , where p, q, m and k indicate the upper asymptote, lower asymptote, maximum slope and time at the maximum slope. Results Parameters q and k for HR in group H were smaller than those in group L, whereas the parameters for sBP and dBP were unchanged among the three groups. Parameter q for HR in group H decreased with age of the patient. There was no significant difference in the landiolol-induced change in HR between males and females. Conclusion The hemodynamic response to landiolol is reliably modeled by the logistic function, especially in terms of HR. Landiolol causes a rapid and dose-dependent decrease in HR, whereas landiolol-induced changes in sBP and dBP are independent of dose. The landiolol-induced decrease in HR becomes larger with aging, but shows no sex difference. The logistic model may be useful for studying hemodynamic responses to landiolol based on age and sex differences, and may allow development of an improved monitoring system. Implication statement The logistic function reliably represents the hemodynamic responses to landiolol. Landiolol reduces HR rapidly and in a dose-dependentl manner whereas landiolol-induced changes in sBP and dBP are independent of dose. A larger decrease in HR is caused by landiolol in elderly patients, but there is no sex difference in the landiolol-induced change in HR.     

Geriatric nutritional risk index as an easy-to-use assessment tool for nutritional status in hepatocellular carcinoma treated with atezolizumab plus bevacizumab

Aim

The present study focused on Geriatric Nutritional Risk Index (GNRI), which is based on bodyweight and serum albumin, and known as an easy-to-use nutritional assessment tool in clinical settings, to elucidate the prognostic predictive ability of GNRI in patients treated with atezolizumab plus bevacizumab (Atez/Bev) for hepatocellular carcinoma (HCC).

Methods

A total of 525 HCC patients treated with Atez/Bev, based on their classification of unsuitable status for curative treatments and/or transarterial catheter chemoembolization, were enrolled (Child–Pugh A:B:C = 484:40:1, Barcelona Clinic Liver Cancer stage 0:A:B:C:D = 7:25:192:283:18). Prognosis was evaluated retrospectively using GNRI.

Results

Atez/Bev was used in 338 of the present cohort as first-line systemic chemotherapy (64.4%). Median progression-free survival based on GNRI indicating normal, mild decline, moderate decline, and severe decline was 8.3, 6.7, 5.3, and 2.4 months, respectively, whereas median overall survival was 21.4, 17.0, 11.5. and 7.3 months, respectively (both p < 0.001). The concordance index (c-index) values of GNRI for predicting prognosis (progression-free survival/overall survival) were superior to those of Child–Pugh class and albumin-bilirubin grade (0.574/0.632 vs. 0.527/0.570 vs. 0.565/0.629). As a subanalysis, muscle volume loss was observed in 37.5% of 256 patients with computed tomography data available. Along with GNRI decline, frequency of muscle volume loss became progressively larger (normal vs. mild vs. moderate vs. severe = 17.6% vs. 29.2% vs. 41.2% vs. 57.9%, p < 0.001), and a GNRI value of 97.8 was predictive of its occurrence (AUC 0.715, 95% CI 0.649–0.781; specificity/sensitivity = 0.644/0.688).

Conclusion

These findings indicate that GNRI is an effective nutritional prognostic tool for predicting prognosis and muscle volume loss complication in HCC patients treated with Atez/Bev.