Search

Overactivated microglia and persistent neuroinflammation hold an important role in the pathophysiology of neurodegenerative diseases. The extract of Lycoris chejuensis (CJ) and its active compound, 7-deoxy-trans-dihydronarciclasine (named E144), attenuated expressions of pro-inflammatory factors, including nitric oxide, prostaglandin E2, inducible nitric oxide synthase, cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), and interleukin 6, secreted by lipopolysaccharide-activated BV-2 microglial cells, as measured by an enzyme-linked immunosorbent assay or western blotting. In contrast, CJ extract and E144 promoted the secretion of the anti-inflammatory cytokine, interleukin 10. Moreover, we found that E144 attenuated the expression of TNF-α and COX-2 in the cerebral cortex of lipopolysaccharide-treated mice and/or T2576 transgenic mice as well as reduced the reactive immune cells visualized by ionized calcium-binding adaptor molecule 1. Our results suggest the possibility of E144 to serve as a potential anti-neuroinflammatory agent by preventing excess production of pro-inflammatory factors.

Overactivated microglia and persistent neuroinflammation hold an important role in the pathophysiology of neurodegenerative diseases. The extract of

Ethnopharmacological relevance Alzheimer’s disease is a neurodegenerative disorder associated with cognitive impairment and cholinergic neuronal death. INM-176 is a standardized ethanolic extract of Angelica gigas Nakai that has been traditionally used in herbal medicine in China, Japan, and Korea to treat anemia or as a sedative. We investigated whether INM-176 exhibits anti-amnesic effects. Materials and methods Memory impairment was induced by scopolamine, a cholinergic muscarinic receptor antagonist, or amyloid β 1–42 (Aβ 1–42 ) protein. Anti-amnesic effects of INM-176 were measured by the passive avoidance and the Morris water maze tasks in mice. We also examined the effect of INM-176 on the acetylcholinesterase activity, as well as Aβ 1–42 protein-induced astrogliosis or cholinergic neuronal loss in the brain. Results Scopolamine-induced cognitive dysfunction was significantly attenuated by a single or sub-chronic administration of INM-176 in the passive avoidance and the Morris water maze tasks. A single or sub-chronic administration of INM-176 also ameliorated memory impairments induced by Aβ 1–42 protein. INM-176 inhibited acetylcholinesterase activity in the hippocampal tissue in vitro and ex vivo . In addition, INM-176 attenuated the Aβ 1–42 protein-induced astrocyte activation in the hippocampus as well as cholinergic neuronal damage in the CA3 region of the hippocampus and the nucleus basalis of Meynert. Conclusion These results suggest that the memory ameliorating effects of INM-176 on scopolamine- or Aβ 1–42 protein-induced memory impairment are mediated, in part, via acetylcholinesterase inhibition and neuroprotective activities.

Ethnopharmacological relevance : Lonicera japonica Thunb and Anemarrhena asphodeloides BUNGE have been used for the treatment of a variety of inflammatory diseases, cold and infective diseases in many countries, including Korea and China. Aim of the study : This study aimed to assess the anti-nociceptive and anti-inflammatory activities of n-butanol fraction (WIN-34B) prepared from dried flowers of Lonicera japonica and dried roots of Anemarrhena asphodeloides as potential novel treatment of osteoarthritis. Materials and methods : Anti-nociceptive activities of WIN-34B (100, 200 and 400 mg/kg, p.o.) were measured using acetic acid-induced writhing response, formalin-induced paw licking, hot plate, radiant heat tail-flick, carrageenan-induced paw pressure, and Hargreaves tests, respectively. Anti-inflammatory activities of WIN-34B (100, 200 and 400 mg/kg, p.o.) were assessed using acetic acid-induced vascular permeability, carrageenan-induced paw edema, and croton oil-induced ear edema. Anti-osteoarthritis effect of WIN-34B was analyzed using monosodium iodoacetate (MIA)-induced osteoarthritis animal model. Results : WIN-34B exhibited better anti-inflammatory activity than that of celecoxib in carrageenan at the dose of 200 mg/kg and croton oil-induced paw edema and ear edema at the doses of 200 and 400 mg/kg. WIN-34B exhibited significant anti-inflammatory effects on vascular permeability. WIN-34B also exhibited significant anti-nociceptive activities in the late phase of formalin-induced paw licking and writhing response model in mice. In radiant heat tail-flick and carrageenan-induced paw pressure tests, WIN-34B at the dose of 400 mg/kg and at the doses of 200 and 400 mg/kg presented similar activities to indomethacin and celecoxib. Compared to indomethacin WIN-34B at 400 mg/kg showed similar or better anti-nociceptive activities after 1 and 2 h of theraphy in the hot plate test and better anti-nociceptive activity than that of celecoxib in Hargreves test. In the MIA-induced osteoarthritis animal models, WIN-34B at 400 mg/kg exhibited similar or better anti-nociceptive property than that of celecoxib throughout the pain measurement periods. Conclusion : When compared to celecoxib, WIN-34B exhibited similar or better anti-nociceptive and anti-inflammatory activities in osteoarthritic animal models, which may become a potential novel treatment for osteoarthritis.

HVC1, a novel formation containing four herbs, was developed and its hypolipidemic effects in rats with high cholesterol diet (HCD)‑induced hyperlipidemia were investigated. The rats were given a HCD for 8 weeks. The HVC1‑treated groups were orally administered HVC1 at doses of 10, 50 or 250 mg/kg, respectively, and the simvastatin group was treated at a dose of 10 mg/kg. The normal diet and HCD control groups were administered with physiological saline. Oral administration of HVC1 (10, 50 or 250 mg/kg) significantly reduced the body weight of rats with hyperlipidemia and regulated the total cholesterol, low‑density lipoprotein cholesterol and high‑density lipoprotein cholesterol levels in the serum. In addition, tissue analysis revealed that lipid accumulation in the liver and aorta was reduced by HVC1 administration. Furthermore, HVC1 significantly reduced the mRNA expression of peroxisome proliferator‑activated receptor‑γ, 3‑hydroxy‑3‑methylglutaryl‑CoA reductase and low‑density lipoprotein receptor, as well as the protein level of 5' adenosine monophosphate‑activated protein kinase in the liver. The results clearly demonstrate that HVC1 has a potent hypolipidemic effect, and suggest that HVC1 should be evaluated as a potential treatment for hyperlipidemia.

SKI306X compound is a herbal mixture. This plant was in oriental medicine and was clinically approved for the treatment of osteoarthritis (OA) in Korea. SKI306X was previously found to have anti-inflammatory, analgesic and cartilage protective effects in several experimental models. In this study, SKI306X was investigated for its gastro-sparing effects on the gastric mucosa comparing with those of diclofenac, a conventional NSAID, and celecoxib, a cyclooxygenase-2 (COX-2) specific inhibitor. To investigate acute gastric damaging properties of SKI306X, the stomach of the animals was histologically and immuno-histochemically examined after single or repeated administration, and SKI306X demonstrated excellent gastric tolerability. SKI306X did not cause significant gastric irritation, erosion, or ulceration up to the orally administered dose of 2 g/kg and the intraperitoneal (i.p.) dose of 125 mg/kg. In contrast, diclofenac caused mucosal erosion, ulceration and bleeding at clinically effective doses. To determine the mode of gastro-sparing action, eicosanoid synthesis was examined in gastric mucosa and blood. SKI306X significantly decreased gastric and blood leukotriene B(4) (LTB(4)) production. However, SKI306X showed either no effect or a slight increase in levels of prostaglandin E(2) (PGE(2)). In addition, gastro-protective effects of SKI306X were exhibited by suppressing diclofenac-induced erosion and ulceration of gastric mucosa in a rat model and the possible mechanism of these effects were investigated. These studies demonstrated that SKI306X did not produce any significant damage up to dose of 2 g/kg and was effective in significantly protecting the damage associated to diclofenac-induced gastric ulcerations. SKI306X could spare the gastric mucosa through significantly suppressing gastric leukotriene (LT) synthesis.

SKI306X was previously reported to have good anti-inflammatory and analgesic efficacy in various studies. To determine its mode of action, an investigation was carried out for some representative mediators. Arachidonic acid metabolism and its products are particularly important in inflammation and pain. The pro-inflammatory cytokines, especially interleukin-1 (IL-1) and tumor necrosis factor (TNF-alpha), and induced nitric oxide (NO) appear to be most involved in the inflammatory process such as osteoarthritis (OA). Thus SKI306X was tested to determine the effects on enzymes related to arachidonic acid metabolism and the release or synthesis of inflammatory mediators. SKI306X did inhibit the expression of cyclooxygenase-2 (COX-2) enzyme without affecting COX-1 and COX-2 activity. Leukotriene B4 (LTB4) production also was inhibited by SKI306X (IC50 = 98.7+/-4.26 microg/ml). SKI306X inhibited significantly TNF-alpha release (IC50 = 97.6+/-17.8 microg/ml) and NO production (IC50 = 280+/-17.8 microg/ml). But IL-1alpha release was not attenuated by SKI306X. This study suggests that inhibition of these mediators by SKI306X may be one of the mechanisms responsible for its anti-inflammatory effects.

The structural relationship of 16 asiatic acid (AA) derivatives, including AA and asiaticoside (AS) to cytotoxicity and anti-hepatofibrotic activity in HSC-T6 cells, were investigated. Cytotoxicities of AA derivatives varied from 5.5 microM to over 2000 microM of IC50 depending on AA functional group modifications. Substituting the hydroxyl group at the C(2) to N[triple bond]C and substituting bulky groups for dihydroxyl groups at (3), (23) of the A-ring increased the cytotoxicity, but keto group at C(11) and benzoyl ester at C(2) were greatly reduced it. Modification of the carboxylic acid group at C28 also reduced the cytotoxicity. The collagen synthesis determined by hydroxyproline content in the cells was inhibited from a maximum of 48% (Zlx-i-85 and 87) to 15% (AS) by AA derivatives. The anti-hepatofibrotic effect of these compounds might be due to the reduced expression of prolyl 4-hydroxylase alpha and beta subunits and TIMP2. However, the inhibition of collagen by asiaticoside derivatives did not show any structural-activity relationship.

The efficacy and safety of SKI306X, an herbal anti-arthritic agent, was compared with that of diclofenac sodium for the treatment of osteoarthritis of the knee. In a randomized, double-blind, active comparator-controlled trial, a total of 249 patients were randomly assigned to receive either 200 mg of SKI306X three times daily or 100 mg of diclofenac sustained release (SR) once daily. Clinical efficacy variables (visual analog scale, Lesquesne index and global satisfaction score) and adverse events were monitored at baseline and 2nd and 4th weeks of treatment. SKI306X demonstrated efficacy statistically comparable to that of diclofenac, as assessed by the VAS and patients' and investigators' global satisfaction score. Both treatments were well tolerated, however, the SKI306X treatment group experienced less heartburn (4.0% versus 13.7%, p=0.015, chi-square test). In this four-week trial, SKI306X was well tolerated and demonstrated clinical efficacy comparable to that of diclofenac SR.

PURPOSE Heptaplatin, a new platinum analog, has favorable toxicity profiles and antitumor activity, comparable to those of cisplatin, in the treatment of gastric cancer. This study was designed to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of heptaplatin administered by an intraperitoneal route in patients with resected advanced gastric cancer. MATERIALS AND METHODS Seventeen patients with resected advanced gastric cancer were entered onto the study. After completion of a curative resection and an astomosis, heptaplatin was administered intraperiton eally in one liter of 5% dextrose solution. The starting heptaplatin dose was 400 mg/m2 of the body surface area, and was escalated in 200 mg/m2 increments, to cohorts of three patients. A pharmacokinetic analysis was carried out to determine the total and ultrafiltratable platinum concentrations in the plasma, peritoneal fluid, and urine. RESULTS Patients were unable to tolerate a 1, 000 mg/m2 dose level, and at 800 mg/m2, reVersible Grade III toxic ities, including elevated creatinine, proteinuria, hypon- atremia, abdominal pain, and intraabdominal bleeding were noted. No significant toxicity was noted up to a 600 mg/m2 dose level. The ratio of the peak peritoneal to peak plasma drug concentrations were 19.4, 16.6 and 22.8 at doses of 400 mg/m2, 600 mg/m2 and 800 mg/m2, respectively. The pharmacological advantage, expressed as the peritoneal to plasma AUC ratio ranged from 4.3 to 7.0. CONCLUSION Heptaplatin can be delivered by an intra peritoneal route, with both an acceptable toxicity profile and a major pharmacokinetic advantage for cavity exposure. The MTD of intraperitoneal heptaplatin was 800 mg/m2. The major DLTs were nephrotoxicity and intraabdominal bleeding. The recommended starting dose for a subsequent study would be 600 mg/m2.

The purpose of this randomized controlled trial was to compare outcomes of limited open and short wrist transverse techniques in patients with carpal tunnel syndrome. In a single centre randomized controlled trial, 84 patients with idiopathic carpal tunnel syndrome were randomized before surgery to limited open or short wrist transverse open carpal tunnel release. The patients were evaluated at 6 weeks, 3 months, 6 months, and 1 and 2 years after surgery. At every follow-up, the Brigham and Women’s Carpal Tunnel Questionnaire scores, scar discomfort, and subjective patient satisfaction were evaluated. Two years after surgery, five patients were lost to follow-up. The groups had similar Brigham and Women’s Carpal Tunnel Questionnaire Symptom Severity and Functional Status scores and subjective satisfaction scores. The incidence of scar discomfort was not significantly different between the two groups on serial postoperative follow-up. Short wrist transverse open release surgery showed similar early postoperative symptoms and subjective and functional outcomes to limited open release. Level of evidence: II

Red ginseng (RG) is the top-selling functional food in Korea, but is not recommended for use in hypertensive patients. This study was performed to determine the pharmacokinetic (PK) interaction between RG and amlodipine, an antihypertensive drug. RG (0, 0.5, 1, or 2 g/kg/d) was administered orally for 2 wk, and then amlodipine (10 mg/kg) was given orally, to Sprague-Dawley (SD) rats. Blood was collected at 0.08, 0.25, 1, 1.5, 2, 3, 6, 12, and 24 h after amlodipine administration. In intravenous (iv) study, RG (0, 1, or 2 g/kg/d) was administered orally to SD rats for 2 wk, followed by amlodipine (2 mg/kg) intravenously (iv). Plasma concentrations of amlodipine were analyzed using a high-pressure liquid chromatography-tandem mass system (LC-MS/MS). Oral administration of amlodipine produced an increase of time to maximum plasma concentration (tmax: 2.6, 4.1, 8.3, and 8.9 h at 0, 0.5, 1, and 2 g/kg/d, respectively), and a decrease of maximum plasma concentration (Cmax: 278.5, 212.4, 232.1, and 238.7 ng/ml at 0, 0.5, 1, and 2 g/kg/d, respectively.). However, the area under the concentration-time curve from time 0 to 24 h measurable concentration (AUC0-24 h was 3487.4, 2895.4, 3158.2, and 3495 ng/h/ml at 0, 0.5, 1, and 2 g/kg/d respectively) was not significantly changed among the different dose groups. Administration of amlodipine iv produced no significant changes in the apparent terminal half-life, volume of distribution, and AUC0-24 hr among the different dose groups. These results suggest that RG induced negligible influence on amlodipine pharmacokinetically in rats.

SKI 306X is a purigied extract from a mixture of three oriental herbal medicines (Clematis mandshurica, Trichosanthes kirilowii and Prunella vulgaris) that have been widely used for the treatment of inflammatory diseases such as lymphadenitis and arthritis in far East Asia. A double-blind, controlled study was performed to evaluate the efficacy and safety of SKI 306X with placebo in 96 patients with classical osteoarthritis of the knee. Patients were randomized to four treatment groups: placebo, 200 mg, 400 mg and 600 mg of SKI 306X t.i.d.. Clinical efficacy and safety were evaluated for 4 weeks continuous treatments. SKI 306X demonstrated its clinical efficacy, as assessed by 100 mm visual analogue scale (VAS), Lequesne index and patients' and investigators opinion of the therapeutic effect compared with placebo (p

BACKGROUND A Phase I study of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-1,3-dioxolane] platinum(II) (SKI 2053R), a new platinum derivative, was performed to determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLTs), and the pharmacokinetic profile of SKI 2053R in patients with advanced, refractory malignancies. METHODS Twenty-one patients were entered into the study. SKI 2053R was administered with an intravenous infusion over 1 hour every 4 weeks. The SKI 2053R dose was escalated from 40 mg/m2 up to 480 mg/m2 using a modified Fibonacci scheme. Pharmacokinetic analysis was done in all patients to determine the total and ultrafiltrable platinum concentrations in both the plasma and the urine. RESULTS All patients were evaluable for toxicity and response. There was no significant toxicity with dosages up to 360 mg/m2. At 480 mg/m2, two of three patients developed Grade 4 hepatotoxicity, Grade 3 leukopenia and thrombocytopenia, and Grade 2 azotemia and proteinuria. Other toxicity included nausea and emesis, but it was controlled with antiemetics. SKI 2053R did not cause significant neurotoxicity or mucositis. There were 4 patients with stable disease among the 21 patients. Plasma decay of the total and free platinum concentrations was best fitted by using a two-compartment, open model. The terminal plasma half-life of the total platinum after SKI 2053R administration ranged from 63.4 hours to 114.1 hours in dosages ranging from 40 mg/m2 to 480 mg/m2 without significant dose dependency. However, the terminal plasma half-life of the free platinum concentration showed a significant dose dependent, incremental pattern. The renal excretion of SKI 2053R measured as platinum ranged from 49% to 75% of the administered dose. CONCLUSIONS The MTD of SKI 2053R was 480 mg/m2. The major DLTs were hepatotoxicity, nephrotoxicity, and myelosuppression. The recommended starting dose for a subsequent Phase II study is 360 mg/m2 once every 4 weeks. Cancer 2001;91:1549–56. © 2001 American Cancer Society.

The effect of exposure time on the in vitro cytotoxicity of a new platinum complex, cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolan e]platinum(II) (SKI 2053R) and cisplatin (CDDP) toward two human lung-adenocarcinoma cell lines (PC-9, PC-14) and two human stomach-adenocarcinoma cell lines (KATO III, MKN-45) was investigated by variation of the exposure time (1, 4, 12, and 24 h) and drug concentration to yield a constant product of drug concentration times exposure time (C x T). Exposure of cancer cells to low concentrations of SKI 2053R for 12 or 24 h resulted in a greater killing effect than did 1- or 4-h exposure to 24- or 6-fold higher concentrations; the inhibitory effects of SKI 2053R on the colony formation of all tumor cell lines except for KATO III were significantly increased with increasing exposure time (P < 0.05). However, the inhibitory effects of CDDP against all tumor cell lines tested except for PC-14 were inversely correlated with increasing exposure time (P < 0.05). The intracellular accumulation of SKI 2053R and CDDP was measured under the same conditions used in the cell-survival assay using MKN-45 cells. The amount of platinum accumulated from SKI 2053R into MKN-45 cells was greater for the treatment involving low concentrations and long-term exposures (12 and 24 h) than for that using high concentrations and short-term exposures (1 and 4 h) at the constant C x T values; however, the increased accumulation of CDDP was more prominent as the concentration was increased, even if the exposure time became shorter. The pharmacokinetics studies of SKI 2053R following 1-, 4-, 12-, and 24-h infusions were performed in beagle dogs. A single dose of SKI 2053R (5.0 mg/kg) was successively given over various infusion periods to three beagle dogs at 3-week intervals. The peak levels of ultrafiltrable platinum observed for SKI 2053R at the 1-, 4-, 12-, and 24-h infusions were 3.10+/-0.49 (mean +/- SD), 1.24+/-0.06, 0.43+/-0.07, and 0.25+/-0.04 microg/ml, respectively. The mean binding ratios of platinum from SKI 2053R to plasma protein at the end of 1-, 4-, 12-, and 24-h infusions were approximately 91%, 73%, 53%, and 51%, respectively. The steady-state level of free platinum was maintained during long-term infusions (12 and 24 h) after short periods (1-3 h) from the start of the infusion. This study strongly suggests that the therapeutic efficacy of SKI 2053R given by continuous long-term infusion should be investigated in future clinical studies.

The synthesis, aqueous solubility and stability, in vitro antiviral activity, and oral bioavailability of the amino acid ester prodrugs of penciclovir, 13–20, 23, and 24, are described. All of the prodrugs were highly soluble (>100 mg/mL) and sufficiently stable in aqueous solution. The oral bioavailability of O-acetyl-O-l-valylpenciclovir (13) (34 %) in mice was comparable to that of famciclovir (33 %) and approximately 4-fold higher than that of penciclovir.

The synthesis and antitumor activity of (2R,3R)-2,3-dihydroxy- and -2,3-dialkoxy-1,4-diaminobutane platinum(II) complexes 10–15 are described. cis-Dichloro[(2R,3R)-2,3-dimethoxy-1,4-diaminobutane]platinum(II) (bd11) and cis-(cyclobutane01,1-dicarboxylato)[(2R,3R)-2,3-dihydroxy-1,4-diaminobutane]platinum(II) (bd13) showed the potent antitumor activity against L1210 leukemia in mice with % T/C values of around 200.

The in vitro and in vivo antitumor activity of a new antitumor platinum complex, cis-malonato[(4R, 5R-4, 5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (SKI 2053R, NSC D644591), were evaluated and compared with those of cisplatin (CDDP) and carboplatin (CBDCA) using murine tumors. SKI 2053R was highly active in vitro against both L1210 murine leukemia and its CDDP-resistant subline, L1210/DDP; the relative resistances were 20.0-, 14.5-, and 2.7-fold for CDDP, CBDCA, and SKI 2053R, respectively. SKI 2053R showed activity comparable with or superior to either CDDP or CBDCA in mice implanted with L1210. In mice implanted with L1210/DDP, as compared with CBDCA, SKI 2053R showed high values for the percentage of treated survivors relative to controls and for numbers of cured mice, whereas CDDP had virtually no activity. In mice implanted with P388, all three drugs were highly active, but the intensity of activity was shown to be ranked in the following order: SKI 2053R > CDDP > CBDCA. The antitumor activity of SKI 2053R against Lewis lung carcinoma was comparable with that of both CDDP and CBDCA. The antitumor activity of SKI 2053R was further investigated against two human tumor xenografts, KATO HI (stomach adenocarcinoma) and WiDr (colon adenocarcinoma), implanted s.c. in nude mice and was compared with that of CDDP. In SKI 2053R-treated groups, the time required for a mean tumor weight of 1,000 mg was 33.1 days in KATO III xenografts and 35.0 days in WiDr xenografts as compared with 30.2 and 27.2 days in CDDP-treated groups, respectively. SKI 205 3R achieved growth-inhibition rates comparable with those of CDDP against KATO III (65% versus 59%) and WiDr xenografts (64% versus 54%) on day 35. These results indicate that SKI 2053R is an attractive candidate for further development as a clinically useful anticancer drug.

The pharmacokinetics and ex vivo pharmacodynamics studies oncis-malonato[(4R,5R)-4,5-bis (aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (SKI 2053R, NSC D644591), cisplatin (CDDP), and carboplatin (CBDCA) were performed in beagle dogs. Equitoxic doses of SKI 2053R, CDDP, and CBDCA (7.5, 2.5, and 15.0 mg/kg, respectively) were given by i.v. bolus to three beagle dogs in a randomized crossover study. Plasma samples were analyzed for platinum by flameless atomic absorption spectrophotometry. Plasma concentrations of total and ultrafiltrable platinum for the three drugs declined in a biexponential fashion. The mean area under the concentration-time curve (AUC0→∞) determined for ultrafiltrable platinum derived from SKI 2053R, as an active component, was 7.72±2.74 μg h ml−1 (mean ± SD), with an initial half-life of 0.37±0.20 h, a terminal half-life of 2.19±0.93 h, a total clearance of 16.83±4.76 ml min−1 kg−1, and a steady-state volume of distribution of 1.57±0.30 l/kg. The ex vivo antitumor activity of SKI 2053R was assessed using the ultrafiltrable plasma against two human lung-adenocarcinoma cell lines (PC-9 and PC-14) and five stomach-adenocarcinoma cell lines (MKN-45, KATO III, SNU-1, SNU-5, and SNU-16) by tetrazolium-dye (MTT) assay and was compared with that of CDDP and CBDCA using an antitumor index (ATI) determined from the ex vivo pharmacodynamic results of inhibition rates (%) versus time curves. The mean ATI value was shown to be ranked in the following order: SKI 2053R > CBDCA > CDDP. The mean ATI values recorded for SKI 2053R and CBDCA were significantly (P

Neuroinflammation plays a critical role in the etiology of chronic neurodegenerative diseases such as Alzheimer's disease. INM-176 is a standardized ethanolic extract of Angelica gigas, which has been traditionally used as a tonic to treat anemia. In the present study, we investigated whether INM-176 exhibits neuroprotective activities against lipopolysaccharide (LPS)-induced neuronal damage in vitro and in vivo. In primary microglial cells, INM-176 significantly inhibited LPS-induced nitric oxide release and expression of tumor necrosis factor-α and interleukin-1β. The expression levels of inducible nitric oxide synthase and cylcooxygenase-2 in BV2 microglial cells were markedly upregulated by LPS, but this increased expression was counteracted by INM-176. LPS-mediated neuronal damage in an organotypic hippocampal slice culture was also attenuated by the administration of INM-176. In addition, LPS (1 μg/2 μl, i.c.v.)-induced cognitive dysfunction in mice, as determined by passive avoidance and Y-maze tasks, was significantly attenuated by the administration of INM-176. Furthermore, the activation of microglia or astrocytes by LPS in the hippocampal regions of mice was suppressed by INM-176. These results suggest that the neuroprotective and cognition ameliorating effects of INM-176 against LPS-induced damage are mediated, in part, by its anti-inflammatory activities.

The synthesis and antitumor activity of (2R,3R)-2,3-dihydroxy- and -2,3-dialkoxy-1,4-diaminobutane platinum(II) complexes 10–15 are described. cis-Dichloro[(2R,3R)-2,3-dimethoxy-1,4-diaminobutane]platinum(II) (bd11) and cis-(cyclobutane01,1-dicarboxylato)[(2R,3R)-2,3-dihydroxy-1,4-diaminobutane]platinum(II) (bd13) showed the potent antitumor activity against L1210 leukemia in mice with % T/C values of around 200.

Heptaplatin (HTP), a newly developed platinum analog, has been approved for the treatment of gastric cancers in South Korea. In this study we explored the potential of HTP for the treatment of head and neck squamous cell cancers (HNSCC). The anti-proliferative activity of HTP was evaluated in FaDu, a human HNSCC cell line. Combinations of HTP with 5-fluorouracil (5-FU) or paclitaxel (PTX) were determined using combination indexes, and were compared with combinations of cisplatin and 5-FU or PTX. In order to evaluate the transport of HTP into tumor tissue, its penetration through multicell layers (MCLs) of cancer cells was measured. Cisplatin+5-FU and HTP+5-FU showed additive to antagonistic interactions. In terms of the HTP+paclitaxel combination, HTP showed antagonism and additivity at the 50 and 80% growth inhibition levels, respectively. An additive interaction was obtained and apoptosis was increased by 2-fold at both inhibition levels when the combinatorial PTX dose was reduced to 1/10. HTP, but not cisplatin or oxaliplatin (L-OHP), maintained its anti-proliferative activity after MCL penetration at clinically relevant concentrations, which can be attributed to lower protein binding of HTP. In conclusion, the present study suggests that low-dose PTX may sensitize tumor cells to HTP. HTP also showed greater penetration through multilayers of tumor cells compared to cisplatin and L-OHP, which may be an important characteristic for solid tumor treatment. Overall, the present study supports the clinical development of HTP in combination with low-dose PTX against HNSCC.

This study was undertaken to elucidate the mechanism of anti-inflammatory action of gentianine, a constituent of Gentiana Macrophylla. The effects of gentianine on lipopolysacharide (LPS)-induced production of pro-inflammatory cytokines were investigated in male Sprague-Dawley rats. For the first time, we found that oral administration of gentianine (10-100 mg/kg) suppressed the increases in tumor necrosis factor-alpha (TNF-alpha) (ED(50), 37.7 mg/kg) and interleukin (IL)-6 (ED(50), 38.5 mg/kg) in the sera from the rats challenged with bacterial LPS (100 microg/kg; i.p.). However, LPS induced production of other interleukins, such as IL-alpha, was not significantly altered by gentianine. These results suggest that the potential anti-inflammatory action of gentianine might be at least partly based on the suppressed production of TNF-alpha and IL-6.

To evaluate the pharmacokinetic/pharmacodynamic characteristics of SKP-450, a novel K+ channel opener, a single blind, randomized, placebo-controlled, dose-rising, parallel-group study was conducted in 28 healthy volunteers. The volunteers were randomly allocated to dosage groups of 50 micrograms, 100 micrograms, 200 micrograms, and 300 micrograms. Single doses of SKP-450 were administered orally, after overnight fasting, and serial blood sampling and pharmacodynamic measurements were performed up to 48 hours after the drug was administered. The 200 micrograms group was further studied for food interactions in a crossover fashion. Drug concentrations in plasma were determined by HPLC. Hemodynamic changes after drug administration were evaluated by serial measurements of blood pressure (BP), pulse rate (PR), cardiac index (CI), and total peripheral resistance (TPR), using computerized impedance cardiography. Changes in plasma renin activity (PRA) and aldosterone concentrations (PAC) were determined 4 and 24 hours after drug administration. Both SKP-450 and SKP-818, an active metabolite, showed linear pharmacokinetic characteristics, and food intake did not significantly affect the pharmacokinetic characteristics of either compound. Dose-related pharmacological effects were obvious for both the 200 micrograms and 300 micrograms groups. Hemodynamic parameters related to vasodilation and reflex tachycardia, such as maximum changes in diastolic BP, PR, CI, and TPR, showed significant dose-dependent changes. The area under the time-effect curve (AUEC) of the parameters also showed a similar dose-dependent pattern. The PRA and PAC exhibited significant changes 4 hours after drug administration in the 300 micrograms group. Adverse effects, such as headaches, were more frequently observed at the higher dose levels. SKP-450 was generally well tolerated by these normotensive subjects. The antihypertensive efficacy of SKP-450 needs to be evaluated in hypertensive patients after multiple dosing.

A series of 2-amino-9-(3-acyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purin es (1-8) and 2-amino-9-(3-alkoxycarbonyl-oxymethyl-4-alkoxycarbonyloxybut -1-yl)purines (9-12) were synthesized as potential prodrugs of penciclovir. Treatment of 6-deoxypenciclovir with trimethyl orthoacetate or triethyl orthopropionate (1.2 equiv) in DMF in the presence of p-TsOH.H2O (0.1 equiv) followed by quenching with excess H2O gave the corresponding mono-O-acetyl or mono-O-propionyl compound, 17 or 18, in excellent yields of 95 and 92%, respectively. Reactions of 17 or 18 with an appropriate alkyl (Me, Et, n-Pr, and i-Pr) 4-nitrophenyl carbonate (1.2 equiv) in pyridine in the presence of a catalytic amount of DMAP (0.1 equiv) at 80 degrees C afforded the monoacyl, monocarbonate derivatives of 6-deoxypenciclovir, 1-8, in 86 94% yields. Similar reactions of 6-deoxypenciclovir with 2.1 equiv of alkyl 4-nitrophenyl carbonate produced the dicarbonate derivatives 9 12 in 81-83% yields. Of the prodrugs tested in rats, 2-amino-9-(3-acetoxymethyl-4-isopropoxycarbonyloxybut-1-yl)purine (4) achieved the highest mean urinary recovery of penciclovir (36%), followed in order by compounds 2 (35%), 6 (35%), 7 (34%), 10 (34%), 8 (32%), 3 (32%), and famciclovir (31%). The mean urinary recovery of penciclovir and concentrations of penciclovir in the blood from 4 in mice were also slightly higher than those from famciclovir. The in vivo antiviral efficacy of 4 in HSV-1-infected normal BALB/c mice was higher than those of famciclovir and valaciclovir in terms of mortality (100, 80, and 40%) and mean survival time ( > 21, 13+/-5.0 (SEM), and 13+/-1.6 days). Compound 4 demonstrated an effective anti-hepadnaviral response with intrahepatic viral load being reduced by 90%, the viral supercoiled DNA levels reduced by 70% and Pre-S expression inhibited by 30% against duck hepatitis B virus (DHBV) in vivo, and did not cause any significant hepatotoxicity after 4 weeks of treatment.

A series of 2-amino-9-(3-hydroxymethyl-4-alkoxycarbonyloxybut-1-yl)purines (4-10) and 2-amino-9-(2-(2-oxo-1,3-dioxan-5-yl)ethyl)purine (1) were synthesized as potential prodrugs of penciclovir and evaluated for their oral penciclovir bioavailability in mice and rats. Treatment of 2-(2-benzyloxyethyl)propane-1,3-diol (11) with 1,1'-carbonyldiimidazole in THF followed by hydrogenolytic removal of the benzyl group of the resulting cyclic carbonate 12 gave 5-(2-hydroxyethyl)-1,3-dioxan-2-one (13). Mesylation of the alcohol 13 and then a coupling reaction of the resulting mesylate 14 with 2-amino-6-chloropurine using anhydrous Cs2CO3 in DMF afforded 2-amino-6-chloro-9-(2-(2-oxo-1,3-dioxan-5-yl)ethyl)purine (16) after purification by flash column chromatography on silica gel using EtOAc/MeCN/Et3N as eluent. Hydrogenation of the 6-chloro cyclic carbonate 16 followed by a ring-opening reaction of the 6-deoxy cyclic carbonate 1 in a mixture of an appropriate alcohol and CHCl3 using activated SiO2 as a Lewis acid afforded the corresponding alkyl monocarbonate derivatives 3-10 in fair to good yields. Of the prodrugs tested in mice, the isopropyl monocarbonate 6 achieved the highest mean urinary recovery of penciclovir (53%), followed in order by the propyl monocarbonate 5 (51%), the isopentyl monocarbonate 10 (51%), the ethyl monocarbonate 4 (50%), and famciclovir (48%). In rats, the methyl monocarbonate 3, 4, 6, the n-butyl monocarbonate 7, and 10 (39-41%) showed levels of mean urinary recovery of penciclovir similar to that from famciclovir (40%). The alkyl monocarbonates 4-10 were found to be quite stable in the aqueous buffer solutions, and among them, 6 was the most stable with the half-lives (t1/2) of 88,200, 61, and 26 days at pH 1.2, 6.0, 7.4, and 8.0, respectively. In addition, 6 was highly soluble in H2O (138.8 mg/mL, 20 degrees C).

The synthesis, physical properties, antitumor activity, structure-activity relationships, and nephrotoxicity of a series of [2-substituted-4,5-bis(aminomethyl)-1,3-dioxolane]platinum(II) complexes are described. The 42 platinum(II) complexes having a seven-membered ring structure in this series have been prepared and characterized by 1H NMR, 13C NMR, IR, FAB-MS, and elemental analysis. All members of the series were designed to have a 1,3-dioxolane ring moiety in their carrier ligands to increase water solubility. The solubility of platinum complexes was related to the nature of leaving ligands and 2-substituents in the 4,5-bis(aminomethyl)-1,3-dioxolane carrier ligands. In general, compounds having two different R1 and R2 substituents in the 4,5-bis(aminomethyl)-1,3-dioxolane moiety were more water-soluble than those having the same substituents. Most members of this series showed the excellent antitumor activity against murine L1210 leukemia cells transplanted in mice and were superior to cisplatin and carboplatin. The (4R,5R)-stereoisomer 1a-h exhibited the higher antitumor activity than the corresponding (4S,5S)-stereoisomer 2a-h in the (1,1-cyclobutanedicarboxylato)platinum(II) complexes. The (glycolato)-platinum(II) complexes were highly cytotoxic toward four human stomach cancer cell lines, SNU-1, SNU-5, SNU-16, and NCI-N87, and among them, complexes 3d-g were even more cytotoxic than cisplatin. The (malonato)platinum(II) complex 1m and the (glycolato)platinum(II) complexes 3d-g were selected for further studies based on the greater in vivo and in vitro antitumor activity and desirable physical properties. The complexes 3e-g were almost equally cytotoxic to cisplatin toward human stomach cancer cell lines, KATO-III and MKN-45, and a human non-small cell lung cancer cell line, PC14. In contrast with cisplatin and carboplatin, five complexes selected significantly increased in life span in mice transplanted with cisplatin-resistant L1210 cells. Nephrotoxicity studies in ICR mice indicated that serum BUN and creatinine levels were not elevated when five complexes were given at a dose equal to 1.5 times the optimal dose determined in the in vivo L1210 screening system.

In the present study, the anti-cancer effects of ginseng fermented with Phellinus linteus (GFPL) extract were examined through in vitro and in vivo assays. GFPL was produced by co-cultivating ginseng and Phellinus linteus together. Ginsenoside Rg3, Rh1 and Rh2 are important mediators of anti-angiogenesis and their levels in GFPL were enriched 24, 19 and 16 times, respectively, more than that of ginseng itself through the fermentation. GFPL exhibited distinct anti-cancer effects, including growth inhibition of the human lung carcinoma cell line A549, and promotion of immune activation by stimulating nitric oxide (NO) production in Raw 264.7 cells. Further evidence supporting anti-cancer effects of GFPL was its significant prolongment of the survival of B16F10 cancer cell-implanted mice. These results suggest that the GFPL may be a candidate for cancer prevention and treatment through immune activation and anti-angiogenic effects by enriching Rg3, Rh1 and Rh2.

A phase II trial of a novel platinum analog, SKI 2053R, was performed in patients with previously untreated extensive-stage disease (ED) small-cell lung cancer (SCLC). SKI 2053R was administered at the dose of 400 mg/m 2 every 3 to 4 weeks as a I-h infusion. After the first cycle, the dose was escalated to 440 mg/m 2 based on toxicity. Thirty-eight patients (31 male) were enrolled between June 1995 and August 1997. The median age was 61 years (range, 36-70 years). Six of 37 evaluable patients achieved a partial response (16.2%; 95% confidence interval [CI], 4.4-28.0%). The durations of response were 1.1, 1.5, 1.7, 1.9, 3.4, and 4.6 months. The estimated median survival time was 7.4 months (95% CI, 5.1-9.7 months). Grade 3 or 4 toxicities were not observed. Grade 1 to 2 leukopenia, anemia, and thrombocytopenia were seen in 5 of 68 cycles, 16 of 68, and 2 of 68, respectively. Nonhematologic toxicities included grade 1 to 2 nausea or vomiting (30 of 68 cycles), nephrotoxicity (27 of 68), and hepatotoxicity (13 of 68). SKI 2053R showed a modest antitumor activity with limited toxicities in patients with ED SCLC. Further clinical trials are warranted in SCLC with a higher dose of SKI 2053R.

In an attempt to develop a new anticancer platinum complex with greater or equivalent antitumor activity but reduced side effects compared with cisplatin (CDDP), a series of new platinum complexes having a glycolate leaving ligand was synthesized. Among them, five complexes were selected for further development on the basis of adequate water solubility, low nephrotoxicity and high antitumor activity in a murine system. The chemosensitivity of these five complexes was examined in MTT assay against two human pulmonary adenocarcinoma cell lines, PC-9 and PC-14, and two human stomach adenocarcinoma cell lines, MKN-45 and KATO III. Their IC50 and relative antitumor activity (RAA) values were compared with those of CDDP and 254-S, a second-generation platinum complex with a glycolate leaving ligand under phase III clinical trial. The lowest mean IC50 value was observed in CDDP, followed by SKI 2034R and SKI 2033R. In this study, the antitumor activity was evaluated in terms of RAA values and SKI 2034R showed the highest RAA value. The order of RAA values was SKI 2034R > CDDP > SKI 2032R > SKI 2033R > SKI 2030R > SKI 2029R > 254-S. Based on the RAA order, we have recommended SKI 2034R as the most promising candidate for further development of a clinically useful platinum complex.