Microbial and chemical transformations of some 12,13-epoxytrichothec-9,10-enes.
Resting cells of Streptomyces griseus, Mucor mucedo, and a growing culture of Acinetobacter calcoaceticus when mixed with compounds related to 12,13-epoxytrichothec-9-ene-4beta,15-diacetoxy-3alpha-ol(anguidine) produced a series of derivatives that were either partially hydrolyzed or selectively acylated. These derivatives showed marked differences in activities as assayed by antifungal and tissue culture cytotoxicity tests. (+info)
Inhibition of angiogenesis induces chromaffin differentiation and apoptosis in neuroblastoma.
Inhibition of angiogenesis has been shown to reduce tumor growth, metastasis, and tumor microvascular density in experimental models. To these effects we would now like to add induction of differentiation, based on biological analysis of xenografted human neuroblastoma (SH-SY5Y, WAG rnu/rnu) treated with the angiogenesis inhibitor TNP-470. Treatment with TNP-470 (10 mg/kg s.c., n = 15) reduced the tumor growth by 66% and stereological vascular parameters (Lv, Vv, Sv) by 36-45%. The tumor cell apoptotic fraction increased more than threefold, resulting in a decrease in viable tumor cells by 33%. In contrast, the mean vascular diameter (29 microm) and the mean tumor cell proliferative index (49%) were unaffected. TNP-470-treated tumors exhibited striking chromaffin differentiation of neuroblastoma cells, observed as increased expression of insulin-like growth factor II gene (+88%), tyrosine hydroxylase (+96%), chromogranin A, and cellular processes. Statistical analysis revealed an inverse correlation between differentiation and angiogenesis. It is suggested that by inhibiting angiogenesis, TNP-470 induces metabolic stress, resulting in chromaffin differentiation and apoptosis in neuroblastoma. Such agonal differentiation may be the link between angiostatic therapy and tumor cell apoptosis. (+info)
Declining concentrations of dihydroartemisinin in plasma during 5-day oral treatment with artesunate for Falciparum malaria.
Six patients with uncomplicated falciparum malaria received artesunate for 5 days. Plasma concentrations of artesunate and dihydroartemisinin were determined by high-performance liquid chromatography with electrochemical detection. The concentrations of dihydroartemisinin in plasma 2 h after a dose showed a time-dependent decline. Concentrations of artesunate in plasma especially after the last dose, were very low. Despite this, all patients responded with a fast recovery. (+info)
Enhanced antitumor activity of 6-hydroxymethylacylfulvene in combination with irinotecan and 5-fluorouracil in the HT29 human colon tumor xenograft model.
6-Hydroxymethylacylfulvene (MGI-114) is a semisynthetic analogue of the toxin illudin S, a product of the Omphalotus mushroom. MGI-114 induces cytotoxicity in a variety of solid tumors in vivo, including the refractory HT29 human colon cancer xenograft. In this study, the potential application of MGI-114 in the treatment of colon cancer was further explored by evaluating the activity of MGI-114 in combination with irinotecan (CPT-11) and 5-fluorouracil (5FU). Groups of 9 nude mice bearing HT29 xenografts were treated with either single agent MGI-114, CPT-11, or 5FU, or MGI-114 in combination with CPT-11 or 5FU. MGI-114 was administered at doses of 3.5 and 7 mg/kg i.p. daily on days 1 through 5, and CPT-11 and 5FU were administered at doses of 50 and 100 mg/kg i.p. on days 1, 12, and 19. In the single agent studies, MGI-114, CPT-11, and 5FU all resulted in decreased final tumor weights compared with vehicle-treated controls (P<0.05), but only MGI-114 at 7 mg/kg produced partial responses. When MGI-114 at 3.5 mg/kg was combined with CPT-11, significant decrements in final tumor weights occurred compared with monotherapy with the same doses of MGI-114 and CPT-11 (P< or =0.001). Also, administration of the low-dose combination (MGI-114 at 35 mg/kg and CPT-11 at 50 mg/kg) resulted in final tumor weights similar to those achieved after administration of high-dose MGI-114 as a single agent. Moreover, the combination of MGI-114 and CPT-11 produced partial responses in nearly all of the animals, with some animals achieving complete responses. The outcome with the combination of MGI-114 and 5FU was less striking, with fewer partial responses and no complete responses. These results suggest enhanced activity when MGI-114 is combined with CPT-11, and clinical trials to further evaluate this combination regimen are planned. (+info)
A randomized, double-blind, comparative trial of a new oral combination of artemether and benflumetol (CGP 56697) with mefloquine in the treatment of acute Plasmodium falciparum malaria in Thailand.
CGP 56697, a new oral fixed combination of artemether and benflumetol, was tested in a double-blinded, randomized trial in 252 adult patients treated either with CGP 56697 (4 x 4 tablets each containing 20 mg of artemether and 120 mg of benflumetol, given at 0, 8, 24, and 48 hr), or with mefloquine (three tablets of 250 mg at initial diagnosis, followed by two tablets of 250 mg at 8 hr). Baseline data of the two groups were comparable. The 28-day cure rate with CGP 56697 was lower than with mefloquine (69.3% versus 82.4%; P = 0.002). However, CGP 56697 was more effective than mefloquine in parasite clearance time (43 hr versus 66 hr; P < 0.001) fever clearance time (32 hr versus 54 hr; P < 0.005), and gametocyte clearance time (152 hr versus 331 hr; P < 0.001). This study revealed that CGP 56697 is effective against multidrug-resistant Plasmodium falciparum malaria in Thailand, but higher doses will probably be needed to improve the cure rate. (+info)
The pharmacokinetics of artemisinin after administration of two different suppositories to healthy Vietnamese subjects.
Eight healthy Vietnamese male subjects received 400 mg artemisinin formulated into fatty suppositories (FS), and six different subjects received 500 mg of artemisinin formulated in polyethylene glycol suppositories (PEGS). Plasma concentrations were measured by high-performance liquid chromatography with electrochemical detection; concentration versus time curves were analyzed with nonparametric methods. No statistically significant differences were found between the two formulations. The maximum concentration (Cmax) was 100 +/- 102 microg/L (mean +/- SD, range = 24-330) microg/L (FS), the pharmacokinetic lag time (Tlag) was 1.3 +/- 1.0 hr (range = 0-3) (FS), and the time of the maximum concentration (Tmax) was 7.1 +/- 2.1 hr (range = 3-10) hr (FS). Because artemisinin is not available for intravenous dosage, absolute bioavailability cannot be assessed. However, compared with a previous study on oral artemisinin in healthy Vietnamese subjects, bioavailability relative to oral administration was estimated to be approximately 30%. We conclude that therapeutic blood concentrations of artemisinin can be reached after rectal dosage. The dose after rectal administration should probably be higher than after oral administration; doubling or tripling the oral dose might be necessary, which would imply a rectal dose of at least 20 mg/kg of body weight given twice a day. (+info)
Comparison between huperzine A, tacrine, and E2020 on cholinergic transmission at mouse neuromuscular junction in vitro.
AIM: To compare the effects of huperzine A (Hup A), tacrine, and E2020 on cholinergic transmission at mouse neuromuscular junction in vitro. METHODS: The isolated mouse phrenic nerve-hemidiaphragm preparations were used with the conventional intracellular recording technique. The miniature end-plate potentials (MEPP), the mean quantal content of end-plate potentials (EPP), and the resting membrane potentials of muscle fiber were recorded. RESULTS: Hup A, tacrine, and E2020 at the concentration of 1.0 mumol.L-1 increased the amplitude, time-to-peak, and half-decay time of MEPP in the potencies of E2020 > Hup A > tacrine. Hup A did not significantly change the frequency of MEPP, the appearance of giant MEPP or slow MEPP, the resting membrane potentials, and the mean quantal content of EPP. CONCLUSION: Hup A is a selective and potent cholinesterase inhibitor, by which activity it facilitates the cholinergic transmission at mouse neuromuscular junction, and devoid of pre- and post-synaptic actions. (+info)
Effect of artemether on glucose uptake and glycogen content in Schistosoma japonicum.
AIM: To study the effect of artemether (Art) on glucose uptake and glycogen content in schistosomes. METHODS: Schistosomes recovered from mice treated intragastrically with Art 300 mg.kg-1 for 24-48 h, were incubated in the drug-free medium containing [U-14C]glucose 11.1 MBq.L-1. The glycogen content, [U-14C]glucose uptake, and incorporation of [U-14C]glucose into worm glycogen in both male and female worms were determined. RESULTS: When above-mentioned schistosomes were exposed to drug-free medium containing [U-14C]glucose for 1-24 h, the glycogen contents of male and female worms decreased 27%-61% and 39%-78%, respectively. Only 3 out of 6 male worm groups showed 23%-35% decrease in glucose uptake, while much less glucose uptake was found in female worms in all groups with reduction rates of 18%-38%. Apart from 2 male groups no apparent change in the incorporation of [U-14C]glucose into the worm glycogen was seen. CONCLUSIONS: Art-induced glycogen reduction in schistosomes was related to an inhibition of glycolysis rather than an interference with glucose uptake. (+info)