SHetA2 is a heteroarotinoid that has shown selective inhibition of cancer cell growth and an induction of apoptosis without activation of nuclear retinoic acid receptors. In the rat study, SHetA2 was administered in 1% aqueous methylcellulose/0.2% Tween 80 by oral gavage at 0, 100, 500, and 2,000 mg/kg/day for 28 days. The high-dose administration induced decreased activity in male rats, decreased body-weight gains and food consumption, and changes in organ weights. The major metabolite of SHetA2 in rat plasma was monohydroxy SHetA2, which was considerably higher than the parent compound after oral and intravenous administration. Pharmacokinetic analysis showed extremely low (<1%) systemic bioavailability of SHetA2 for all doses tested. The dose of 2,000 mg/kg/day was considered as the lowest observed adverse effect level. The no observed adverse effect level (NOAEL) was 500 mg/kg/day. In the dog study, no toxicity of SHetA2 in 30% aqueous Solutol(®) HS 15 was observed in any tested dose groups (0, 100, 400, and 1,500 mg/kg/day). The major metabolite of SHetA2 in dog plasma was also monohydroxy SHetA2, which was equal to or lower than the parent compound after oral administration. SHetA2 levels in dog plasma were notably higher, when compared to levels in rat plasma. However, exposure was not dose proportional, as exemplified by a lack of proportional increase in maximum concentration or area under the plasma concentration-time curve with increasing dose. The NOAEL was not established and was considered to be above 1,500 mg/kg/day.
Moringaceae, which belongs to the Moringa oleifera Lam. family, is a well-known herb used in Asian medicine as an antiallergic drug. In the present study, the efficacy of the n-butanol extract of the seeds of the plant (MONB) is examined against ovalbumin-induced airway inflammation in guinea pigs. The test drugs (MONB or dexamethasone) are administered orally prior to challenge with aerosolized 0.5% ovalbumin. During the experimental period, bronchoconstriction tests are performed, and lung function parameters are measured. The blood and bronchoalveolar lavage fluid are collected to assess cellular content, and serum is used for cytokine (tumor necrosis factor-alpha, interleukin-4, and interleukin-6) assays. Histamine assays of lung tissue are performed using lung tissue homogenate. The results suggest that in ovalbumin-sensitized model control animals, tidal volume is decreased, respiration rate is increased, and both the total and differential cell counts in blood and bronchoalveolar lavage fluid are increased significantly compared with nonsensitized controls. MONB treatment shows improvement in all parameters except bronchoalveolar lavage tumor necrosis factor-alpha and interleukin-4. Moreover, MONB treatment demonstrates protection against acetylcholine-induced bronchoconstriction and airway inflammation. These results indicate that MONB has an inhibitory effect on airway inflammation. Thus, MONB possesses an antiasthmatic property through modulation of the relationship between Th1/Th2 cytokine imbalances.
Adhatoda vasica Nees (Acantheceae), commonly known as Vasaka, is a well-known plant in indigenous systems of medicine and is used for its beneficial effects, particularly in bronchitis. The present investigation was carried out to study the anti-ulcer activity of Adhatoda vasica leaves using two ulcer models (1) Ethanol-induced, and (2) Pylorus ligation plus aspirin-induced models. Adhatoda vasica leaf powder showeda considerable degree of anti-ulcer activity in experimental rats when compared with a control. The highest degree of activity (80%) was observed in the ethanol-induced ulceration model. Results of the study suggest that in addition to its classically established pharmacological activities, the plant also has immense potential as an anti-ulcer agent of great therapeutic relevance.
The proinflammatory blastocyst implantation cascade involves important mediators like prostaglandins (PG). The influx of calcium via the calcium channel acts as a trigger for the activation of the PG synthesis pathway. Hence, it was hypothesized that calcium channel blockers that are known to possess anti-inflammatory activity may interfere with normal implantation. Pregnant Swiss albino mice (Mus musculus) were treated with diltiazem (1) 4 mg/kg, po on days 1-6 of pregnancy, n=6/day) or (2) at the implantation site (25 microg/animal) via intrauterine injection in the right horn at 5:00 pm on day 4. The intact uterus was used to assay lipid peroxidation and superoxide dismutase activity as markers of membrane fluidity or to observe the day 15 fetus. Oral diltiazem treatment in therapeutic dosage before and during the implantation period did not cause any change in normal uterine milieu during the window of implantation. When injected into the uterine lumen 12-14 h before the average implantation time, however, a complete failure in implantation was observed. Thus, the site specific action of diltiazem may be blocking prostaglandin synthesis, hence causing implantation failure. Oral diltiazem treatment did not mimic this action, indicating that although orally safe in pregnancy in therapeutic dosage, calcium channel blockers may provide a new and yet unknown target in female contraceptive research.
The site specific action of the calcium channel blocker diltiazem in blocking prostaglandin synthesis and hence causing blastocyst implantation failure has been previously described. Based on this understanding it was important to learn if this pathway was under the control of the fine balance in estradiol-progesterone (E2-P4) milieu, considered to be of the utmost significance for effective implantation. In the current study the circulating E2-P4 levels were monitored on the first 6 d of pregnancy at various time points using sensitive chemiluminescence based assays. Next, diltiazem was administered intra-luminally into the uterus at 10-20 h prior to implantation as this time has been previously implicated to be when the best anti-implantation activity of diltiazem can be observed. Following this, the E2-P4 in peripheral circulation was again monitored. On d 6 (post implantation) the implantation sites were observed in the uterus of both diltiazem treated and untreated groups using Chicago blue dye and correlated to the hormonal activity. The levels of both estradiol and progesterone were very similar in both untreated and diltiazem treated groups during and post implantation. However complete implantation failure was noted in the diltiazem treated group whereas prominent implantation sites were observed in the untreated animals. Thus, the previously reported inhibition of blastocyst implantation cascade by calcium channel blockers during the 'implantation window' seems to be an independent mechanism interfering with uterine receptivity without any direct estrogen-progesterone control and further studies to understand its regulation need to be performed.
Adhatoda vasica Nees (Acantheceae), commonly known as Vasaka, is a well-known plant in indigenous systems of medicine and is used for its beneficial effects, particularly in bronchitis. The present investigation was carried out to study the anti-ulcer activity of Adhatoda vasica leaves using two ulcer models (1) Ethanol-induced, and (2) Pylorus ligation plus aspirin-induced models. Adhatoda vasica leaf powder showeda considerable degree of anti-ulcer activity in experimental rats when compared with a control. The highest degree of activity (80%) was observed in the ethanol-induced ulceration model. Results of the study suggest that in addition to its classically established pharmacological activities, the plant also has immense potential as an anti-ulcer agent of great therapeutic relevance.
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