Pharmacologic interaction between cannabinoid and either clonidine or neostigmine in the rat formalin test

BACKGROUND: Although spinal cannabinoid receptor agonist (WIN 55,212-2) has been shown to encounter various models of pain, the role of two subtypes of cannabinoid receptor for the antinociceptive effect of cannabinoids has not been investigated at the spinal level. Spinal alpha 2 receptor agonist (clonidine) and cholinesterase inhibitor (neostigmine) are also active in the modulation of nociception. The authors examined the properties of drug interaction after coadministration of WIN 55,212-2-clonidine, and intrathecal WIN 55,212-2-neostigmine, and further clarified the role of cannabinoid 1 and 2 receptors in cannabinoid-induced antinociception at the spinal level. METHODS: Catheters were inserted into the intrathecal space of male Sprague-Dawley rats, and 50 microl of 5% formalin solution was injected into the hind paw to evoke the pain. Isobolographic analysis was used for evaluation of pharmacologic interaction. RESULTS: Intrathecal 55,212-2, clonidine, and neostigmine dose-dependently suppressed the flinching observed during phase 1 and 2 in the formalin test. Isobolographic analysis revealed a synergistic interaction after intrathecal delivery of WIN 55,212-2-clonidine or WIN 55,212-2-neostigmine mixture in both phases. The antinociceptive effect of WIN 55,212-2 was antagonized by cannabinoid 1 receptor antagonist (AM 251) but not by cannabinoid 2 receptor antagonist (AM 630). No antinociceptive effect was seen after intrathecal administration of cannabinoid 2 receptor agonist (JWH 133). CONCLUSIONS: Intrathecal 55,212-2, clonidine, and neostigmine attenuate the facilitated state and acute pain. WIN 55,212-2 interacts synergistically with either clonidine or neostigmine. The antinociception of WIN 55,212-2 is mediated through the cannabinoid 1 receptor, but not the cannabinoid 2 receptor, at the spinal level.     

Small bowel complication caused by magnetic foreign body ingestion of children: two case reports

Accidental ingestion of foreign bodies is a common pediatric problem. The majority of such cases occur between 6 months and 3 years. When several magnets are ingested, they can be attracted to each other through the intestinal wall, causing necrosis and intestinal perforation or fistula, so they should be removed while they are still in the stomach. The authors experienced 2 cases of unusual small bowel complication caused by the ingestion of magnets. The first case was in a 10-month-old boy with ileal perforation caused by to 2 ingested magnetic beads, and the second case was in a 22-month-old boy with ileo-ileal fistula caused by to 7 ingested magnetic beads.     

New type of reconstruction method after subtotal gastrectomy (Noh's operation)

Abstract The aim of this study was to compare a new type of reconstruction method (Noh’s operation) with Roux-en-Y operation after subtotal gastrectomy. Noh’s operation described herein includes a jejunal occlusion, an end-to-side gastrojejunostomy, a side-to-end jejunoduodenostomy, and a side-to-side jejunojejunostomy after subtotal gastrectomy. A series of 43 patients who had the new operation were compared with 47 patients with the Roux-en-Y procedure. The postgastrectomy syndromes, and the mucosal change of the remnant stomach and esophagus were evaluated after surgery. In the new operation, the Roux stasis syndrome occurred in 34.9% at 3 months, in 23.3% at 6 months, in 14.0% at 12 months, and in 11.6% at 24 months. In patients undergoing the Roux-en-Y operation, the syndrome occurred in 42.6% at 3 months, in 34.0% at 6 months, in 31.9% at 12 months, and in 29.8% at 24 months. This study shows that the new type of operation (Noh’s operation) can be a good option for reconstruction after subtotal gastrectomy. Electronic Publication     

ACE inhibition modulates transforming growth factor-β receptors in the young rat

The renin-angiotensin system plays an important role in renal growth and development. Exposure of the neonate to angiotensin converting enzyme (ACE) inhibitors increases mortality and results in growth retardation and abnormal renal development. It has been demonstrated that ACE inhibition in the developing kidney reduces the renal expression of growth factors, which may account for renal growth impairment. This study was designed to investigate the relationship between renal growth impairment and the expression of transforming growth factor-1 (TGF-1), TGF- receptor I [TRI, activin-like kinase (ALK)-1 and ALK-5], and TGF- receptor II (TRII). Newborn rat pups were treated with enalapril (30 mg/kg per day) or vehicle for 7 days, and kidneys were removed for Western blotting of TGF-1, ALK-1, ALK-5, and TRII, and for RT-PCR of ALK-5 and TRII. TGF-1, ALK-1, ALK-5, and TRII were also detected by immunohistochemistry. Enalapril treatment resulted in an increased mortality (30.4%) by day 7, and reduced body weight and kidney weight (P<0.05 versus vehicle). Enalapril decreased renal TGF-1, ALK-1, and ALK-5 protein expression (P<0.05). Also, enalapril decreased ALK-5 mRNA expression (P<0.05). TRII expression was not changed by enalapril treatment. These results indicate that ACE inhibition in the developing kidney decreases TGF-1, ALK-1, and ALK-5 expression, which may account for renal growth impairment. TRII may not be modulated by ACE inhibition in the developing kidney.     

Effect of Scutellariae radix extract on the high glucose-induced apoptosis in cultured vascular endothelial cells

Endothelial cell apoptosis has been postulated as the initial trigger of the progression of microvascular disease in patients with diabetes mellitus. To investigate the role of Scutellariae radix extract, we examined its effect on the endothelial cell proliferation using the [3H]-thymidine incorporation method. Scutellariae radix extract significantly stimulated endothelial cell proliferation in a dose-dependent manner. We focused on the protective action of Scutellariae radix extract on the endothelial cell apoptosis induced by high glucose concentrations. Determination of endothelial cell apoptosis was performed using DNA gel electrophoresis, terminal deoxynuclotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay, and an ELISA kit. Exposure of vascular endothelial cell to high glucose (16.7 mM) for 72 h resulted in a significant increase in apoptosis, compared with the normal glucose concentrations (5.5 mM). Scutellariae radix extract inhibited high glucose-induced endothelial cell apoptosis. This result suggests that Scutellariae radix extract may contribute to antiapoptotic action against vascular endothelial cells, resulting in a beneficial effect in preventing diabetes-associated microvascular complications.     

Novel phosphoramidite building blocks in synthesis and applications toward modified oligonucleotides

In recent years modified oligonucleotides (oligos) have become an area of increased research activity. These synthetic biopolymers have long been used as molecular probes to understand better the interaction between proteins and nucleic acids at molecular level, which in fact is responsible for all aspects of cellular or viral gene expression. Modified oligos have also been used as therapeutic and diagnostic agents. For example, the antisense oligos are used to block gene expression by binding especially with complimentary sequences of target mRNA. Also, over the past decade efforts are made to modify the native phosphodiester linkages to improve nuclease resistance and membrane permeation of naturally occurring oligonucleotide for therapeutic applications. Therefore, design and synthesis of modified oligonucleotides for a wide range of applications are of interest for bioorganic chemists and biologists. The advent of the phosphoramidite chemistry has accelerated the development of oligos with modified nucleobases, phosphate-protecting groups and modified sugars. In this review, we have presented the recently reported nucleoside based phosphoramidites with modified base, sugar or backbone units and their subsequent conversion into modified DNA and RNA analogs. The effect of such modification on structural, thermodynamic, and hybridization properties of the modified oligos and their duplex with natural complementary oligos have also been discussed for some cases. Similarly, we have highlighted the role of modified nucleoside phosphoramidite building blocks in synthesis of oligos modified with optically or electrochemically active molecules. Nucleoside phosphoramidites or small oligos immobilized over solid supports through different linkages or groups and their biological applications has also been mentioned.     

General pharmacology of indole [2',3':3,4]pyrido[2,1-b]quinazolinium- 5,7,8,13-tetrahydro-14-methyl-5-oxo-chloride,a new anti-dementia agent

The general pharmacological properties of indolo[2',3':3,4]pyrido[2,1-b]quinazolinium-5,7,8,13-tetrahydro-14- methyl-5-oxo-chloride (dehydroevodiamine-HCl, DHED, CAS 67909-49-3), a new potential anti-dementia agent, were studied to investigate side effects using various experimental animals. Both oral and intraperitoneal administration of DHED had no effects on the central nervous system except that they showed an analgesic activity. DHED had no significant effect on heart rate, blood pressure and coronary flow in isolated rat hearts. DHED had negligible effects on the autonomic nervous system and smooth muscle in isolated rat ileum, rat vas deferens and rat aorta. DHED did not influence the gastrointestinal system except that it inhibited the intestinal travel of a charcoal meal in mice. Neither blood coagulation mechanism nor liver function was affected by DHED. Therefore, it is concluded from these general pharmacological studies that DHED does not induce any serious side effects at the dose levels showing anticholinesterase and memory enhancing activities in the experimental animals.     

A parametric model for long-term follow-up data from phase III breast cancer clinical trials

We propose a parametric version of a univariate gamma frailty model. The proposed model is shown to be flexible enough to model long-term follow-up survival data from breast cancer clinical trials when the treatment effect diminishes as time progresses, a case for which neither the proportional hazards nor proportional odds assumptions are satisfied. The observed information matrix is computed to evaluate the variances of parameter estimates. A simple parametric test statistic to test proportional odds assumption is also constructed. The model is applied to a data set from a phase III clinical trial on breast cancer.     

Ginsenoside RB<Subscript>1</Subscript> the anti-ulcer constituent from the head of<Emphasis Type="Italic">Panax ginseng</Emphasis>

We previously reported that the butanol (BuOH) fraction of the head of Panax ginseng exhibited gastroprotective activity in peptic and chronic ulcer models. In order to identify the active constituent, an activity-guided isolation of the BuOH faction was conducted with a HCl x ethanol-induced gastric lesion model. The BuOH fraction was passed through a silica-gel column using a chloroform-methanol gradient solvent system, and six fractions (frs. 1-6) were obtained. The active fr. 5 was further separated by silica-gel column, to yield 6 subfractions (subfrs. a-f). Subfr. d was composed of ginsenosides Re, Rc and Rb1. The most active constituent was ginsenoside Rb1 (GRb1), a protopanaxadiol glycoside, which was investigated for its anti-ulcer effect. Gastric injury induced by HCl x ethanol, indomethacin and pyloric ligation (Shay ulcer) was apparently reduced with oral GRb1 doses of 150 and 300 mg/kg. GRb1 at these dosage significantly increased the amount of mucus secretion in an ethanol-induced model. The anti-ulcer effects were consistent with the result of histological examination. These results suggest that the major active constituent in the head of Panax ginseng is GRb1, and that anti-ulcer effect is produced through an increase in mucus secretion.     

Buccal mucosal ulcer healing effect of rhEGF/Eudispert hv hydrogel

We have studied the effect of rhEGF on the buccal mucosal ulcer healing. rhEGF was rapidly degraded upon incubation with the hamster buccal mucosal homogenates; The degradation of rhEGF was significantly inhibited by sodium lauryl sulfate (SLS). Eudispert hv hydrogel and Polycarbophil 974P hydrogel were prepared for rhEGF delivery and their mucoadhesiveness was measured by the Instron method. The mucoadhesive force of Eudispert hv was significantly greater than that of Polycarbophil 974P. Moreover, rhEGF in Eudispert hv hydrogel remained stable for about 2 months. To evaluate the ulcer healing effect of rhEGF, the buccal mucosal ulcer was induced in golden hamsters using acetic acid. At 24 h after administration of rhEGF/Eudispert hv hydrogel, the ulcerous area was decreased compared with rhEGF solution and, as a result, the curative ratio was 36.8 +/- 5.68%. By the addition of SLS (0.5%) to Eudispert hv hydrogel, the curative ratio increased 1.5 times. The mechanism of the action was probably due to a combination of protection of the drug against proteases present in mucosa and prolongation of the release of rhEGF from the formulation at the site of action.