Copaiba oil enhances in vitro/in vivo cutaneous permeability and in vivo anti-inflammatory effect of celecoxib.

OBJECTIVES: The aim of this article was to use copaiba oil (C.O) to improve skin permeability and topical anti-inflammatory activity of celecoxib (Cxb). METHODS: Formulations containing C.O (1-50%) were associated with Cxb (2%). In vitro skin permeability studies were conducted using porcine ear skin. Histological analysis of the hairless mice skin samples after application of formulations was achieved with the routine haematoxylin/eosin technique. The anti-inflammatory activity was assessed using the AA-induced ear oedema mice model. KEY FINDINGS: The formulation containing 25% C.O promoted the highest levels of in vitro Cxb permeation through pig ear skin, retention in the stratum corneum (SC) and epidermis/dermis of pig ear skin in vitro (~5-fold) and hairless mice skin in vivo (~2.0-fold), as compared with the control formulation. At 25%, C.O caused SC disorganization and increased cell infiltration and induced angiogenesis without clear signs of skin irritation. The formulation added to 25% C.O as adjuvant inhibited ear oedema and protein extravasation by 77.51 and 89.7%, respectively, and that it was, respectively, 2.0- and 3.4-fold more efficient than the commercial diethylammonium diclofenac cream gel to suppress these inflammatory parameters. CONCLUSIONS: 25% C.O is a potential penetration enhancer for lipophilic drugs like Cxb that can improve cutaneous drug penetration and its anti-inflammatory activity.

Protective effect of Juzen-taiho-to on hepatocarcinogenesis is mediated through the inhibition of Kupffer cell-induced oxidative stress.

Traditional herbal formulations, such as Juzen-taiho-to (TJ-48), are used extensively in medical practice in Asia even though their mechanism of action remains elusive. This study tested a hypothesis that TJ-48 is protective against hepatocarcinogenesis by impeding Kupffer cell-induced oxidative stress. Forty-eight patients were randomly assigned to receive TJ-48 (n = 10), or no supplementation (n = 38) for up to 6 years after surgical treatment for hepatocellular carcinoma (HCC). In addition, to investigate the mechanism of protective action of TJ-48, diethylnitrosamine-containing water was administered for 22 weeks to male mice that were fed regular chow or TJ-48-containing diet. Liver tumor incidence, cell proliferation, number of 8-hydroxy-2'-deoxyguanosine- or F4/80-positive cells, and cytokine expression were evaluated. Although most of the patients experienced recurrence of HCC, a significantly longer intrahepatic recurrence-free survival was observed in the TJ-48 group. In mice, TJ-48 inhibited the development of liver tumors, reduced oxidative DNA damage, inflammatory cell infiltration and cytokine expression. Administration of TJ-48 improves intrahepatic recurrence-free survival after surgical treatment of hepatocellular carcinoma. On the basis of animal experiments, we reason that the protective mechanism of TJ-48 involves inhibition of Kupffer cells. This leads to lower levels of pro-inflammatory cytokines and oxidants in liver which may slow down the process of hepatocarcinogenesis and improves hepatic recurrence-free survival in patients with HCC.

Nitric oxide modulation of norepinephrine production in acupuncture points.

The purpose of this study was to examine the levels of norepinephrine (NE) turnover in skin tissues and to determine the effect of nitric oxide (NO) on NE production in acupuncture points (acupoints) and meridians. The rats were pretreated with alpha-methyl-tyrosine methyl ester and intravenously infused with L-(2,3,5,6-(3)H)-tyrosine. Blood was withdrawn and skin tissues were excised from the low skin resistance points, non-acupoint, and non-meridian areas located on leg, arm, or trunk. The results showed that the skin NE concentration and (3)H-NE release in acupoints were significantly higher than those in non-acupoints and non-meridian controls. (3)H-NE releases in the acupoints were increased by intravenous infusion of 2-N,N-diethylamino-diazenolate-2-oxide, an NO donor, but lowered by N(G)-Propyl-L-arginine, an inhibitor of neuronal NO synthesis. NE turnover rates in the acupoints were lower in the NO donor treated group while the inhibitor of NO synthesis reversed the trend. In contrast, NE turnover rates were not altered by NO donor and inhibitor of NO synthesis in non-acupoint and non-meridian control tissues. This is the first evidence that NE turnover was consistently decreased in acupoints and enhanced NE synthesis/release in acupoints were facilitated by presence of an NO donor and inhibited by an inhibitor of NO synthesis. The data suggest that skin NE synthesis/release in acupoints/meridians is increased in skin acupoints, which is modulated by L-arginine-derived NO synthesis in sympathetic nervous system.

Involvement of YY1 and its correlation with c-myc in NDEA induced hepatocarcinogenesis, its prevention by d-limonene.

Anticarcinogenic activity of d-limonene has been well documented within last few years. We have also reported the anticarcinogenic activity of d-limonene in N-nitrosodiethylamine (NDEA) induced hepatocarcinogenesis. The involvement of oncogenes which adds to the mechanisms of d-limonene mediated chemprevention were also suggested in the same model system. The overexpression of c-myc oncoprotein in different durations of NDEA induced hepatrocarcinogenesis is observed which is inhibited completely when d-limonene was treated prior to and along with NDEA. To work further in this direction, an attempt has been made here to know the role of YY1 (Yin Yang 1) transcription factor in N-nitrodiethylamine (NDEA) induced hepatocarcinogenesis and its chemoprevention by d-limonene. Electrophoretic mobility shift assay results have clearly indicated the binding of YY1 in control liver tissue. But this binding is blocked in 60 days and 150 days NDEA treated liver tumors. Thus, it is assumed that there is deregulation of YY1 transcription factor in NDEA induced hepatocarcinogenesis. A similar type of binding to that of control liver tissue has also observed when limonene was given prior to NDEA administration. Western blot analysis has shown inhibition of YY1 protein in NDEA induced liver tumor samples in comparison to normal and both NDEA and limonene treated samples. On the otherhand RT-PCR analysis does not indicate any correlation between YY1 mRNA level and inhibition of YY1 protein. However, along with our earlier information about c-myc with the present study, clearly indicated the involvement of YY1 in NDEA induced hepatocarcinogenesis and d-limonene mediated chemoprevention which might be regulated by c-myc oncoprotein.

Nitric oxide influences the release of histamine and glutamate in the rat hypothalamus.

To investigate the influence of nitric oxide (NO) on the release of histamine and glutamate, the anterior hypothalamus of anaesthetized rats was superfused through a push-pull cannula either with artificial cerebrospinal fluid (CSF) or with various drugs dissolved in CSF. Hypothalamic superfusion with the NO-donating compounds linsidomine (200 mumol/l) or diethylamine-NO (DEANO, 100 mumol/l) led to a pronounced and sustained decrease in the histamine release rate, whereas the release rate of glutamate was enhanced. Superfusion with the inhibitor of NO synthase L-NG-nitro-L-arginine methyl ester (L-NAME, 200 mumol/l) increased the histamine release rate. The inhibitory effect of 200 mumol/l linsidomine was abolished by atropine (10 mumol/l). Superfusion with the glutamate receptor agonists glutamate (100 mumol/l) or N-methyl-D-aspartate (NMDA, 50 mumol/l) enhanced the histamine release rate. In the presence of linsidomine, the releasing effect of NMDA was not changed. These findings demonstrate that the release of histamine in the hypothalamus is diminished by endogenous NO. This effect of NO on histamine release seems to be due to enhanced release of acetylcholine from vicinal cholinergic neurons via stimulation of muscarinic acetylcholine receptors located presynaptically on histaminergic neurons. The NO-induced glutamate release seems to exert a subordinate stimulatory effect on histamine release. Finally, the inhibition of histamine release by NO is not due to blockade of NMDA receptors.

The effects of dietary iron on initiation and promotion in chemical hepatocarcinogenesis.

The aim of this study was to evaluate the effects of dietary iron on hepatocarcinogenesis in an animal model mimicking noncirrhotic genetic hemochromatosis. Iron overload may lead to liver cirrhosis and an increased risk of developing primary hepatocellular carcinoma. It is unknown if iron is of pathogenic importance for the carcinogenic process, or whether the increased cancer risk results solely from the cirrhotic process. We investigated the initiating, promoting, and mitogenic properties of carbonyl iron in the Solt-Farber model of chemical hepatocarcinogenesis. A diet supplemented with 2.5% to 3.0% carbonyl iron was either added to, or replaced, the initiating and promoting events in the model. None of the animals developed hepatic fibrosis. Hepatic iron was increased 6- to 13-fold in iron-treated animals, and predominantly located in periportal hepatocytes. Iron as an initiator did not increase the number of glutathione-S-transferase-Yp-positive foci. Iron reduced the number of foci when added to low-dose diethylnitrosamine plus partial hepatectomy, which may be explained by a delayed hepatic regeneration in iron-loaded liver. As a promoter, iron did not selectively induce proliferation of initiated cells. Added to a complete promotive regimen, iron decreased the volume density of preneoplastic nodules, possibly because of a mitostimulatory effect of iron on normal hepatocytes surrounding the nodules. Iron increased the hepatocyte labeling index and counteracted the mitoinhibitory effect of 2-acetylaminofluorene on regenerating liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacology of new glutarimide compounds.

New glutarimide compounds were synthesized by incorporating piperidine (compounds 1 to 7), diethylamine (8 and 9), morpholine moities (10 to 13), and alkyl derivatives of 3,5 dicyanoglutarimide (14 to 20) at position -1 of the nitrogen atom. Only compounds 1 to 7 at a dose of 8 mg/kg i.p. caused hypermotility, ataxia, tachypnoea and mild tremors in mice. At higher doses (32 mg/kg i.p.), all compounds induced tonic and clonic convulsions, respiratory paralysis and death. The LD50 values of compounds 1 to 20 in mice range from 152 to 488 mg/kg i.p. and for compounds 21 to 23, the p.o. values are 484, 500 and 525 mg/kg. The relative toxicity of compounds 1 to 7 and 14 to 20 showed inverse ratio in their numbers. Basic compounds 21 to 23 at high dose levels (64 mg/kg i.p.) induced only hypnotic depression. No change was observed in organ-wise histopathological study except patchy necrosis at the site of injection of basic compounds. The CNS pharmacological studies were negative with reference to anti-convulsion, analgesic, antipyretic tests by conventional methods except at higher doses (32 or 64 mg/kg i.p.), which exhibited synergistic effects in mice and rats.

[Characteristics of the super-slow electrical activity of the brain when exposed to the action of neurotropic substances altering short-term memory]. / Kharakteristika sverkhmedlennoi élektricheskoi aktivnosti mozga pri deistvii neirotropnykh veshchestv, meniaiushchikh kratkosrochnuiu pamiat'

Superslow electrical activity was studied after the action of neurotropic drugs on curarized rabbits with gold electrodes implanted in the deep brain structures. Intramuscular administration of 1/5 mg/kg dose of ethimizol, of 5 mg/kg of ethipyrol, or of 1/5 mg/kg of metamizyl led to a reciprocity of the oscillation amplitudes between the field CA-3 of the dorsal hippocampus and the medial nuclear groups of the reticular formation. Ethimizol and ethipyrol, though producing a similar final effect, act differently on the duration and phases of slow oscillations. Micropolarization of the dorsal hippocampus field CA-3 with a 2.5 microampere current lengthened the action of the neurotropic drugs, up to six hours in the case of ethimyzol. A mathematical vector analysis has shown that the angle of the wave amplitude vector in space depends both on the characteristics of the neurotropic drug and the excitability level of field CA-3 of the dorsl hippo-campus. A slow electrical potential reflecting the capacity of the electric field of a brain structure is likely to be one the major components controlling the conformation position of the receptor proteins.

[Experimental data on a new cholinesterase reactivator from the group of thiohydroximic esters]. / Eksperimental'nye dannye o novom reaktivatore kholinésterazy iz gruppy tiogidroksimovykh éfirov

Experimental data on the effectiveness of p-brombenzothiohydroximic S-diethylaminoethylate (diethyxime) -a new cholinesterase reactivator - are presented. The diethyximetoxicity with its single and multiple administration to animals was studied. The drug is shown to display a marked antidotal action when used in a dosage range of 490-10 mg/kg. Diethyxime is shown capable of restoring the activity of cholinesterase inhibited by dimethyldichlorovenylphosphate, of preventing the neuro-muscular block of the impulses conduction and of normalizing the function of the cardiovascular system. The drug is less toxic than is presently employed reactivator diproxime and it does not produce any side-effects on a number of organs and systems of the organism with its multiple administration to worm-blooded animals.

A study of the anticholinergic and antispasmodic activity of oxybutynin (Ditropan) on rabbit detrusor.

Experiments have been conducted which show that while the tertiary amine oxybutynin has only moderate in vitro anticholinergic and antihistaminic activity, it is a potent inhibitor of barium chloride-induced spasms of rabbit detrusor muscle. Oxybutynin exerts 1/13 the anticholinergic activity of propantheline and 1/4 that of atropine, but produces approximately 2x the inhibition of barium chloride-induced spasm than propantheline and 10x the inhibition produced by atropine. In sum, oxybutynin possesses a notable antispasmodic activity distinct from its anticholinergic activity and stronger than that of atropine, propantheline, or methantheline, which may prove useful in the treatment of smooth muscle hypermotility.