Immunomodulation by quinones

The therapeutic application of quinones in areas other than oncology, such as in chronic inflammation, has been proposed. However, because of the adverse side-effects on the function and vitality of almost all investigated cell types the therapeutical margin is small. The thiol-conjugating capacity of quinones may, however, be applied to reduce the tissue-damaging effects of stimulated neutrophils. In this paper evidence is provided that particular phenols may be used as precursor molecules of quinones. Secretory products from stimulated neutrophils can convert such phenols into quinones. As under normal conditions stimulated neutrophils are present only in inflamed tissues, quinones will be formed only at these sites.This article is based on a lecture given at the 16th LOF Symposium, 27 October 1989, Utrecht, the Netherlands.     

Comparison of two non-absorbable antibiotics for treatment of bacterial enteritis in children.

Thirty-one children with bacterial diarrhoea were administered an oral suspension of rifaximin (14 children, mean age: 4.3 yrs; dosage: 5 ml, equal to 100 mg, x 4/day for 3 days on average) or of neomycin + bacitracin (17 children, mean age: 3.6 yrs; dosage: 5 ml x 4/ day for 4 days on average). Etiologic agents were: minor Salmonella spp in 9 and 7 cases respectively; enteropathogenic E. coli in 5 and 10 cases. Rifaximin yielded bacteriological cure in 12/14 children; the reference drug in 13/17. With both antibiotics, stool number/day fell, after one day, from 6 on average, to normality (2-3 stools); within two days stool consistency and characteristics shifted to normal. Symptomatology was quickly eliminated in all of the cured children. Both treatments showed excellent systemic tolerability; rifaximin was completely tolerated also locally, while two cases of stomach ache were reported with the reference drug.     

An investigation of premedication with morphine given by the buccal or intramuscular route.

1. Premedication with 30 mg buccal morphine or 10 mg intramuscular morphine was evaluated in 40 healthy women undergoing major gynaecological surgery. 2. Buccal administration of morphine produced lower plasma morphine concentrations than intramuscular injection of morphine (P less than 0.01). 3. The mean systemic availability of the buccal tablet, during the first 5 h after administration, was approximately 3% relative to that of the intramuscular preparation. 4. Poor absorption of buccal morphine resulted in inadequate sedation prior to surgery and poor post-operative analgesia. 5. Patients experienced difficulty with the buccal formulation of morphine; tablet bitterness and failure to dissolve were particular problems.     

Immunomodulation by Metals

A symposium entitled Immunomodulation by Metals was held atthe 32nd Annual Meeting of the Society of Toxicology (SOT) inNew Orleans, Louisiana. The symposium was cosponsored by theImmunotoxicology and Metals Specialty Sections of SOT and wasdesigned to describe the types of adverse immunological reactionswhich occur in response to environmental and/or occupationalexposure to metals. Epidemiological evidence and underlyingmechanisms responsible for the observed alterations were alsodiscussed. The following is a summary of each of the individualpresentations.     

Immunomodulation by Metals

Immunomodulation by Metals. Zelikoff, J. T., Smialowicz, R., Bigazzi, P. E., Goyer, R. A., Lawrence, D. A., Maibach, H. I., and Gardner, D. (1994). Fundam. Appl. Toxicol. 22, 1-7.A symposium entitled Immunomodulation by Metals was held at the 32nd Annual Meeting of the Society of Toxicology (SOT) in New Orleans, Louisiana. The symposium was cosponsored by the Immunotoxicology and Metals Specialty Sections of SOT and was designed to describe the types of adverse immunological reactions which occur in response to environmental and/or occupational exposure to metals. Epidemiological evidence and underlying mechanisms responsible for the observed alterations were also discussed. The following is a summary of each of the individual presentations.     

Immunomodulation by quinones

The therapeutic application of quinones in areas other than oncology, such as in chronic inflammation, has been proposed. However, because of the adverse side-effects on the function and vitality of almost all investigated cell types the therapeutical margin is small. The thiol-conjugating capacity of quinones may, however, be applied to reduce the tissue-damaging effects of stimulated neutrophils. In this paper evidence is provided that particular phenols may be used as precursor molecules of quinones. Secretory products from stimulated neutrophils can convert such phenols into quinones. As under normal conditions stimulated neutrophils are present only in inflamed tissues, quinones will be formed only at these sites.

     

Immunomodulation by some oligopeptides

The influence of bradykinin, some of its analogues, substance P and different partial sequences on lymphoid cells was studied under in vitro conditions. The oligopeptides bradykinin and substance P were found to be able to induce the secretion of charge-changing and chemokinetic lymphokines in very low concentrations. In each case, bell-shaped dose-response curves were registered in a concentration range from 10(-12) to 10(-6) M. An analysis of the lymphokine patterns suggests that T cells are the producer cells of charge-changing lymphokines. Comparing the structure-activity relationships of the peptides, the amino acid sequence Arg-Pro at the N-terminal region of bradykinin and substance P or Pro-Arg at the C-terminal part of tuftsin and rigin appear to be responsible for the lymphokine secretion.     

Immunomodulation by metals.

Occupational or environmental exposure to metals is believed to affect human health adversely. One mechanism whereby metals can alter health is through modulation of immune homeostasis. Imbalances in immune regulation by metals can lead to inadequate or excessive production of inflammatory cytokines. Alternatively, metals can lead to inappropriate activation of lymphoid subsets involved in acquired immunity to specific antigens. Some resultant pathologies may include chronic inflammatory processes and autoimmune diseases. Metals may change the response repertoire by direct and indirect means by influencing expression of new antigens, new peptides, and/or antigen presentation by modifying the antigen-presenting complex. The differences in metal-induced immune responses between humans and the mechanisms of metal immunomodulation are discussed.     

Immunomodulation by fungal toxins

The availability of immunotoxicity data for fungal toxins varies considerably for different toxins. The following is a comprehensive review of the most recent literature on the immunotoxicity of aflatoxins, fumonisins, gliotoxin, ochratoxins, patulin, and trichothecenes. Aflatoxin is an immunomodulating agent that acts primarily on cell-mediated immunity and phagocytic cell function. In addition to further characterization of aflatoxin-induced immunotoxicity in various species, some recent studies have focused on ameliorating the effects of aflatoxin by supplementing or amending the diet. The immunomodulatory effects of ochratoxins have also been considered for many years. Notably, recent studies have examined immune function in the offspring of rats and mice exposed to ochratoxin pre- and perinatally. Fumonisin toxicity has been characterized relatively recently in comparison to aflatoxin and ochratoxin, and fumonisin-induced immunotoxicity is an area of active research. As these studies progress, they may also clarify the role of sphingolipid metabolism in immune function. The most recent study of patulin immunotoxicity in mice indicates that exposure to levels found in foods and feeds would not likely result in immunotoxicity. Exposure to gliotoxin would most likely be by infection with gliotoxin-producing fungi. Although the toxin is immunosuppressive in vitro, the link between immunosuppression and the presence of gliotoxin in infected tissues in vivo has yet to be made. The trichothecenes can both suppress and stimulate immune function. By comparison, more information is available on the molecular events associated with trichothecene-induced immunomodulation than for any other fungal toxins. The molecular basis of immune function modulation by fungal toxins remains a frontier for future research.     

Engineering a GABA endowed with pharmacological CNS activity when given by an extracerebral route

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter physiologically active in the central nervous system (CNS), being synthesised and delivered by GABAergic neurons. It is, however, pharmacologically devoid of CNS activity when presented externally to brain because of limited blood–brain barrier diffusion and intensive breakdown by astrocyte GABA transaminase. We show herein that extracerebral administration may be, however, pharmacologically effective in controlling experimental convulsive attacks when GABA is submitted to sublimation under vacuum just before use. Though initially enigmatic because nuclear magnetic resonance (NMR) and infrared (IR) analyses identified the sublimation-derived compound to be the reference zwitterionic GABA, this observation was understood by showing that the reference and sublimated GABAs were monoclinic and tetragonal phases of GABA solid, respectively. This work is dedicated to Yves Feutelais, Professor of Physical Chemistry, Pharmacy, Paris-Sud University, who died in 2002.     

The absorption of (99m)Tc-alendronate given by rectal route in rabbits

Alendronate sodium (ALD) is a bisphosphonate medication used in the treatment and prevention of osteoporosis. Absorption of ALD as oral formulation is very poor (0.5%-1%). Its bioavailability can decrease with food effect. It has some gastrointestinal adverse effects such as gastritis, gastric ulcer, and esophagitis. The aim of this study was to develop a rectal formulation of ALD as an alternative to oral route and to investigate the absorption of it by using gamma scintigraphy. For this reason, ALD was labeled with Technetium-99m ((99m)Tc) by direct method. The radiochemical characterization of the (99m)Tc-ALD was carried out by paper chromatography, thin layer chromatography, and electrophoresis methods. The labeling efficiency of (99m)Tc-ALD was found 99% without significant changes until 6 h postlabeling at room temperature. The rectal suppositories containing (99m)Tc-ALD were prepared by fusion method using polyethylene glycol (PEG) 1500. The (99m)Tc-labeled ALD suppositories were administrated to rabbits by rectal route. Serial scintigrams over all bodies of the rabbits were obtained at different time intervals using a gamma camera. We found that the rectal absorption of (99m)Tc-ALD from suppository formulation was possible. According to our results, this formulation of ALD can be suggested for the therapy of osteoporosis as an alternative route.     

Absorbable vs. non-absorbable antibiotics in the treatment of small intestine bacterial overgrowth in patients with blind-loop syndrome

BACKGROUND: Small intestine bacterial overgrowth is associated with the presence of predisposing conditions, acting through different mechanisms. Therefore, the failure to define a standardized therapy may be due to a methodological bias: to treat a condition characterized by different pathophysiological mechanisms with the same pharmacological approach. Non-absorbable antibiotics could have a lower efficacy than absorbable drugs in patients with blind loops which exclude a portion of the intestine from the transit. AIM: To evaluate the efficacy of absorbable vs. non-absorbable antibiotics in this subgroup of patients. METHODS: A group of small intestine bacterial overgrowth patients with total gastrectomy or gastrojejunostomy and blind loop underwent a therapeutic trial comparing rifaximin to metronidazole. Seven patients underwent a course of rifaximin followed by a course of metronidazole on recurrence of symptoms. To compare the effect of the drugs, another two groups of patients underwent two consecutive courses of rifaximin or metronidazole. Hydrogen breath test after glucose administration and symptom severity measurement were performed. RESULTS: Both drugs reduced breath H(2) excretion but a much better improvement was achieved after metronidazole. Symptom improvement was higher after metronidazole. CONCLUSION: Metronidazole is more effective than rifaximin for the treatment of small intestine bacterial overgrowth associated with the presence of a blind loop.     

Immunomodulation by tamoxifen and pergolide

Treatment of rats with tamoxifen citrate or pergolide mesylate was as effective in inhibiting antibody formation and contact sensitivity skin reactions as was hypophysectomy. The immunocompetence of tamoxifen citrate- and pergolide mesylate-suppressed animals could be fully restored by additional treatment with prolactin or growth hormone.     

Immunomodulation by chemotherapeutic agents against Leishmaniasis

Leishmaniasis is caused by protozoan parasites of the genus Leishmania and causes a wide spectrum of clinical manifestations ranging from self-healing cutaneous lesions to the fatal visceral form. The use of pentavalent antimony, the mainstay of therapy of Leishmaniasis is now limited by its toxicity and alarming increase in unresponsiveness, especially in the Indian subcontinent. Furthermore, other anti-leishmanial drugs are unaffordable in many affected countries and as vaccination based approaches have not yet proved to be effective, chemotherapy remains the only alternative, emphasizing the need for identifying novel drug targets. In this review, we have described the different host immune signaling pathways that could be considered as potential drug targets for Leishmania chemotherapy.     

Acute toxicity in rats of chlorinated hydrocarbons given via the intratracheal route.

1. The approximate lethal dose (ALD) of six chlorinated hydrocarbons via the intratracheal route has been determined in rats and compared with published oral LD50 values. 2. The compounds tested in this study were dichloromethane, perchloroethylene, trichloroethylene, carbon tetrachloride, chloroform and ethylene dichloride. 3. A method of administering the materials intratracheally to unanaesthetized animals was developed. 4. The intratracheal ALD of the chlorinated hydrocarbons ranged from 3.1 to 17.5% of the oral LD50 and death was peracute. 5. Aspiration of chlorinated hydrocarbons may present more of a hazard than oral toxicity and should be considered when rendering first aid or emergency medical treatment.     

Study of the pharmacokinetics and intragastric pH of rabeprazole given as successive intravenous infusion to healthy Chinese volunteers

Objectives

To investigate the pharmacokinetics and pharmacodynamics of rabeprazole (RPZ) given as successive intravenous infusion to healthy Chinese volunteers.

Methods

A total of 63 subjects (33 males and 30 females) were recruited at four research centers and given a 5-day therapeutic course of RPZ (10, 20, or 40 mg) administered as single daily doses during a 30-min period. Plasma concentrations were monitored by sampling at very short intervals for the first 330, 360, or 420 min post-RPZ administration. Intragastric pH was recorded 24 h post-RPZ administration on day 1 and day 5.

Results

After receiving a single and repeated doses of RPZ, the area under the plasma concentration–time curve (AUC_0-τ) was 51.9?±?22.1, 96.7?±?27.6, and 188.4?±?65.8 mg·min/L on day 1 and 59.3?±?23.9, 106.7?±?27.8, and 200.3?±?79.0 mg·min/L on day 5 for the low-, middle-, and high-dose groups, respectively. The corresponding peak concentrations (C_max) were 0.64?±?0.11, 1.30?±?0.26, and 2.6?±?0.54 μg/mL on day 1 and 0.76?±?0.15, 1.39?±?0.25, and 2.91?±?0.53 μg/mL on day 5, respectively. Although the mean AUC and C_max values increased from a single dose to repeated doses in the three groups, the difference was not significant. The mean AUC_{(0, τ)} and C_max ratios of repeated dose to single dose were 1.14, 1.10, and 1.06 on day 1 and 1.19, 1.07, and 1.12 on day 5 for the low-, middle-, and high-dose groups, respectively. After administration of a single dose, the 24-h pH value was significantly higher in the high-dose group than in the low-dose group. After repeated doses, significant increases in pH were observed in the low-, middle-, and high-dose groups; however, the between-group differences were not statistically significant.

Conclusions

There is a relationship between the pharmacokinetics and pharmacodynamics of RPZ, with the latter depending in part on the duration of administration, as evidenced by a higher AUC or C_max and intragastric pH from repeated dosing.     

软木酰苯胺氧肟酸免疫调节功能研究

目的通过体外实验观察软木酰苯胺氧肟酸（SAHA）对效应T细胞和调节性T细胞的作用。方法①淋巴细胞增殖的检测：取CFSE标记的淋巴细胞、CD＋4或CD＋8T细胞作为反应细胞,实验组加入不同浓度SAHA及CD3/CD28单抗作为刺激原培养,设阴性对照组（仅加入CD3/CD28单抗）和空白对照组,96 h后检测各组细胞增殖情况;②以淋巴细胞作为反应细胞,实验组中加入不同浓度SAHA及CD3/CD28单抗作为刺激原培养,设阴性对照组（仅加入CD3/CD28单抗）和空白对照组。96 h后检测各组CD＋4Foxp3＋T细胞比例。结果①SAHA剂量依赖性抑制CD3/CD28单抗诱导的淋巴细胞、CD＋4和CD＋8T细胞增殖（均P＜0.05）;②CD3/CD28单抗不能诱导CD＋4Foxp3＋ T细胞比例增高,1 μmol&;#8226;L 1SAHA也未能诱导CD＋4Foxp3＋ T细胞比例上调。但给予3和5 μmol&;#8226;L 1SAHA后,CD＋4Foxp3＋ T细胞比例显著提高,组内和组间比较,均差异有显著性（均P＜0.05）。结论体外实验表明,SAHA具有免疫调节功能,不仅能抑制效应性T细胞增殖,而且一定浓度药物作用能够促使调节性T细胞比例上调。     

Immunomodulation of various autoimmune diseases by intravenous immunoglobulin

Intravenous immunoglobulin (IVIg) is currently an accepted treatment for some autoimmune diseases and it has recently been used empirically in various other autoimmune conditions. This review discusses the role of IVIg in autoimmunity, mainly in systemic lupus erythematosus and systemic vasculitis. Clinical experience with IVIg, as well as its mechanisms of action with special emphasis on modulation of the idiotypic network, are also presented.