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Iron absorption and therapy after gastric bypass.

BACKGROUND: Iron deficiency anemia is a common complication of gastric bypass. The authors assessed the value of taking vitamin C with oral iron in correcting deficiencies in iron stores and anemia postoperatively. MATERIALS AND METHODS: Iron absorption tests were performed on 55 patients 3.2+/-2.0 years after isolated gastric bypass to identify those at higher risk for the late development of anemia. Twenty-nine of this group agreed to a therapeutic trial of iron alone or with vitamin C over a 2-month period. All 55 patients were followed up for 27.1+/-1.0 months following the study. RESULTS: The iron absorption test identified patients with low iron stores, as indicated by low serum ferritin, and those with sufficient absorption surface to benefit from oral iron. The addition of vitamin C appears to enhance the therapeutic effect of iron by correcting ferritin deficits (P < 0.01) and anemia (P < 0.05). Differences in intestine length bypassed by the operation (10 vs. 100 cm) did not affect late ferritin and hemoglobin values. CONCLUSION: This study suggests but does not prove that the addition of vitamin C to iron therapy after gastric bypass is more effective in restoring ferritin and hemoglobin than iron alone. These results are in contrast with the outcome 22.8 months later, when approximately 50% of study patients were again anemic. Closer follow-up of patients is urgently needed.

Adult↗

Therapeutic strategies for the inherited neuropathies.

More than 30 genetic causes have been identified for the inherited neuropathies collectively referred to as Charcot-Marie-Tooth (CMT) disease. Previous therapies for CMT were limited to traditional approaches such as rehabilitation medicine, ambulation aids, and pain management. Identification of the genes causing CMT has led to improved genetic counseling and assistance in family planning. Identification of these genes is beginning to delineate common molecular pathways in multiple forms of CMT that can be exploited in future molecular therapies. Scientifically based clinical trials for CMT are currently being implemented. Techniques of gene therapy are advancing to the point that they may become feasible options for patients with CMT and other neurodegenerative diseases.

Animals↗

[A report on the therapeutical experiences of which have successfully made several antibiotics-resistant bacteria (MRSA etc) negative on bedsores and respiratory organs].

Scattering Vitamin C of a small dose on a bedsore, enhances remarkably bactericidal effect of antibiotics. With scattering of it, 1% cream of Sulfadiazine made antibiotics-resistant bacteria (Methicillin-resistant Staphylococcus aureus = MRSA, Pseudomonas aeruginosa etc.) negative on a bedsore. Also in MRSA-infection of respiratory organs, combined administration of Vitamin C gives more effective bactericidal efficacy to some antibiotics. In a case infected with MRSA, of which the Minocycline-therapy had been ineffective, the combined administration of Vitamin C with Minocycline led him successfully to the negativeness of MRSA.

Administration, Oral↗

Milrinone reduces cerebral vasospasm after subarachnoid hemorrhage of WFNS grade IV or V.

The preventative effect of cisternal irrigation with milrinone against vasospasm was evaluated in 12 patients with subarachnoid hemorrhage (SAH) of World Federation of Neurosurgical Societies grade IV or V treated between September 1999 and September 2000. All aneurysms were clipped or embolized within 72 hours of the onset of SAH. Inlet and outlet tubes were placed in either the supratentorial cisternal space, lateral ventricle, or spinal subarachnoid space. Lactated Ringer solution containing urokinase (120 IU/ml), ascorbic acid (3.5 mg/ml), and milrinone (3.6 microg/ml) was continuously infused at 30 ml/hr for as long as 2 weeks. Angiographical vasospasm was detected in only two of the 11 patients who received milrinone irrigation and underwent postoperative angiography. Vasospasm may have resulted from irrigation obstruction associated with pneumocephalus in one patient and clot in the sylvian fissure in the other patient. The outcome of the milrinone irrigation therapy was significantly better than that of the conventional therapy. This study suggests that cisternal irrigation with milrinone is safe and effective, and reduces the occurrence of vasospasm in patients with poor grade aneurysmal SAH.

Adult↗

Subject-reported compliance in a chemoprevention trial for familial adenomatous polyposis.

A high level of compliance with an assigned treatment regimen is fundamental to accurate assessment of treatment effectiveness in any clinical trial. If compliance is poor, an effective treatment may be confounded by inadequate delivery of the regimen. Although much research has focused on broad aspects of compliance dealing with clinical therapeutic situations, there was a need for further research dealing specifically with adherence issues in a long-term chemoprevention trial since subject motivation in the latter is likely to differ from that of the former. Examining subject-reported compliance over the first 2-year treatment periods of a long-term chemoprevention trial for familial adenomatous polyposis, it was found that (1) compliance decreased over time, (2) fiber compliance was lower than vitamin compliance, and (3) four explanatory variables which may be amenable to individualized study-team interventions emerged as useful prognosticators of fiber compliance.

Activities of Daily Living↗

Role of inflammation and infection in vascular disease.

Relationship of infection, inflammation, and atherosclerosis has been a subject of intensive investigation in recent years. Potential mechanisms whereby chronic infections may play a role in atherogenesis are myriad. Chlamydia pneumoniae (Cp) infection in early life may accelerate atherosclerosis, leading to cardiovascular complications. Other infections, simultaneously occurring with Cp, may result in a synergistic effect to promote atherosclerosis. Chronic Helicobacter pylori infection is known to increase the pH level of the gastric juice and to decrease ascorbic acid levels, both of which will lead to a reduced folate absorption. Low folate hampers the methionine synthase reaction. This leads to an increased concentration of homocysteine in the blood, resulting in damage of endothelial cells. Cytomegalovirus (CMV) infection is associated with accelerated atherosclerosis following cardiac transplantation; several studies have found that patients with a previous CMV infection had a high independent risk of restenosis after coronary angiography. Inflammatory markers are independent predictors of cardiovascular and cerebrovascular events. Large population-based studies such as the study from the MONICA (MONItoring trends and determinants in Cardiovascular disease) Augsberg Center in Germany, the Atherosclerosis Risk in Communities Study, the Women's Health Study, the Honolulu Heart Study, have also suggested the relation between the levels of CRP and risk of coronary disease. Over the past decade also another marker of inflammation has been studied; fibrinogen has been identified as an independent risk factor for CAD in several large prospective studies. All these studies suggested a new, possible role of markers of infection and inflammation beyond traditional cardiovascular risk factors, in the development and progression of atherosclerosis. However, the clinical and therapeutic implications of these results remain to be evaluated. Although antibiotic treatment of infections in CAD patients had no impact on mortality in large prospective trials, promising data is coming from smaller studies and further studies are needed to investigate the possibility to submit this category of high-risk patients to therapeutical approaches of primary prevention.

Atherosclerosis↗

Phenylbutazone peroxidatic metabolism and conjugation.

Phenylbutazone, a nonsteroidal anti-inflammatory drug, elicits therapeutic as well as toxic effects by unknown pathways. Phenylbutazone was shown to form a conjugate with the heterocyclic amine bladder carcinogen 2-amino-4-(5-nitro-2-furyl)-thiazole (ANFT). To understand further the reactivity of these compounds, this study was conducted to identify the conjugate formed and determine the mechanism of conjugate formation. Both prostaglandin H synthase and horseradish peroxidase catalyzed conjugate formation. This conjugate was identified by 1H-NMR to be 4-[2-amino-4-(5-nitro-2-furyl)-5-thiazolyl]-4-butyl-1,2-diphenyl-3,5- pyrazolidinedione. Phenylbutazone-mediated oxygen uptake was inhibited by ANFT (0.1 mM) and the spin traps 5,5-dimethyl-1-pyrroline-N-oxide (200 mM) and tert-nitrosobutane (4 mM). By contrast, phenol (0.005 to 0.25 mM) and aminopyrine (0.4 mM) stimulated oxygen uptake. None of these agents mediated oxygen uptake in the absence of phenylbutazone. Conjugate formation was significantly increased by phenol (0.005-0.25 mM) and aminopyrine (0.4 mM), as well as in the absence of oxygen. Conjugate formation was inhibited by 5,5-dimethyl-1-pyrroline-N-oxide (200 mM), tert-nitrosobutane (4 mM), ascorbic acid (2 mM), and 95% oxygen. Horseradish peroxidase initiated conjugate formation at much lower concentrations than it metabolized ANFT. The stoichiometric relationship between phenylbutazone and ANFT, with respect to conjugate formation, was complex. With the concentration of ANFT fixed at 0.05 mM, phenylbutazone exhibited saturation kinetics with a Km of 0.2 mM. In contrast, saturation kinetics were not observed with ANFT.Km values for ANFT varied with the concentration of phenylbutazone used.(ABSTRACT TRUNCATED AT 250 WORDS)

Biotransformation↗

Megadoses of vitamin C prevent the development of tolerance and physical dependence on morphine in mice.

In mice ascorbate, when co-administered with morphine, suppresses the development of tolerance and physical dependence on the drug, without significantly affecting its analgesic properties as inferred from unaltered ED50 values. The duration of morphine-induced analgesia, however, is progressively reduced with an increase in the amounts of ascorbate. Ascorbate at 1g/kg body weight does not alter the pH of blood, and has no effect on the levels of lipid-peroxides in blood and brain. Studies presented in this paper suggest the potential use of ascorbate in the prevention of development of tolerance in therapeutic applications of narcotics as analgesics. Cultured Neuroblastoma X Glioma hybrid cells (NG 108-15) respond to opiates in two different ways. The rapid receptor mediated inhibition of adenylate cyclase is followed by a long-lived compensatory increase in its activity (1-4). In a recent report (5) we have shown that ascorbate suppresses the delayed etorphine-induced compensatory increase in cAMP levels in NG 108-15 cells without affecting the short-term inhibitory response of cells to the drug. It has been suggested that while the former may be the basis of narcotic dependence and tolerance, the latter is responsible for the analgesic effect. These observations, based on a model system, prompted us to examine the effect of ascorbate on the pharmacological properties of morphine at the organismal level.

Analgesia↗

Antiviral agents: action and clinical use.

The development of antiviral agents has been hindered by a variety of problems. There are fundamental biological differences between viruses and other infectious agents. Viruses are strictly dependent on cellular metabolic processes and possess very limited intrinsic enzyme systems and building blocks which may serve as targets for drugs. Antiviral drugs must also possess the ability to enter the host cell. Viral replication consists of a series of events, each of which can be interfered with, leading to interruption of the viral replication cycle. Currently, the major antiviral agents in therapeutic use are amantadine, idoxuridine and vidarabine. Methisazone and isoprinosine are also used in some areas. Immunoglobulins have some antiviral activity. Immune serum globulin and high titred hepatitis B immune globulin have both been used in prophylaxis of viral hepatitis. However, studies in this area have not been well controlled and results in some areas are conflicting. Interferon appears to be the most exciting antiviral agent yet discovered. However, its potential is limited by its availability, which remains dependent on biological method. Significant progress has been made recently, though, which may lead to the chemical synthesis of interferon and thus to an antiviral agent active against many viruses.

Amantadine↗

Dihydrolipoic acid--a universal antioxidant both in the membrane and in the aqueous phase. Reduction of peroxyl, ascorbyl and chromanoxyl radicals.

Thioctic (lipoic) acid is used as a therapeutic agent in a variety of diseases in which enhanced free radical peroxidation of membrane phospholipids has been shown to be a characteristic feature. It was suggested that the antioxidant properties of thioctic acid and its reduced form, dihydrolipoic acid, are at least in part responsible for the therapeutic potential. The reported results on the antioxidant efficiency of thioctic and dihydrolipoic acids obtained in oxidation models with complex multicomponent initiation systems are controversial. In the present work we used relatively simple oxidation systems to study the antioxidant effects of dihydrolipoic and thioctic acids based on their interactions with: (1) peroxyl radicals which are essential for the initiation of lipid peroxidation, (2) chromanoxyl radicals of vitamin E, and (3) ascorbyl radicals of vitamin C, the two major lipid- and water-soluble antioxidants, respectively. We demonstrated that: (1) dihydrolipoic acid (but not thioctic acid) was an efficient direct scavenger of peroxyl radicals generated in the aqueous phase by the water-soluble azoinitiator 2,2'-azobis(2-amidinopropane)-dihydrochloride, and in liposomes or in microsomal membranes by the lipid-soluble azoinitiator 2,2'-azobis(2,4-dimethylvaleronitrile); (2) both dihydrolipoic acid and thioctic acid did not interact directly with chromanoxyl radicals of vitamin E (or its synthetic homologues) generated in liposomes or in the membranes by three different ways: UV-irradiation, peroxyl radicals of 2,2'-azobis(2,4-dimethylvaleronitrile), or peroxyl radicals of linolenic acid formed by the lipoxygenase-catalyzed oxidation; and (3) dihydrolipoic acid (but not thioctic acid) reduced ascorbyl radicals (and dehydroascorbate) generated in the course of ascorbate oxidation by chromanoxyl radicals. This interaction resulted in ascorbate-mediated dihydrolipoic acid-dependent reduction of the vitamin E chromanoxyl radicals, i.e. vitamin E recycling. We conclude that dihydrolipoic acid may act as a strong direct chain-breaking antioxidant and may enhance the antioxidant potency of other antioxidants (ascorbate and vitamin E) in both the aqueous and the hydrophobic membraneous phases.

Animals↗

Diet and atherosclerosis.

Diet and atherosclerosis are closely linked, both aetiologically and therapeutically. The aetiological association can be demonstrated most satisfactorily in animal experiments. In human beings the evidence must necessarily be more indirect and is largely based on dietary trials and epidemiological surveys linking the intake of cholesterol and saturated fat with morbidity and mortality from coronary disease. A modifying influence which has gained increasing recognition over recent years is the individual response to a given diet. This variability appears to be largely genetically determined, certainly in the defined primary hyperlipidaemic states, and possibly within the normal ranges of serum cholesterol levels. A change in food habits should be fully utilized therapeutically in any form of hyperlipidaemia, whether as a primary preventive measure before clinical diseases of atherosclerotic origin become manifest or in secondary prevention to delay further morbidity and mortality. With good dietary adherence, lipid levels may return to normal and there may be additional favourable effects on intravascular thrombosis. Many problems remain to be solved on the public health issue of advising changes in the national diet. A number of countries in which an atherogenic diet is habitually eaten have decided in favour of such a recommendation. Public education, identification of persons at risk and provision of readily available skilled medical and dietary counselling should constitute a national health project with rewarding long-term results.

Adult↗

Antioxidant properties of ticlopidine on human low density lipoprotein oxidation.

We found that ticlopidine, at therapeutically relevant concentrations (2.5-10 microM), but not aspirin nor salicylate, significantly counteracted copper-driven human LDL oxidation. Ticlopidine, at 5 and 10 microM, was also antioxidant on peroxyl radical-induced LDL oxidation; yet it was ineffectual on thiol and ascorbate oxidation mediated by peroxyl radicals themselves, suggesting that drug antioxidant capacity is somehow related to the lipoprotein nature of the oxidizable substrate, but not to radical scavenging. The drug could not indeed react with the stable free radical 1,1-diphenyl-2-pycrylhydrazyl, nor had apparent metal complexing-inactivating activity. Thus, ticlopidine has antioxidant effects on LDL oxidation, which, together with its anti-platelet activity, could confer peculiar antiatherogenic properties to the drug in vivo.

Amidines↗

The effects of general anesthetics on norepinephrine release from isolated rat cortical nerve terminals.

UNLABELLED: Intravenous and volatile general anesthetics inhibit norepinephrine (NE) release from sympathetic neurons and other neurosecretory cells. However, the actions of general anesthetics on NE release from central nervous system (CNS) neurons are unclear. We investigated the effects of representative IV and volatile anesthetics on [(3)H]NE release from isolated rat cortical nerve terminals (synaptosomes). Purified synaptosomes prepared from rat cerebral cortex were preloaded with [(3)H]NE and superfused with buffer containing pargyline (a monoamine oxidase inhibitor) and ascorbic acid (an antioxidant). Basal (spontaneous) and stimulus-evoked [(3)H]NE release was evaluated in the superfusate in the absence or presence of various anesthetics. Depolarization with increased concentrations of KCl (15-20 mM) or 4-aminopyridine (0.5-1.0 mM) evoked concentration- and Ca(2+)-dependent increases in [(3)H]NE release from rat cortical synaptosomes. The IV anesthetics etomidate (5-40 microM), ketamine (5-30 microM), or pentobarbital (25-100 microM) did not affect basal or stimulus-evoked [(3)H]NE release. Propofol (5-40 microM) increased basal [(3)H]NE release and, at larger concentrations, reduced stimulus-evoked release. The volatile anesthetic halothane (0.15-0.70 mM) increased basal [(3)H]NE release, but did not affect stimulus-evoked release. These findings demonstrate drug-specific stimulation of basal NE release. Noradrenergic transmission may represent a presynaptic target for selected general anesthetics in the CNS. Given the contrasting effects of general anesthetics on the release of other CNS transmitters, the presynaptic actions of general anesthetics are both drug- and transmitter-specific. IMPLICATIONS: General anesthetics affect synaptic transmission both by altering neurotransmitter release and by modulating postsynaptic responses to transmitter. Anesthetics exert both drug-specific and transmitter-specific effects on transmitter release: therapeutic concentrations of some anesthetics stimulate basal, but not evoked, norepinephrine release, in contrast to evoked glutamate release, which is inhibited.

Adjuvants, Anesthesia↗

Oxidative stress and hemodynamic maladjustment in chronic renal disease: a therapeutic implication.

Hemodynamic maladjustment with predominant constriction at the efferent arteriole has been encountered in a variety of clinical settings of glomerulonephropathy. In essence, it induces not only intraglomerular hypertension but also exaggeratedly reduces the peritubular capillary flow, which supplies the tubulointerstitial compartment. The hemodynamic maladjustment is believed to reflect a glomerular endothelial cell dysfunction. In this regard, oxidative stress and antioxidant defect are likely responsible for the glomerular endothelial dysfunction. Improvement in renal function was accomplished following the correction of oxidant and antioxidant imbalance with antioxidant therapy and vasodilators. Following such therapy, there was a correction in hemodynamic maladjustment with a decline in intraglomerular hydrostatic pressure and an increase in renal perfusion with a subsequent increase in renal functions namely creatinine clearance, glomerular filtration rate and a decline in FEMg.

Ascorbic Acid↗

[Carotid intima-media thickness measured by ultrasonography: effect of different pharmacotherapies on atherosclerosis progression].

The clinical manifestations of arteriosclerosis (cardiovascular, stroke and peripheral artery diseases) represent the leading causes of morbidity and mortality in industrialized countries. The early in vivo diagnosis and follow up of subclinical progression of arteriosclerosis is important for the evaluation of efficient preventive and therapeutic interventions. The carotid artery intima-media thickness (IMT) is a reliable surrogate marker of the arteriosclerosis and could be easily investigated with high resolution B-mode sonography. Due to its good reproducibility, the IMT measurement is optimal for tracking the progression or regression of atherosclerotic disease. The increase of IMT is influenced by numerous vascular risk factors (age, smoking, hypertension, dyslipidemia, alcohol etc.) and positively associated with the incidence of vascular events in the arterial vasculature (stroke, myocardial infarct). Studies with lipid-lowering, antihypertensive, antidiabetic drugs, hormones confirmed, that modifying of vascular risk factors significantly reduces the progression of IMT. It is probable, that reduced progression of IMT is also accompanied with the decrease of future vascular events.

Antihypertensive Agents↗

In-vitro and in-vivo antioxidant activity of different extracts of the leaves of Clerodendron colebrookianum Walp in the rat.

The in-vitro antioxidant activities of different concentrations of the water, alcoholic, petroleum ether and ethyl acetate extracts of the dried leaves of Clerodendron colebrookianum Walp, and in-vivo antioxidant activity of the water extract was studied in experimental rat models. The results obtained from in-vitro lipid peroxidation induced by FeSO4-ascorbate in rat liver homogenate showed a significant inhibition of lipid peroxidation by different extracts of C. colebrookianum leaf. Water extracts at concentrations (w/v) of 1:30, 1:50, 1:200 and 1:1000 showed the strongest inhibitory activity over the other organic extracts, suggesting maximum antioxidant effect. Chronic feeding of the water extract to Wistar albino rats (both sexes, 150-200 g) in 1 or 2 g kg-1/day doses for 14 days significantly increased the ferric reducing ability of plasma by 19% and 40% on the seventh day, and by 45% and 57% on the fourteenth day of treatment, respectively. Thiobarbituric acid reactive substances (TBARS), as a marker of lipid peroxidation, and some cellular antioxidants (superoxide dismutase, catalase and reduced glutathione) were estimated in heart, liver and kidney. There was a significant reduction in hepatic and renal TBARS with both the doses, without any change in myocardial TBARS. There was no change in the level of antioxidants in heart, liver and kidney, except for the hepatic superoxide dismutase. The findings of this study showed that the leaf extract of C. colebrookianum increased the antioxidant capacity of blood and had an inhibitory effect on the basal level of lipid peroxidation of liver and kidney. This lends scientific support to the therapeutic use of the plant leaves, as claimed by the tribal medicine of North-East India.

Animals↗

Monooxygenase-mediated activation of chlorotrianisene (TACE) in covalent binding to rat hepatic microsomal proteins.

Chlorotrianisene is a therapeutic estrogen and contaminant of the pesticide methoxychlor. Incubation of [3H]chlorotrianisene with rat liver microsomes, supplemented with NADPH, yielded covalent binding of radiolabeled metabolite(s) to microsomal components. This binding was dramatically stimulated when microsomes from methylcholanthrene-treated rats were used. However, microsomes from phenobarbital-treated animals did not enhance binding. Analysis of solubilized microsomes by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed radiolabeled bands in the 45- to 66-kDa range. Furthermore, these bands were sensitive to protease degradation, indicating that the recipient macromolecules were proteins and possibly cytochrome P-450(s). Selective inhibition of binding to microsomes prepared from control, phenobarbital-, and methylcholanthrene-treated rats by inhibitors of monooxygenase activity [beta-diethylaminoethyl diphenylpropylacetate (SKF-525A) and metyrapone], by alternate substrates (ethylmorphine and benzo[a]pyrene), and by oxygen exclusion indicated that the binding was dependent upon monooxygenase activity and that a specific P-450 may be involved. Compounds containing free sulfhydryls markedly inhibited covalent binding, suggesting that the reactive intermediate is an epoxide or a free radical. The epoxide hydratase inhibitor (1,1,1-trichloropropane oxide) failed to enhance covalent binding, suggesting that an epoxide of chlorotrianisene was not the reactive intermediate. By contrast, free radical scavengers (propyl gallate, N,N'-diphenylenediamine, and ascorbic acid) markedly inhibited covalent binding, indicating that binding was mediated via a free radical. Since both methylcholanthrene and phenobarbital did not enhance demethylation of chlorotrianisene and methylcholanthrene increased covalent binding, it appears that demethylation products are not involved in covalent binding or that demethylation is not the rate-limiting step. A possible pathway for the metabolism and covalent binding of chlorotrianisene is presented.

Animals↗

[A use of Magne-B6 in the treatment of anxiety-depressive states in patients with epilepsy].

Magne-B6 was used, together with anticonvulsive therapy, in the treatment of 25 patients with different forms of epilepsy. In all cases, psychiatric status of patients featured by depression, anxiety and some psychotic sighs. The drug was prescribed in the mean therapeutic dose during 28 days. Along with psychopathologic examination, a psychometric method, using self-rating scales for Zung anxiety and depression scale, SCL-90 and Global clinical impression (CGI) scale, was administered. Magne-B6 exerted a positive non-specific influence on patient's mental state, especially with regard to affective disorders. The positive effect of the drug emerged on 14th day of the treatment and achieved a statistically significant level to 28th day. The medication was more effective in asthenic and subdepressive syndromes, in encephalopathic syndrome the efficacy was lower. The drug was well tolerated and did not cause any side effects.

Adult↗