Life Extension Magazine®

Issue: May 2013


L-tryptophan in neuropsychiatric disorders: a review.

Animal data indicate that serotonin (5-HT) is a major neurotransmitter involved in the control of numerous central nervous system functions including mood, aggression, pain, anxiety, sleep, memory, eating behavior, addictive behavior, temperature control, endocrine regulation, and motor behavior. Moreover, there is evidence that abnormalities of 5-HT functions are related to the pathophysiology of diverse neurological conditions including Parkinson’s disease, tardive dyskinesia, akathisia, dystonia, Huntington’s disease, familial tremor, restless legs syndrome, myoclonus, Gilles de la Tourette’s syndrome, multiple sclerosis, sleep disorders, and dementia. The psychiatric disorders of schizophrenia, mania, depression, aggressive and self-injurious behavior, obsessive compulsive disorder, seasonal affective disorder, substance abuse, hypersexuality, anxiety disorders, bulimia, childhood hyperactivity, and behavioral disorders in geriatric patients have been linked to impaired central 5-HT functions. Tryptophan, the natural amino acid precursor in 5-HT biosynthesis, increases 5-HT synthesis in the brain and, therefore, may stimulate 5-HT release and function. Since it is a natural constituent of the diet, tryptophan should have low toxicity and produce few side effects. Based on these advantages, dietary tryptophan supplementation has been used in the management of neuropsychiatric disorders with variable success. This review summarizes current clinical use of tryptophan supplementation in neuropsychiatric disorders.

Int J Neurosci. 1992 Nov-Dec;67(1-4):127-44

Effects and side effects associated with the non-nutritional use of tryptophan by humans.

The daily nutritional requirement for L-tryptophan (Trp) is modest (5 mg/kg). However, many adults choose to consume much more, up to 4-5 g/d (60-70 mg/kg), typically to improve mood or sleep. Ingesting L-Trp raises brain tryptophan levels and stimulates its conversion to serotonin in neurons, which is thought to mediate its actions. Are there side effects from Trp supplementation? Some consider drowsiness a side effect, but not those who use it to improve sleep. Though the literature is thin, occasional side effects, seen mainly at higher doses (70-200 mg/kg), include tremor, nausea, and dizziness, and may occur when Trp is taken alone or with a drug that enhances serotonin function (e.g., antidepressants). In rare cases, the “serotonin syndrome” occurs, the result of too much serotonin stimulation when Trp is combined with serotonin drugs. Symptoms include delirium, myoclonus, hyperthermia, and coma. In 1989 a new syndrome appeared, dubbed eosinophilia myalgia syndrome (EMS), and was quickly linked to supplemental Trp use. Key symptoms included debilitating myalgia (muscle pain) and a high peripheral eosinophil count. The cause was shown not to be Trp but a contaminant in certain production batches. This is not surprising, because side effects long associated with Trp use were not those associated with the EMS. Over 5 decades, Trp has been taken as a supplement and as an adjunct to medications with occasional modest, short-lived side effects. Still, the database is small and largely anecdotal. A thorough, dose-related assessment of side effects remains to be conducted.

J Nutr. 2012 Dec;142(12):2236S-2244S

Tryptophan as an evolutionarily conserved signal to brain serotonin: molecular evidence and psychiatric implications.

The role of serotonin (5-HT) in psychopathology has been investigated for decades. Among others, symptoms of depression, panic, aggression and suicidality have been associated with serotonergic dysfunction. Here we summarize the evidence that low brain 5-HT signals a metabolic imbalance that is evolutionarily conserved and not specific for any specific psychiatric diagnosis. The synthesis and neuronal release of brain 5-HT depends on the concentration of free tryptophan in blood and brain because the affinity constant of neuronal tryptophan hydroxylase is in that concentration range. This relationship is evolutionarily conserved. Degradation of tryptophan, resulting in lower blood levels and impaired cerebral production and release of serotonin, is enhanced by inter alia inflammation, pregnancy and stress in all species investigated, including humans. Consequently, tryptophan may not only serve as a nutrient, but also as a bona fide signalling amino acid. Humans suffering from inflammatory and other somatic diseases accompanied by low tryptophan levels, exhibit disturbed social behaviour, increased irritability and lack of impulse control, rather than depression. Under particular circumstances, such behaviour may have survival value. Drugs that increase brain levels of serotonin may therefore be useful in a variety of psychiatric disorders and symptoms associated with low availability of tryptophan.

World J Biol Psychiatry. 2009;10(4):258-68

Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity.

Neuropsychiatric disorders characterized by behavioral disinhibition, including disorders of compulsivity (e.g. obsessive-compulsive disorder; OCD) and impulse-control (e.g. impulsive aggression), are severe, highly prevalent and chronically disabling. Treatment options for these diseases are extremely limited. The pathophysiological bases of disorders of behavioral disinhibition are poorly understood but it has been suggested that serotonin dysfunction may play a role. Mice lacking the gene encoding brain tryptophan hydroxylase 2 (Tph2-/-), the initial and rate-limiting enzyme in the synthesis of serotonin, were tested in numerous behavioral assays that are well known for their utility in modeling human neuropsychiatric diseases. Mice lacking Tph2 (and brain 5HT) show intense compulsive and impulsive behaviors to include extreme aggression. The impulsivity is motor in form and not cognitive because Tph2-/- mice show normal acquisition and reversal learning on a spatial learning task. Restoration of 5HT levels by treatment of Tph2-/- mice with its immediate precursor 5-hydroxytryptophan attenuated compulsive and impulsive-aggressive behaviors. Surprisingly, in Tph2-/- mice, the lack of 5HT was not associated with anxiety-like behaviors. The results indicate that 5HT mediates behavioral disinhibition in the mammalian brain independent of anxiogenesis.

J Neurochem. 2012 Jun;121(6):974-84

Modulation of central serotonin affects emotional information processing in impulsive aggressive personality disorder.

BACKGROUND: The mechanistic model whereby serotonin affects impulsive aggression is not completely understood. The purpose of this study was to test the hypothesis that depletion of serotonin reserves by tryptophan depletion affects emotional information processing in susceptible individuals. METHODS: The effect of tryptophan (vs placebo) depletion on processing of Ekman emotional faces was compared in impulsive aggressive personality disordered, male and female adults with normal controls. All subjects were free of psychotropic medications, medically healthy, nondepressed, and substance free. Additionally, subjective mood state and vital signs were monitored. RESULTS: For emotion recognition, a significant interaction of Aggression × Drug × Sex (F(1, 31) = 7.687, P = 0.009) was found, with male normal controls but not impulsive aggressive males showing increased recognition of fear. For intensity ratings of emotional faces, a significant interaction was discovered of Drug × Group × Sex (F(1, 31) = 5.924, P = 0.021), with follow-up tests revealing that males with intermittent explosive disorder tended to increase intensity ratings of angry faces after tryptophan depletion. Additionally, tryptophan depletion was associated with increased heart rate in all subjects, and increased intensity of the subjective emotional state of “anger” in impulsive aggressive subjects. CONCLUSIONS: Individuals with clinically relevant levels of impulsive aggression may be susceptible to effects of serotonergic depletion on emotional information processing, showing a tendency to exaggerate their impression of the intensity of angry expressions and to report an angry mood state after tryptophan depletion. This may reflect heightened sensitivity to the effects of serotonergic dysregulation, and suggests that what underlies impulsive aggression is either supersensitivity to serotonergic disturbances or susceptibility to fluctuations in central serotonergic availability.

J Clin Psychopharmacol.2012 Jun; 32(3):329-35

The effects of acute tryptophan depletion on reactive aggression in adults with attention-deficit/hyperactivity disorder (ADHD) and healthy controls.

BACKGROUND: The neurotransmitter serotonin (5-HT) has been linked to the underlying neurobiology of aggressive behavior, particularly with evidence from studies in animals and humans. However, the underlying neurobiology of aggression remains unclear in the context of attention-deficit/hyperactivity disorder (ADHD), a disorder known to be associated with aggression and impulsivity. We investigated the effects of acute tryptophan depletion (ATD), and the resulting diminished central nervous serotonergic neurotransmission, on reactive aggression in healthy controls and adults with ADHD. METHODOLOGY/PRINCIPAL FINDINGS:  Twenty male patients with ADHD and twenty healthy male controls were subjected to ATD with an amino acid (AA) beverage that lacked tryptophan (TRP, the physiological precursor of 5-HT) and a TRP-balanced AA beverage (BAL) in a double-blind, within-subject crossover-study over two study days. We assessed reactive aggression 3.25 hours after ATD/BAL intake using a point-subtraction aggression game (PSAG) in which participants played for points against a fictitious opponent. Point subtraction was taken as a measure for reactive aggression. Lowered rates of reactive aggression were found in the ADHD group under ATD after low provocation (LP), with controls showing the opposite effect. In patients with ADHD, trait-impulsivity was negatively correlated with the ATD effect on reactive aggression after LP. Statistical power was limited due to large standard deviations observed in the data on point subtraction, which may limit the use of this particular paradigm in adults with ADHD. CONCLUSIONS/SIGNIFICANCE:  Together with previous findings, the data provide preliminary evidence of an inverse association between trait-impulsivity and the ATD effect on reactive aggression after LP (as assessed by the PSAG) in patients with ADHD and that this relationship can be found in both adolescents and adults. Because of limited statistical power larger sample sizes are needed to find main effects of ATD/BAL administration on reactive aggression in adults with ADHD.

PLoS One.2012;7(3):e32023

Simultaneous determination of tyrosine, tryptophan and 5-hydroxytryptamine in serum of MDD patients by high performance liquid chromatography with fluorescence detection.

BACKGROUND: Tyrosine (Tyr), Tryptophan (Trp) and 5-hydroxytryptamine (5-HT) are important amino acids in vivo and have been hypothesized to be involved in many mental disorders. We developed a rapid and sensitive HPLC method for simultaneous measurement of serum Tyr, Trp and 5-HT and explored the clinical

significances of Tyr, Trp and 5-HT and the 5-HT/Trp ratio for patients with major depressive disorder (MDD) disease. METHODS: Serum samples were deproteinized by 5% perchloric acid and separated on an Atlantis C18 column (4.6 × 150 mm, 5 µm) with the mobile phase consisting of 0.1 mol/l KH(2)PO(4) and methanol (85:15, V/V).The eluates were monitored by the fluorescence detection with programmed wavelength. RESULTS: Analysis was achieved in <12.0 min. The limits of quantification were 0.014, 0.005, and 0.024 µmol/l for Tyr, Trp and 5-HT, respectively. Reproducibility and recovery were satisfactory. Tyr, Trp and 5-HT and the 5-HT/Trp ratio were significantly decreased in patients with MDD. CONCLUSIONS: In diseases, like MDD, Tyr, Trp and 5-HT play an important role. This method can potentially be applied as prognostic or diagnostic tool or even to follow the evolution of the illness or of the treatment.

Clin Chim Acta. 2012 Jun 14;413(11-12):973-7

Tryptophan depletion and emotional processing in healthy volunteers at high risk for depression.

BACKGROUND: Studies in depressed patients have demonstrated the presence of emotional bias toward negative stimuli, as well as dysregulated brain serotonin function. The present study compared the effects of acute tryptophan depletion (ATD) on both an emotional processing and a planning task in never-depressed healthy volunteers at high and low familial risk for depression. METHODS: Young adults with no personal psychiatric history were stratified into two groups based on family history (n = 25). Participants were enrolled in a randomized, double-blind, placebo-controlled crossover ATD study and completed the affective go/no-go and Tower of London tasks once during each condition. RESULTS: There was a significant treatment by valence by group interaction on the affective go/no-go, driven primarily by a greater frequency of inappropriate responses to sad than to happy distracters in the high-risk group during ATD. No group differences were observed on the Tower of London. CONCLUSIONS: Asymptomatic individuals at high familial risk for depression showed abnormalities in emotional processing while undergoing experimentally induced tryptophan depletion. These findings support emotional processing disturbances as potential trait-level abnormalities associated with the risk of mood disorder.

Biol Psychiatry.2011 Apr 15;69(8):804-7

Acute tryptophan depletion increases translational indices of anxiety but not fear: serotonergic modulation of the bed nucleus of the stria terminalis?

Serotonin is strongly implicated in the mammalian stress response, but surprisingly little is known about its mode of action. Recent data suggest that serotonin can inhibit aversive responding in humans, but this remains underspecified. In particular, data in rodents suggest that global serotonin depletion may specifically increase long-duration bed nucleus of the stria terminalis (BNST)-mediated aversive responses (ie, anxiety), but not short-duration BNST-independent responses (ie, fear). Here, we extend these findings to humans. In a balanced, placebo-controlled crossover design, healthy volunteers (n=20) received a controlled diet with and without the serotonin precursor tryptophan (acute tryptophan depletion; ATD). Aversive states were indexed by translational acoustic startle measures. Fear and anxiety were operationally defined as the increase in startle reactivity during short- and long-duration threat periods evoked by predictable shock (fear-potentiated startle) and by the context in which the shocks were administered (anxiety-potentiated startle), respectively. ATD significantly increased long-duration anxiety-potentiated startle but had no effect on short-duration fear-potentiated startle. These results suggest that serotonin depletion in humans selectively increases anxiety but not fear. Current translational frameworks support the proposition that ATD thus disinhibits dorsal raphé-originating serotonergic control of corticotropin-releasing hormone-mediated excitation of the BNST. This generates a candidate neuropharmacological mechanism by which depleted serotonin may increase response to sustained threats, alongside clear implications for our understanding of the manifestation and treatment of mood and anxiety disorders.

Neuropsychopharmacology. 2012 Jul;37(8):1963-71

The consumption of a Jerte Valley cherry product in humans enhances mood, and increases 5-hydroxyindoleacetic acid but reduces cortisol levels in urine.

PURPOSE: Jerte Valley cherries contain high levels of tryptophan, serotonin, and melatonin. These molecules have been shown to be involved in mood regulation. It has been suggested that a complex inter-relationship between brain serotonin, circulating levels of cortisol (the major stress hormone), and the hypothalamus-pituitary-adrenal axis exists in the regulation of stress responses, where cortisol and serotonin act as markers of mood disturbances. Moreover there is growing evidence that altered HPA activity is associated with various age-related pathologies. The present study evaluated the effect of the ingestion of a Jerte Valley cherry-based product, compared to a placebo product, on urine cortisol and 5-hydroxyindoleacetic acid (5-HIAA) levels, and on mood in young, middle-aged, and elderly participants.  METHODS: Cortisol and 5-HIAA acid levels were measured by commercial enzyme-linked immunosorbent assay kits. The mood state profile was analysed using a visual analogue scale and the state-trait anxiety inventory. RESULTS: Our findings showed that the ingestion of the Jerte Valley cherry product decreased urinary cortisol and increased urinary 5-HIAA levels in all the experimental groups. Moreover, the cherry product was able to lessen anxiety status in the middle-aged and elderly participants, and enhanced subjective mood parameters, particularly family relationships in young participants, and frame of mind and fitness in both middle-aged and elderly subjects. CONCLUSIONS: The consumption of the Jerte Valley cherry product may protect against stress and act as a mood enhancer by increasing serotonin availability to the organism, particularly with advancing age.

Exp Gerontol. 2012 Aug;47(8):573-80

Supplementation of ascorbic acid and alpha-tocopherol is useful to preventing bone loss linked to oxidative stress in elderly.

OBJECTIVE: To determine the effect of ascorbic acid and alpha-tocopherol on oxidative stress and bone mineral density (BMD) in elderly people. DESIGN: A double-blind, controlled clinical assay was carried out in a sample of 90 elderly subjects divided into three age-paired random groups with 30 subjects in each group. Group Tx0 received placebo, group Tx1 received 500 mg of ascorbic acid and 400 IU of alpha-tocopherol, whereas group Tx2 received 1,000 mg of ascorbic acid and 400 IU of alpha-tocopherol, for a 12-month period. MEASUREMENTS: We measured thiobarbituric acid reactive substances (TBARS), total antioxidant status (TAS), superoxide dismutase (SOD), and glutation peroxidase (GPx); BMD was obtained on DXA of hip and spine before and after the 12-month treatment period with supplementation of vitamins C and E. RESULTS: We found a positive correlation between hip-BMD and SOD (r = 0.298, p < 0.05) and GPx (r = 0.214, p < 0.05). Also, a significantly lower decrease of LPO (p < 0.05) was observed as linked with hip bone loss in the Tx2 group than in the Tx0 group. CONCLUSIONS: Our findings suggest that that administration of 1,000 mg of ascorbic acid together with 400 IU of alpha-tocopherol could be useful in preventing or aiding in the treatment of age-related osteoporosis.

J Nutr Health Aging. 2010 Jun;14(6):467-72

Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries.

A concentration-function approach to vitamin C (ascorbate) has yielded new physiology and pharmacology discoveries. To determine the range of vitamin C concentrations possible in humans, pharmacokinetics studies were conducted. They showed that when vitamin C is ingested by mouth, plasma and tissue concentrations are tightly controlled by at least 3 mechanisms in healthy humans: absorption, tissue accumulation, and renal reabsorption. A 4th mechanism, rate of utilization, may be important in disease. With ingested amounts found in foods, vitamin C plasma concentrations do not exceed 100 µmol/L. Even with supplementation approaching maximally tolerated doses, ascorbate plasma concentrations are always <250 µmol/L and frequently <150 µmol/L. By contrast, when ascorbate is i.v. injected, tight control is bypassed until excess ascorbate is eliminated by glomerular filtration and renal excretion. With i.v. infusion, pharmacologic ascorbate concentrations of 25-30 mmol/L are safely achieved. Pharmacologic ascorbate can act as a pro-drug for hydrogen peroxide (H(2)O(2)) formation, which can lead to extracellular fluid at concentrations as high as 200 µmol/L. Pharmacologic ascorbate can elicit cytotoxicity toward cancer cells and slow the growth of tumors in experimental murine models. The effects of pharmacologic ascorbate should be further studied in diseases, such as cancer and infections, which may respond to generation of reactive oxygen species via H(2)O(2).

Adv Nutr. 2011 Mar;2(2):78-88

Dihydroquercetin: More than just an impurity?

Dihydroquercetin (taxifolin) is a potent flavonoid found in onions, French maritime bark, milk thistle, tamarind seeds and commercially available semi-synthetic monoHER marketed as Venoruton. This review focuses on the therapeutic promise of dihydroquercetin in major disease states such as cancer, cardiovascular disease and liver disease by reviewing the proposed mechanism(s) of action, including the activation of the antioxidant response element (ARE) and detoxifying phase II enzymes, inhibition of cytochrome P(450) and fatty acid synthase in carcinogenesis. TNF-alpha and NF-ĸB dependent transcription in hepatitis C infections, the scavenging effect of myeloperoxidase (MPO) derived reactive nitrogen species and subsequent effects on cholesterol biosynthesis as well as the effects on apob/apoA-I, HMG-CoA reductase and apoptosis are reviewed. The stereochemistry and pro-oxidant effect of dihydroquercetin are also considered. Although the majority of research on dihydroquercetin to date has focused on the identification of molecular targets in vitro, this review will bring together evidence of the potency and mode of action of dihydroquercetin and will propose a role for the therapeutic potential of flavonoid antioxidants.

Eur J Pharmacol. 2012 Jun 5;684(1-3):19-26

Vitamin C and E consumption and coronary heart disease in men.

Atherosclerotic cardiovascular diseases (CVD) are a major source of mortality and morbidity in general population. Oxidative modification of low density lipoprotein (LDL) represent the most important determinant factor in the development and progression of atherosclerotic lesions. Oxidative damage and the production of free radicals (FRs) in the endothelium are some of the main factors involved in the pathogenesis of the atherosclerotic process which causes CVD. Appropriate nutritional practices are of central importance in managing risk and treatment of CVD; indeed, many current guidelines contain nutritional recommendations to reduce the risk of these diseases. In observational studies vitamin C and E, the most prevalent natural antioxidant vitamins, have suggested that supplemental users have lower rate of coronary events. Despite these data, several large randomized controlled trials (RCTs) have failed to confirm the benefits for vitamin C and E in cardiovascular (CV) prevention. The aim of this review is to examine the studies published in literature which report the effect of supplementation with antioxidant vitamins (C,E) in the primary and secondary prevention of CVD in men due to atherosclerotic process.

Front Biosci (Elite Ed). 2012 Jan 1;4:373-80

Plasma vitamin C predicts incident heart failure in men and women in European Prospective Investigation into Cancer.

BACKGROUND: Fruit and vegetable intake has been associated with lower risk for cardiovascular risk factors and disease, but data on heart failure are sparse and inconsistent. The association of plasma vitamin C, a biomarker reflecting fruit and vegetable intake, with heart failure has not been studied. METHODS: We examined the prospective association of plasma vitamin C concentrations with incident fatal and nonfatal heart failure events in apparently healthy 9,187 men and 11,112 women aged 39 to 79 years participating in the “European Prospective Investigation into Cancer and Nutrition” study in Norfolk. RESULTS: The risk of heart failure decreased with increasing plasma vitamin C; the hazard ratios comparing each quartile with the lowest were 0.76 (95% CI 0.65-0.88), 0.70 (95% CI 0.60-0.81), and 0.62 (95% CI 0.53-0.74) in age- and sex-adjusted analyses (P for trend <.0001). Every 20 µmol/L increase in plasma vitamin C concentration (1 SD) was associated with a 9% relative reduction in risk of heart failure after adjustment for age, sex, smoking, alcohol consumption, physical activity, occupational social class, educational level, systolic blood pressure, diabetes, cholesterol concentration, and body mass index, with similar result if adjusting for interim coronary heart disease. CONCLUSIONS: Plasma vitamin C, a biomarker reflecting fruit and vegetable intake, was inversely associated with the risk of heart failure in this healthy population. This observation should be regarded as hypothesis generating for further prospective trials aimed at examining the effect of a diet rich in fruit and vegetables for prevention of heart failure.

Am Heart J.2011 Aug;162(2):246-53.

Association between plasma vitamin C concentrations and blood pressure in the European prospective investigation into cancer-Norfolk population-based study.

The effect of fruit and vegetable consumption and blood pressure is unclear. A population-based cross-sectional study was conducted in 20,926 men and women aged 40 to 79 years participating in the European Prospective Investigation Into Cancer-Norfolk who completed a health questionnaire and attended a clinic from 1993 to 1997. The relationship between plasma vitamin C concentrations, as an indicator of fruit and vegetable intake, and systolic BP was examined. The magnitude of their association was assessed using dichotomized values of high (≥140 mm Hg) and low (<140 mm Hg) systolic blood pressure. A total of 20,926 participants (46% men; mean [SD] 58.5 years [9.2 years]) were included after excluding participants with any missing data for variables of interest. People with high vitamin C concentrations had lower clinic blood pressure. The likelihood of having high blood pressure was 22% lower (odds ratio: 0.78 [95% CI: 0.71 to 0.86]) for those who were in the top quartiles of plasma vitamin C levels compared with the bottom quartiles after adjusting for age, sex, body mass index, cholesterol, prevalent medical conditions, smoking, physical activity, alcohol consumption, social class, education, use of vitamin C-containing supplement, and antihypertensive medication. Sex-specific analysis, as well as repeated analysis after exclusion of people who used vitamin C-containing supplements or who were taking antihypertensive medication, did not alter the results. There appears to be a strong association between vitamin C concentrations, an indicator of fruit and vegetable consumption, and a lower level of blood pressure. This may provide further evidence for health benefits of dietary patterns with higher fruit and vegetable consumption.

Hypertension. 2011 Sep;58(3):372-9

Effect of acute administration of vitamin C on muscle sympathetic activity, cardiac sympathovagal balance, and baroreflex sensitivity in hypertensive patients.

BACKGROUND: Essential hypertension is characterized by both increased oxidative stress and sympathetic traffic. Experimental studies have shown that reactive oxygen species can modulate autonomic activity. OBJECTIVE: The aim of this study was to determine whether acute administration of the antioxidant vitamin C modifies sympathetic nerve activity in essential hypertension. DESIGN: Thirty-two untreated patients with essential hypertension and 20 normotensive subjects received vitamin C (3 g intravenously in 5 min) or vehicle. Heart rate, noninvasive beat-to-beat blood pressure, and muscle sympathetic nerve activity (microneurography) were monitored at baseline and up to 20 min after the infusion. Spectral analysis of RR interval variability and spontaneous baroreflex sensitivity were also computed. RESULTS: Vitamin C infusion significantly lowered blood pressure in hypertensive patients but not in normotensive subjects (maximal changes in systolic blood pressure: -4.9 ± 10.1 compared with -0.7 ± 4.0 mm Hg, respectively; P < 0.05). Moreover, muscle sympathetic nerve activity was significantly reduced after vitamin C infusion in hypertensive patients (from 53.3 ± 12.2 to 47.4 ± 11.5 bursts/100 heart beats; P < 0.01) but not in healthy subjects (from 42.0 ± 10.1 to 42.7 ± 11.8 bursts/100 heart beats; NS). On the contrary, in 16 hypertensive patients, sodium nitroprusside in equidepressor doses induced a significant increase in muscle sympathetic nerve activity compared with vitamin C (+10.0 ± 6.9 bursts/100 heart beats). Sympathovagal balance and spontaneous baroreflex sensitivity were restored during vitamin C infusion in hypertensive subjects. CONCLUSIONS: These results indicate that acute administration of vitamin C is able to reduce cardiovascular adrenergic drive in hypertensive patients, which suggests that oxidative stress is involved in the regulation of sympathetic activity in essential hypertension.

Am J Clin Nutr. 2012 Aug;96(2):302-8

Effect of vitamin C supplementation on postprandial oxidative stress and lipid profile in type 2 diabetic patients.

Diabetes mellitus is one of the most wide spread endocrine disorders and an important developing health problem in the world. Cardiovascular disease is a common complication of type 2 diabetes. Several risk factors for coronary heart disease cosegregate in type 2 diabetes, including hyperglycemia, hyperlipaemia, increases production of free radical and decrease in antioxidant defense system. In this study we evaluated the effect of vitamin C supplementation on fasting and postprandial oxidative stress and lipid profile in type 2 diabetic patients. 30 patients with type 2 diabetes from Nader Kazemi Clinic, Shiraz, Iran were randomly divided into 2 groups; vitamin C treatment group (1,000 mg d(-1)) and placebo group from May to September 2010. Fasting and postprandial lipid profile and Malondialdehyde (MDA) level were measured at the beginning of the study and after six weeks of supplementation. Data analysis was carried out using Mann-Whitney U test with p < 0.05 being significant by SPSS software version 16. The result of the study showed a significantly decrease in fasting (p = 0.006) and postprandial MDA (p < 0.001) in vitamin C group compare to placebo group but not in lipid profile. This study suggests that vitamin C supplementation can decrease fasting and postprandial oxidative stress and may prevent diabetes complication.

Pak J Biol Sci. 2011 Oct 1;14(19):900-4

Vitamin-C as anti-Helicobacter pylori agent: More prophylactic than curative- Critical review.

Potential of nonantibiotic therapies for treatment of Helicobacter pylori-related acid peptic disease remains underexplored. Several clinical studies have shown that higher prevalence of H. pylori infection is associated with low Vitamin C (Vit C) level in serum and gastric juice. However, there is no consensus regarding the usefulness of Vit C supplementation in the management of H. pylori infection. Surveying the existing literature we conclude that high concentration of Vit C in gastric juice might inactivate H. pylori urease, the key enzyme for the pathogen’s survival and colonization into acidic stomach. Once infection established, urease is not very important for its survival. The role of Vit-C as anti-H. pylori agent in peptic ulcer diseases appears to be preventive rather than curative. Rather than supplementing high dose of Vit C along with conventional triple therapy, it is preferable to complete the conventional therapy and thereafter start Vit C supplementation for extended period which would prevent reinfection in susceptible individuals, provided the patients are not achlorhydric. Further studies are required to prove the role of Vit C in susceptible population.

Indian J Pharmacol.2011 Nov;43(6):624-7

Vitamin C prevents hypogonadal bone loss.

Epidemiologic studies correlate low vitamin C intake with bone loss. The genetic deletion of enzymes involved in de novo vitamin C synthesis in mice, likewise, causes severe osteoporosis. However, very few studies have evaluated a protective role of this dietary supplement on the skeleton. Here, we show that the ingestion of vitamin C prevents the low-turnover bone loss following ovariectomy in mice. We show that this prevention in areal bone mineral density and micro-CT parameters results from the stimulation of bone formation, demonstrable in vivo by histomorphometry, bone marker measurements, and quantitative PCR. Notably, the reductions in the bone formation rate, plasma osteocalcin levels, and ex vivo osteoblast gene expression 8 weeks post-ovariectomy are all returned to levels of sham-operated controls. The study establishes vitamin C as a skeletal anabolic agent.

PLoS One. 2012;7(10):e47058

The recombinant hepatitis B surface antigen vaccine in persons with HIV: is seroconversion sufficient for long-term protection?

A cohort of human immunodeficiency virus (HIV)-infected individuals with documented vaccine-induced hepatitis B surface antibody (HBsAb) seroconversion was evaluated retrospectively to determine factors associated with loss of protective levels of HBsAb. After a median follow-up of 43 months, 111 of the 152 participants (73%) maintained protective levels of HBsAb. HIV RNA suppression at vaccination was associated with persistence of protective levels of HBsAb (odds ratio, 3.83; P < .01). Booster doses were provided for those with loss of protective antibody levels, and hepatitis B virus-specific immune memory, as evaluated with T-cell proliferation assays, was poor despite the observation that boosters successfully reinduced protective levels of HBsAb.

J Infect Dis. 2012 May 15;205(10):1534-8

Spleen tyrosine kinase inhibition in the treatment of autoimmune, allergic and autoinflammatory diseases.

Spleen tyrosine kinase (Syk) is involved in the development of the adaptive immune system and has been recognized as being important in the function of additional cell types, including platelets, phagocytes, fibroblasts, and osteoclasts, and in the generation of the inflammasome. Preclinical studies presented compelling evidence that Syk inhibition may have therapeutic value in the treatment of rheumatoid arthritis and other forms of arthritis, systemic lupus erythematosus, autoimmune cytopenias, and allergic and autoinflammatory diseases. In addition, Syk inhibition may have a place in limiting tissue injury associated with organ transplant and revascularization procedures. Clinical trials have documented exciting success in the treatment of patients with rheumatoid arthritis, autoimmune cytopenias, and allergic rhinitis. While the extent and severity of side effects appear to be limited so far, larger studies will unravel the risk involved with the clinical benefit.

Arthritis Res Ther. 2010;12(6):222

Future immunosuppression in organ transplantation: treating the innate immune system of the deceased donor—start tomorrow.

This article, based in part on an invited talk at the Annual International Conference of Saudi Society of Nephrology & Transplantation in 2012, reviews current notions of the emerging field of innate alloimmunity by highlighting novel thoughts regarding future immunosuppressive therapy in organ transplantation. In light of new insights into the mechanisms of innate immunity on one hand and the essential role of regulatory T cells in controlling alloimmune responses on the other hand, potential clinical tools to generate tolerogenic dendritic cells are explored. These cells have been shown to promote induction of regulatory T cells that possess the potential to prevent acute and chronic allograft rejection. Experimental findings from both research areas are discussed in support of the notion that presentation of alloantigens under subimmunogenic noninflammatory conditions, achieved by vigorous inhibition of oxidative injury-induced allograft inflammation (known to occur in both the deceased donor and the recipient during allograft reperfusion), may lead to the induction of tolerogenic dendritic cell-mediated regulatory T cells, thereby offering a realistic opportunity to induce allotolerance in transplant recipients. However, before planning clinical trials in recipients, the start of such a novel therapeutic strategy to prevent allograft rejection could consist of designing and performing a quadruple drug treatment of deceased (brain-dead) donors aimed at generating donor-derived tolerogenic dendritic cells. The combination use of (1) an antioxidant, (2) a complement-inhibiting agent, (3) an IL-1β inhibitor, and (4) a polyclonal antilymphocytic preparation is recommended as the preferred choice of such a donor treatment. If proven successful in organ donors, similar therapeutic modalities should subsequently be considered to apply to the recipient during allograft reperfusion under strict study conditions.

Exp Clin Transplant. 2012 Jun;10(3):195-208

The evolving role of mTOR inhibition in transplantation tolerance.

The mammalian target of rapamycin (mTOR) plays a key role in the immune response. mTOR inhibitors suppress T cell activation and proliferation and are effective immunosuppressants. Today there is growing interest in their potential role in inducing tolerance after transplantation. mTOR inhibitors induce anergy in naïve T cells, promote the expansion of regulatory T cells, and inhibit the maturation of dendritic cells, thus promoting immunologic tolerance. Here we review the mechanisms by which mTOR inhibitors promote tolerance. We discuss the clinical relevance of these mechanisms and suggest how they might be used in the design of future protocols to induce tolerance.

J Am Soc Nephrol. 2011 Mar;22(3):408-15

Investigating the role of immunomodulation for colon cancer prevention: results of an in vivo dose escalation trial of levamisole with immunologic endpoints.

The potential role of immunomodulatory agents for colon cancer prevention has not been studied systematically. Levamisole (LMS), which is immunostimulatory, is synergistic with 5-fluorouracil in the adjuvant therapy of patients with stage III colon cancer. This pilot study was initiated to explore the potential utility of LMS as a colon cancer prevention agent and to define the minimum dose at which it retains potentially beneficial effects on the immune system. Normal volunteers were treated over 3 days with LMS at four different dose levels and were monitored for toxicity and immunologic changes. Immunologic endpoints included lymphocyte antigen expression, serum cytokine levels, and two new ex vivo assays that defined LMS’s activity in modulating T-helper-1 (Th1) cytokine production. In addition, in vitro dose-response analyses of LMS’s effects on cellular immune function were performed. LMS was tolerated without toxicity at low dosages only. Significant increases (P < .0001) in the proportion of peripheral blood mononuclear cells expressing the natural killer antigen CD16 were noted at all dose levels. LMS did not alter serum cytokine levels and only minimally affected Th1 cellular immune function. In vitro analysis demonstrated that LMS is synergistic with interleukin 12 in the induction of a Th1 cytokine response at very low concentrations (1microM). This study suggests that short-term LMS is only minimally immunomodulatory but that immune activity is equivalent at low dosages where the medication is better tolerated. Additional, longer-term, studies of low-dose LMS as a potential colon cancer chemopreventive agent should be considered.

Cancer Detect Prev. 2001;25(2):183-91

Systemic therapies for psoriasis: methotrexate, retinoids, and cyclosporine.

Despite the current use and ongoing development of the biological therapies ‘traditional’ systemic agents will continue to form a key part of the therapeutic armamentarium for patients with severe psoriasis. Long-term maintenance therapy with retinoids and methotrexate is cost-effective and, for many patients with psoriasis, life changing. Regular monitoring is required for both treatments, particularly methotrexate to prevent significant bone marrow suppression and hepatotoxicity. Ideally, cyclosporine should be used for short courses of 3 to 4 months duration, within which it provides excellent disease control. Close assessment of renal function and blood pressure is essential.

Clin Dermatol. 2008 Sep-Oct;26(5):438-47

Systems biology approaches and tools for analysis of interactomes and multi-target drugs.

Systems biology is essentially a proteomic and epigenetic exercise because the relatively condensed information of genomes unfolds on the level of proteins. The flexibility of cellular architectures is not only mediated by a dazzling number of proteinaceous species but moreover by the kinetics of their molecular changes: The time scales of posttranslational modifications range from milliseconds to years. The genetic framework of an organism only provides the blue print of protein embodiments which are constantly shaped by external input. Indeed, posttranslational modifications of proteins represent the scope and velocity of these inputs and fulfil the requirements of integration of external spatiotemporal signal transduction inside an organism. The optimization of biochemical networks for this type of information processing and storage results in chemically extremely fine tuned molecular entities. The huge dynamic range of concentrations, the chemical diversity and the necessity of synchronisation of complex protein expression patterns pose the major challenge of systemic analysis of biological models. One further message is that many of the key reactions in living systems are essentially based on interactions of moderate affinities and moderate selectivities. This principle is responsible for the enormous flexibility and redundancy of cellular circuitries. In complex disorders such as cancer or neurodegenerative diseases, which initially appear to be rooted in relatively subtle dysfunctions of multimodal physiologic pathways, drug discovery programs based on the concept of high affinity/high specificity compounds (“one-target, one-disease”), which has been dominating the pharmaceutical industry for a long time, increasingly turn out to be unsuccessful. Despite improvements in rational drug design and high throughput screening methods, the number of novel, single-target drugs fell much behind expectations during the past decade, and the treatment of “complex diseases” remains a most pressing medical need. Currently, a change of paradigm can be observed with regard to a new interest in agents that modulate multiple targets simultaneously, essentially “dirty drugs.” Targeting cellular function as a system rather than on the level of the single target, significantly increases the size of the drugable proteome and is expected to introduce novel classes of multi-target drugs with fewer adverse effects and toxicity. Multiple target approaches have recently been used to design medications against atherosclerosis, cancer, depression, psychosis and neurodegenerative diseases. A focussed approach towards “systemic” drugs will certainly require the development of novel computational and mathematical concepts for appropriate modelling of complex data. But the key is the extraction of relevant molecular information from biological systems by implementing rigid statistical procedures to differential proteomic analytics.

Methods Mol Biol. 2010;662:29-58

Modulation of cytokine expression by traditional medicines: a review of herbal immunomodulators.

Modulation of cytokine secretion may offer novel approaches in the treatment of a variety of diseases. One strategy in the modulation of cytokine expression may be through the use of herbal medicines. A class of herbal medicines, known as immunomodulators, alters the activity of immune function through the dynamic regulation of informational molecules such as cytokines. This may offer an explanation of the effects of herbs on the immune system and other tissues. For this informal review, the authors surveyed the primary literature on medicinal plants and their effects on cytokine expression, taking special care to analyze research that utilized the multi-component extracts equivalent to or similar to what are used in traditional medicine, clinical phytotherapy, or in the marketplace. METHODOLOGY: MEDLINE, EBSCO, and BIOSIS were used to identify research on botanical medicines, in whole or standardized form, that act on cytokine activity through different models, i.e., in vivo (human and animal), ex vivo, or in vitro. RESULTS: Many medicinal plant extracts had effects on at least one cytokine. The most frequently studied cytokines were IL-1, IL-6, TNF, and IFN. Acalypha wilkesiana, Acanthopanax gracilistylus, Allium sativum, Ananus comosus, Cissampelos sympodialis, Coriolus versicolor, Curcuma longa, Echinacea purpurea, Grifola frondosa, Harpagophytum procumbens, Panax ginseng, Polygala tenuifolia, Poria cocos, Silybum marianum, Smilax glabra, Tinospora cordifolia, Uncaria tomentosa, and Withania somnifera demonstrate modulation of multiple cytokines. CONCLUSION: The in vitro and in vivo research demonstrates that the reviewed botanical medicines modulate the secretion of multiple cytokines. The reported therapeutic success of these plants by traditional cultures and modern clinicians may be partially due to their effects on cytokines. Phytotherapy offers a potential therapeutic modality for the treatment of many differing conditions involving cytokines. Given the activity demonstrated by many of the reviewed herbal medicines and the increasing awareness of the broad-spectrum effects of cytokines on autoimmune conditions and chronic degenerative processes, further study of phytotherapy for cytokine-related diseases and syndromes is warranted

Altern Med Rev. 2006 Jun;11(2):128-50

Immunomodulatory active compounds from Tinospora cordifolia.

ETHNOPHARMACOLOGICAL RELEVANCE: Tinospora cordifolia mentioned as “Rasayana” is extensively used in various herbal preparations for the treatment of different ailments for its general tonic, antiperiodic, antispasmodic, antiinflammatory, antiarthritic, antiallergic and antidiabetic properties. It is extensively used in Ayurveda due to its potential in improving the immune system and the body resistance against infections. AIM OF THE STUDY:  The aim of the study was to isolate and characterise the immunomodulatory active compounds of Tinospora cordifolia. MATERIALS AND METHODS: The immunomodulatory activity of different extracts, fractions and isolated compounds in relation to phagocytosis and reactive oxygen species production in human neutrophil cells have been investigated using the PMN phagocytic function studies, NBT, NO and chemiluminescence assay. RESULTS: The results obtained indicate that ethyl acetate, water fractions and hot water extract exhibited significant immunomodulatory activity with an increase in percentage phagocyctosis. Chromatographic purification of these fraction led to the isolation of a mixture of two compounds 2, 3 isolated for the first time from natural source and five known compounds 1, 4-7 which were characterized as 11-hydroxymustakone (2), N-methyl-2-pyrrolidone (3), N-formylannonain (1), cordifolioside A (4), magnoflorine (5), tinocordiside (6), syringin (7) by nuclear magnetic resonance (NMR) and mass spectrometry (MS) and comparing the spectral data with reported one. Cordifolioside A and syringin have been reported to possess immunomodulatory activity. Other five compounds showed significant enhancement in phagocytic activity and increase in nitric oxide and reactive oxygen species generation at concentration 0.1-2.5 µg/ml. CONCLUSIONS: Seven immunomodulatory active compounds belonging to different classes have been isolated and characterised indicating that the immunomodulatory activity of Tinospora cordifolia may be attributed to the synergistic effect of group of compounds.

J Ethnopharmacol. 2012 Jun 14;141(3):918-26

Comparative studies of the immunomodulatory activity of Tinospora cordifolia and Tinospora sinensis.

The water and ethanol extracts of stems of Tinospora cordifolia and T. sinensis inhibit immunosuppression produced by cyclophosphamide. Ethanol extracts of stems of both the plants inhibit cyclophosphamide-induced anemia. The water extract of T. sinensis is found to be more potent than the other extracts.

Fitoterapia. 2000 Jun;71(3):254-7

Tinospora cordifolia (Willd.) Hook. f. and Thoms. (Guduchi) - validation of the Ayurvedic pharmacology through experimental and clinical studies.

T. cordifolia (Guduchi) is a large, glabrous, perennial, deciduous, climbing shrub of weak and fleshy stem found throughout India. It is a widely used plant in folk and Ayurvedic systems of medicine. The chemical constituents reported from this shrub belong to different classes, such as alkaloids, diterpenoid lactones, glycosides, steroids, sesquiterpenoid, phenolics, aliphatic compounds and polysaccharides. Various properties of T. cordifolia, described in ancient texts of Ayurveda, like Rasayana, Sangrahi, Balya, Agnideepana, Tridoshshamaka, Dahnashaka, Mehnashaka, Kasa-swasahara, Pandunashaka, Kamla-Kushta-Vataraktanashaka, Jwarhara, Krimihara, Prameha, Arshnashaka, Kricch-Hridroganashak, etc., are acquiring scientific validity through modern research adopting “reverse pharmacological” approach. Potential medicinal properties reported by scientific research include anti-diabetic, antipyretic, antispasmodic, anti-inflammatory, anti-arthritic, antioxidant, anti-allergic, anti-stress, anti-leprotic, antimalarial, hepato-protective, immuno-modulatory and anti-neoplastic activities. This review brings together various properties and medicinal uses of T. cordifolia described in Ayurveda, along with phytochemical and pharmacological reports.

Int J Ayurveda Res. 2010 Apr;1(2):112-21

Effect of Tinospora cordifolia on blood glucose and total lipid levels of normal and alloxan-diabetic rabbits.

The aqueous, alcoholic, and chloroform extracts of the leaves of Tinospora cordifolia were administered in doses of 50, 100, 150 and 200 mg/kg body weight to normal and alloxan-diabetic rabbits. The blood glucose and total lipid levels were estimated before and 2, 4, 6, and 8 hours after administration of the extract. The extract exerted a significant (P less than 0.5) hypoglycaemic effect in normal as well as in alloxan-treated rabbits. The extracts, however, had no significant (P greater than 0.05) effect on total lipid levels in normal as well as in alloxan-treated diabetic rabbits. The doses used did not show acute toxicity or result in behavioural changes. From this study, it may be concluded that extracts of the leaves of Tinospora cordifolia have an insulin-like action and can significantly reduce the blood glucose but not the total lipid levels in normal rabbits and in alloxan-induced diabetic rabbits.

Planta Med. 1992 Apr;58(2):131-6

Cardioprotective activity of alcoholic extract of Tinospora cordifolia in ischemia-reperfusion induced myocardial infarction in rats.

It has been suggested that the beneficial effects of reperfusing the myocardium might be in part reversed by the occurrence of reperfusion injury. Oxidative stress was suggested to be implicating in the pathogenesis of ischemia-reperfusion (I/R) injury. Many antioxidative plants were shown to be cardioprotective in experimental models of myocardial ischemia-reperfusion (I/R) injury. The present study was designed to investigate the effects of pretreatment with alcoholic extract of Tinospora cordifolia in an in vivo rat model. The model adopted was that of surgically-induced myocardial ischemia, performed by means of left anterior descending coronary artery occlusion (LAD) for 30 min followed by reperfusion for another 4 h. Infarct size was measured by using the staining agent TTC (2,3,5-triphenyl tetrazolium chloride). Lipid peroxide levels in serum and in heart tissue were estimated spectrophotometrically by the methods developed by Yagi and Ohkawa et al. respectively. A lead II electrocardiogram was monitored at various intervals throughout the experiment. A dose dependent reduction in infarct size and in lipid peroxide levels of serum and heart tissue were observed with the prior treatment of T. cordifolia with various doses for 7 d compared to control animals. Hence, the present study suggests the cardioprotective activity of T. cordifolia in limiting ischemia-reperfusion induced myocardial infarction.

Biol Pharm Bull. 2005 Dec;28(12):2319-22

Immunotherapy with Tinospora cordifolia: a new lead in the management of obstructive jaundice.

OBJECTIVE: Immunosuppre-ssion associated with deranged hepatic function and sepsis results in poor surgical outcome in extrahepatic obstructive jaundice. The effect of an ayurvedic agent, Tinospora cordifolia (TC), which has been shown to have hepatoprotective and immunomodulatory properties in experimental studies, on surgical outcome in patients with malignant obstructive jaundice was evaluated.  METHODS: Thirty patients were randomly divided into two groups, matched with respect to clinical features, impairment of hepatic function (as judged by liver function tests including antipyrine elimination) and immunosuppression (phagocytic and killing capacities of neutrophils). Group I received conventional management, ie vitamin K, antibiotics and biliary drainage; Group II received Tinospora cordifolia (16 mg/kg/day orally) in addition, during the period of biliary drainage. RESULTS:  Hepatic function remained comparable in the two groups after drainage. However, the phagocytic and killing capacities of neutrophils normalized only in patients receiving Tinospora cordifolia (28.2 +/- 5.5% and 29.47 +/- 6.5% respectively). Post-drainage bactobilia was observed in 8 patients in Group I and 7 in Group II, but clinical evidence of septicemia was observed in 50% of patients in Group I as against none in Group II (p < 0.05). Post-operative survival in Groups I and II was 40% and 92.4% respectively (p < 0.01). CONCLUSION: Tinospora cordifolia appears to improve surgical outcome by strengthening host defenses.

Indian J Gastroenterol. 1993 Jan;12(1):5-8

Immunomodulatory role of Tinospora cordifolia as an adjuvant in surgical treatment of diabetic foot ulcers: a prospective randomized controlled study.

BACKGROUND: Chronic diabetic patients with wounds have deficient growth factors and impaired local and systemic cellular immunity. Treatment with growth factors is expensive with risk of infection transmission and these factors may not achieve optimum wound concentration. We evaluated the role of generalized immunomodulation in diabetic ulcers by using Tinospora cordifolia as an adjuvant therapy and studied its influence on parameters/determinants of healing, on bacterial eradication and on polymorphonuclear phagocytosis. MATERIALS AND METHODS: A prospective double-blind randomized controlled study lasting for over 18 months in 50 patients. The ulcer was classified by wound morphology and severity with Wound Severity Score (Pecoraro-Reiber system). Mean ulcer area, depth and perimeter were measured and swabs taken for culture. Blood was collected to assess polymorphonuclear % phagocytosis (PMN function by Lehrer-Cline C. albicans method). Medical therapy, glycemic control, debridement, wound care were optimized. At 4 weeks, parameters were reassessed. PMN function was reviewed at 3 months. RESULTS AND ANALYSIS: Forty-five patients completed the trial: study group - 23 (M:F = 17:1; mean age = 56.3 years; mean ulcer duration = 21.1 days); control group 22 (M:F = 19:3; mean age = 56.3 years; mean ulcer duration = 30.4 days). Net improvement was seen in 17 patients (73.9%) in the study group; while in the control group, in 13 patients (59.1%); P = 0.292. Specific parameters included rate of change of ulcer area - cm(2) /day (study - 0.15; control - 0.07; P = 0.145); rate of change of ulcer perimeter - mm/day (study - 0.09; control = - 0.07; P = 0.089); change of depth - mm (study - 2.2; control - 1.4; P = 0.096); change of wound score (study - 14.4; control - 10.6; P = 0.149); total number of debridements (study - 1.9; control - 2.5; P = 0.03) and change in % phagocytosis (study - 3.9; control - 2.3; P = 0.048). CONCLUSION: Diabetic patients with foot ulcers on T. cordifolia as an adjuvant therapy showed significantly better final outcome with improvement in wound healing. Reduced debridements and improved phagocytosis were statistically significant, indicating beneficial effects of immunomodulation for ulcer healing.

Indian J Med Sci. 2007 Jun;61(6):347-55

Subcutaneous immunotherapy for allergic rhinitis: an evidence based review of the recent literature with recommendations.

BACKGROUND: Allergic rhinitis is a common allergic disease with increasing prevalence in Western Societies. Medical therapy is first line treatment, and is aimed at reducing symptoms of immunoglobulin E (IgE)-mediated inflammation of the nasal passages. In patients with disease refractory to medical therapy, subcutaneous immunotherapy is an option. The aim of this study is to update a recent Cochrane review with available level 1 evidence for seasonal and perennial allergic rhinitis. METHODS: A systematic review of the literature was performed from 2006 to 2011 and compared with data from a 2007 Cochrane review on immunotherapy for seasonal allergic rhinitis. We included all studies of level 1 evidence. All forms of single extract immunotherapy were considered. Studies with primary asthma related end-points were excluded. Primary end-points were instruments of clinical efficacy (ie, symptom-medication scores) and adverse events. RESULTS: We retrieved 12 level 1 studies for review. In total, 1,512 patients were randomized into treatment groups, alternative study groups (alternative duration of therapy or sublingual immunotherapy [SLIT]), or placebo. Efficacy was evaluated based on reported symptom and/or medication score, validated quality of life instruments, immunological assays, challenge testing, and adverse events. CONCLUSION: Subcutaneous immunotherapy improves symptom and/or medication scores and validated quality of life measures. In addition, associated changes in surrogate markers of immunologic protection are observed. Subcutaneous immunotherapy is safe when administered to carefully selected patients and in settings capable of responding to systemic reactions. Subcutaneous immunotherapy is recommended for patients with seasonal or perennial allergic rhinitis not responsive to conservative medical therapy, and whose symptoms significantly affect quality of life.

Int Forum Allergy Rhinol. 2013 Jan 11

Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease.

One theory of immune regulation involves homeostasis between T-helper 1 (Th1) and T-helper 2 (Th2) activity. The Th1/Th2 hypothesis arose from 1986 research suggesting mouse T-helper cells expressed differing cytokine patterns. This hypothesis was adapted to human immunity, with Th1- and Th2-helper cells directing different immune response pathways. Th1 cells drive the type-1 pathway (“cellular immunity”) to fight viruses and other intracellular pathogens, eliminate cancerous cells, and stimulate delayed-type hypersensitivity (DTH) skin reactions. Th2 cells drive the type-2 pathway (“humoral immunity”) and up-regulate antibody production to fight extracellular organisms; type 2 dominance is credited with tolerance of xenografts and of the fetus during pregnancy. Overactivation of either pattern can cause disease, and either pathway can down-regulate the other. But the hypothesis has major inconsistencies; human cytokine activities rarely fall into exclusive pro-Th1 or -Th2 patterns. The non-helper regulatory T cells, or the antigen-presenting cells (APC), likely influence immunity in a manner comparable to Th1 and Th2 cells. Many diseases previously classified as Th1 or Th2 dominant fail to meet the set criteria. Experimentally, Th1 polarization is readily transformed to Th2 dominance through depletion of intracellular glutathione, and vice versa. Mercury depletes glutathione and polarizes toward Th2 dominance. Several nutrients and hormones measurably influence Th1/Th2 balance, including plant sterols/sterolins, melatonin, probiotics, progesterone, and the minerals selenium and zinc. The long-chain omega-3 fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) significantly benefit diverse inflammatory and autoimmune conditions without any specific Th1/Th2 effect. Th1/Th2-based immunotherapies, e.g., T-cell receptor (TCR) peptides and interleukin-4 (IL-4) injections, have produced mixed results to date.

Altern Med Rev. 2003 Aug;8(3):223-46

Cancer and immune response: old and new evidence for future challenges.

Cancer may occur as a result of abnormal host immune system tolerance. Recent studies have confirmed the occurrence of spontaneous and induced antitumor immune responses expressed as the presence of tumor-infiltrating T cells in the tumor microenvironment in some cancer models. This finding has been recognized as a good prognostic factor in several types of tumors. Some chemotherapy agents, such as anthracyclines and gemcitabine, are effective boosters of the immune response through tumor-specific antigen overexpression after apoptotic tumor cell destruction. Other strategies, such as GM-CSF or interleukin-2, are pursued to increase immune cell availability in the tumor vicinity, and thus improve both antigen presentation and T-cell activation and proliferation. In addition, cytotoxic T lymphocyte antigen 4-blocking monoclonal antibodies enhance immune activity by prolonging T-cell activation. Strategies to stimulate the dormant immune system against tumors are varied and warrant further investigation of their applications to cancer therapy in the future.

Oncologist. 2008 Dec;13(12):1246-54

Efficacy of Tinospora cordifolia in allergic rhinitis.

The efficacy of Tinospora cordifolia (TC) extract in patients of allergic rhinitis was assessed in a randomized double blind placebo controlled trial. Seventy-five patients were randomly given either TC or placebo for 8 weeks. They were clinically examined and Hb %, TLC, DLC and nasal smear was done. At the end of trial baseline investigations were repeated, drug decoded and results analyzed. With TC treatment 100% relief was reported from sneezing in 83% patients, in 69% from nasal discharge, in 61% from nasal obstruction and in 71% from nasal pruritus. In placebo group, there was no relief in 79% from sneezing, in 84.8% from nasal discharge, in 83% from nasal obstruction, and in 88% from nasal pruritus. The difference between TC and placebo groups was highly significant. TLC increased in 69% patients in drug treated group and in only 11% with placebo. After TC, eosinophil and neutrophil count decreased and goblet cells were absent in nasal smear. After placebo, decrease in eosinophil and neutrophil count was marginal and goblet cells were present. TC significantly decreased all symptoms of allergic rhinitis. Nasal smear cytology and leukocyte count correlated with clinical findings. TC was well tolerated.

J Ethnopharmacol. 2005 Jan 15;96(3):445-9

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