Life Extension Magazine®

Issue: May 2012

Tinnitus

The effect of sclerotherapy on restless legs syndrome.

BACKGROUND: Restless Legs syndrome (RLS) is a disorder of unknown etiology characterized by relentless leg discomfort when stationary, which compels voluntary leg movement to obtain temporary relief. We have received anecdotal reports of coincidental relief from symptoms of RLS in patients following sclerotherapy for varicose vein disease. OBJECTIVE: To prospectively evaluate the concomitant occurrence of RLS and varicose veins in a population seeking treatment for varicose veins, and to assess the therapeutic response of RLS to sclerotherapy. METHODS: One thousand three hundred and ninety-seven patients were screened for RLS symptoms by questionnaire and interview, and for saphenous vein disease by clinical examination, including continuous-wave Doppler. Sclerotherapy with sodium tetradecyl sulphate was performed on 113 RLS patients. RESULTS: RLS symptoms were present in 22% (312/1,397), with a Doppler-negative to Doppler-positive ratio of 3:2. One hundred and eleven of the 113 treated patients (98%) reported initial relief from RLS symptoms. Follow-up thus far shows a recurrence rate of 8% and 28% at 1 and 2 years, respectively. CONCLUSIONS: RLS is common in patients with both saphenous and nontruncal varicose vein disease, and can respond frequently and rapidly to sclerotherapy. This subpopulation of RLS sufferers should be considered for phlebological evaluation and possible treatment before being consigned to chronic drug therapy.

Dermatol Surg. 1995 Apr;21(4):328-32

Restless legs syndrome in patients with chronic venous disorders: an untold story.

OBJECTIVES: To prospectively study the profile of restless leg syndrome (RLS) in patients presenting to a phlebology practice. METHODS: The study uses prospective questionnaire and clinical observation study. In all, 174 consecutive patients and 174 matched controls were evaluated in detail. The diagnosis of restless legs syndrome (RLS) was established by the International RLS study group (IRLSSG) criteria. Detailed clinical, systemic and Duplex ultrasound evaluations were done to establish the presence of chronic venous disorders (CVD) (reflux > 0.5 s on augmentation manoeuvers and revised clinical, aetiological, anatomical and pathological [CEAP] criteria). RESULTS: Of the 174 consecutive subjects studied (22M: 152F), 63 (36%) had evidence of RLS compared with only 34 of 174 of the controls (19%, P < 0.05). Sixty-two (98%) of these RLS-positive study subjects were subsequently diagnosed with CVD. In comparison, 31 (91%) of the RLS-positive control subjects (n = 34) were found to have CVD. This prevalence of CVD was comparable with RLS-positive study subjects, but was significantly higher than the prevalence in CVD in RLS-negative controls (P < 0.01). Only three (9%) of the controls had RLS without CVD. RLS-positive subjects were typically women above the age of 40 years (P < 0.01 vs. men, P < 0.01 vs. below 40 years). A significant difference in clinical presentation in the study subjects was the high prevalence of leg cramps in the RLS-positive subjects (P < 0.01). None of the patients with RLS in this series gave history of anaemia, chronic renal failure or an established psychiatric or neurological disease as found pathognomic for RLS by others. CONCLUSIONS: RLS appears to be a common overlapping clinical syndrome in patients with CVD. Prospective blinded therapeutic trials are planned to study the influence of definitive treatments for CVD on sequential RLS scores.

Phlebology. 2007;22(4):156-63

Pharmacological agents in the treatment of venous disease: an update of the available evidence.

Varicose veins and the complications of venous disease are thought to affect over a quarter of the adult population and the management of these conditions are a major cause of health service expense. Advances in the understanding of venous pathophysiology have highlighted numerous potential targets for pharmacotherapy. This review considers the evidence for pharmacological agents used for the treatment of chronic venous disease. A literature search using Pubmed, Embase and Cinahl databases was performed. The initial search terms ‘varicose vein’, ‘venous ulcer’ and ‘venous disease’ were used with appropriate search limits to identify prospective studies of pharmacotherapy in venous disease. A wide range of venoactive and non-venoactive drugs have been studied in patients with venous disease. The use of micronized purified flavonoid fraction (Daflon) can reduce symptoms of pain, heaviness and oedema in patients with venous reflux and a recent meta-analysis concluded that Daflon improves healing in patients with venous ulceration treated with compression. Pentoxifylline may be a useful adjunct to compression therapy for patients with venous ulceration. Oxerutins and calcium dobesilate may be of benefit in reducing oedema and rutosides may help to relieve the symptoms of varicose veins in pregnancy. The clinical benefits of other medications remain unproven. Although numerous pharmacological agents have been proposed and studied, Daflon has demonstrated the greatest clinical benefits in patients with venous disease. Further research is needed to define the role of venoactive drugs in clinical care and improve our understanding of the pathophysiology of venous disease to help identify new therapeutic avenues.

Curr Vasc Pharmacol. 2009 Jul;7(3):303-8

Phlebotonics for venous insufficiency.

BACKGROUND: Chronic venous insufficiency (CVI) is a common condition caused by inadequate blood flow through the veins, usually in the lower limbs. It can result in considerable discomfort with symptoms such as pain, itchiness and tiredness in the legs. Sufferers may also experience swelling and ulcers. Phlebotonics are a class of drugs that are often used to treat CVI. OBJECTIVES: To assess the efficacy of oral or topical phlebotonics. SEARCH STRATEGY: We searched the Cochrane Peripheral Vascular Diseases Group trials register (April 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2005), MEDLINE (January 1966 to April 2005), EMBASE (January 1980 to April 2005) and reference lists of articles. We also contacted pharmaceutical companies. SELECTION CRITERIA: Randomised, double blind, placebo-controlled trials (RCTs) assessing the efficacy of rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, centella asiatica, disodium flavodate, french maritime pine bark extract, grape seed extract and aminaftone in CVI patients at any stage of the disease. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. The effects of treatment were estimated by relative risk (RR) or by standardised mean differences (SMD) by applying a random effects statistical model. Sensitivity analyses were also performed. MAIN RESULTS: Fifty-nine RCTs of oral phlebotonics were included, but only 44 trials involving 4,413 participants contained quantifiable data for the efficacy analysis: 23 of rutosides, ten of hidrosmine and diosmine, six of calcium dobesilate, two of centella asiatica, one of french maritime pine bark extract, one of aminaftone and one of grape seed extract. No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria. Outcomes included oedema, venous ulcers, trophic disorders, subjective symptoms (pain, cramps, restless legs, itching, heaviness, swelling and paraesthesias), global assessment measures and side effects. The results of many variables were heterogeneous. Phlebotonics showed some global benefit (i.e. oedema reduction) (relative risk 0.72, 95% confidence interval 0.65 to 0.81). The benefit for the remaining CVI signs and symptoms must be evaluated by phlebotonic group. There were no quantifiable data on quality of life. AUTHORS’ CONCLUSIONS: There is not enough evidence to globally support the efficacy of phlebotonics for chronic venous insufficiency. There is a suggestion of some efficacy of phlebotonics on oedema but this is of uncertain clinical relevance. Due to the limitations of current evidence, there is a need for further randomised, controlled clinical trials with greater attention paid to methodological quality.

Cochrane Database Syst Rev. 2005 Jul 20;(3):CD003229

Veno-active drugs in the management of chronic venous disease. An international consensus statement: current medical position, prospective views and final resolution.

BACKGROUND: Veno-active drugs (VAD) have effects on edema and symptoms related to chronic venous disease (CVD), especially so-called venous pain. VAD’s effectiveness, although well established, is regularly debated. OBJECTIVE: Our purpose was to select all randomized controlled trials (RCTs) and meta-analyses devoted to VAD and symptoms in CVD, to submit them to a group of international experts in CVD and to vote with secrete ballot to determine the level of efficacy of each drug, according to EBM (Evidence-Based Medicine) rules and critical analysis. METHODS: Publications in any language devoted to VAD and venous symptoms were searched for in different databanks and submitted to the experts prior to the meeting. RESULTS: 83 papers were analyzed, including 72 RCTs or meta-analyses. Experts determined the level of EBM of each drug, according to the literature and personal experience, using 3 levels of recommendation, A, B and C (from large RCTs to non-randomized trials). CONCLUSIONS: VAD are effective and may be applied in CVD when symptomatic, from C0s to C6s. However, etiological treatment of venous reflux and venous hypertension has always priority. In some cases VAD may replace compression and/or complement its effects. If respecting these prerequisites, VAD are safe and effective.

Clin Hemorheol Microcirc. 2005;33(4):309-19

Medicamentous treatment of chronic venous insufficiency using semisynthetic diosmin—a prospective study.

INTRODUCTION: Chronic venous insufficiency (HVI) is manifested by the progressive signs of venous stasis. This disorder is treated by: compressive bandaging, medicaments, sclerotherapy, surgery, etc. AIM: Prospective study of the effects of semisynthetic diosmin (clinical signs, quality of life, local biochemical parameters) on patients with HVI to whom no other method of treatment has previously been administered. METHOD APPLIED: This prospective study analysed the presence of risk factors and personal history of 80 patients with HVI. Diagnosis of HVI was based on the clinical apperance and the color duplex scan. Each patient’s clinical signs (pain, oedma, feeling of heaviness and tightness in the lower leg), quality of life (physical, social, and psychological), and CEAP stage were assessed prior to and 30 days after the treatment with Phlebodia 600. For 15 patients with unilateral varicose veins, local values of lactates and gass analysis were taken under the conditions before and following the static load, and venous control samples were taken from the healthy leg. The acquired data were processed by means of descriptive statistics, while the significance of nonparametric features was measured by Wilcoxon test. RESULTS: HVI is somewhat more frequent among females than among mails, on the left than on the right leg, and at the average age of 52.3 +/- 10.5. The patients with HVI are basicly engaged in professions with static load and have positive family history. The patients mainly started medical treatment 12.5 +/- 8.6 years after the first symptoms of the disease. Clinical improvement was recorded on the state of 65/80 patients. After the treatment numerical values of some of the clinical signs were statisticaly lower compared to the values before the administration of semisynthetic diosmin: oedema (0.94:1.50), pain (1.10:1.84), feeling of heaviness (1.20:1.96), and tightness (1.14:1.78). After the administration of the tested medication, parameters of physical, social, and psychological quality-of life were significantly improved (p<0,0001), accompanied with significantly improved (p<0,0001) CEAP stage of HVI (3.00:3.40). Local biochemical parameters had not been significantly changed. CONCLUSION: Administration of semisynthetic diosmin during 30 days results in significant improvement of clinical signs, quality of life and CEAP stage of HVI.

Acta Chir Iugosl. 2008;55(4):53-9

Restless legs syndrome: pathophysiology, clinical presentation and management.

Restless legs syndrome (RLS) is a somatosensory network disorder that is clinically diagnosed according to four main criteria: an urge to move the legs, usually associated with unpleasant leg sensations; induction or exacerbation of symptoms by rest; symptom relief on activity; and diurnal fluctuations in symptoms with worsening in the evening and at night. Genetic variants in four chromosomal regions have been identified that increase the risk of RLS. In addition, various different lesions, ranging from peripheral neuropathies to spinal cord lesions or alterations of brain metabolism, are implicated in RLS. In most cases, sleep disorders with frequent sleep fragmentation and characteristic periodic limb movements during sleep can be identified during a polysomnographic recording. The first-line drugs for RLS are dopaminergic agents, which are effective in low to moderate doses. Alternative or additional treatments include opioids and anticonvulsants. Augmentation-paradoxical worsening of symptoms by dopaminergic treatment-is the main problem encountered in difficult-to-treat patients. Iron deficiency must be identified and treated by supplementation, both to improve RLS symptoms and to potentially lower the risk of augmentation. Here, we review the latest studies pertaining to the pathophysiology, clinical presentation and management of RLS.

Nat Rev Neurol. 2010 Jun;6(6):337-46

Epidemiology of restless legs syndrome in French adults: a nationwide survey: the INSTANT Study.

OBJECTIVE: To evaluate the prevalence, characteristics, and treatment of restless legs syndrome (RLS) in France. METHODS: In this population-based survey, face-to-face home interviews were conducted among a random sample of 10,263 French adults. A French translation of the four features defined by the International RLS Study Group in 1995 was used to assess the prevalence of symptoms consistent with a diagnosis of RLS. Data on severity of symptoms and their management were also collected. RESULTS: The 12-month prevalence of RLS symptoms in the French adult population was estimated to be 8.5% (95% CI 8.0%, 9.0%), with a higher prevalence (p < 0.001) observed in women (10.8%) than in men (5.8%). Prevalence increases with age until 64 years and decreases thereafter in both sexes. Half of the identified subjects reported symptoms once a week at least. Symptoms were more severe in subjects reporting symptoms once a week at least compared to subjects with less frequent symptoms. In this group, half of the subjects reported a family history, the age at onset was earlier, and severity of symptoms higher. RLS had been previously diagnosed in only 5.3% of the subjects who reported previous medical diagnosis, and recommended RLS drug treatment was received by 3.4% of the 28.7% currently treated subjects. CONCLUSIONS: Restless legs syndrome (RLS) occurred in 10% of women and 5% of men. RLS prevalence decreases after the age of 64. RLS is often underdiagnosed and few subjects receive recommended RLS drug treatment.

Neurology. 2005 Jul 26;65(2):239-46

Abnormally increased CSF 3-Ortho-methyldopa (3-OMD) in untreated restless legs syndrome (RLS) patients indicates more severe disease and possibly abnormally increased dopamine synthesis.

BACKGROUND: Abnormally high CSF 3-OMD occurs frequently for RLS patients indicating either increased l-dopa synthesis, limitations in l-dopa decarboxylation or increased MAT/COMT activity, or some combination of these. Increased tyrosine hydroxylase activity was found on both the RLS autopsy and the rodent iron-deprivation model of RLS, suggesting increased DA synthesis in RLS. We, therefore, hypothesized elevated 3-OMD in RLS results from increased DA synthesis and that this should occur accordingly with increased HVA. It would then also reflect both the more severe iron insufficiency pathology of RLS and greater clinical severity, shown by the objective measure of PLMS/hr. METHODS: Patients off RLS medications and matched controls had lumbar punctures at either 10 a.m. or 10 p.m.; RLS patients were grouped by normal or abnormally high 3-OMD (>10 nmol/l). RESULTS: Forty-nine RLS patients (30 high, 19 normal 3-OMD) and 36 age- and gender-matched controls, analyzed separately by time of CSF collection, did not significantly differ in age or gender. RLS patients with high 3-OMD had significantly higher CSF HVA, while those with normal 3-OMD had consistently lower CSF HVA than controls. CSF ferritin was consistently lower compared to controls for the high 3-OMD but not the normal 3-OMD RLS patients. The PLMS/hr was significantly higher for RLS patients with high compared to normal 3-OMD, indicating high 3-OMD patients had more severe RLS. CONCLUSIONS: Abnormal elevation in 3-OMD for RLS patients may reflect increased dopamine synthesis for more severe but perhaps not mild RLS. These differences in the putative dopamine pathology of RLS may indicate different phases or expression of RLS biology or different underlying disease processes.

Sleep Med. 2009 Jan;10(1):123-8

Different strategies in treating noiseinduced hearing loss with N-acetylcysteine.

BACKGROUND: The cellular mechanisms leading to noise-induced hearing loss (NIHL) involve the generation of reactive oxygen species (ROS). Recent studies on glutathione (GSH) and N-acetylcysteine (NAC) show that they can protect the cochlea from ROS-derived damage, increasing the levels of endogenous cellular defences. The purpose of this study was to verify NAC’s oto-protective efficacy and determine if drug administration timing influences the degree of oto-protection. MATERIAL/METHODS: Forty male Sprague Dawley albino rats were divided in four groups exposed to 8-kHz 105-dB SPL continuous noise. The groups were treated with diverse NAC administration modalities: group A received 4 injections during 48 hours (pre- and post-noise exposure), group B 1 injection prior to exposure, group C 1 injection 24 h after exposure, and group D served as untreated controls. The single injection dosage was 375 mg/kg; the controls received an equal volume of saline solution. Cochlear function was assessed by pre- and post-noise (after 168 hours) recordings of distortion product otoacoustic emissions (DPOAEs) and auditory brainstem responses (ABR). DPOAEs were obtained by three different asymmetric protocols (P1=60-50, P2=50-40, P3=40-30 dB SPL) for frequencies of 4-16 kHz. ABR responses were elicited by tone-bursts at 8 and 16 kHz. RESULTS: The most important outcome of the study was that the administration of NAC significantly reduced the threshold shifts in the treated animals. NAC provided different degrees of threshold reduction according to the timing of the drug injection. CONCLUSIONS: The role played by the timing of NAC injection was important for the OHC protection index. From a DPOAE perspective, the best protection scheme was observed in the group receiving NAC after noise exposure, but full recovery of cochlear function was not observed in any of the tested groups.

Med Sci Monit. 2008 Aug;14(8):BR159-64

Protective effects of N-acetylcysteine on noise-induced hearing loss in guinea pigs.

Increasing evidence suggests the involvement of oxidative stress in noise-induced hearing loss. The present study analysed, in an animal experimental model, the time course of the pathogenic mechanisms of noise-induced cochlear damage and the efficacy of the antioxidant drug N-acetylcysteine in reducing noise ototoxicity. Animals were divided into two groups, exposed to noise one treated with N-acetylcysteine for 3 days and one (the control group) with saline. Acoustic trauma was induced by a continuous pure tone of 6 kHz, at 120 dB SPL for 30 minutes. Electrocochleographic recordings were made from an implanted round window electrode and the compound action potentials were measured daily at 2-16 kHz for 7 days. Morphological changes were analysed by scanning electron microscopy. The acoustic threshold measured 1 hour after acoustic trauma was elevated in the control group to 70-90 dB in the higher frequencies of the compound action potential audiogram, with a maximum threshold elevation ranging between 12 and 16 kHz. During the first 24 h, following acoustic trauma, there was a partial recovery of compound action potential thresholds of about 20 dB to reach a final threshold elevation of about 50-70 dB; there was no further improvement over the remaining experimental week. Animals treated with N-acetylcysteine showed a similar temporary threshold shift but a clear improvement in the recovery of compound action potential thresholds, with significantly reduced permanent threshold shift and hair cell loss. These data suggest that N-acetylcysteine is able to attenuate the toxic effect of acoustic trauma and could represent an interesting molecule for preventing inner ear injuries.

Acta Otorhinolaryngol Ital. 2009 Apr;29(2):70-5

N-Acetyl-cysteine against noise-induced temporary threshold shift in male workers.

Previous animal studies showed protective effects of antioxidant medicines against noise-induced hearing loss (NIHL). It is unclear whether antioxidants would protect humans from NIHL. We conducted a study to determine whether N-Acetyl-cysteine (NAC) protected men against noise-induced temporary threshold shift (TTS), and whether subgroups with genetic polymorphisms of glutathione S-transferase (GST) T1 and M1 responded to NAC differently. In this prospective, double-blind, crossover study, 53 male workers were randomly assigned to receive either NAC (1200 mg/day, 14 days) during the first period and placebo during the second period, or placebo during the first period and NAC during the second period. Dosing periods were separated by a washout period of 2 weeks. The hearing threshold changes were determined before and after each dosing period. Pre-shift hearing threshold for high frequencies was 19.1 dB. Daily exposure to noise ranged from 88.4 to 89.4 dB. The noise levels of different frequencies ranged from 80.0 to 89.4 dB with a peak-value at 4 kHz. NAC significantly reduced TTS (p = 0.03). When the participants were grouped by GST M1/T1 genotypes, the NAC effect was only significant among workers with null genotypes in both GSTM1 and GSTT1 (p = 0.004). NAC may prevent noise-induced TTS among occupationally noise-exposed men. The protective effect of NAC was more prominent in subjects with both GSTM1-null and GSTT1-null genotypes. (clinicaltrials.gov Identifier: NCT00552786).

Hear Res. 2010 Oct 1;269(1-2):42-7

The efficacy of N-acetylcysteine to protect the human cochlea from subclinical hearing loss caused by impulse noise: a controlled trial.

In military outdoor shooting training, with safety measures enforced, the risk of a permanent, noise-induced hearing loss is very small. But urban warfare training performed indoors, with reflections from walls, might increase the risk. A question is whether antioxidants can reduce the negative effects of noise on human hearing as it does on research animals. Hearing tests were performed on a control group of 23 military officers before and after a shooting session in a bunker-like room. The experiments were repeated on another group of 11 officers with peroral adminstration of N-acetyl-cysteine (NAC), directly after the shooting. The measurements performed were tone thresholds; transient-evoked otoacoustic emissions, with and without contralateral noise; and psycho-acoustical modulation transfer function (PMTF), thresholds for brief tones in modulated noise. Effects from shooting on hearing thresholds were small, but threshold behavior supports use of NAC treatment. On the PMTF, shooting without NAC gave strong effects. Those effects were like those from continuous noise, which means that strict safety measures should be enforced. The most striking finding was that the non-linearity of the cochlea, that was strongly reduced in the group without NAC, as manifested by the PMTF-results, was practically unchanged in the NAC-group throughout the study. NAC treatment directly after shooting in a bunkerlike room seems to give some protection of the cochlea.

Noise Health. 2011 Nov-Dec;13(55):392-401

Exploring the reasons why melatonin can improve tinnitus.

Melatonin has been proposed as a treatment for tinnitus, especially on the basis of its favourable effects on sleep and its vasoactive and antioxidant properties. However, to our knowledge no attempts of interpretation have been advanced through a detailed analysis of the various specific properties of melatonin possibly cooperating in a coincidental way to relieve tinnitus: among these, its modulatory effect on central nervous system resulting in a protective mechanism against an exaggerated sympathetic drive; its capacity to induce a more steady hemodynamic condition, through a multifactorial and multi-organ activity, resulting in a more regular labyrinthine perfusion; a possible action on the skeletal muscle tending to a reduction of the muscular tone, which could relieve tinnitus of muscular origin deriving from tensor tympani tonic contractions; its possible reported antidepressive effect, which could indirectly act on tinnitus; a direct regulation of inner ear immunity as proposed in literature when melatonin was reported to be present in the inner ear. All these observations seem to indicate melatonin as a tool deserving a greater attention than other antioxidants in the attempt of relieving tinnitus, justifying its application from a more precise rationale based on a series of physio-pathological aspects.

Med Hypotheses. 2010 Aug;75(2):190-1

Sulpiride and melatonin decrease tinnitus perception modulating the auditolimbic dopaminergic pathway.

OBJECTIVES: Sulpiride and melatonin decrease dopamine activity. Sulpiride, a D2 antagonist of dopamine receptors, and melatonin, a pineal substance with antidopaminergic action, are administered to tinnitus patients to decrease tinnitus perception. DESIGN: A prospective, randomized, double-blinded, placebo-controlled study was done. SETTING: General otorhinolaryngologic consultation for 2002-2004 in Seville, Spain. METHODS: One hundred twenty patients consulted for subjective tinnitus. They were included randomly in four groups of 30. One group took sulpiride (50 mg/8 h) alone, the second group took melatonin (3 mg/24 h), the third group took the same doses of sulpiride (50 mg/8 h) plus melatonin (3 mg/24 h), and the fourth group took placebo (lactose 50 mg/8 h), all for 1 month. Ninety-nine patients completed the study. MAIN OUTCOME MEASURES: Clinical history, tonal audiometry, tympanometry, and tinnitometry were done at the beginning and end of the study. Subjective grading of tinnitus perception and a visual analogue scale (0-10) were done for evaluation of results. RESULTS: Based on the subjective grading, tinnitus perception diminished by 56% in patients treated with sulpiride, by 40% in patients treated with melatonin, by 81% in patients treated with sulpiride plus melatonin, and by 22% in patients treated with placebo. Based on the visual analogue scale, tinnitus perception diminished from 7.7 to 6.3 in patients treated with sulpiride, to 6.5 in those treated with melatonin, to 4.8 in patients treated with sulpiride plus melatonin, and to 7.0 in those treated with placebo. CONCLUSIONS: Sulpiride and melatonin reduce tinnitus perception, decreasing dopamine activity. The tinnitus auditolimbic dopaminergic pathway has broad therapeutic implications.

J Otolaryngol. 2007 Aug;36(4):213-9

The role of free oxygen radicals in noise induced hearing loss: effects of melatonin and methylprednisolone.

The aim of this study was to investigate the role of cochlear damage caused by free oxygen radicals occurring as a result of exposure to noise and to determine the prophylactic effects of melatonin and methylprednisolone. Fifty male albino guinea pigs were randomly divided into five groups. All groups were exposed to 60 h of continuous wide band noise at 100+/-2 dB, except group I. Group I was not exposed to noise or treated with drugs. Group II was exposed to noise and not treated with drugs. Group III was exposed to noise and treated with melatonin. Group IV was exposed to noise and treated with methylprednisolone. Group V was exposed to noise and treated with melatonin and methylprednisolone. A high dose of 40 mg/kg methylprednisolone and/or 20 mg/kg melatonin were administered intramuscularly 24 h before exposure to noise, immediately before noise exposure and once a day until noise exposure was completed. Just after the noise ended, guinea pigs were decapitated. Venous blood was obtained into tubes with EDTA and it was used to measure activity levels of plasma malondialdehyde, erythrocyte glutathione peroxidase and the cochlear tissue malondialdehyde. After the noise ended, in comparison group II with I; it was found that the malondialdehyde activity of the plasma and tissue had increased, the erythrocyte glutathione peroxidase activity levels had decreased and consequently, hearing thresholds had increased (P<0.01). A significant difference was found in the malondialdehyde and erythrocyte glutathione peroxidase activity levels between groups II and III (P<0.01) and the hearing thresholds exhibited a parallel trend (P<0.05). The hearing threshold and malondialdehyde activity levels obtained from groups IV and V were found to be similar to those of group II (P>0.05). As a conclusion, we suggest that the use of methlyprednisolone in order to prevent the cochlear damage caused by noise does not provide sufficient prophylaxy, however the use of melatonin provides a more effective prophylaxy, thus being a promising alternative.

Auris Nasus Larynx. 2002 Apr;29(2):147-52

An experimental comparative study of dexamethasone, melatonin and tacrolimus in noise-induced hearing loss.

CONCLUSION: The calcineurin inhibitor tacrolimus (TCR) and the pineal gland hormone and antioxidant melatonin (MLT) have been shown to possess otoprotective properties against noise-induced hearing loss (NIHL). In contrast, dexamethasone (DXM) was not effective as an otoprotective agent against NIHL. Further studies are needed to understand the exact molecular mechanisms involved. OBJECTIVE: Exposure to noise pollution and use of audio devices for long periods of time at high volume is known to cause hearing loss or NIHL. Our goal was to evaluate the effectiveness of various known compounds such as the anti-inflammatory DXM, the antioxidant MLT and the immunosuppressant TCR against NIHL. MATERIALS AND METHODS: Thirty-two Wistar rats were randomly divided into groups that were then exposed to intense white noise at 120 dB SPL for 4 h. The day before and for a period of 14 days, test groups were administered one of the three compounds. The efficacy of the compounds against NIHL was determined after examining the shifts in the levels of distortion product otoacoustic emissions (DPOAEs) and changes in the threshold of auditory brainstem responses (ABRs). Cytocochleograms and determination of gene expression in whole rat cochlea were carried out at day 21. RESULTS: Treatment with DXM had no otoprotective effect, while animals treated with MLT experienced an improvement in their hearing functionality. This effect, which is probably linked to MLT’s ability to reduce c-fos and TNF-alpha gene expression thereby preventing outer hair cell (OHC) loss, was even more pronounced in week 3. For its part, TCR provided protection against injury to the cochlea from week 1, eventually leading to a full recovery in hearing. The compound reduced both c-fos and TNF-alpha expression, as well as OHC loss.

Acta Otolaryngol. 2009 Apr;129(4):385-9

Antioxidants in treatment of idiopathic sudden hearing loss.

OBJECTIVE: Assuming that superoxide anion radicals (O(2)-) may play a role in damage to the inner ear, the authors investigated the possible benefit of vitamin E as an antioxidant in the treatment of idiopathic sudden hearing loss. STUDY DESIGN: Prospective, double-blind study. SETTING: The Department of Otolaryngology of Rambam Medical Center serves as a tertiary referral center for a population of 1.2 million people. PATIENTS: A total of 66 patients, aged 15 to 70 years, with diagnoses of idiopathic sudden hearing loss of less than 7 days’ duration during 1998 to 2001, were included in the study. All were treated with bed rest, steroids, magnesium, and carbogen inhalation. The study group received vitamin E in addition. RESULTS: The recovery rate, calculated as hearing gain divided by the difference in hearing level between the affected and unaffected ear, was better than 75% in 41 of 66 (62.12%) patients. This rate was achieved in 26 (78.78%) patients in the study group treated with vitamin E, compared with 15 (45.45%) patients in the control group. CONCLUSIONS: Patients treated with the addition of vitamin E achieved better recovery than did the control patients. Further studies should be directed toward a better understanding of the role of antioxidants in idiopathic sudden hearing loss.

Otol Neurotol. 2003 Jul;24(4):572-5

Effects of alpha-tocopherol on noise-induced hearing loss in guinea pigs.

Preventing noise-induced hearing loss (NIHL) by antioxidants is based on the hypothesis that generation of reactive oxygen species is one of the causes of NIHL. alpha-Tocopherol is a naturally occurring antioxidant with no noticeable side effects. In this study, we attempted to protect guinea pigs from developing NIHL by administering alpha-tocopherol. Pigmented male guinea pigs were exposed to a noise (4 kHz octave band, 100 dB SPL), 8 h/day for 3 days consecutively. alpha-Tocopherol (10 mg/kg or 50 mg/kg daily) was given by intraperitoneal injection from 3 days before through 3 days after the noise exposure. Auditory evoked brainstem response (ABR) thresholds at 2, 4 and 8 kHz were recorded prior to the experiment, immediately post-noise, 2 and 8 days post-noise. On day 8 post-noise, after the ABR recording, guinea pigs were decapitated and the cochleae were removed for cochlear surface preparations and scanning electron microscope (SEM) study. ABR threshold shifts of groups receiving alpha-tocopherol were significantly smaller than those of groups not receiving alpha-tocopherol at all frequencies and all time points tested except that of group 3 at 8 kHz 8 days post-noise. No hair cell loss was seen on the surface preparations, but stereocilia loss was found by SEM study. The noise-induced stereocilia loss was significantly decreased by alpha-tocopherol. These results indicate that alpha-tocopherol can attenuate the noise-induced cochlear damage. Further investigations on the preventive effect of alpha-tocopherol on NIHL in noise-exposed workers are necessary.

Hear Res. 2003 May;179(1-2):1-8

Preventive effects of vitamin E on short-term noise-induced hearing loss in guinea pigs.

OBJECTIVE: To study the preventive effects of vitamin E on short-term noise-induced hearing loss (NIHL). METHODS: Forty-eight male pigmented guinea pigs were randomly divided into 6 groups, 8 animals in each group. The animals of group 1, 2, 3, 4 were exposed to the noise (4 kHz octave band noise, 100 dB SPL), 8 hours per day for 3 days consecutively and received normal saline, corn oil, 10 mg/kg vitamin E, 50 mg/kg vitamin E respectively daily by intraperitoneal injection from 3 days before the noise exposure, through the 3 noise exposure days to 3 days after the noise exposure. The animals of group 5 and group 6 days were not exposed to the noise but received normal saline and 50 mg/kg vitamin E injection respectively at the same time as that of group 1, 2, 3, 4. The preventive effects of vitamin E on NIHL were determined by comparing the threshold shifts of auditory brainstem responses (ABR) immediately, on the second day and on the 8th day after the exposure. RESULTS: The ABR threshold shifts immediately, on the second day and on the 8th day after the exposure for group 3 at 2, 4 and 8 kHz were (15.9 +/- 6.8), (39.4 +/- 4.8), (42.5 +/- 6.3), (0.3 +/- 2.5), (19.1 +/- 7.9), (21.9 +/- 6.4), (0.3 +/- 1.6), (10.9 +/- 8.6), (12.2 +/- 8.1) dB, respectively, which were significantly lower than those for group 1 [(30.9 +/- 11.3), (47.8 +/- 8.8), (49.7 +/- 6.9), (10.0 +/- 3.5), (29.1 +/- 6.5), (29.1 +/- 7.6), (4.7 +/- 3.6), (20.3 +/- 6.5), (17.5 +/- 9.0) dB, respectively] (P < 0.05). The ABR threshold shifts immediately, on the second day and on the 8th day after the exposure for group 4 at 2, 4 and 8 kHz were respectively (14.4 +/- 5.3), (36.6 +/- 4.4), (43.1 +/- 2.9), (0.3 +/- 2.5), (16.9 +/- 4.6), (19.4 +/- 3.2), (0.0 +/- 3.7), (7.5 +/- 4.2), (9.1 +/- 4.2) dB, which were significantly lower than those for group 1 (P < 0.05). CONCLUSION: Vitamin E has some preventive effects on the NIHL.

Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2005 Dec;23(6):408-10

Anti-inflammation effects of Cordyceps sinensis mycelium in focal cerebral ischemic injury rats.

Brain ischemia-reperfusion (IR) triggers a complex series of biochemical events including inflammation. To test the neuroprotective efficacy of Cordyceps sinensis mycelium (CSM) in a rat model of focal cerebral IR, ischemic animals were treated with CSM. They were evaluated at 24 h after reperfusion for neurological deficit score. Furthermore, the mechanism of the anti-inflammatory potential of CSM in the regulation of nuclear factor kappaB, polymorphonuclear cells (PMN), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), adhesion molecule (ICAM-1), and cyclooxygenase-2 (COX-2) was determined by ELISA and immunohistochemistry. CSM significantly inhibited IR-induced up-regulation of NF-kappaB activation and the brain production of IL-1β, TNF-α, iNOS, ICAM-1, and COX-2. Moreover, CSM suppressed infiltration of PMN. The study demonstrates the neuroprotective potential of CSM inhibition through anti-inflammation in a rat model of ischemia-reperfusion.

Inflammation. 2011 Dec;34(6):639-44

Influence of Cordyceps sinensis (Berk.) Sacc. and rat serum containing same medicine on IL-1, IFN and TNF produced by rat Kupffer cells.

The results indicated that the levels of IL-1, IFN, and TNF, especially those of IL-1 and INF, produced by cultured rat kupffer cells were increased in the presence of Cordyceps sinensis (CS) or the drug serum (DS) from rats fed on CS. The experimental result of DS was similar to that of CS. However, the former had a better repeatability and stability.

Zhongguo Zhong Yao Za Zhi. 1996 Jun;21(6):367-9, 384

Investigation of the tuber constituents of maca (Lepidium meyenii Walp.).

Lepidium meyenii, known in South America as maca, has received attention worldwide as a powerful energizer that improves physical and mental conditions and increases fertility. Because of these reports, we investigated the secondary metabolites of the tuber of maca. The methanol extract of the tuber of maca contained, in addition to free sugars and amino acids, the following: uridine, malic acid and its benzoyl derivative, and the glucosinolates, glucotropaeolin and m-methoxyglucotropaeolin. Because glucosinolates and their derived products have received increasing attention due to their biological activities, the occurrence of glucosinolate degradation products in the hexane extract was also investigated, and benzylisothiocyanate and its m-methoxy derivative were isolated. The two glucosinolates were semiquantified by HPLC, and benzylisothiocyanate was semiquantified by GC/MS. The methanol extract of maca tuber also contained (1R,3S)-1-methyltetrahydro-beta-carboline-3-carboxylic acid, a molecule which is reported to exert many activities on the central nervous system.

J Agric Food Chem. 2002 Sep 25;50(20):5621-5

Effect of Lepidium meyenii (Maca), a root with aphrodisiac and fertility-enhancing properties, on serum reproductive hormone levels in adult healthy men.

Lepidium meyenii (Maca) is a Peruvian hypocotyl that grows exclusively between 4,000 and 4,500 m in the central Andes. Maca is traditionally employed in the Andean region for its supposed aphrodisiac and/or fertility-enhancing properties. This study was a 12-week double-blind, placebo-controlled, randomized, parallel trial in which active treatment with different doses of Maca Gelatinizada was compared with a placebo. The study aimed to test the hypothesis that Maca has no effect on serum reproductive hormone levels in apparently healthy men when administered in doses used for aphrodisiac and/or fertility-enhancing properties. Men aged between 21 and 56 Years received 1,500 mg or 3,000 mg Maca. Serum levels of luteinizing hormone, follicle-stimulating hormone, prolactin, 17-alpha hydroxyprogesterone, testosterone and 17-beta estradiol were measured before and at 2, 4, 8 and 12 weeks of treatment with placebo or Maca (1.5 g or 3.0 g per day). Data showed that compared with placebo Maca had no effect on any of the hormones studied nor did the hormones show any changes over time. Multiple regression analysis showed that serum testosterone levels were not affected by treatment with Maca at any of the times studied (P, not significant). In conclusion, treatment with Maca does not affect serum reproductive hormone levels.

J Endocrinol. 2003 Jan;176(1):163-8

Beneficial effects of Lepidium meyenii (Maca) on psychological symptoms and measures of sexual dysfunction in postmenopausal women are not related to estrogen or androgen content.

OBJECTIVE: To examine the estrogenic and androgenic activity of Lepidium meyenii (Maca) and its effect on the hormonal profile and symptoms in postmenopausal women. DESIGN: Fourteen postmenopausal women completed a randomized, double-blind, placebo-controlled, crossover trial. They received 3.5 g/day of powered Maca for 6 weeks and matching placebo for 6 weeks, in either order, over a total of 12 weeks. At baseline and weeks 6 and 12 blood samples were collected for the measurement of estradiol, follicle-stimulating hormone, luteinizing hormone, and sex hormone-binding globulin, and the women completed the Greene Climacteric Scale to assess the severity of menopausal symptoms. In addition, aqueous and methanolic Maca extracts were tested for androgenic and estrogenic activity using a yeast-based hormone-dependent reporter assay. RESULTS: No differences were seen in serum concentrations of estradiol, follicle-stimulating hormone, luteinizing hormone, and sex hormone-binding globulin between baseline, Maca treatment, and placebo (P > 0.05). The Greene Climacteric Scale revealed a significant reduction in scores in the areas of psychological symptoms, including the subscales for anxiety and depression and sexual dysfunction after Maca consumption compared with both baseline and placebo (P < 0.05). These findings did not correlate with androgenic or alpha-estrogenic activity present in the Maca as no physiologically significant activity was observed in yeast-based assays employing up to 4 mg/mL Maca extract (equivalent to 200 mg/mL Maca). CONCLUSIONS: Preliminary findings show that Lepidium meyenii (Maca) (3.5 g/d) reduces psychological symptoms, including anxiety and depression, and lowers measures of sexual dysfunction in postmenopausal women independent of estrogenic and androgenic activity.

Menopause. 2008 Nov-Dec;15(6):1157-62

Lepidium meyenii (Maca) does not exert direct androgenic activities.

Maca is the edible root of the Peruvian plant Lepidum meyenii, traditionally employed for its purported aphrodisiac and fertility-enhancing properties. This study aimed at testing the hypothesis that Maca contains testosterone-like compounds, able to bind the human androgen receptor and promote transcription pathways regulated by steroid hormone signaling. Maca extracts (obtained with different solvents: methanol, ethanol, hexane and chloroform) are not able to regulate GRE (glucocorticoid response element) activation. Further experiments are needed to assess which compound, of the several Maca’s components, is responsible of the observed in vivo effects.

J Ethnopharmacol. 2006 Apr 6;104(3):415-7

Beneficial effects of Lepidium meyenii (Maca) on psychological symptoms and measures of sexual dysfunction in postmenopausal women are not related to estrogen or androgen content.

OBJECTIVE: To examine the estrogenic and androgenic activity of Lepidium meyenii (Maca) and its effect on the hormonal profile and symptoms in postmenopausal women. DESIGN: Fourteen postmenopausal women completed a randomized, double-blind, placebo-controlled, crossover trial. They received 3.5 g/day of powered Maca for 6 weeks and matching placebo for 6 weeks, in either order, over a total of 12 weeks. At baseline and weeks 6 and 12 blood samples were collected for the measurement of estradiol, follicle-stimulating hormone, luteinizing hormone, and sex hormone-binding globulin, and the women completed the Greene Climacteric Scale to assess the severity of menopausal symptoms. In addition, aqueous and methanolic Maca extracts were tested for androgenic and estrogenic activity using a yeast-based hormone-dependent reporter assay. RESULTS: No differences were seen in serum concentrations of estradiol, follicle-stimulating hormone, luteinizing hormone, and sex hormone-binding globulin between baseline, Maca treatment, and placebo (P > 0.05). The Greene Climacteric Scale revealed a significant reduction in scores in the areas of psychological symptoms, including the subscales for anxiety and depression and sexual dysfunction after Maca consumption compared with both baseline and placebo (P < 0.05). These findings did not correlate with androgenic or alpha-estrogenic activity present in the Maca as no physiologically significant activity was observed in yeast-based assays employing up to 4 mg/mL Maca extract (equivalent to 200 mg/mL Maca). CONCLUSIONS: Preliminary findings show that Lepidium meyenii (Maca) (3.5 g/d) reduces psychological symptoms, including anxiety and depression, and lowers measures of sexual dysfunction in postmenopausal women independent of estrogenic and androgenic activity.

Menopause. 2008 Nov-Dec;15(6):1157-62

Ethnobiology and Ethnopharmacology of Lepidium meyenii (Maca), a Plant from the Peruvian Highlands.

Lepidium meyenii (maca) is a Peruvian plant of the Brassicaceae family cultivated for more than 2000 years, which grows exclusively in the central Andes between 4000 and 4500 m altitude. Maca is used as a food supplement and also for its medicinal properties described traditionally. Since the 90s of the XX century, an increasing interest in products from maca has been observed in many parts of the world. In the last decade, exportation of maca from Peru has increased from 1,415,000 USD in 2001 to USD 6,170,000 USD in 2010. Experimental scientific evidence showed that maca has nutritional, energizer, and fertility-enhancer properties, and it acts on sexual dysfunctions, osteoporosis, benign prostatic hyperplasia, memory and learning, and protects skin against ultraviolet radiation. Clinical trials showed efficacy of maca on sexual dysfunctions as well as increasing sperm count and motility. Maca is a plant with great potential as an adaptogen and appears to be promising as a nutraceutical in the prevention of several diseases.

Evid Based Complement Alternat Med. 2012;2012:193496

A double-blind, randomized, pilot dose-finding study of maca root (L. meyenii) for the management of SSRI-induced sexual dysfunction.

We sought to determine whether maca, a Peruvian plant, is effective for selective-serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction. We conducted a double-blind, randomized, parallel group dose-finding pilot study comparing a low-dose (1.5 g/day) to a high-dose (3.0 g/day) maca regimen in 20 remitted depressed outpatients (mean age 36+/-13 years; 17 women) with SSRI-induced sexual dysfunction. The Arizona Sexual Experience Scale (ASEX) and the Massachusetts General Hospital Sexual Function Questionnaire (MGH-SFQ) were used to measure sexual dysfunction. Ten subjects completed the study, and 16 subjects (9 on 3.0 g/day; 7 on 1.5 g/day) were eligible for intent-to-treat (ITT) analyses on the basis of having had at least one postbaseline visit. ITT subjects on 3.0 g/day maca had a significant improvement in ASEX (from 22.8+/-3.8 to 16.9+/-6.2; z=-2.20, P=0.028) and in MGH-SFQ scores (from 24.1+/-1.9 to 17.0+/-5.7; z=-2.39, P=0.017), but subjects on 1.5 g/day maca did not. Libido improved significantly (P<0.05) for the ITT and completer groups based on ASEX item #1, but not by dosing groups. Maca was well tolerated. Maca root may alleviate SSRI-induced sexual dysfunction, and there may be a dose-related effect. Maca may also have a beneficial effect on libido.

CNS Neurosci Ther. 2008 Fall;14(3):182-91

The Effect of Herbal Extract (EstroG-100) on Pre-, Peri- and Post-Menopausal Women: A Randomized Double-blind, Placebo-controlled Study.

This clinical research study was designed to evaluate the efficacy of a new herbal product, EstroG-100, containing a mixture of standardized extracts of Cynanchum wilfordii, Phlomis umbrosa and Angelica gigas, on menopausal symptoms. This randomized double-blind, placebo-controlled trial was performed for 12 weeks with 64 pre-, peri- and postmenopausal White Hispanic, White non-Hispanic and African American women who were randomly allocated to either the EstroG-100 group (n = 31) or the placebo group (n = 33). Primary end-points were the mean change in scores of the Kupperman menopause index (KMI) that evaluates 11 symptoms, and the mean change in scores of vaginal dryness. The mean KMI score was significantly reduced in the EstroG-100 group from 29.5 ± 7.4 at baseline to 11.3 ± 5.8 (p < 0.01) compared with change of the placebo group (29.2 ± 6.6 at baseline vs 23.7 ± 7.7 at week 12). The constituting symptoms of vasomotor, paresthesia, insomnia, nervousness, melancholia, vertigo, fatigue and rheumatic pain were significantly improved in the EstroG-100 group in comparison with the placebo group (p < 0.05). Statistically significant improvement in vaginal dryness in the EstroG-100 group was also observed compared with that of the placebo group (p < 0.05). In conclusion, EstroG-100 significantly improved the menopausal symptoms of pre-, peri- and post-menopausal women without weight gain or any serious side effects.

Phytother Res. 2011 Sep 2. doi: 10.1002/ptr.3597

Vulvovaginal atrophy is strongly associated with female sexual dysfunction among sexually active postmenopausal women.

OBJECTIVE: The relationship between vulvovaginal atrophy and female sexual dysfunction is unclear. We investigated this association among sexually active postmenopausal women. DESIGN: The Menopause Epidemiology Study is a cross-sectional, population-based study of women 40 to 65 years old in the United States chosen from a source population selected by random digit dialing and probability sampling. We focused on sexually active postmenopausal women (N = 1,480) for our analyses. Vulvovaginal atrophy was defined as one or more of the following: vaginal dryness, itching, irritation; pain on urination; or pain or bleeding on intercourse. The Arizona Sexual Experience Survey was used to define female sexual dysfunction. Sexual dysfunction subtypes for desire, arousal, and orgasm difficulties were individually scored. We evaluated demographic, behavioral, reproductive history, and medication covariates for effect modification and confounding. Multivariate logistic regression was used to assess the relationship between vulvovaginal atrophy and female sexual dysfunction. RESULTS: The prevalence of vulvovaginal atrophy (57%) and female sexual dysfunction (55%) was high. Women with female sexual dysfunction were 3.84 times more likely to have vulvovaginal atrophy than women without female sexual dysfunction (95% CI: 2.99-4.94). Hot flashes modified the association between vulvovaginal atrophy and desire difficulty. Educational level modified the association between vulvovaginal atrophy and arousal difficulty. Parity modified the association between vulvovaginal atrophy and orgasm difficulty. CONCLUSIONS: This large population-based study provides evidence of an association between vulvovaginal atrophy and overall female sexual dysfunction and its subtypes. Therapies aiming to reduce symptoms of one condition may also relieve symptoms of the other.

Menopause. 2008 Jul-Aug;15(4 Pt 1):661-6

Hepatocellular carcinoma and vitamin D: a review.

The non-classical actions of vitamin D, namely antiproliferation, pro-differentiation, pro-apoptosis, anti-inflammation, and immune regulation, have received great attention during the past decade. Increasing evidence from epidemiological studies showing the inverse association between vitamin D status and incidence of many forms of cancer as well as biochemical studies has suggested that vitamin D deficiency may play a role in the cause and progression of these types of cancer. Recently, vitamin D and its analogs have been deemed as potential regimen to treat a variety of cancers alone or in combination with other drugs. Although, the epidemiologic evidence regarding the association of vitamin D and hepatocellular carcinoma (HCC) is still inconclusive, biochemical evidence clearly indicates that HCC cells are responsive to the inhibitory effect of vitamin D and its analogs. In this review, we discuss the current status of HCC and its treatment, the source, metabolism, functions, and the mechanism of actions of vitamin D, and the biochemical studies of vitamin D analogs and their implications in the prevention and treatment of HCC.

J Gastroenterol Hepatol. 2011 Nov;26(11):1597-603

Flaxseed and cardiovascular health.

Flaxseed and its components may improve cardiovascular health because of their numerous attributes. Flaxseed contains 35% of its mass as oil, of which 55% is alpha-linolenic acid (ALA). Flax meal, which is devoid of oil, contains the lignan secoisolariciresinol diglucoside (SDG). Flaxseed, flaxseed with very low ALA, flaxseed oil, flax lignan complex (FLC), and SDG reduce the development of hypercholesterolemic atherosclerosis by 46%, 69%, 0%, 73%, and 34%, respectively, in the rabbit model. FLC and SDG slow the progression of atherosclerosis but have no effect in regression of atherosclerosis. Suppression of atherosclerosis by flaxseed is the result of its lignan content and not the result of ALA content. Suppression of atherosclerosis is associated with lowering of serum lipids and antioxidant activity. Effects of flaxseed on serum lipids in experimental animals are variable from no change to slight reduction. Flaxseed oil does not affect serum lipids, except for a slight reduction in serum triglycerides. Lignan in general reduces serum total cholesterol and low-density lipoprotein cholesterol and raises serum high-density lipoprotein cholesterol. SDG and its metabolites have antioxidant activity. Flaxseed and flaxseed oil do not have antioxidant activity except they suppress oxygen radical production by white blood cells. Flaxseed oil/ALA has variable effects on inflammatory mediators/markers (interleukin [IL]-1beta, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor-alpha, interferon-gamma, C-reactive protein, and serum amyloid A). Doses of ALA less than 14 g/d do not affect inflammatory mediators/markers, but 14 g/d or greater reduce inflammatory mediators/markers. Flaxseed oil decreases soluble vascular cell adhesion molecule-1 but has no effect on soluble intracellular adhesion molecule-1, soluble E-selectin, and monocyte colony-stimulating factor. Flaxseed has variable effects on IL-6, high-sensitivity C-reactive protein, and soluble vascular cell adhesion molecule-1. FLC reduces plasma levels of C-reactive protein but has no effects on IL-6, tumor necrosis factor-alpha, soluble intracellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, or monocyte chemoattractant protein. Flaxseed has a very small hypotensive effect, but flaxseed oil does not lower blood pressure. However, SDG is a very potent hypotensive agent. Flaxseed oil decreases platelet aggregation and increases platelet activating inhibitor-1 and bleeding time. Flaxseed and FLC have no effect on the hemopoietic system. SDG is a potent angiogenic and antiapoptotic agent that may have a role in cardioprotection in ischemic heart disease. In conclusion, flaxseed, FLC, and SDG, but not flaxseed oil, suppress atherosclerosis, and FLC and SDG slow progression of atherosclerosis but have no effect on regression. Flaxseed oil suppresses oxygen radical production by white blood cells, prolongs bleeding time, and in higher doses suppresses serum levels of inflammatory mediators and does not lower serum lipids.

J Cardiovasc Pharmacol. 2009 Nov;54(5):369-77

Dose-dependent effects of omega-3-polyunsaturated fatty acids on systolic left ventricular function, endothelial function, and markers of inflammation in chronic heart failure of nonischemic origin: a double-blind, placebo-controlled, 3-arm study.

BACKGROUND: Supplemen-tation with 1 g/d omega-3-polyunsaturated fatty acids (n3-PUFAs) demonstrated a small survival advantage in patients with chronic heart failure (CHF) in the GISSI-HF trial. However, a dose-efficacy relationship was postulated for the beneficial effects of n3-PUFA before. Therefore, we evaluated dose-dependent effects of n3-PUFA in patients with severe CHF. METHODS: In a double-blind, randomized, controlled pilot trial, 43 patients with severe, nonischemic heart failure received 1 g/d n3-PUFA (n = 14), 4 g/d n3-PUFA (n = 13), or placebo (n = 16) for 3 months. Changes in left ventricular ejection fraction (LVEF), flow-mediated vasodilation, plasma high-sensitive interleukin 6 and high-sensitive tumor necrosis factor, and exercise peak oxygen consumption were assessed. RESULTS: Left ventricular ejection fraction increased in a dose-dependent manner (P = .01 for linear trend) in the 4 (baseline vs 3 months [mean ± SD]: 24% ± 7% vs 29% ± 8%, P = .005) and 1 g/d treatment groups (24% ± 8% vs 27% ± 8%, P = .02). Flow-mediated vasodilation increased significantly with high-dose 4 g/d n3-PUFA (8.4% ± 4.8% vs 11.6% ± 7.0%, P = .01) but only trendwise with low-dose 1 g/d (8.3% ± 5.3% vs 10.2% ± 4.3%, P = .07). Interleukin 6 significantly decreased with 4 g/d n3-PUFA (3.0 ± 2.9 pg/mL vs 0.7 ± 0.8 pg/mL, P = .03) but only trendwise with 1 g/d (4.5 ± 6.6 pg/mL to 1.6 ± 2.1 pg/mL, P = .1). High-sensitive tumor necrosis factor α decreased trendwise with 4 g/d n3-PUFA but remained unchanged with 1 g/d. In patients with maximal exercise effort, only 4 g/d increased the peak oxygen consumption. No changes in any investigated parameters were noted with placebo. CONCLUSION: Treatment with n3-PUFA for 3 months exerts a dose-dependent increase of LVEF in patients with CHF. In parallel, a significant improvement of endothelial function and decrease of interleukin 6 is found with high-dose n3-PUFA intervention.

Am Heart J. 2011 May;161(5):915.e1-9

Anti-inflammatory effects of different drugs/agents with antioxidant property on endothelial expression of adhesion molecules.

Atherosclerosis is a chronic inflammatory process. The adhesion of leukocytes to the vascular endothelium, mediated by endothelial cell adhesion molecules including vascular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin, is the pivotal early event in atherogenesis. Inflammatory cytokines could activate redox-sensitive transcription factors and induce endothelial expression of adhesion molecules, which could be inhibited to various degrees by different antioxidants suggesting the potential role of endogenous reactive oxygen species (ROS) in atherogenesis. Many clinical drugs that against cardiovascular diseases have exhibited antioxidant effects; these drugs simultaneously inhibit endothelial adhesion molecule expression, such as aspirin, probucol, HMG-CoA reductase inhibitors, angiotensin receptor blockers, angiotensin converting enzyme inhibitors, peroxisome proliferator-activated receptor alpha and gamma ligands, calcium channel blockers, beta-adrenergic blockers, etc. In addition, we have previously demonstrated that Ginkgo biloba extract, a Chinese herb with antioxidant activity, could significantly suppress inflammatory cytokine-stimulated endothelial adhesiveness to human monocytic cells by attenuating intracellular ROS formation, redox-senstive transcription factor activation, and VCAM-1 as well as ICAM-1 expression in human aortic endothelial cells. The similar anti-atherosclerosis effects have been also shown in other Chinese herbs or dietary supplements with antioxidant activity such as magnolol and salvianolic acid B either in vitro or in vivo. Thus, oxidative stress is critical to endothelial adhesiveness in atherogenesis. The inhibition of endothelial adhesion molecule expression by drugs/agents with antioxidant activity may serve as a potential therapeutic strategy for clinical atherosclerosis.

Cardiovasc Hematol Disord Drug Targets. 2006 Dec;6(4):279-304

Role of lipoxins and resolvins as anti-inflammatory and proresolving mediators in colon cancer.

Recently, lipoxins (LXs) and resolvins (Rvs) have become the topic of intense interest because of expanding views of their action, particularly in chronic disorders where unresolved inflammation is a key factor leading to colon carcinogenesis. Rvs are biosynthesized from omega-3 fatty acids eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) via cyclooxygenase-2/lipoxygenase (COX-2/LOX) pathways; Rvs are shown to dramatically reduce dermal inflammation, peritonitis, dendritic cell migration, and interleukin production. This explains that dietary supplementation of omega-3 fatty acids generates potent local endogenous mediators that control inflammation. LXs are biosynthesized from COX-2/LOX pathways. Metabolites of 15-LOX-1 and 2 are anti-tumorigenic; similarly, 15-epi-LXA(4) synthesized during COX-2 acetylation by low doses of aspirin too possesses anti-tumorigenic effects. Acetylating nonsteroidal anti-inflammatory drugs (NSAIDs), like aspirin, switches COX-2 from forming PGE(2) (promoting tumorigenesis) to 15-epi-LXA(4) (antitumorigenesis). LXs and Rvs are endogenously generated during the spontaneous resolution phase. These newly identified LXs and Rvs have proved to be potent regulators of both leukocytes and cytokine productions, thereby regulating the events of interest in inflammation and resolution. In light of existing knowledge on interconnected pathways of pro-inflammatory mediators (leukotrienes, chemokines (IL8, SDF-1 alpha, MIP-1 alpha, MCP-1,2 etc), and cytokines (IL3, IL6, IL12, IL-1 beta, GM-CSF, B94, TNF-alpha etc)), the anti-inflammatory properties of pro-resolving mediators in preventing chronic inflammation which leads to carcinogenesis needs further understanding. In this review, we explore the mechanisms that trigger formation of LXs and Rvs, to highlight the relative importance of LXs and Rvs in carcinogenesis in relation to pro-inflammatory mediators.

Curr Mol Med. 2009 Jun;9(5):565-79

Neuroprotection by spice-derived nutraceuticals: you are what you eat!

Numerous lines of evidence indicate that chronic inflammation plays a major role in the development of various neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, brain tumor, and meningitis. Why these diseases are more common among people from some countries than others is not fully understood, but lifestyle factors have been linked to the development of neurodegenerative diseases. For example, the incidence of certain neurodegenerative diseases among people living in the Asian subcontinent, where people regularly consume spices, is much lower than in countries of the western world. Extensive research over the last 10 years has indicated that nutraceuticals derived from such spices as turmeric, red pepper, black pepper, licorice, clove, ginger, garlic, coriander, and cinnamon target inflammatory pathways, thereby may prevent neurodegenerative diseases. How these nutraceuticals modulate various pathways and how they exert neuroprotection are the focus of this review.

Mol Neurobiol. 2011 Oct;44(2):142-59

Aged garlic extract improves endothelial function in men with coronary artery disease.

Endothelium-dependent vasodilation is impaired and predicts the risk of a coronary event in patients with coronary artery disease (CAD). Oxidant stress and increased systemic inflammation may contribute to this endothelial dysfunction. Aged garlic extract (AGE) contains antioxidant compounds and increases nitric oxide production and decreases the output of inflammatory cytokines from cultured cells. The aim of this study was to test the effect of treatment with AGE on brachial artery flow mediated endothelium-dependent dilation (FMD) and circulating markers of oxidative stress and systemic inflammation. The trial included 15 men with angiographically proven CAD in a randomized, placebo-controlled, cross-over design with 2-week treatment and washout periods. During AGE supplementation, FMD increased (44%) significantly (p = 0.04) from the baseline and mainly in men with lower baseline FMD. Levels of FMD at the end of AGE treatment were significantly (p = 0.03) higher compared with the corresponding levels at the end of placebo treatment when the variation in baseline body weight was taken into account. Markers of oxidant stress (plasma oxidized low density lipoprotein and peroxides), systemic inflammation (plasma C-reactive protein ad interleukin-6) and endothelial activation (VCAM-1) did not change significantly during the study. These data suggest that short-term treatment with AGE may improve impaired endothelial function in men with CAD treated with aspirin and a statin. Whether improvement in endothelial function decreases the risk of future cardiovascular events remains to be determined.

Phytother Res. 2005 Apr;19(4):314-9

Melatonin as a neuroprotective agent in the rodent models of Parkinson’s disease: is it all set to irrefutable clinical translation?

Parkinson’s disease (PD), a neurodegenerative disorder, is characterized by the selective degeneration of the nigrostriatal dopaminergic neurons, continuing or permanent deficiency of dopamine, accretion of an abnormal form of alpha synuclein in the adjacent neurons, and dysregulation of ubiquitin proteasomal system, mitochondrial metabolism, permeability and integrity, and cellular apoptosis resulting in rigidity, bradykinesia, resting tremor, and postural instability. Melatonin, an indoleamine produced almost in all the organisms, has anti-inflammatory, anti-apoptotic, and anti-oxidant nature. Experimental studies employing 1-methyl 4-phenyl 1, 2, 3, 6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), methamphetamine, rotenone, and maneb and paraquat models have shown an enormous potential of melatonin in amelioration of the symptomatic features of PD. Although a few reviews published previously have described the multifaceted efficacy of melatonin against MPTP and 6-OHDA rodent models, due to development and validation of the newer models as well as the extensive studies on the usage of melatonin in entrenched PD models, it is worthwhile to bring up to date note on the usage of melatonin as a neuroprotective agent in PD. This article presents an update on the usage and applications of melatonin in PD models along with incongruous observations. The impending implications in the clinics, success, limitations, and future prospective have also been discussed in this article.

Mol Neurobiol. 2012 Feb;45(1):186-99

Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of melatonin in a transgenic model of Alzheimer disease.

The neurohormone melatonin has been reported to exert anti-beta-amyloid aggregation, antioxidant, and anti-inflammatory actions in various in vitro and animal models. To comprehensively determine the potential for long-term melatonin treatment to protect Alzheimer’s transgenic mice against cognitive impairment and development of beta-amyloid (Abeta) neuropathology, we administered melatonin (100 mg/L drinking water) to APP + PS1 double transgenic (Tg) mice from 2-2.5 months of age to their killing at age 7.5 months. A comprehensive behavioral battery administered during the final 6 weeks of treatment revealed that Tg mice given melatonin were protected from cognitive impairment in a variety of tasks of working memory, spatial reference learning/memory, and basic mnemonic function; Tg control mice remained impaired in all of these cognitive tasks/domains. Immunoreactive Abeta deposition was significantly reduced in hippocampus (43%) and entorhinal cortex (37%) of melatonin-treated Tg mice. Although soluble and oligomeric forms of Abeta1-40 and 1-42 were unchanged in the hippocampus and cortex of the same melatonin-treated Tg mice, their plasma Abeta levels were elevated. These Abeta results, together with our concurrent demonstration that melatonin suppresses Abeta aggregation in brain homogenates, are consistent with a melatonin-facilitated removal of Abeta from the brain. Inflammatory cytokines such as tumor necrosis factor (TNF)-alpha were decreased in hippocampus (but not plasma) of Tg+ melatonin mice. Finally, the cortical mRNA expression of three antioxidant enzymes (SOD-1, glutathione peroxidase, and catalase) was significantly reduced to non-Tg levels by long-term melatonin treatment in Tg mice. Thus, melatonin’s cognitive benefits could involve its anti-Abeta aggregation, anti-inflammatory, and/or antioxidant properties. Our findings provide support for long-term melatonin therapy as a primary or complementary strategy for abating the progression of Alzheimer disease.

J Pineal Res. 2009 Aug;47(1):82-96

Melatonin treatment following stroke induction modulates L-arginine metabolism.

The efficacy of melatonin treatment in experimental stroke has been established. Some of the neuroprotective properties have been attributed to its anti-oxidant and anti-inflammatory effects. Nitric oxide synthases (NOS) and cyclooxygenases (COX) are considered to have a significant role in the inflammatory milieu occurring in acute stroke. While previous reports have shown that pretreatment with melatonin in a stroke model can modulate NOS isoforms, the effect of post-treatment with melatonin on l-arginine metabolism has not been investigated. This study initially examined the effect of melatonin (1 nm-1 mm) on l-arginine metabolism pathways in human fibrosarcoma fibroblasts (HT-1080) fibroblasts. Evidence of neuroprotection with melatonin was evaluated in rats subjected to middle cerebral artery occlusion (MCAO). Animals were treated with three daily doses of 5 mg/kg i.p., starting 1 hr after the onset of ischemia. Constitutive NOS activity but not expression was significantly increased by in vitro exposure (72 hr) to melatonin. In addition, melatonin treatment increased arginase activity by increasing arginase II expression. In vivo studies showed that melatonin treatment after MCAO significantly inhibited inducible NOS activity and attenuated expression of the inducible isoform, resulting in decreased total NOS activity and tissue nitrite levels. COX activity was significantly reduced with melatonin treatment. The neuroprotective anti-inflammatory effects of melatonin were consistent with the substantial reduction in infarct volume throughout the cortex and striatum and recovery of mitochondrial enzyme activities. The evidence presented here suggests that modulation of l-arginine metabolism by melatonin make it a valuable neuroprotective therapy for stroke.

J Pineal Res. 2011 Oct;51(3):313-23

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