ALC/ALA Miscellaneous Health Benefits
in the treatment of smell dysfunction following viral infection of the upper respiratory tract.
Laryngoscope 2002 Nov;112(11):2076-80
Hummel T, Heilmann S, Huttenbriuk KB.
Department of Otorhinolaryngology, University of Dresden Medical School, Germany. email@example.com
OBJECTIVES/HYPOTHESIS: The study aimed to investigate the potential therapeutic effects of alpha-lipoic acid in olfactory loss following infections of the upper respiratory tract. Possible mechanisms of actions include the release of nerve growth factor and antioxidative effects, both of which may be helpful in the regeneration of olfactory receptor neurons. STUDY DESIGN: Unblinded, prospective clinical trial. METHODS: A total of 23 patients participated (13 women, 10 men; mean age 57 y, age range 22-79 y; mean duration of olfactory loss, 14 mo; range, 4 to 33 mo); 19 of them were hyposmic and 4 had functional anosmia. Alpha-lipoic acid was used orally at a dose of 600 mg/day; it was prescribed for an average period of 4.5 months. Olfactory function was assessed using olfactory tests for phenyl ethyl alcohol odor threshold, odor discrimination, and odor identification. RESULTS: Seven patients (30%) showed no change in olfactory function. Two patients (9%) exhibited a moderate decrease in olfactory function; in contrast, six patients (26%) showed moderate and eight patients (35%) remarkable increase in olfactory function. Two of the 4 patients with functional anosmia reached hyposmia; 5 of 19 hyposmic patients became normosmic. Overall, this resulted in a significant improvement in olfactory function following treatment (P =.002). At the end of treatment parosmias were less frequent (22%) than at the beginning of therapy (48%). Interestingly, recovery of olfactory function appeared to be more pronounced in younger patients than in patients above the age of 60 years (P =.018). CONCLUSIONS: The results indicate that alpha-lipoic acid may be helpful in patients with olfactory loss after upper respiratory tract infection. However, to judge the true potential of this treatment, the outcome of double-blind, placebo-controlled studies in large groups of patients must be awaited, especially when considering the relatively high rate of spontaneous recovery in olfactory loss after upper respiratory tract infection.
reduces oxidative stress induced by high-energy impulse
noise (blast) exposure.
Toxicology 2000 Nov 30;155(1-3):91-9
Elsayed NM, Armstrong KL, William MT, Cooper MF.
Walter Reed Army Institute of Research, Washington, DC, USA. firstname.lastname@example.org
Detonation of explosives, firing of large caliber weapons and occupational explosions, professional or accidental, produce high-energy impulse noise (blast) waves characterized by a rapid rise in atmospheric pressure (overpressure) followed by gradual decay to ambient level. Exposure to blast waves causes injury, predominantly to the hollow organs such as ears and lungs. We have previously reported that blast exposure can induce free radical-mediated oxidative stress in the lung characterized by antioxidant depletion, lipid peroxidation, and hemoglobin (Hb) oxidation. In this study, we examined whether pre-loading, adequately fed rats, with pharmacological doses of antioxidants would reduce the response to blast. Sprague-Dawley rats weighing 300-350 g were loaded with either 800 IU vitamin E (VE), 1000 mg vitamin C (VC) or 25 mg lipoic acid (LA) for 3 consecutive days by gavage before exposure to blast. Both VE, and LA were dissolved in 2 ml corn oil, but VC in 2 ml water. After the 3-day antioxidant loading, the rats were divided into six groups (five rats per group), deeply anesthetized with sodium pentobarbital (60 mg/kg body weight), then exposed to a low-level blast (62+/-2 kPa peak pressure and 5 ms duration). A matched number of groups were sham exposed and served as controls. One hour after exposure, all rats were euthanized then blood, and lung tissue was analyzed. We found that antioxidant loading resulted in restored Hb oxygenation, and reduced lipid peroxidation. Lung tissue VE content was elevated after loading but VC did not change possibly due to their different bioavailability and saturation kinetics. These observations, suggest that brief antioxidant loading with pharmacological doses can reduce blast-induced oxidative stress, and may have occupational and clinical implications.
PMID: 11154801 [PubMed - indexed for MEDLINE]
protects the retina
Neuropharmacology 2002 Nov;43(6):1015-25
Chidlow G, Schmidt KG, Wood JP, Melena J, Osborne NN.
Nuffield Laboratory of Ophthalmology, University of Oxford, Walton Street, OX2 6AW, Oxford, UK
The aim of this study was to examine whether the antioxidant alpha-lipoic acid protects retinal neurons from ischemia-reperfusion injury. Rats were injected intraperitoneally with either vehicle or alpha-lipoic acid (100 mg/kg) once daily for 11 days. On the third day, ischemia was delivered to the rat retina by raising the intraocular pressure above systolic blood pressure for 45 min. The electroretinogram was measured prior to ischemia and 5 days after reperfusion. Rats were killed 5 or 8 days after reperfusion and the retinas were processed for immunohistochemistry and for determination of mRNA levels by RT-PCR. Ischemia-reperfusion caused a significant reduction of the a- and b-wave amplitudes of the electroretinogram, a decrease in nitric oxide synthase and Thy-1 immunoreactivities, a decrease of retinal ganglion cell-specific mRNAs and an increase in bFGF and CNTF mRNA levels. All of these changes were clearly counteracted by alpha-lipoic acid. Moreover, in mixed rat retinal cultures, alpha-lipoic acid partially counteracted the loss of GABA-immunoreactive neurons induced by anoxia. The results of the study demonstrate that alpha-lipoic acid provides protection to the retina as a whole, and to ganglion cells in particular, from ischemia-reperfusion injuries. alpha-Lipoic acid also displayed negligible affinity for voltage-dependent sodium and calcium channels.
PMID: 12423671 [PubMed - in process]
HIV / AIDS
Decrease of elevated N,N-dimethylglycine and N-methylglycine in human immunodeficiency virus infection during short-term highly active antiretroviral therapy.
Metabolism 2001 Nov;50(11):1275-81
Look MP, Riezler R, Berthold HK, Stabler SP, Schliefer K, Allen RH, Sauerbruch T, Rockstroh JK.
Department of Internal Medicine I, University of Bonn, Bonn, Germany.
This study investigates fasting serum levels of methionine and related metabolites, vitamin B6, and folate during highly active antiretroviral therapy in therapy-naive human immunodeficiency virus (HIV)-1-infected outpatients. The research design consisted of before and during therapy measurements with a median treatment period of 100 days (range, 50 to 188) in frozen samples. The subjects included 17 consecutive HIV-1-infected outpatients (15 men and 2 women; 25 to 65-years-old). Controls were 42 healthy individuals (28 men and 14 women; 24- to 82-years-old) without serologic evidence of HIV and/or hepatitis C infection and normal clinical chemistry. Subjects received treatment with the reverse transcriptase inhibitors, azidothymidine (AZT) or stavudine (D4T) plus lamivudine (3TC) and either the protease inhibitors, indinavir (IND), nelfinavir (NELF), ritonavir (RITV), or saquinavir (SAQ) at the standard dosage. Serum concentrations of methionine, total homocysteine (tHcy), cystathionine (CYSTA), N,N-dimethylglycine (DMG), N-methylglycine (MG), methylmalonic acid (MMA), and total cysteine, as well as vitamin B6, folate, and soluble tumor necrosis factor receptor p75 were taken at baseline and during highly active antiretroviral therapy. Baseline, serum tHcy, MMA, CYSTA, vitamin B6 concentrations were not significantly different from healthy controls. There was, however, a trend towards lower folate serum concentrations at baseline in HIV-infected patients as compared with healthy controls (P =.06). There were no significant correlations between tHcy and vitamin B6, folate, or MMA. Elevated baseline levels of DMG and MG decreased significantly during antiretroviral therapy (P =.0019 and.04, respectively), whereas no significant changes in serum concentrations of CYSTA, MMA, or methionine were detected. tHcy increased in 12 of 17 patients (P =.09). HIV-infected patients displayed significant alterations (elevated DMG and MG serum concentrations) in metabolite levels of the betaine pathway in methionine metabolism, which might be positively influenced by newly initiated antiretroviral combination therapy.Copyright 2001 by W.B. Saunders Company
PMID: 11699044 [PubMed - indexed for MEDLINE]
Alpha-lipoic acid increases intracellular glutathione in a human T-lymphocyte Jurkat cell line.
Biochem Biophys Res Commun 1995 Feb 6;207(1):258-64
Han D, Tritschler HJ, Packer L.
Department of Molecular and Cell Biology, University of California at Berkeley 94720-3200.
The addition of exogenous alpha-lipoic acid to cellular medium causes a rapid increase of intracellular unbound thiols in Jurkat cells, a human T-lymphocyte cell line. The rise of cellular thiols is a result of the cellular uptake and reduction of lipoic acid to dihydrolipoic acid and a rise in intracellular glutathione. Although the level of dihydrolipoic acid is 100-fold lower than glutathione, the cellular concentration of dihydrolipoic acid might be responsible for the modulation of total cellular thiol levels. Rises in glutathione correlate with the levels of intracellular dihydrolipoic acid (p is less than .01). This increase in glutathione is not the result of expression of new proteins like gamma-glutamylcysteine synthetase, since the rise in glutathione was not inhibited by cycloheximide, a protein synthesis inhibitor. Lipoic acid administration is therefore a potential therapeutic agent in an array of diseases with glutathione anomalies including HIV infection.
PMID: 7857274 [PubMed - indexed for MEDLINE]
Vitamin E and alpha-lipoate: role in antioxidant recycling and activation of the NF-kappa B transcription factor.
Mol Aspects Med 1993;14(3):229-39
Packer L, Suzuki YJ.
Department of Molecular and Cell Biology, University of California, Berkeley 94720.
Nuclear factor kappa B (NF-kappa B) is believed to play an important role in the activation of human immunodeficiency virus (HIV) which causes acquired immunodeficiency syndrome (AIDS). Recent findings suggesting an involvement of reactive oxygen species in signal transduction pathways leading to NF-kappa B activation have encouraged the possible clinical use of antioxidants in blocking HIV activation. We have examined the effects of vitamin E and alpha-lipoate derivatives on NF-kappa B activation, and have observed that each of these antioxidants behave differently. Here we propose mechanisms of antioxidant actions in influencing cell signalling for NF-kappa B activation.
PMID: 8264337 [PubMed - indexed for MEDLINE]
Alpha-lipoic acid is an effective inhibitor of human immuno-deficiency virus (HIV-1) replication.
Klin Wochenschr 1991 Oct 2;69(15):722-4
Baur A, Harrer T, Peukert M, Jahn G, Kalden JR, Fleckenstein B.
Institut fur Klinische und Molekulare Virologie der Universitat Erlangen-Nurnberg.
Alpha-lipoic acid, a naturally occurring disulfide-compound that acts as a cellular coenzyme, inhibits replication of HIV-1 in cultured lymphoid T-cells. Alpha-lipoic acid was added 16 hours after infection of the T-cell lines Jurkat, SupT1 and Molt-4 with HTLV IIIB and HIV-1 Wal (a wild type HIV-1 isolate). We observed a dose dependent inhibition of HIV-1-replication in CPE (Cytopathic effect) formation, reverse transcriptase activity and plaque formation on CD4-transformed HeLa-cells. An over 90% reduction of reverse transcriptase activity could be achieved with 70 micrograms alpha-lipoic acid/ml, a complete reduction of plaque-forming units at concentrations of greater than or equal to 35 micrograms alpha-lipoic acid/ml. An augmentation of the antiviral activity was seen by combination of zidovudine and low dose of alpha-lipoic acid (7 micrograms/ml). Trypan blue staining revealed no toxic effects of alpha-lipoic acids on peripheral blood mono-nuclear cells and T-cell lines even in concentrations of greater than or equal to 70 micrograms/ml. Therefore, we propose the inclusion of alpha-lipoic acid into chemotherapy trials in combination with zidovudine.
PMID: 1724477 [PubMed - indexed for MEDLINE]
Studies on lipoate effects on blood redox state in human immunodeficiency virus infected patients.
Arzneimittelforschung 1993 Dec;43(12):1359-62
Fuchs J, Schofer H, Milbradt R, Freisleben HJ, Buhl R, Siems W, Grune T.
Department of Dermatology, University Hospital, Frankfurt/Main, Fed. Rep. of Germany.
Several investigators have implicated that human immunodeficiency virus (HIV) infected patients have a compromised antioxidant defense system. Blood antioxidants are decreased and peroxidation products of lipids and proteins are increased in the patients. This may have pathophysiological implications, because antioxidants, such as glutathione, and reactive oxidants are involved in the regulation of the human immunodeficiency virus. Consequently it was suggested that HIV infected patients may benefit from antioxidant supplementation therapy. In a open and unblinded pilot study the short term effect of the natural antioxidant lipoate (Thioctacid) on blood antioxidants and peroxidation products was investigated in HIV positive patients (CDC IV). In the majority of the patients, lipoate increased plasma ascorbate (9 of 10 patients) total glutathione (7 of 7 patients), total plasma thiol groups (8 of 9 patients); T helper lymphocytes and T helper/suppressor cell ratio (6 of 10 patients), while the lipid peroxidation products malondialdehyde (8 of 9 patients) and 4-hydroxynonenal (7 of 9 patients) were decreased. The results of this pilot study indicate that lipoate supplementation changes the blood redox state of HIV infected patients. A prospective and longitudinal therapy study is warranted to investigate the long term effects of lipoate therapy on blood redox state, disease progression and incidence of opportunistic infections in HIV infected patients.
PMID: 8141828 [PubMed - indexed for MEDLINE]
HIV, CFS and Immunomodulation
HIV infection presents numerous problems related to the carnitines. Human and animal studies show an increased urinary excretion of carnitine when pivampicillin is administered. Animal studies indicate that pivampicillin interferes with myocardial carnitine metabolism subsequent to pivalocarnitine formation in the heart, leading to increased excretion. AZT can result in muscle carnitine depletion, contributing to the lipid accumulation and mitochondrial dysfunction characteristic of this myopathy. Malabsorption may decrease carnitine availability at the cellular level, while HIV-related renal dysfunction may increase excretion of the compound. Thus it is postulated that a subgroup of HIV-infected individuals are burdened with secondary carnitine deficiencies.7-9
ALC and L-Carnitine's effect on leukocyte proliferation and production of tumor necrosis factor-a (TNF-a) provide new potential applications of the compounds in HIV-infected individuals. Both mitogenic and antigenic proliferation of lymphocytes have been increased with LC and ALC in vitro.7
Peripheral blood monocytes in AIDS patients are low in intracellular carnitine. Serum levels may be high, low or normal and is therefore unreliable as an indicator of carnitine metabolism.10,11 Peripheral blood monocytes from HIV-infected individuals were cultured with the mitogen PHA and ALC for 48 hours. PHA-induced proliferation was significantly improved and a dimunition of TNF-a released by the cultured monocytes was also observed to be significant. As TNF-a has a key role in HIV-mediated apoptotic cell destruction, decreased levels of this cytokine may have protective effects on CD4+ cell populations.12
In a brief clinical trial with AIDS patients, L-Carnitine was administered (6 g/day for 14 days) and lymphocyte proliferation improved in response to mitogen stimulation. Importantly, the increased monocyte production did not lead to increased HIV proliferation. TNF-a levels were decreased and B-2 microglobulin, an indicator of HIV progression to AIDS was also diminished.13,14 Thus, LC and ALC represent novel approaches in complementary treatment of HIV infections and may correct secondary carnitine deficiencies found in these patients.
7. Famularo G, Tzantzoglou S, Santini G, et al. L-carnitine - a partner between immune response and lipid metabolism. Mediators Inflamm 1993;2: s29-s32.
8. Diep QN, Brors O, Bohmer T. Formation of pivaloylcarnitine in isolated rat heart cells. Biochem Biophys Acta 1995;1259:161-165.
9. Mintz M. Carnitine in human immunodeficiency virus type I infection / acquired immune deficiency syndrome. J Child Neurol 1995;10:s40-s44.
10. DeSimone C, Tzantzglou S, Jirillo E, et al. L-carnitine deficiency in AIDS patients. AIDS 1992;6:203-205.
11. DeSimone C, Famularo G, Tzantzoglou S, et al. Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: effect of oral L-carnitine. AIDS 1994; 8:655-660.
12. Famularo G, DeSimone C. Apoptosis, anti-apoptotic compounds and TNF-a release. Immunol Today 1994;5:495-496.
13. Famularo G, DeSimone C. A new era for carnitine? Imunol Today 1995; 16:211-213.
14. DeSimone C, Tzantzoglou S, Famularo G, et al. High dose L-carnitine improves immunologic and metabolic parameters in AIDS patients. Immunopharmacol Immunotoxicol 1993;15:1-12.
Cinnoxicam and l-Carnitine/Acetyl-l-Carnitine Treatment for Idiopathic and Varicocele-Associated Oligoasthenospermia
GIORGIO CAVALLINI,a ANNA PIA FERRARETTI,a LUCA GIANAROLI,a GIULIO BIAGIOTTI,b and GIOVANNI VITALIa
aHeadquarters of Società Italiana di Studi di Medicina della Riproduzione (SISMER), Bologna, Italy
bSatellite Center of SISMER, Reproductive Medicine Unit, Fermo (Ascoli Piceno), Italy
Journal of Andrology: Vol. 25, No. 5, pp. 761–770.
The objective of this study was to detect a therapy for idiopathic and varicocele-associated oligoasthenospermia (OAT). Idiopathic and varicocele OAT patients were randomized into 3 groups. Each group was composed of varying degrees of left varicoceles (graded into 5 grades with echo-color Doppler) and of idiopathic OATs. Group 1 used a placebo, group 2 used oral l-carnitine (2 g/d) + acetyl-l-carnitine (1 g/d), group 3 used l-carnitine/acetyl-l-carnitine + 1 × 30-mg cinnoxicam suppository every 4 days. Drugs were administered for 6 months. The groups were composed as follows: group 1, 71 varicoceles and 47 idiopathic OATs; group 2, 62 varicoceles and 39 idiopathic OATs; group 3, 62 varicoceles and 44 idiopathic OATs. Sperm concentration, motility, and morphology before during and after treatments were assessed. Pregnancy rates and side effects were recorded. Group 1 did not havemodified sperm patterns during treatment. Group 2 had significantly increased sperm patterns at 3 and 6 months into therapy in idiopathic patients and in patients with grades I, II, and III varicocele, but not in grades IV and V. Group 3 had significantly increased sperm parameters in all patients, with the exception of grade V varicocele. Group 3 sperm patterns proved significantly higher during therapy than group 2. All sperm patterns fell to baseline after therapy suspension. Minor side effects occurred. Pregnancy rates were 1.7% (group 1), 21.8% (group 2), and 38.0% (group 3) (P is less than .01). l-Carnitine/acetyl-l-carnitine + cinnoxicam suppositories proved a reliable treatment for low-grade varicoceles and idiopathic OATs.
Chronic Fatigue Syndrome (CFS)
Exploratory Open Label, Randomized Study of Acetyl- and Propionylcarnitine in Chronic Fatigue Syndrome
Ruud C. W. Vermeulen, MD, PhD and Hans R. Scholte, PhD
OBJECTIVES: We compared the effects of acetylcarnitine, propionylcarnitine and both compounds on the symptoms of chronic fatigue syndrome (CFS).
METHODS: In an open, randomized fashion we compared 2 g/d acetyl-L-carnitine, 2 g/d propionyl-L-carnitine, and its combination in 3 groups of 30 CFS patients during 24 weeks. Effects were rated by clinical global impression of change. Secondary endpoints were the Multidimensional Fatigue Inventory, McGill Pain Questionnaire, and the Stroop attention concentration test. Scores were assessed 8 weeks before treatment; at randomization; after 8, 16, and 24 weeks of treatment; and 2 weeks later.
RESULTS: Clinical global impression of change after treatment showed considerable improvement in 59% of the patients in the acetylcarnitine group and 63% in the propionylcarnitine group, but less in the acetylcarnitine plus propionylcarnitine group (37%). Acetylcarnitine significantly improved mental fatigue (p = .015) and propionylcarnitine improved general fatigue (p = .004). Attention concentration improved in all groups, whereas pain complaints did not decrease in any group. Two weeks after treatment, worsening of fatigue was experienced by 52%, 50%, and 37% in the acetylcarnitine, propionylcarnitine, and combined group, respectively. In the acetylcarnitine group, but not in the other groups, the changes in plasma carnitine levels correlated with clinical improvement.
CONCLUSIONS: Acetylcarnitine and propionylcarnitine showed beneficial effect on fatigue and attention concentration. Less improvement was found by the combined treatment. Acetylcarnitine had main effect on mental fatigue and propionylcarnitine on general fatigue.
Another potential application of ALC involving immunomodulation is in the management of Chronic Fatigue Syndrome (CFS). Low serum levels of ALC have been observed in many CFS patients. The clinical presentation of marked fatigue correlates with periods of low serum ALC while periods of recovery are characterized by higher levels of ALC. 15 Further implications for ALC treatment of CFS patients are findings that plasma levels of B-endorphin and cortisol are raised in humans given an I.V. bolus of ALC.16 As abnormal cortisol levels have been observed in some patients with CFS, and the myalgic symptoms in this condition are well known, ALC administration might be particularly helpful in normalizing HPA perturbations via feedback mechanisms and decreasing myalgic pain via peripheral neuron response to B-endorphin.17
John H. Furlong N.D.
15. Kuratsune H, Yamaguti K, Takahashi M, et al. Acylcarnitine deficiency in chronic fatigue syndrome. Clin Infect Dis 1994:18; s62-s67.
16. Martignoni E, Facchinetti F, Sances G, et al. Acetyl-L-carnitine acutely administered raises B-endorphin and cortisol plasma levels in humans. Clin Neuropharmacol 1988;11:472-477.
17. Blalock JE. The syntax of immune-neuroendocrine communication. Immunol Today 1994;15:504-511.
Clinical pharmacodynamics of acetyl-L-carnitine in patients with Parkinson's disease.
Int J Clin Pharmacol Res. 1990. 10(1-2). P 139-43
Two groups of 10 patients with Parkinson's disease received doses of either 1g acetyl-L-carnitine (ALC) per day for seven days or 2g. The effects of this drug on intermittent luminous stimulation and on nocturnal sleep patterns were studied. In both cases with either dose of ALC the effect was an improvement of the H response, sleep stages and spindling activity. However a further study of the complexity of action of acetyl-L-carnitine is necessary.
Multiple Sclerosis (MS)
Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses and treats experimental autoimmune encephalomyelitis.
J Neuroimmunol 2002 Oct;131(1-2):104-14
Marracci GH, Jones RE, McKeon GP, Bourdette DN.
Department of Neurology, Oregon Health and Science University, Portland, OR 97201, USA.
Oxidative injury may be important to the pathogenesis of multiple sclerosis (MS). We tested the antioxidant alpha lipoic acid (ALA) in an experimental murine model of MS, experimental autoimmune encephalomyelitis (EAE). ALA was administered to SJL mice 7 days after immunization with proteolipid protein (PLP) 139-151 peptide. Mice that received 5-100 mg/kg/day of ALA had dose-dependent reductions in their 10-Day Cumulative Disease Scores (10-Day CDS) by 23-100%. Minimal inflammation, demyelination and axonal loss occurred in the spinal cords (SC) of ALA-suppressed mice, and there was a marked reduction in CD3+ T cells and CD11b+ monocyte/macrophage cells within the SC. Mice treated with ALA (100 mg/kg/day) commencing on the first day of clinical EAE had a significant reduction in 10-Day CDS. SC of ALA-treated mice had reduced demyelination and axonal loss and a rapid reduction in CD3+ T cells. In vitro, ALA and its reduced form, dihydrolipoic acid, inhibited the activity of matrix metalloproteinase-9 (MMP-9) in a dose-dependent fashion. ALA is highly effective at suppressing and treating EAE and does so by inhibiting T cell trafficking into the SC, perhaps by acting as a matrix metalloproteinase inhibitor.
PMID: 12458042 [PubMed - indexed for MEDLINE]