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Zur Behandlung der Neuropathia diabetica
Abstract
Die Neuropathia diabetica wurde bei 20 Patienten mit Thioctsäure behandelt. 15 Kranke wurden in meist 3—5 Tagen besdiwerdefrei, 5 gebessert. Wir gaben 2 mal 20 mg pro Tag; zweimalige Injektion pro die scheint wichtig zu sein. Zur Vermeidung von Rezidiven sollte man die Behandlung nach Eintritt des Effekts noch bis insgesamt 7—10 Tagen fortsetzen. Nebenwirkungen kamen nicht vor. Die Wirkung trat bei kompensiertem wie dekompensiertem Diabetes gleich zuverlässig ein. Die Wirkungsweise ist noch unklar.
Summary
This condition was treated with thioctic acid in 20 patients: 15 patients became free of symptoms usually within 3—5 days, while the remaining five were improved. The drug was given by injection, 20 mg. twice daily. To avoid recurrences treatment should be continued for 7—10 days after onset of improvement. No side-effects were observed. There was no difference in response between controlled and uncontrolled diabetes. The mechanism of action remains obscure.
Resumen
Sobre el tratamiento de la neuropatía diabética
20 casos de neuropatía diabética fueron tratados con ácido tióctico. 15 enfermos quedaron libres de molestias, las más de las veces en 3 a 5 días; 5 mejoraron. Administramos 2 veces 20 mgrs. al día; inyectar dos veces, al día nos parece de importancia. El tratamiento debería proseguirse hasta un total de 7 a 10 días después de producirse el efecto, con el fin de evitar recidivas. No ocurrieron efectos secundarios. El efecto se produjo con igual seguridad en la diabetes compensada como en la descompensada. El modo de acción no está aclarado todavía.
... Injection (i.v.) of 1,200 mg of lipoic acid induced adverse reactions such as nausea or vomiting in 28 of 86 diabetic patients (Ziegler et al., 1995). After i.m. injection of 40 mg, a burning pain on the place of injection was reported (von Schreiber, 1961 ). ...
1. Lipoic acid is an example of an existing drug whose therapeutic effect has been related to its antioxidant activity. 2. Antioxidant activity is a relative concept: it depends on the kind of oxidative stress and the kind of oxidizable substrate (e.g., DNA, lipid, protein). 3. In vitro, the final antioxidant activity of lipoic acid is determined by its concentration and by its antioxidant properties. Four antioxidant properties of lipoic acid have been studied: its metal chelating capacity, its ability to scavenge reactive oxygen species (ROS), its ability to regenerate endogenous antioxidants and its ability to repair oxidative damage. 4. Dihydrolipoic acid (DHLA), formed by reduction of lipoic acid, has more antioxidant properties than does lipoic acid. Both DHLA and lipoic acid have metal chelating capacity and scavenge ROS, whereas only DHLA is able to regenerate endogenous antioxidants and to repair oxidative damage. 5. As a metal chelator, lipoic acid was shown to provide antioxidant activity by chelating Fe2+ and CU2+; DHLA can do so by chelating Cd2+. 6. As scavengers of ROS, lipoic acid and DHLA display antioxidant activity in most experiments, whereas, in particular cases, pro oxidant activity has been observed. However, lipoic acid can act as an antioxidant against the pro oxidant activity produced by DHLA. 7. DHLA has the capacity to regenerate the endogenous antioxidants vitamin E, vitamin C and glutathione. 8. DHLA can provide peptide methionine sulfoxide reductase with reducing equivalents. This enhances the repair of oxidatively damaged proteins such as α-1 antiprotease. 9. Through the lipoamide dehydrogenase-dependent reduction of lipoic acid, the cell can draw on its NADH pool for antioxidant activity additionally to its NADPH pool, which is usually consumed during oxidative stress. 10. Within drug-related antioxidant pharmacology, lipoic acid is a model compound that enhances understanding of the mode of action of antioxidants in drug therapy.
Der Begriff „Diabetisches Spätsyndrom“ faßt übergeordnet die generalisierte Erkrankung der Arteriolen und Kapillaren zusammen. Die „Capillaropathia diabetica“ ist an vielen Organ-Gefäßsystemen nachgewiesen. Im weiteren Sinne wird auch die Arteriosklerose der großen Gefäße (Makroangiopathia diabetica) dazugezählt. Als nahezu eigenständige Organerkrankungen eines generalisierten Gefäßprozesses haben sich aus diesem Komplex die Retinopathia diabetica, die Nephropathia diabetica, die Neuropathia diabetica, die diabetische Gangrän und die Kombination Arteriosklerose-Hypertonie-Organdurchblutungsstörungen eingeführt. Die Pathogenese der Mikro- und die der Makroangiopathie ist ziemlich unbekannt.
Während der Diabetiker in der Vor-Insulin-Ära meist einer metabolischen Entgleisung erlag, wurden ihm in den letzten Jahrzehnten immer mehr Gefäßkomplikationen zum Schicksal. „Insulin und Antibiotika lassen den Diabetiker heute seine Angiopathie erleben“ (Alexander u.Mitarb., 1965). 1968 starb an der Joslin-Klinik nur noch 1% der Diabetiker im hyperglykämischen Koma, während 78% einer Gefäßkomplikation erlagen (Marble, 1974). Diese Zahlen dokumentieren eindrucksvoll den grundlegenden Gestaltwandel der Zuckerkrankheit (Abb. 1).
Symptoms of diabetic neuropathy are variable, including peripheral neuropathic and myopathic symptoms and signs, as well defined and summarized by Ellenberg (1973).
Three cases of diabetic neuropathy are described. In case 1 (41-year-old male), Adie pupil with symmetrical sensory polyneuropathy is observed. The Adie pupil is scarcely described in literature in contrast to Argyll Robertson pupil. In case 2 (66-year-old male), mixture of sensory and motor polyneuropathy and astasia-abasia are observed, the latter presenting diabetic pseudotabes. Pathogenesis of astasia-abasia, moreover, was also interpreted as due to muscular.asthenia (Ellenberg, 1968) or failure of neuro-muscular transmission (Miglietta et al, 1973). Typical diabetic ophthalmoplegia is observed in case 3 (50-year-old male).
Alpha lipoic acid (ALA, thioctic acid), among other actions, is an essential coenzyme in the conversion of pyruvate to acetyl co-enzyme A. Therefore, it is necessary for the production of energy for aerobic organisms. Scientists have found that it can be used medically to help regenerate liver tissue, reverse the complications of diabetes mellitus, slow or stop the growth of cancer cells, and chelate heavy metals, among other actions. In this article, the authors describe the cellular mitochondrial damage from excessively high doses of this beneficial agent.
Viscoelastic properties of polymer fluids are single-valued functions of shear stress or shear rate only at high total applied shear. These parameters may vary with applied shear under milder shear histories. The mean total shear in capillary extrusion is shown to be a function of orifice geometry. Apparent flow curves can be measured at various total shear values by changing the length/radius ratio of the capillary. The true shear stress and true shear rate at the orifice wall correspond to infinite total shear conditions. The true flow curve and elastic parameters like die swell are not measured at equivalent total shear unless the capillary is extremely long.
"Eumetabolic" therapies of diabetes are defined as those which promote and potentiate a normal physiological pattern of insulin activity--in contrast to the less subtle effects of exogenous insulin or sulfonylureas. Effective eumetabolic therapy would provide better metabolic control and reduce the risk of secondary complications, would be more convenient to administer, and would be especially appropriate for preventive use in the early stages of diabetes. Possible components of a eumetabolic therapy include: aspirin, as a potentiator of glucose-stimulated insulin secretion; GTF, to directly enhance the efficacy of insulin; weight loss, exercise, and fasting, to help reduce tissue resistance to insulin; mitochondrial "metavitamins", to optimize the oxidative disposal of excess substrate; a high-fiber, low-fat diet, which appears superior to traditional diabetic diets as a promoter of glucose tolerance. Following a prolonged fast, obese diabetics show substantial improvement in most parameters of insulin function--an effect which is to some degree independent of weight loss; long-term remission of diabetes may be possible if the benefits of therapeutic fasting are conserved by appropriate eumetabolic measures.
Available evidence--some well-documented, some only preliminary--suggests that properly-designed nutritional insurance supplementation may have particular value in diabetes. Comprehensive micronutrient supplementation providing ample doses of antioxidants, yeast-chromium, magnesium, zinc, pyridoxine, gamma-linolenic acid, and carnitine, may aid glucose tolerance, stimulate immune defenses, and promote wound healing, while reducing the risk and severity of some of the secondary complications of diabetes.
A broad-spectrum approach to the nutritional optimization of bioenergetics is discussed as a specific example of the principle of functional orthomolecular supplementation. Experimental and clinical studies with "metavitamins" such as lipoic acid, carnitine, coenzyme Q, and creatine, and with mitochondrial antioxidants, indicate that many nutritional agents involved in bioenergetics are often functionally sub-saturated. Numerous therapeutic applications for a well-designed "bio-energy supplement" can be postulated.
T his article reviews the biochemical background as shows some pre-clinical and clinical evidence for the beneficial effects of the natural compound α-lipoic acid in the treatment of diabetic polyneuropathy. α-lipoic acid, which has been widely used for decades in Germany for this indication, may become an important treatment agent for this and other complications of diabetes.
Diabetic neuropathy represents a major health problem, as it is responsible for substantial morbidity, increased mortality, and impaired quality of life. Near-normoglycemia is now generally accepted as the primary approach to prevention of diabetic neuropathy, but is not achievable in a considerable number of patients. A growing body of evidence suggests that oxidative stress resulting from enhanced free-radical formation and/or defects in antioxidant defense is implicated in the pathogenesis of diabetic neuropathy. Markers of oxidative stress such as superoxide anion and peroxynitrite production are increased in diabetic patients in relation to the severity of polyneuropathy. In experimental diabetic neuropathy, oxygen free-radical activity in the sciatic nerve is increased, and treatment with thioctic acid, a potent lipophilic antioxidant, results in prevention or improvement of the diabetes-induced neurovascular and metabolic abnormalities in various organ systems. Pharmacodynamic studies have shown that thioctic acid favorably influences the vascular abnormalities of diabetic polyneuropathy such as impaired microcirculation, increased indices of oxidative stress, and increased levels of markers for vascular dysfunction, such as thrombomodulin, albuminuria, and nuclear factor-κB.
Thus far, seven controlled randomized clinical trials of thioctic acid in patients with diabetic neuropathy have been completed (Alpha-Lipoic Acid in Diabetic Neuropathy [ALADIN I-III], Deutsche Kardiale Autonome Neuropathie [DEKAN], Oral Pilot [ORPIL], Symptomatic Diabetic Neuropathy [SYDNEY], Neurological Assessment of Thioctic Acid in Neuropathy [NATHAN] II) using different study designs, durations of treatment, doses, sample sizes, and patient populations. Recently, a comprehensive analysis was undertaken of trials with comparable designs that met specific eligibility criteria for a meta-analysis to obtain a more precise estimate of the efficacy and safety of thioctic acid (600mg intravenously for 3 weeks) in diabetic patients with symptomatic polyneuropathy. This meta-analysis included the largest sample of diabetic patients (n = 1258) ever to have been treated with a single drug or class of drugs to reduce neuropathic symptoms, and confirmed the favorable effects of thioctic acid based on the highest level of evidence (Class Ia: evidence from meta-analyses of randomized, controlled trials). The following conclusions can be drawn from these trials: (i) short-term treatment for 3 weeks using intravenous thioctic acid 600 mg/day reduces the chief symptoms of diabetic polyneuropathy to a clinically meaningful degree; (ii) this effect on neuropathic symptoms is accompanied by an improvement of neuropathic deficits, suggesting potential for the drug to favorably influence underlying neuropathy; (iii) oral treatment for 4–7 months tends to reduce neuropathic deficits and improve cardiac autonomic neuropathy; and (iv) clinical and postmarketing surveillance studies have revealed a highly favorable safety profile of the drug.
Based on these findings, a pivotal long-term multicenter trial of oral treatment with thioctic acid (NATHAN I) is being conducted in North America and Europe to investigate effects on progression of diabetic polyneuropathy, using a clinically meaningful and reliable primary outcome measure that combines clinical and neurophysiological assessment.
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