Fursultiamine Alleviates Choroidal Neovascularization by Suppressing Inflammation and Metabolic Reprogramming.

Purpose: To assess the therapeutic effects of fursultiamine on choroidal neovascularization (CNV) through its modulation of inflammation and metabolic reprogramming in the retinal pigment epithelium (RPE). Methods: The anti-angiogenic effects of fursultiamine were assessed by measuring vascular leakage and CNV lesion size in the laser-induced CNV mouse model. Inflammatory responses were evaluated by quantitative polymerase chain reaction, western blot, and ELISA in both CNV eye tissues and in vitro cell cultures using ARPE-19 cells or primary human RPE (hRPE) cells under lipopolysaccharide (LPS) treatment or hypoxia. Mitochondrial respiration was assessed by measuring oxygen consumption in ARPE-19 cells treated with LPS with or without fursultiamine, and lactate production was measured in ARPE-19 cells subjected to hypoxia with or without fursultiamine. Results: In laser-induced CNV, fursultiamine significantly decreased vascular leakage and lesion size, as well as the numbers of both choroidal and retinal inflammatory cytokines, including IL-1ß, IL-6, IL-8, and TNF-α. In LPS-treated ARPE-19 cells, fursultiamine decreased proinflammatory cytokine secretion and nuclear factor kappa B phosphorylation. Furthermore, fursultiamine suppressed LPS-induced upregulation of IL-6, IL-8, and monocyte chemoattractant protein-1 in a dose-dependent and time-dependent manner in primary hRPE cells. Interestingly, fursultiamine significantly enhanced mitochondrial respiration in the LPS-treated ARPE-19 cells. Additionally, fursultiamine attenuated hypoxia-induced aberrations, including lactate production and inhibitory phosphorylation of pyruvate dehydrogenase. Furthermore, fursultiamine attenuated hypoxia-induced VEGF secretion and mitochondrial fission in primary hRPE cells that were replicated in ARPE-19 cells. Conclusions: Our findings show that fursultiamine is a viable putative therapeutic for neovascular age-related macular degeneration by modulating the inflammatory response and metabolic reprogramming by enhancing mitochondrial respiration in the RPE.

Thiamine Deficiency in a Nondrinker and Secondary Pulmonary Edema after Thiamine Replenishment.

A 48-year-old man was brought to our emergency room with acute abdominal pain and systemic edema, indicating acute circulatory failure with lactic acidosis. Furosemide treatment paradoxically worsened the systemic edema and induced confusion. He had no drinking history but hardly ate legumes or meats containing thiamine. Administration of fursultiamine dramatically improved the symptoms and subsequently caused pulmonary edema. Thiamine deficiency may occur in nondrinkers with an unbalanced diet. In this condition, diuretic therapy can worsen the symptoms before thiamine supplementation by promoting the flushing of water-soluble vitamins but is needed for the management of secondary pulmonary edema after thiamine replenishment.

Thiamine tetrahydrofurfuryl disulfide promotes voluntary activity through dopaminergic activation in the medial prefrontal cortex.

A physically active lifestyle is associated with better health in body and mind, and it is urgent that supporting agents for such lifestyles be developed. In rodents, voluntary locomotor activity as an active physical behavior may be mediated by dopaminergic neurons (DNs). Thiamine phosphate esters can stimulate DNs, and we thus hypothesized that thiamine tetrahydrofurfuryl disulfide (TTFD), a thiamine derivative, promotes locomotor activity via DNs in rats. Acute i.p. administration of TTFD enhanced rat locomotor activity in a normal cage. In vivo microdialysis revealed that TTFD-enhanced locomotor activity was synchronized with dopamine release in the medial prefrontal cortex (mPFC). Antagonism of the dopamine D1 receptor, but not D2 receptor, in the mPFC fully suppressed TTFD-enhanced locomotor activity. Finally, we found a TTFD dose-dependent increase in voluntary wheel running. Our findings demonstrate that DNs in the mPFC mediates TTFD-enhanced locomotor activity, suggesting the potential of TTFD to induce active physical behavior.

Myopathy in thiamine deficiency: analysis of a case.

BACKGROUND: Tenderness in the limb muscles has been reported anecdotally in patients with beriberi neuropathy, but clinical effects of thiamine deficiency on skeletal muscle have received little attention. OBJECTIVE: To describe a patient with thiamine deficiency who manifested myopathic symptoms and responded well to thiamine supplementation. PATIENT: A 26-year-old woman with neuropathy and heart failure associated with thiamine deficiency also complained of myalgia and weakness, most troublesome in the proximal portions of the limbs. RESULTS: Serum creatine kinase, myoglobin, and aldolase concentrations were abnormally elevated. Magnetic resonance imaging of lower limb muscles demonstrated areas of high signal intensity in T2-weighted images and showed Gd-DTPA enhancement. A biopsy specimen from the quadriceps muscle showed myopathic changes without neurogenic changes. Abnormalities improved well with thiamine administration. CONCLUSION: Myopathy may occur in patients with thiamine deficiency.

Peripheral neuropathy due to thiamine deficiency after inappropriate diet and total gastrectomy.

Peripheral polyneuropathy due to vitamin B1 deficiency was encountered after total gastrectomy for gastric signet cell carcinoma in a patient with a history of breast-conserving surgery for breast cancer. She had greatly reduced her intake of animal foods, believing that would be effective for the prevention of re-occurrence of cancer. Her daily intake of vitamin B1 was less than half of the usual daily requirement. Patients with malignancy tend to adopt unusual diets, and proper advice about food intake is important for such patients, especially those with gastrectomy.

ST-segment elevation of electrocardiogram in a patient with Shoshin beriberi.

We report a case of a 58-year-old man with Shoshin beriberi who demonstrated ST-segment elevation and myocardial damage without coronary artery stenosis. The patient subsequently recovered with thiamine treatment. We conclude that it is important to consider Shoshin beriberi as part of the differential diagnosis in patients with shock and ST-segment elevation.

Fursultiamine, a vitamin B1 derivative, enhances chondroprotective effects of glucosamine hydrochloride and chondroitin sulfate in rabbit experimental osteoarthritis.

OBJECT AND DESIGN: The therapeutic effect of glucosamine hydrochloride (GH) and chondroitin sulfate (CS) in combination with fursultiamine, a vitamin B1 derivative, on the development of cartilage lesions was investigated in an animal model of osteoarthritis (OA). METHODS: The OA model was created by partial medial meniscectomy of the right knee joint (day 0). The rabbits were placed into three experimental groups: operated (OA) rabbits that received placebo treatment, OA rabbits that received GH (1000 mg/kg) + CS (800 mg/kg), and OA rabbits that received GH + CS + fursultiamine (100 mg/kg). Each treatment was initiated on day 3 and continued for 8 weeks. Macroscopic and histologic analyses were performed on the cartilage. The level of MMP-1 in OA cartilage chondrocytes was evaluated by immunohistochemistry. RESULTS: Only the group receiving combined treatment with GH + CS + fursultiamine showed a significant reduction in the severity of macroscopic and histologic lesions on tibial plateau, which is the weight bearing cartilage surface of the tibia, compared with placebo-treated OA rabbits. This treatment group also revealed a small, but significant, decrease in the body weight gain of the rabbits. In cartilage from placebo-treated OA rabbits, a significantly higher percentage of chondrocytes in superficial layer stained positive for MMP-1 compared with unoperated control. Rabbits treated with the GH + CS + fursultiamine revealed a significant reduction in the level of MMP-1. CONCLUSION: These results suggest that the chondroprotective effect of GH + CS is enhanced by the addition of fursultiamine in experimental OA. This effect was associated with a reduction in the level of MMP-1, which are known to play an important role in the pathophysiology of OA lesions.

Thiamine tetrahydrofurfuryl disulfide: a little known therapeutic agent.

Thiamine tetrahydrofurfuryl disulfide (TTFD) is the synthetic counterpart of allithiamine, occurring naturally in garlic. Allithiamine was discovered in Japan in 1951. Its extensive research was reported by a group known as the Vitamin B Research Committee of Japan, and given this name because of its existence in the bulbs of many of the allium species of plants. It was found to be a disulfide derivative of thiamine, produced as a result of enzymatic action on the thiamine molecule in garlic bulbs when the bulb is cut or crushed. Subsequent experimental work in both animals and human subjects revealed that its metabolic effect was much more powerful than the thiamine from which it was derived. Japanese investigators created a number of synthetic forms and investigated their use in a number of human disease conditions. Although some derivatives have been synthesized without a disulfide bond in the molecule, these investigators emphasized that the disulfide was an extremely important part of its biologic action and TTFD is the most modern of the disulfide derivatives. Because at least part of its beneficial effects are the same as water soluble thiamine salts, this review deals first with the clinical uses of thiamine (vitamin B1) in medicine.

Taste disturbance after tonsillectomy.

Of the 3583 outpatients treated at our taste disorder clinic over a period of 15 years, 11 (0.31%) complained of taste disorder after tonsillectomy. The cause of taste disorder was identified in 8 of the 11 cases: in 3 cases it was caused by direct or indirect damage to the lingual branch of the glossopharyngeal nerve; in 2 cases it was attributable to medication taken by the patient after tonsillectomy; and in 3 cases taste disturbance was caused by a lack of dietary zinc, even though this was identified at the time of tonsillectomy. These findings indicate the importance of (i) informing patients when consent for tonsillectomy is obtained that there is a risk of postoperative taste disorder; (ii) measuring the patient's taste threshold and serum zinc level preoperatively; and (iii) obtaining a thorough drug history, including details of non-prescription medications habitually taken by the patient.

Thiamine therapy in Alzheimer's disease.

Fursultiamine (TTFD), a derivative of thiamine, at an oral dose of 100 mg/day had a mild beneficial effect in patients with Alzheimer's disease in a 12-week open trial. The improvement could be observed not only in their emotional or other mental symptoms but also in intellectual function. Only mildly impaired subjects showed cognitive improvement. Alzheimer patients' blood levels of thiamine before the trial were within the normal range. No adverse reactions were observed and all patients tolerated the trial well. TTFD could afford an alternate treatment to large doses of thiamine hydrochloride in Alzheimer patients. However, further investigations of the therapeutic implications of thiamine and its possible etiologic clues to Alzheimer's disease are necessary.

Beriberi cardiomyopathy.

In Indonesia beriberi is still endemic, but subclinical cases are not uncommon. Three patients suffering from beriberi presented with different clinical manifestations. One had the classical features of Shoshin beriberi and the other two had the non-alcoholic cardiac beriberi (chronic type). The cardiac symptoms of all three patients responded dramatically to thiamine tetrahydrofurfuryl disulfide; there was also some improvement of their polyneuropathy, consistent with the neurophysiologic findings and somatosensory evoked potentials (SSEPs). We conclude that SSEPs provide additional clinical information on beriberi polyneuropathy. The mortality of untreated cardiovascular beriberi is high. In view of the harmless nature of the treatment, a good case could be made for routine administration of thiamine to all patients in whom heart failure is present without clear evidence of the cause.

[A case of beriberi heart--with special reference to the rapid effect of fursultiamine on hemodynamics].

A 33-year-old man was admitted to Kushiro City General Hospital on February 27, 1989, because of palpitation, shortness of breath and anasarca. Eight months previously he had noted the onset of pretibial edema, which had progressed to anasarca. He had had a meal only once a day for nine months. Physical examination revealed a blood pressure of 114/46 mmHg and pulse rate of 80/min. The 3rd sound was audible. No rales in the chest and no hepatosplenomegaly were noted. Ascites, pretibial edema and anasarca were present. Vibration sensation was diminished, and the deep tendon reflexes were absent in the legs. The blood thiamine level on the 4th day of hospitalization decreased to 2.9 micrograms/dl. The red cell transketolase activity and TPP effect on the 10th hospital day were 0.76 IU/gHb and 11%, respectively. A chest roentogenogram showed pulmonary congestion and cardiomegaly (CTR 61.3%). The electrocardiogram showed non-specific T wave changes. On the echocardiogram, remarkable pericardial effusion and diffuse hypertrophy of the left ventricular wall were observed. In addition, the left ventricular wall motion showed a hyperkinetic state. On the basis of these findings, the diagnosis of beriberi heart was made. The hemodynamic study performed on the 10th hospital day showed a remarkable high cardiac output (CO) of 10.7 l/min and an extremely reduced total peripheral resistance (TPR) of 352 dynes.sec.cm-5. 15 min after intravenous administration of Fursultiamine 100 mg, CO decreased to 7.24 l/min and TPR increased to 848 dynes.sec.cm-5. Following the administration of Fursultiamine 75 mg, po/day, his symptoms and abnormal findings of clinical examination data rapidly improved.(ABSTRACT TRUNCATED AT 250 WORDS)

Erythrocyte transketolase activity in the Wernicke-Korsakoff syndrome.

Erythrocyte transketolase activity and the effect of adding thiamine pyrophosphate (% TPP effect) were measured in subjects suffering from Wernicke-Korsakoff syndrome both before and during treatment with thiamine and/or thiamine tetrahydrofurfuryldisulphide (TTFD). Transketolase activity was significantly lower in untreated patients than in healthy volunteers. Treatment with either thiamine or with TTFD restored enzyme levels to control values but TTFD produced a greater increase than thiamine in enzyme activity. In a group of seven patients there was no correlation between duration of TTFD therapy and either increase in erythrocyte transketolase activity or % decrease in the TPP effect. However, when three patients were followed at intervals during treatment with TTFD, their erythrocyte transketolase increased progressively. Neither thiamine nor TTFD produced clinical improvement in the mental symptoms of Wernicke-Korsakoff psychosis unless administered early in the course of the disease.

Wernicke-Korsakoff syndrome in monozygotic twins: a biochemical peculiarity.

A pair of monozygotic twins, one suffering from the Wernicke-Korsakoff syndrome, verified at autopsy, and the other healthy, was studied biochemically. The erythrocyte transketolase of each twin showed abnormalities, though these differed in the two individuals. In the healthy twin, the basal transketolase was low, but responded normally to thiamine pyrophosphate (TPP) added in vitro. In the twin with the Wernicke-Korsakoff syndrome the basal level of the enzyme and its response in vitro were normal, but a period of treatment with thiamine tetrahydrofurfuryldisulphide, led to loss of the in vitro response. It is suggested that, initially, an inborn error of metabolism may have been common to both twins.

Deficiency of dihydrolipoyl dehydrogenase (a component of the pyruvate and alpha-ketoglutarate dehydrogenase complexes): a cause of congenital chronic lactic acidosis in infancy.

A male child died at 7 months of age with progressive neurologic deterioration and persistent metabolic acidosis. Investigations during life showed this child to have elevated blood pyruvate, lactate, and alpha-ketoglutarate as well as elevation of branched chain amino acids and occasional hypoglycemia. Cofactor therapy using either thiamine-HCl (2 g/kg/24 hr) or thiamine tetrahydrofurfuryl disulfide had no measurable effect on the clinical or biochemical status of the patient. Tissue taken postmortem showed normal levels of key gluconeogenic enzymes but a deficiency in the activity of pyruvate dehydrogenase in all tissues tested (liver, brain, kidney, skeletal muscle, and heart). Examination of the individual activities of pyruvate dehydrogenase complex showed pyruvate decarboxylase (E1) to be normal in liver and other tissues. Dihydrolipoyl dehydrogenase (E3), on the other hand, was deficient in all tissues tested. alpha-Ketoglutarate dehydrogenase complex, which depends of E3 for its total activity, was also deficient in all tissues tested. The absence of this enzyme id discussed in relation to the clinical and biochemical status of the patient.

Effects of low temperature and electrical (square wave) stimulation on spontaneous contractions in isolated guinea pig atria and influence of thiamine tetrahydrofurfuryl disulfide (TTFD) on these effects.

The spontaneous contractions of isolated guinea pig atria were arrested by a temperature change in the medium for 30 to 20 degrees C within 20 min. 2. When thiamine tetrahydrofurfuryl sulfide (TTFD) at concentration of 10-5 g/ml was added in the medium, the arrest was not seen for more than 30 min. 3. Arrhythmic contractions induced by the electrical square wave stimulation of threshold intensity were prevented by TTFD at 10-4 g/ml which was added to the medium. 4. These effects of TTFD at respective concentrations were seen even 30 min after the drug was removed from the medium, when the atria had been pre-incubated with the drug for one hour before the removal. 5. From these results, it was assumed that TTFD might show these effects against the extrinsic physical invasions through the stabilization of the tissue membrane.