Thiamine Propyl Disulfide Research Articles

Effects of Some Novel Thiamine Derivatives in Chickens

The present experiment was designed to compare the effects of thiamine chloride hydrochloride (B-HCL) and its derivatives, thiamine propyldisulfide (TPD), thiamine tetrahydrofurfuryldisulfide (TTFD) in chickens.The first experiment was performed to examine the replacing possibility of thiamine derivatives to thiamine in the test of body weight, egg laying ability, fertility ratio and hatchability as well as to examine thiamine content transported into egg and liver.Generally speaking, better results were obtained in the use of thiamine derivatives than that of thiamine, and this tendency was most remarkable in the case of thiamine propyldisulfide. With respect to the transportation of thiamine into egg and liver, no difference was found among trials in case of egg, but thiamine volume decreased in all trials. In case of liver, thiamine content was less in the derivatives trial than in thiamine trial.The second experiment was performed to examine the influence of thiamine propyl disulfide added to the diet of mother chickens on the growth of chicks. Female chickens that were fed on the standard diet into which various levels of thiamine derivatives added (1mg, 5mg, 5mg/kg: increased by every other week) were inseminated to male chickens that were fed on the standard diet. The growth of chicks was compared from day old to four weeks.Chicks hatched from 5mg group showed better growth than that of other groups. Unfavorable influence was not found in case of an excessive addition of thiamine derivatives.

Electroencephalographic studies on thiamine derivatives in the rabbit.

It has been demonstrated by several investigators that the cardiac effects of alkyldisulfide derivatives of thiamine are considerably different from those of thiamine HCl. Misu et al. (1) in this laboratory have observed the effects of thiamine derivatives on the spontaneous contraction and transmembrane potentials of the isolated rabbit's atria. Thiamine tetrahydrofurfuryl disulfide (TTFD) prolonged the repolarization phase of the action potential and antagonized the shortening of the same phase caused by hypoxia. Furthermore, TTFD prolonged the time length required to abolish the spontaneous contraction of the atria induced by hypoxia, but thiamine HCl did not so. The positive inotropic effect and prolongation of the repolarization time in the isolated guinea-pig's atria have been confirmed by Nakazawa and Ueno (2) and Kanno (3) in TTFD and thiamine propyldisulfide but not in thiamine HCl. The blocking effects of thiamine derivatives on the neuro-muscular junction (4-6) and the sympathetic ganglion (7, 8) have been reported. Thiamine was also described to inhibit the activity of cholinesterase (9). These findings indicate the possibility that thiamine derivatives, especially the alkyldisulfides, exert cholinergic excitement in the central nervous system. The present report deals with effects of thiamine derivatives on the spontaneous EEG of rabbits, when these drugs are administered into the ear marginal vein, common carotid artery or lateral ventricle.

Rapid formation of thiamine triphosphate in heart muscle after administration of disulfide derivatives of thiamine

Massive doses of 35S-labeled disulfide derivatives of thiamine and 35S-labeled thiamine-HCl were administered to rats, and a comparative study was made of the formation of phosphorylated thiamine in the heart and liver by means of starch block electrophoretic techniques. It was noted that thiamine propyl disulfide and thiamine tetrahydrofurfuryl disulfide, when compared with thiamine-HCl, transferred far more rapidly into heart muscle cells and subsequently were converted into thiamine phosphates. It was also shown that the thiamine triphosphate fraction in the extract of heart tissues showed higher amounts of radioactivity than the thiamine diphosphate fraction. It was conjectured that thiamine triphosphate might play an important role in the contraction processes of the heart.

Effects of thiamine and its derivatives on the isolated toad heart muscle.

In order to reevaluate the effects of thiamine and its derivatives in large dosis on heart muscle, the following experiments on the isolated toad heart were performed.1. Using Yagi's apparatus of recycling, the action on the contractile power was observed. It was confirmed that thiamine-HCl, thiamine propyl disulfide (TPD), thiamine tetrahydrofurfuryl disulfide (TTFD), thiamine disulfide and oxythiamine increased the contractile power. Especially, in the concentration of 1.4mM, the action of TPD and TTFD was so pronounced that approximately doubled values of the contractile deflection, cardiac output and aortic pressure were recorded. However, thiamine diphosphate showed no action during the period of time tested. Thiaminic acid showed even the inhibitory action.2. In the concentration of 1.4mM, TPD caused the prolongation of latent period and repolarization phase of transmembrane action potential.3. The oxygen consumption of recycling toad heart was measured manometrically with a modified Warburg chamber. When the contractile power increased on the administration of TPD, the cardiac efficiency did not diminish in spite of the increase of oxygen consumption.

Interaction of disulfide-type thiamines with SS-groups of proteins.

1. When 10μmoles of thiamine disulfide (TDS) or O-benzoylthiamine disulfide was added to 0.2μmoles of SH-blocked urea-denatured bovine serum albumin and the mixture was incubated at pH 9.0 and 37°, the formation of protein-thiamine mixed disulfide, at most 4.5 moles per mole protein, was observed.2. This reaction was almost completely inhibited by SH-reagents, such as p-chloromercuribenzoate (PCMB) and N-ethylmaleimide, about 1/10 mole of TDS, whereas it was markedly accelerated by the addition of thiamine, corresponding to 1/50 to 1/10 mole of TDS.3. In the reaction with iodine-oxidized egg albumin, the formation of similar compound and its inhibition by PCMB were observed.4. From these results, it was assumed that protein-thiamine mixed disulfides were formed from protein SS-groups and symmetric disulfide-type thiamines by the similar disulfide-disulfide exchange reaction of low molecules catalyzed by a trace amount of thiols.5. Asymmetric disulfide-type thiamines such as thiamine benzyl disulfide and thiamine propyl disulfide were found to produce both protein-bound thiamine and protein-bound alkylmercaptan under the same conditions.6. Considering the results of this paper and those of the previous findings, it was concluded that there are three types of exchange reaction between thiamine derivatives and proteins.

The fate and urinary metabolites of thiamine propyl disulfide in rats.

The fate and urinary metabolites of thiamine propyl disulfide in rats.

INHIBITION OF PAPAIN BY MODIFIED THIAMINE COMPOUNDS

By investigating the reaction of papain with thiamine derivatives of various disulfide types following facts were found.1. The amount of thiamine formed in the reaction of papain with thiamine propyl disulfide (TPD) or thiamine disulfide (TDS) was nearly equimolar.2. Remarkable differences were found between asymmetric disulfide compounds of thiamine such as TPD and symmetric ones such as TDS in the inhibitory action on papain, the former being more marked than the latter.3. Inhibition of papain by TPD or TDS was completely recovered by cysteine.4. The reaction product of papain with TPD or TDS was investigated by paper chromatography. In the case of TDS, thiamine was detected at the starting point, whereas no thiamine was found in the case of TPD.

A STUDY ON THE CARDIAC ACTION OF THIAMINE DERIVATIVES IN ISOLATED GUINEA PIG ATRIA (I)

During the investigation of atrial anaphylaxis, positive inotropic effects of various drugs have been compared with that of the anaphylactic manifestation in the isolated guinea pig atria, it was observed that thiamine derivatives increased the contractile force of the atrium. Thiamine propyl disulfide (TPD) and thiamine tetrahydrofurfuryl disulfide (TTFD) are allithiamine derivatives discovered by Fujiwara (1), having a marked vitamin B1 action on the process of glucose and lipid metabolism in the body because these compounds readily penetrate the living tissue. Clinically these drugs are used for the treatment, not only of vitamin B, deficiency but also, of various heart diseases, postoperative intestinal paralysis etc, and their effects have been reported (2-4). However, nothing more than effect of these drugs on energy metabolism of the cardiac muscles has been known. Very few investigation has been attempted to elucidate the nature of their clinical effectiveness. Katsura (5) has reported the increased amplitude of the isotonic contraction and prolongation of the repolarization phase of the action potential of cardiac muscle fibers in the isolated toad heart by TPD. H. Simonnet et al. (6) have made a comparative study of pharmaco-dynamic action of thiamine and TPD but they could not obtain any findings to explain the effect of TPD. In the present study, attempts were made to describe a positive inotropic action of the thiamine derivatives and to compare their influences on transmembrane action potential pattern, potassium contracture and Ca uptake with those of other drugs that act inotropically in guinea pig atria in vitro.

ACTIVITY OF CARBETHOXYTHIAMINE AND THIAMINE PROPYL DISULFIDE ON KLOECKERA APICULATA

Both thiamine propyl disulfide (TPD) and S-carbethoxythiamine (CET) stimulate the growth of K. apiculata but they show the following different behaviors.1. When CET is reduced to thiamine extracellularly by Takadiastase, it shows the same activity as thiamine on the growth of the bacterium.2. When TPD is reduced to thiamine by cysteine extracellularly, it shows the activity greater than thiamine.3. When TPD accumulated in the cells in saline are diluted with the medium and incubated, they show the same activity as thiamine, but when CET is treated in the same way, it showes the activity greater than thiamine.4. TPD is easily reduced to thiamine in the presence of the yeast suspension but CET is slowly converted to thiamine on the same treatment.

Intestinal absorption of thiamine propyl disulfide.

1. Thiamine propyl disulfide (TPD) is rapidly reduced in blood even at low temperature while it is relatively stable in a metaphosphoric acid-treated solution of blood.2. The content of TPD in the mesenteric venous blood was maximum 1 minute after infusion into a ligated intestine, showing 25% absorption by a method of TPD determination. The value decreased with time.3. The existance of TPD in the mesenteric venous blood was demonstrated bioautographically using a thiamine-less mutant (70-23) of E. coli.

INHIBITION OF ALCOHOL DEHYDROGENASE BY MODIFIED THIAMINE COMPOUNDS.

1. Yeast alcohol dehydrogenase activity is inhibited by incubation at pH 6-8 with several thiamine disulfide derivatives and the inhibition is partially reversed by addition of cysteine.2. Inhibition by thiamine disulfide derivatives increases with the rise of concentration and pH. The inhibition by asymmetric thiamine disulfide derivatives is stronger than that by symmetric thiamine disulfide derivatives. It was proved by paper chromatography that the enzyme was bound with the thiamine moiety of thiamine disulfide or the propylmercaptan moiety of of thiamine propyl disulfide in the reaction of the enzyme with both disulfides but no thiamine was detected from the enzyme protein after the reaction of the enzyme with thiamine propyl disulfide.

騒音性一過性聴力損失に関する研究

NITTS at C5 dip and its recovery process were experimentally observed after 1 hour exposure to some noises which were characterized with the octave-band filter, as white noise, high cut noise, and low cut noise. The subjects were 11 healthy men aged 22∼32 years and 7 healthy women aged 20∼24 years. And the results were as follows: 1) The dip was appeared more deeply in the exposures to white and low cut noises at higher sound levels than the others. But the recovery curves from the dip were shown almost parallel in the time scale, without concerning the differences of the dip values. 2) Individual differences, especially sexual differences were observed in the value and the recovery process of the dip, after 1 hour exposure to white noise in 90∼95 phones; women had little loss in the value of NITTS and showed more rapid recovery process, compared with men. 3) In preventive administrations of adrenochrom, chondroitin sulfate, and thiamine propyldisulfide, significant improvements on the recovery process were observed at the dip. But as for the dip value, no significant difference was observed between the control and the administered groups. 4) In order to resolve the sexual differences in the dip and its recovery process, we administered testosterone to women, and estradiol and estriol to men. In testosterone administration, the dip and its recovery process tended to grow worse, but no significant differences were observed between the control and the experimental groups of women. While significant improvements on the dip and its recovery process were observed in administrations of estradiol and estriol to men. 5) From the results of 4), the sexual differences in the dip and its recovery process seem to appear as an affection of follicular hormones.

THIAMINE ACTIVITY OF THIAMINE PROPYL DISULFIDE ON THE GROWTH OF LACTOBACILLUS FERMENTI 36.

1. Thiamine propyl disulfide (TPD) was more effective than thiamine, and thiamine disulfide (TDS) was of the same activity as thiamine on the growth of L. ferementi in the Macias R medium containing cysteine, but in the medium without cysteine, both TPD and TDS were scarcely effective. In the medium containing sodium thiosulfate in place of cysteine, the same effects were observed.2. TPD or TDS was easily converted to thiamine by preincubation with the cysteine contained in the Macias R medium. When the medium was inoculated with L. fermenti, it was showed that TPD was more effective than thiamine, but TDS was almost equally effective to thiamine. Cysteine in the medium can be replaced by thiosulfate.3. The solution in which TPD or TDS had been previously reduced by cysteine to thiamine was added to the medium for L. fermenti and the growth-stimulating effects of TPD or TDS were found to be almost the same as thiamine.4. It was confirmed using TPD-S35 (outer) that the propylmercaptan moiety produced from TPD during thiamine formation by cysteine became S-propylmercapto-L-cysteine and that this compound had no effect on the growth of L. fermenti.5. Taking these findings into consideration, it was discussed on the reason why TPD was more effective than thiamine alone in the cysteine (+) Macias R medium on the growth of L. fermenti.

METABOLISM AND BIOLOGICAL ACTIVITY OF BENZENESULFONYLTHIAMINE DISULFIDE.

1. Urinary excretion of thiamine in 24 hours after intraperitoneal injection of benzenesulfonylthiamine disulfide (BSTDS), equivalent to 5mg of thiamine-HCl, to rats was about 3 per cent (as thiamine or benzenesulfonyl-thiamine). It is markedly low as compared with thiamine disulfide or thiamine propyl disulfide, suggesting the conversion of BSTDS to thiamine anhydride (TA) in the body. BSTDS was degraded nonenzymatically by rat liver homogenate and it was converted to TA by the reaction with thioglycolate. Its low urinary excretion is possibly due to the conversion of BSTDS to thiamne anhydride. However, thiamine anhydride or its sulfoxide could not be demonstrated as the urinary metabolite.2. The thiamine activity of BSTDS was studied in rats by determining the increase of the body weight. Daily administration of BSTDS equivalent to 100μg of thiamine showed a significant increase but its administration equivalent to 10μg of thiamine was inffective. Oral administration resulted in more rapid rise of body weight than after intraperitoneal injection.

Analysis of Nutritional Requirement in the Nervous System with Tissue Culture and Autoradiographic Techniques. (1)

Relating to thiamine complex effects on regeneration metabolism of nerve cells in vitro and in vivo, thiamine propyl disulfide incorporation of the spinal cord of rabbits and mice was investigated by means of autoradiographic technique.The thiamine propyl disulfide incorporation procedure in nerve cells differs from each other between centrifugal passways, centripetal passway and cornu anterius. Though incorporating procedure should not mean utilizing procedure, it should be said that thiamine part of administrated thiamine propyl disulfide penetrates into nerve cells and plays a role in the function and metabolism directly.

THIAMINE-MASKING EFFECT OF THE COMPOUNDS PRODUCED BY THE REACTION OF ALLICIN-RELATED COMPOUNDS WITH PROTEIN.

1. Protein-bound compound, protein-SS-C3H7 (III) formed by the reaction of egg albumin and C3H7SSC3H7 (I) or C3H7SSOC3H7 (II) as well as S-propylmercapto-L-cysteine (IV), reacts with thiamine to form thiamine propyl disulfide (TPD), whereby thiamine was masked.2. The thiamine-masking reaction of III and IV did not proceed stoichiometrically as II; the masking activity of III was 15% of that of II and that of IV about 40%. On the contrary, I had scarcely any activity.3. The thiamine-masking rate of III was about the same, whether it was produced from. I or II. The masking activity was dependent on the amount of C3H7SH bound with the protein.4. It was confirmed that the thiamine-masking activity was increased with the rise in the concentration of either III (or IV) or thiamine, suggesting the existence of chemical equilibrium.5. From the above findings the thiamine-masking activity of III or IV is considered to be due to the thiol disulfide exchange reaction between the thiol form of thiamine and these disulfides.

AFFINITY OF THIAMINE PROPYL DISULFIDE-S35 TO BLOOD.

In order to investigate in detail the increase in blood thiamine level after administration of thiamine propyl disulfide, TPD-S35 (outer), and TPD-S35 (inner), and of thiamine-S35 in rabbits, the distribution of S35 in the blood was examined and the following interesting findings were obtained.1. The thiamine part of TPD was shown to be found in large quantities in blood cells, while the majority of S35 was found in plasma after oral or parenteral administration of TPD-S35 (outer).2. S35 was found in the albumin fraction rather than in the globulin fraction of plasma after administration of TPD-S35.3. After parenteral administration of TPD-S35 (inner), S35 was found mainly in blood cells, and extremely poorly in plasma.4. The SH group in blood cells is shown to be involved in the mechanism of the penetration of the thiamine part of TPD into blood cells.5. S35 was increased in blood cells after oral administration of TPD-S35 (inner), though it was less than after subcutaneous injection, whereas the increase in S35 was scarcely noted in blood cells after administration of thiamine-S35. The finding suggests that TPD passes through the intestinal tract without alternation.

ABSORPTION AND EXCRETION OF THIAMINE PROPYL DISULFIDE-S35. II. ABSORPTION AND EXCRETION OF THIAMINE PROPYL DISULFIDE-S35 (INNER).

After injecting the labeled thiamine propyl disulfide, TPD-S35(outer), in the ligated intestines of dogs and rats, the total and free thiamine was measured. The amount of S35 was estimated in the contents of the ligated intestinal canal, the ligated portion of the intestine and the blood of mesenteric vein from the ligated portion. The results show that TPD moves rapidly into the tissues, where it is then reduced to thiamine, separating the propylmercapto radical.Matsubara (3) submitted a hypothesis concerning the absorption of TPD that the compound might be mainly reduced to thiamine in the intestinal canal, but some of it may pass through the intestinal canal in the form of TPD. A part of the reduced TPD might be resynthetheized to TPD, and the S-alkylmercaptocysteine, produced by reduction of TPD, may aid the absorption of thiamine in the intestinal canal.The results of our experiments revealed that a majority of the TPD administered entered the intestinal walls without being reduced, although some part of it may be reduced in the intestinal canal. The propylmercapto radical of TPD was separated shortly after its invasion into the intestinal canal. The S35 of the propylmercapto radical separated from TPD was excreted rapidly after absorption. 80 to 90 per cent of the S35 was excreted in urine and feces during a 41-hour period following oral administration of TPD-S35 (outer). However, 50 to 80 per cent was excreted in the urine and feces within 48 hours after intramuscular injection. In the contents of the small intestine, only 0.5-0.8 per cent of the administered radioactivity was found. The radioactive S35 found in the viscera following intramuscular injection were 1.5-4.5 per cent. Consequently, higher counts of S35 were found in the urine and feces after oral administration than after intramuscular injection.Marked discrepancies were noted when the results obtained after intravenous and oral administrations were compared. The findings suggest that TPD passes through the tissues in various ways according to the mode of administration. A part of the propylmercapto radical is separated when TPD was absorbed from the intestine and excreted through the lymphatic system.

Bacteriostatic Action of Dibenzoyl Thiamine (DBT) (I)

The bacteriostatic action of the following three vitamin B1 derivatives on some sporeforming, aerobic bacilli was tested.(1) TPD (Thiamine propyl disulfide)(2) TAD (Thiamine allyl disulfide)(3) TATD (Thiamine 8-methyl 6-acetyl dihydro thioctate disulfide)None of B. cereus OM-2, B. pantothenticus NN and B. thiaminolyticus Matsukawa et Misawa was found to develop colonies when inoculated on the autoclaved agar basal medium containing 60mg/dl of any of these substances.The similar bacteriostatic action was exhibited by the substances on B. cereus OM-2, BMM and Strain No. 3 isolated by the authors from spoiled cooked rice (presumably a variety of B. cereus) which were inoculated to peptone water sterilized with the Seitz filter instead of the autoclave.

DECOMPOSITION OF THIAMINE DERIVATIVES BY ULTRAVIOLET IRRADIATION.

When thiamine derivatives were irradiated by a ultraviolet lamp with a maximum spectral energy at 365 mμ, the symmetric disulfides (thiamine disulfide, O-benzoylthiamine disulfide, O-benzenesulfonylthiamine disulfide, deoxythiamine disulfide, thiamine disulfide-O-methylether) and S-acylated thiamine (diacethylthiamine, O-acetyl-S-benzoylthiamine, O-benzoyl-S-acetylthiamine) were unstable, being remarkably decomposed, whereas the unsymmetric disulfides (thiamine propyl disulfide, thiamine tetrahydrofurfuryl disulfide) were somewhat resistant and S-carbethoxy-B1, (S-carbethoxythiamine, dicarbethoxythiamine) and S-benzoylthiamine monophosphate were decomposed most slowly. On the other hand, thiamine, deoxythiamine or thiothiamine were hardly or not at all decomposed under the same condition. As a decomposition product of O-benzoylthiamine disulfide, 2-methyl-4-amino-5-aminomethyl pyrimidine was isolated and was identified as its picrate.