The stability of polystyrene latex particles, 2000 Å in diameter, in suspension, both uncoated and coated with human gamma globulin, was studied as a function of pH, electrolyte concentration and valence. Uncoated latex particle suspensions became unstable in the presence of polyvalent cations but not anions. When particles were coated with human gamma globulin, they acquired the characteristics of the protein coating, including its amphoteric properties. At pH 5.0 (net charge positive) the presence of polyvalent anions resulted in instability of the coated particles, while at pH 9.0 (net charge negative) the coated particles became unstable in the presence of polyvalent cations.
A method is described for the colorimetric determination of calcium in 0.5 ml of serum with eerie sulfate. Data are presented to show that the results agree within 0.3 mg per 100 ml of those determined by titration with permanganate.
Forty-one pregnant Wistar strain rats were irradiated with 0.6-Gy X rays or were sham irradiated on the 9th or 17th days of gestation to determine if this dosage level would result in alterations in postnatal neurophysiologic development. Half of the mothers were sacrificed at term, and the developmental status of 221 newborns was evaluated. The remaining mothers delivered and raised their litters. The 161 offspring were observed for the age of attainment of the following physiologic parameters: pinna detachment, eye opening, testes opening. Offspring were also tested for the acquisition of the following selected reflexes: surface righting, negative geotaxis, auditory startle, air righting, and visual placing. Term fetal weight was lower than the controls in the group irradiated on the 9th day but was recuperable postnatally. None of the 9 developmental tests performed postnatally were abnormal in the animals irradiated on the 9th day. Thus, at least with regard to these measures, the surviving embryos exposed during the all-or-none period could not be differentiated from the controls. Offspring irradiated on the 17th day exhibited retarded growth which persisted during neonatal life. The three-day-mean neonatal weight was significantly lower in the group irradiated on the 17th day compared to controls. There were no significant maternal body weight or organ/weight differences between the groups. Rats exposed in utero on the 17th day had a significantly delayed acquisition of air righting. These results demonstrate that 0.6-Gy in utero irradiation on the 17th day of gestation can cause subtle alterations in growth and development of the Wistar strain rat during postnatal life.
An investigation was undertaken to determine the immunologic sequence of events during attacks of diarrhea associated with the presence of “normal” fecal flora, E. coli serotype 01 through 025, in the intestinal tract. It revealed that 12 of 30 or almost half of those infants from whom acute and convalescent phase sera were available exhibited a rise in hemagglutinin titer. At some time during their illness a greater number, two-thirds, had inhibitors present in their sera which were antigenically related to the E. coli serotype isolated from their fecal flora.
12-O-Tetradecanoylphorbol 13-acetate (TPA) induces rapid changes in the morphology of the human megakaryoblastic leukemia cell line, MEG-01, as well as changes in adhesion and megakaryocytic differentiation. To investigate the signal transduction pathway of these three phenomena, we studied the effect of herbimycin A, an inhibitor of tyrosine kinase (TK) and the effects of calphostin C, a specific inhibitor protein kinase C (PKC) on TPA treated MEG-01 cells. Both herbimycin A and calphostin C inhibited all three TPA-induced phenomena, suggesting that both pathways are required for these phenomena. Herbimycin A but not calphostin C blocked the tyrosine phosphorylation of cellular proteins. Immunohistochemical staining of PKC using an anti-PKC monoclonal antibody showed that herbimycin A did not interfere with the translocation and subsequent down regulation of PKC induced by TPA, suggesting that the TPA-induced effect on PKC (translocation and probably its activation) is not dependent on TK. Induction of c-fos and c-jun expression by TPA was inhibited by both herbimycin A and calphostin C, suggesting that both PKC and TK pathways are necessary for the induction of the TPA-induced transcription factor AP1, which is a known TPA-inducible early immediate gene product. Taken together, our results show that the tyrosine kinase signal transduction system as well as the PKC pathway is indispensable for the TPA-induced phenomena of morphologic change, cell attachment, early immediate gene expression, and lineage-specific phenotypic expression in the MEG-01 cell line.
(1) Boiled broth cultures and sterile Seitz filtrates thereof of Escherichia coli serogroups 055 and 0111 render red blood cells of man and rabbit specifically agglutinable by the homologous group-specific antisera. Unheated cultures, and nitrates are only slightly effective. Trypsinized red blood cells are somewhat better agglutinated than non-tryp-sinized cells. (2) The significance of the findings regarding the indirect bacterial hemagglutination test is discussed with particular reference to the phenomenon of bacterial inagglutinability.
1. In a study of the influence of O2 in high concentrations (94% at atmospheric pressure) it was found that the administration of desiccated thyroid augments the adverse effects of O2 on normal and on hypophysectomized rats as shown 1) by a shortening of both the onset of the symptoms—hyperpnea, lethargy, dyspnea, coma—and the survival times, and 2) by increasing the severity of macroscopic pathological changes, including massive pleural effusion and hydrothorax, congestion, oedema and hepatization of the lungs and enlargement and congestion of the liver. 2. The pronounced protection which hypophy-sectomy provides against the adverse pulmonary effects of increased O2 is in large degree counteracted by the administration of thyroid to the hypophysectomized animal. This protection is, therefore, attributable not only to the loss of adrenocortical principles but also to the loss of thyrotropin. The possible involvement of an increased CO2 in the thyroid effects is discussed.
α-Chloromethyl-2-methyl-5-nitro-1-imidazoleethanol was found to exert marked chemotherapeutic effects against experimentally induced infections of rodents with Endamoeba histolytica, Trichomonas vaginalis, Trichomonas foetus, and against a natural pinworm infection of mice produced by Syphacia obvelata. The substance was also highly active in vitro against anaerobic bacteria but not against facultative or aerobic microorganisms. Except for a slight effect noted in the case of the sarcoma-180 tumor, this 5-nitroimidazole derivative was inactive in all other experimental models tested in vivo including bacteria, fungi, and viruses.
The effects of several inotropic interventions on the isometric developed tension (IDT) of isolated left rat atrium, electrically driven at several frequencies were investigated. The experimental stimulating procedure allowed the attainment at all the rates tested (25, 50, 100, and 200 per min), similar magnitudes of IDT prior to drug addition. Two types of contractile responses to the inotropic agents at different beating frequencies were found: (1) Norepinephrine and isoproterenol enhanced the IDT less at the slower rates (25 and 50 per min) than at the highest rate (200 per min); (2) phenylephrine and CaCl2 similarly augmented atrial IDT at all driving rates. The presence of cocaine potentiated the effect of norepinephrine at lower frequencies but not at 200 beats per min; in addition, it did not modify the inotropic influence of isoproterenol at any of the rates explored. U-0521 enhanced the positive inotropism of both norepinephrine and isoproterenol only at low stimulating frequencies. The results suggest that: (a) The dissimilar effects of norepinephrine and isoproterenol at low and high rates could be associated with a different importance of the inactivating processes of these amines at the various frequencies, namely, presynaptic neuronal uptake and metabolization via COMT. Both mechanisms appear to be more important at lower rates and this could be the reason underlying a diminished influence of norepinephrine or isoproterenol over slowly beating atria. (b) The positive influence of frequency over the inotropic effects of norepinephrine and isoproterenol is not due to the magnitude of atrial contractions existing before their addition.
The E. coli hemagglutinin response of adult volunteers to ingestion of E. coli 055 and a “normal” strain of E. coli, respectively, was determined. 1. Increase in E. coli 055 hemagglutinin titers was observed in all subjects following administration of living organisms in large numbers and in two-thirds of individuals who received smaller numbers. 2. None of the controls who received milk without E. coli showed such an antibody response, nor did the volunteers who ingested large numbers of killed 055 organisms or viable bacteria of a “normal” strain of E. coli. 3. Good correlation was found between increases of E. coli 055 hemagglutinin titers and the appearance of bacterial O agglutinins. 4. The E. coli hemagglutination test proved to be more sensitive than the conventional bacterial agglutination test, inasmuch as the former method with the postfeeding serum specimens yielded antibody titers which were from 5 to 20 times higher and detected antibodies in prefeeding serum specimens which were not demonstrated by the latter method.
Blood group A activity was demonstrated in purified Vi antigen preparations and blood group B activity in whole cells of Escherichia coli 086. The immunological implications of these findings were investigated. The antigenicity of Vi antigen was essentially as great in group A or AB individuals as in those of other groups. Anti-B exerted a bactericidal effect upon E. coli 086, but further studies are obviously needed to determine the protective effect, if any, of anti-B against E. coli 086 or, indeed, of either isoantibody against any microbial agent which may possess blood group antigens. Nevertheless, cross-reactivity between blood group substance B and E. coli 086 affords a model for the possible influence of blood groups in resistance to infection against those microbial agents which may possess blood group antigens.
Various natural substances especially whey were found to contain a substance required for growth of Lactobacillus bulgaricus 09. In the survey of known compounds orotic acid was found to satisfy the requirement of this organism for natural material. The microbiologically active material was isolated from one of the natural sources, whey, and identified with orotic acid.
Growth and isotopically-la-belled incorporation studies have shown that Lactobacillus bulgaricus 09 utilizes uracil in lieu of orotic acid provided the incubation time is greatly prolonged. Some implications of this finding are discussed.
A microbiological method for the determination of “strepogenin” activity is presented that depends upon the essential nature of the material for a strain of Lactobacillus bulgaricus. The method is believed to possess advantages over existing methods that depend upon the stimulation of the growth of Lactobacillus casei.
The orotic acid requirement of Lactobacillus bulgaricus 09 can be met by ureidosuccinic acid (10-20% as active as orotic acid) or by 5-(carboxy-methylidine)-hydantoin (30-40% as active as orotic acid but not by any one of a large group of lated or unrelated compounds studied. The data are taken as microbiological evidence that ureidosuccinic acid and possibly ureidofumaric acid (derived from 5-(carboxy-methylidine)-hydantoin) are precursors of the pyrimidine ring.
A number of ureides were tested for orotic acid-like activity using L. bulgaricus 09. Ureidosuccinic acid, the only compound that could be visualized to yield a substituted pyrimidine ring by cyclization, was the only ureide with significant activity.
(1) A new chemical compound has been found which has high oral and parenteral parasympathetic blocking activity. This compound, N,N dimethyl 4-piperidyli-dene 1,1 diphenylmethane methyl sulfate (Prantal), is unique in its specificity of action within the parasympathetic system, i.e., it primarily inhibits gastric motility and gastric secretion. The intravenous sympathetic ganglion blocking dose is 50 to 100 times that required for intravenous parasympathetic blockade. (2) In dogs, roentgenologic observations of the movement of barium sulfate from the stomach indicate that orally administered Prantal delays gastric emptying time more effectively, and is longer acting than methantheline bromide. Additional dog experiments showed the ability of Prantal to reduce the volume and titratable total acid of gastric secretions. (3) After oral medication in dogs, Prantal produced no mydriasis at doses which inhibit gastric motility for several hours, whereas methantheline bromide caused mydriasis which persisted for one to 3 hours. In rabbit (tests by topical application to the eye, mydriasis occurred with a 0.1% concentration of methantheline bromide, whereas 1.0% of Prantal was not mydriatic; mydriasis occurred at the 2.0% concentration of Prantal. By intravenous injection in rabbits methantheline bromide caused mydriasis at 1.0 and 2.0 mg/kg doses; no mydriasis occurred at 2.0, 4.0 or 8.0 mg/kg doses of Prantal.
DMPP has been shown, like nicotine, to augment the peristaltic reflex of an isolated ileum to increasing pressure at low concentrations but inhibits it at high concentrations. This is apparently due to its stimulating and paralyzing action on the parasympathetic ganglion at low and high concentrations, respectively. The fact that the paralyzing effect of DMPP on the ganglia was not evident on repeated administrations in animals of submaximal doses may be explained by the rapid elimination of it from the site of action. Whereas physostigmine antagonized the blocking effect of d-tubocurarine, it does not influence that of DMPP on peristaltic reflexes of the ileum.
The blood pressure response of the rat to the ganglionic stimulant 1,1-dimethylphenylpiperazinium iodide (DMPP) was much less sensitive than that of the cat. Acute bilateral adrenalectomy did not diminish the pressor response to DMPP in the rat. Bretylium or guanethidine completely or virtually abolished the pressor response produced by DMPP. It was concluded that, in the rat, the adrenals appear not to play a role in the pressor response produced by DMPP.
1) The effect of 8 derivatives of 2.2-bis-(p-chlorophenyl) − 1,1-dichloroethane (DDD, TDE) on responsiveness of the adrenal cortex to ACTH, as determined by changes in plasma 17-hydroxycorticoids, has been studied in dogs. The following derivatives decreased the corticoid response: those with para-phenyl modifications; bromine substitution of the aliphatic chlorines; hydroxylation on the 2-position of the ethane moiety. No change in response was noted with a derivative in which hydrogen replaced chlorine in the 1-position of the ethane moiety, and with benzophenone, a possible DDD metabolite. Somewhat equivocal results were obtained with an ethylene analogue. 2) The relationship between these biochemical findings and the histopathologic effects recorded for this series of compounds is discussed.
1,1-aminopropanesulfonic acid was synthesized by the addition of ammonium bisulfite to propanal. The aminosulfonic acid inhibited the growth of Lactobacillus casei at levels from 10−4 to 10−2 molar. Single amino acids as well as combinations of amino acids were ineffective in relieving the inhibition.
Administration of 1,1,3-tricyano-2-amino-1-propene (U-9189) increased total CO2 output and oxidation of C14-labeled acetate, tripalmitin, DL-leucine, and glycine in intact fasting rats. U-9189 also increased C14 specific activity of exhaled CO2 suggesting increased utilization in excess of increased metabolic rate. Total oxidation of C14-glucose was not influenced; resultant specific activity was therefore decreased. Although in thyroidectomized rats U-9189 produced a similar increase in total CO2 expired and oxidation of C14-DL-leucine, specific activity of total CO2 increased only slightly compared to intact rats given U-9189. Total “oxidative effect” of U-9189 appeared to be lacking in the absence of thyroid gland.
1. A method of inducing fibrillation in isolated rabbit atria was explored. Atrial fibrillation can be readily produced and maintained under the conditions described by Holland and Burn(2). The method is improved here by the use of much lower concentration of acetylcholine. 2. 1,10-Phenanthroline is as effective as quinidine in stopping induced fibrillation in isolated rabbit atria. 3. 1,10-Phenanthroline, like quinidine, reduces the maximal following rate of isolated rabbit atria, but to a lesser extent. 4. The lowering of maximal following rate by 1,10-Phenanthroline and quinidine can be lessened by reduction of potassium in the medium. 5. At comparable concentrations, 1,10-Phenanthroline does not affect the intrinsic sinus rate of isolated rabbit atria, while quinidine reduces the intrinsic rate markedly. 6. 1,10-Phenanthroline, like quinidine, produces distinct reduction of the rate of depolarization and repolarization of the action potential of the rat atria.
Dihydropteroylglutamic acid, N10-formylpteroylglutamic acid and citro vorum factor are inhibited non-competitively by a number of 1,2-dihydro-s-triazines when substituted for pteroylglutamic acid in 5. faecalis No. 8043 assay systems, but only by inhibitor:metabolite ratios considerably higher than those required for the inhibition of pteroylglutamic acid in the same microbiological system. Citrovorum factor also is similarly inhibited in L. citrovorum No. 8081 assay systems. The phenyl- and 3′- and 4′- halophenyl-2,2-dimethyl derivatives were the most active compounds of the series and certain correlations can be made between structure and microbiological activity vs these metabolites.
Oral administration of 1,2-dimethylhydrazine (DMH) induced intestinal neoplasms in germfree rats. A supplement of 2% cholestyramine resin in the diet increased the frequency of DMH-induced intestinal tumors and accelerated malignant transformation. Bile acids in the cecal content were determined with and without cholestyramine in order to obtain a correlation between the bile acid metabolism and the enteric carcinogenesis.
The amounts of vit. B12 and of riboflavin which were formed during growth of Bacillus megatherium were decreased by l,2-dichloro-4,5-diaminobenzene when the latter was present in quantities insufficient to inhibit growth. l,2-Dimethyl-4,5-diamino-benzene caused stimulation of the production of vit. B12. These facts have been viewed as being compatible with the previously expressed postulates that the dimethyldiamine is a precursor of riboflavin and of vit. B12, and that the dichloro-analog exerts its selective toxicity, at least in part, by inhibition of biosynthetical processes in the formation of these vitamins.
1. Mephenesin is oxidatively metabolized in vitro by rat and mouse liver slices to 3-(o-tolyloxy) lactic acid. 2. Mephenesin metabolism was markedly inhibited by increasing substrate concentration, but was not altered by presence of increasing concentrations of the product, 3-(o-tolyloxy)lactic acid, in the medium. 3. Metabolism of mephenesin was readily inhibited by iodoacetic acid, but was unaltered by aldehyde trapping agents at 10-3 M.
Mephenesin in concentrations up to 0.3% caused no change in the swelling resulting from immersion in high-potassium Ringers. Mephenesin at a concentration of 0.3%, but not at 0.1%, caused a large, reversible increase in swelling resulting from immersion in sodiumpoor, hypotonic Ringers. This relatively high drug concentration also caused a 20% loss of muscle potassium both in regular Ringers and in hypotonic, sodium-poor Ringers. These changes are thought to be related to muscle contraction produced by Mephenesin. Confirming results of similar experiments by Fenn (7), the procedure of disturbing or handling muscles at intervals throughout an experiment was seen to result in muscle weight gain, a small sodium increase, and little alteration of potassium content; this process was intensified by Mephenesin.
Epidemiologic studies suggest that the consumption of cruciferous vegetables is associated with a reduced risk for several types of cancer including cancer of colon. Experimental studies indicate that dithiolthiones, naturally occurring substances in cruciferous vegetables, possess anticarcinogenic properties. 5-(2-Pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz), a substituted dithiolthione, has been tested for its chemopreventive activity. We studied the effect of dietary oltipraz on liver and colonic mucosal enzymes and DNA adducts to evaluate the modulating role of this agent during the early period of azoxymethane (AOM)-induced carcinogenesis. At 6 weeks of age, groups of animals were fed the AIN-76A diet containing 0 and 300 ppm oltipraz. At 8 weeks of age, all of the animals except vehicle-treated animals were administered a subcutaneous injection of AOM (15 mg/kg body wt/week for 2 weeks). Animals intended for vehicle treatment were administered normal saline subcutaneously. Fifteen hours after the second AOM injection, six animals each from control oltipraz diet groups were sacrificed and liver and colonic mucosa from each animal were used for DNA adduct analysis. Animals intended for liver and colonic mucosal glutathione S-transferase, tyrosine specific protein kinase (TPK), and ornithine decarboxylase (ODC) enzyme assays were killed 5 days after the second AOM or saline injection. The results of this study indicated that dietary oltipraz significantly increased liver (P less than 0.001) and colonic mucosal (P greater than 0.05) weights, but had no effect on body weights (P greater than 0.05). In saline-treated animals, feeding of oltipraz significantly increased the cytosolic glutathione S-transferase (P less than 0.001) and ODC (P less than 0.05) activities in the liver and colon when compared with those fed the control diet. Although our unpublished results indicate an inhibitory role of oltipraz when fed during the initiation and postinitiation phases of intestinal carcinogenesis, the increased ODC activity may indicate a possible role of oltipraz in colon tumor promotion. Additional studies are indicated to test the antitumor properties of oltipraz administered during the postinitiation phases. AOM treatment significantly increased the TPK (P less than 0.0001) and ODC (P less than 0.01) activities in the liver and colon of animals fed the control diet. Dietary oltipraz significantly suppressed the AOM-induced TPK (P less than 0.001) activities in liver and colon and ODC (P less than 0.01) activity of colon. Analysis of nucleic acid bases, O6-methylguanine, and 7-methylguanine revealed that dietary oltipraz significantly (P less than 0.05) inhibited the AOM-induced adduct species. These results suggest that dietary oltipraz enhances the colonic and liver glutathione S-transferase activity and reduced the formation of DNA adducts. In addition, dietary oltipraz modulates liver and colonic ODC and TPK activities that have been shown to play a role in tumor promotion.
Flectol H, a polymer of 1,2-dihydro-2,2,4-trimethylquinoline, when fed to rats produced fatty change frequently localized to the midzonal area of the hepatic lobule. Chronic administration led to alteration of hepatic cells, necrosis, and atypical biliary-duct hyperplasia.
A number of strains have been isolated from stock cultures of S. faecalis No. 8043 which are resistant to inhibition by the 1,2-dihydro-s-triazines in pteroylglutamic acid assay systems. The strains studied so far exhibit cross-resistance with related aldehyde and ketone derivatives of the dihydrotriazine series but not with 4-aminopteroylglutamic acid, 4-amino-N10-methylpteroylglutamic acid or certain 2,4-diaminopyrimidines.
The polycyclic aromatic hydrocarbon, 9,10-dimethyl-1,2-benzanthracene (DMBA) produced malignancy involving the spleen in SJL/J and B10SJF1 mice when injected ip at 500 micrograms per mouse either alone or in combination with threshold doses of Friend leukemia virus (FLV). The mice that received both chemical and virus died significantly sooner than mice that received either chemical or virus alone, and a synergism between DMBA and FLV was demonstrated in both the virus-resistant B10SJF1 hybrids and virus-sensitive SJL/J mice.
Oral administration of 3-chloro-1,2-propanediol (6.5-15 mg/kg daily) produces an antifertility effect in males without interfering with spermatogenesis or diminishing libido. With the lowest effective dose tested, 6.5 mg/kg daily, there is no histological evidence by 14 days which reveals a mechanism of action. With slightly higher doses, beginning with 9.5 mg/kg, peritubular edema, intratubular dilatation and increased tissue weights, beginning in the initial segment of the caput, suggests an interference with absorptive capacities of the epididymis.
Determination of the proportion of free 9,10-dimethyl-1,2-benzanthracene remaining in newborn and in adult mice following intraperitoneal injection, revealed that this compound disappeared more quickly from the adult than from the newborn animals. This supports the view that the greater susceptibility of the newborn to tumor induction by this carcinogen is due to longer persistence of the compound in the newborn than in the adult.
1. A single subcutaneous injection of 2.14 mg of 4′-fluoro-10-methyl-1,2-benzanthracene in albino rats produced a severe and fatal periarteritis in 4 to 8 weeks. Similar lesions were seen after injection of one-half as much of this hydrocarbon, but they developed more slowly. Equivalent levels of 10-methyl-1,2-benzanthracene or the solvent alone were ineffective. 2. The most severe lesions were observed in pulmonary arteries; this finding is in accord with the cyanotic conditions of some rats. Hyaline necrotic lesions were observed in renal arterioles and glomerular capillaries. 3. A possible immunological basis for these lesions is discussed.
The relative degrees of in vitro incorporation of 14C labeled precursors into surgical specimens of human femoral, tibial, and popliteal arteries were choline>ethanolamine>serine>formate>glycerol. Formate appeared to be incorporated primarily into phosphatidyl serine, probably by fixation to glycine. In addition to de novo synthesis, the pathway of transmethylation of phosphatidyl ethanolamine to phosphatidyl choline seemed to be operative in these arterial preparations.
A series of 71 1,2-dihydro-s-tri-azines have been studied in Streptococcus faecalis No. 8 043-pteroylglutamic acid assay systems. The active derivatives exhibit noncompetitive inhibition over a wide range of concentrations of PGA and differ from 4-aminopteroylglutamic acid in that inhibition is not relieved by adenine or guanine and is irreversible with pteroylglutamic acid. Differences in microbiological activity could be correlated with certain variations in structure and substitution in the molecule with the series. Maximum activity is obtained with 2,2-dimethyl substitution in the triazine ring together with para-and meta-halogen sub-stituents in the phenyl ring. The inhibitory effect of these compounds on Streptococcus faecalis No. 8043 is reversed by appropriate concentrations of dihydropteroylglutamic acid, N10-formylpteroylglutamic acid, synthetic and natural citrovorum factor and thymine, suggesting that these compounds interfere with the conversion of pteroylglutamic acid to citrovorum factor.
Two compounds, 5,6-dimethylbenzimidazole and 1,2-dimethyl 4,5-diaminobenzene, which have been previously implicated in vit. B12 metabolism, were found to inhibit the growth of Mycobacterium tuberculosis, strain H37Rv, in Dubos Medium.
The administration of a high nonlethal dose of propylene glycol (10 ml/kg) was found to affect the carbohydrate metabolism of young rats. There was a marked increase in the blood glucose in 15 min, with the maximum increase in 1 1/2 hr; the overall increase in blood glucose lasted for a period of 6 hr. The amount of liver glycogen in propylene glycol and saline control was the same for 6 hr. A severe depletion in the liver glycogen was noticed 12 hr after propylene glycol treatment. Evidence has been provided that the rats treated with a high dose of propylene glycol have a drastically reduced capacity to synthesize or to store liver glycogen. Some of the possible mechanisms for the inhibitory effects of propylene glycol on synthesis of liver glycogen have been discussed. The present work provides the proof for the metabolic upsets associated with a large dose of propylene glycol used either as such or as a carrier vehicle in a drug study.
Three strains of germfree rats (Sprague-Dawley, Lobund-Wistar, Buffalo) were tested for their susceptibility to DMH-induced enteric neoplasms; Sprague-Dawley rats were most susceptible, Lobund-Wistar rats were not susceptible, and Buffalo rats were intermediate in susceptibility.
Experiments in rats revealed that the parkinsonian drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) given in multiple daily doses either per os (p.o.) or subcutaneously (s.c.) induced in a dose-dependent manner solitary or double ("kissing") duodenal ulcers in the rat. MPTP also diminished cerebral concentrations of DOPAC and the duodenal ulcers were prevented by pretreatment with dopamine agonists (e.g., bromocriptine, lergotrile) or monoamine oxidase inhibitors (e.g., pargyline, 1-deprenyl). High doses of MPTP also caused gastric erosions and motility changes resembling parkinsonism (e.g., akinesia, rigidity, forward bending of trunk). This chemical decreased gastric secretion of acid and pepsin, as well as pancreatic bicarbonate, trypsin and amylase. Thus, MPTP causes duodenal ulcers that are possibly associated with impaired defense in the duodenal bulb (e.g., decreased availability of duodenal and pancreatic bicarbonate).