Amnuay Thithapandha

Effects of Caffeine and Theophylline on Activity of Rats in Relation to Brain Xanthine Concentrations

Summary Caffeine and theophylline were equally effective in increasing confinement motor activity when administered ip in doses up to 0.10–0.12 mmole/kg. Higher doses of caffeine produced some toxicity as evident from less stimulation of motor activity. Theophylline produced its peak effect at a dose of 0.17 mmole/kg (30 mg/kg). Doses of either xanthine as great as 0.25 mmole/kg produced much less activity than the optimum doses. Equimolecular doses of caffeine and theophylline produced approximately equal brain xanthine levels.

Genetic Polymorphisms and Haplotypes of DNA Repair Genes in Childhood Acute Lymphoblastic Leukemia

Polymorphisms of DNA repair genes can alter protein structure and may impair DNA repair capacity. Defects in repairing damaged DNA lead to genetic instability and carcinogenesis. This study was performed to evaluate the effect of the polymorphisms of DNA repair genes on risk of childhood acute lymphoblastic leukemia (ALL).

Genetic polymorphisms of folate metabolic enzymes and toxicities of high dose methotrexate in children with acute lymphoblastic leukemia

Dear Editor,Methotrexate (MTX) inhibits several enzymes in folatemetabolic pathway, including dihydrofolate reductase,thymidylate synthase (TYMS), and methylenetetrahydrofo-late reductase (MTHFR), causing defects in DNA and RNAsyntheses and methylation process [1]. Genetic polymor-phisms of genes encoding proteins in folate metabolismaffect their structures and functions. MTHFR C677T andA1298C are associated with decreased enzyme activity andhyperhomocysteinemia [1]. There are 28 nucleotide-tandemrepeat variations in 5’untranslated region of the TYMSgene. The most common variations of this polymorphismare two and three repeats (2R and 3R). TYMS gene with3R polymorphism has a higher expression level than theone with 2R [1, 2]. Reduced folate carrier (RFC) is anessential carrier protein for folate and MTX. RFC G80Apolymorphism affects MTX level in patients treated withhigh dose of MTX. MTX level has been found to besignificantly higher in patients with RFC 80 AA genotypethan other genotypes [1, 3].Our institute normally uses two courses of high-doseMTX (1.5 g/m

Influence of caffeine on aspirin pharmacokinetics

SummaryThe effects of caffeine on the pharmacokinetics and bioavailability of aspirin were studied in 12 healthy adult male volunteers. The subjects received 650 mg of aspirin or 650 mg of aspirin with 120 mg of caffeine citrate orally. It was found that caffeine significantly increased the rate of appearance as well as the maximum concentration of salicylate in the plasma by about 25% and 17%, respectively. Moreover, area under the plasma concentration-time curve of salicylate was significantly higher in the subjects given the drug combination as compared to those given aspirin alone. There was no change in the plasma half-life, volume of distribution and clearance of salicylate.

Substrate specificity and heterogeneity of N-methyltransferases

Abstract Histamine N-methyltransferase ( EC. 2.1.1.8 ) from cat intestine and guinea pig brain was compared with indoleamine N-methyltransferase from rabbit lung and chick brain. Histamine N-methyltransferase, regardless of its source, methylated specifically histamine and not other imidazoles or aromatic amines. In contrast, indoleamine N-methyltransferase from rabbit lung had different substrate specificity from that of chick brain enzyme. The best substrate for lung indoleamine N-methyltransferase was N-methyltryptamine whereas serotonin was the best substrate for the chick brain enzyme. Both histamine N-methyltransferase and indoleamine N-methyltransferase appeared to occur in these species in multiple forms. They had different kinetic parameters, different pH optimum values, displayed different response towards inhibitors, and had different heat stability.

Distribution and heterogeneity of histamine N-methyltransferase

Abstract The distribution of histamine N-methyltransferase (HMT) was studied in several tissues of various animal species including mice, rat, guinea pig, rabbit, cat and dog. The highest activity of the enzyme was found in the cat kidney and cat intestine which was two-fold higher than that in guinea-pig brain. This is in sharp contrast to the findings of Brown et al. (1) who reported that guinea-pig brain had highest activity of this enzyme. The enzyme from the four best sources (cat kidney, cat intestine, guinea pig brain and rabbit intestine) was studied and shown to exist in multiple forms. It was concluded that there were at least three multiple forms of HMT in the four sources tested, whereas the homogeneity of the enzyme was found in the two tissues from cat. Further, there appeared to be no correlation between histamine content and HMT activity in at least eight different enzyme sources tested including cat brain, kidney and intestine, guinea pig brain and liver, rat intestine and kidney, and rabbit intestine. This suggests that HMT may not be the only enzyme responsible for histamine metabolism in these tissues.

The effects of xanthines on mouse liver cell

Abstract Pretreatment of mice with caffeine or theophylline for 3 days (100 mg/kg, intraperitoneally, twice daily) resulted in an increase in microsomal protein, RNA content, and cytochrome P-450 content. Caffeine but not theophylline also shortened the duration of action of pentobarbital in mice. Both xanthines, however, had no effect on the onset and duration of action of hexobarbital in these animals. Chemical measurements revealed that the activities of two drug-metabolizing enzymes, aminopyrine N-demethylase and p-nitroanisole O-demethylase, were markedly increased by this schedule of pretreatment with caffeine but slightly increased by theophylline. Further, it was found that the inductive effect of caffeine, but not of theophylline, was accompanied by complete depletion of glycogen granules in the liver and a high degree of proliferation of the smooth endoplasmic reticulum. This effect on glycogen depletion, which was followed by an elevation of blood glucose, may be the result of caffeine inhibition on hepatic phosphodiesterase, because the cyclic AMP content was more than doubled in caffeine-treated hepatocytes. It was concluded that the stronger stimulatory effect of caffeine on drug metabolism than theophylline might be attributed to a much more pronounced proliferation of hepatic endoplasmic reticulum caused by caffeine.

Characteristics of drugs that penetrate the preimplantation blastocyst

Abstract Experiments were performed to evaluate the role of physicochemical properties of drugs and chemicals in determining their passage into the preimplantation blastocysts of 6-day pregnant rabbits. It was found that compounds with molecular weight less than ouabain (mol. wt 585) readily traversed the blastocyst, whereas the blastocyst was relatively impermeable to those with molecular weight greater than 5000. However, for compounds with small molecular weights (100–300), the blastocyst/plasma radioactivity ratios varied considerably (0.001–1.24), suggesting that factors other than molecular weight played a role in determining their passage. Further experiments revealed that there was no correlation between blastocyst/plasma radioactivity ratio and degree of protein binding of the drugs. It was concluded that the degree of ionization and lipid solubility of the compounds are important factors in determining their rates of penetration into the preimplantation blastocysts. These findings prove that a variety of foreign compounds can enter the blastocyst during the preimplantation stages of gestation and their rates of penetration are governed by the possible interactions among their physicochemical properties. The lexicological implications of these findings were also discussed.

Biphasic effect of methadone on hepatic drug metabolism.

When methadone HC1 (30 mg/kg, po) was given acutely to mice, it was found to inhibit drug metabolism as evidenced by a prolongation of hexobarbital sleeping time and zoxazolamine paralysis time. Pharmacokinetic studies revealed that this acute dose of the narcotic analgesic could also prolong the plasma half-life of aminopyrine without any change in its volume of distribution. When added to the incubation mixture containing 10,000 g mouse liver supernatant fraction and a complete system for measuring aminopyrine .N-demethylase or aniline hydroxylase, metadone showed a dose-dependent inhibition of the enzymes; the former enzyme was inhibited to a greater extent than the latter one. However, subacute treatment of mice with methadone HC1 (30 mg/kg, po, twice daily for 3 days) resulted in increases in liver weight, microsomal protein, and cytochrome P-450 content in consonant with the increased activities of four hepatic drug-metabolizing enzymes: aminopyrine N-demethylase, aniline hydroxylase, p-nitroanisole, O-demethylase, and benzphetamine N-demethylase. Moreover, both hexobarbital sleeping time and zoxazolamine paralysis time were shortened. The plasma half-life of aminopyrine was decreased. These changes were prevented by simultaneous administration of puromycin diHCl (80 mg/kg, ip). Methadone thus seems to act in a manner very similar to that of propoxyphene or SKF-525A, acting as a potent inhibitor of hepatic drug metabolism when given acutely and as an inducer when given subacutely.

Detection of Human Intestinal Bacterial Overgrowth by Sulfasalazine

November-December 1978 549 S ULFASALAZINE (SSZ; salicylazosulfapyridine) is the drug of choice in ulcerative colitis. After being ingested by normal volunteers the drug is absorbed high in the gastrointestinal tract but is then returned in the bile to the intestinal tract where it is extensitively metabolized to sulfapyridine (SP) and 5-aminosalicylate by the bacteria of the colon and cecum.3 Of these two metabolites, only sulfapyridine is significantly absorbed from the colon.2’4 After absorption into the circulation sulfapyridine is metabolized to N4-acetylsulfapyridine (AeSP), sulfapyridine-O-glucuronide (SP-O..G), and N4-acetylsulfapyridine-O-glucuronide (AcSP-O-G) 1,56 Like isoniazid, hydralazinc, and sulfamethazine sulfapyridine exhibits acetylation polymorphism.7 Recently, it has been reported that rats having a self-filling blind loop created surgically in the proximal jejunum and given an oral dose of sulfasalazine excreted sulfapyridine in the urine at a faster rate than did the controls.8 Further, it was established that this difference in the pattern of urinary excretion of the sulfonamide was attril)uted exclusively to the action of the Inicrofiora colonizing the blind loop.8’9 Thus, bacterial overgrowth in rats could be detected after an oral