A neutral N-methyltransferase activity in the striatum determines the level of an endogenous MPP+-like neurotoxin, 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion, in the substantia nigra of human brains.

An endogenous MPTP-like dopaminergic neurotoxin, N-methyl(R)salsolinol, increases in the parkinsonian cerebrospinal fluid and accumulates in the human nigro-striatum. An N-methyltransferase specific for (R)salsolinol was found in human brain with optimal pH at 7.0 and 8.5. The correlation of the enzyme activity with the level of N-methyl(R)salsolinol and its oxidation product, 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion was examined in the brain regions. Neutral N-methyltransferase activity in the striatum was found to correlate with the level of the endogenous MPP+-like isoquinolinium ion in the substantia nigra (P < 0.001). Considering that this neutral N-methyltransferase activity increases in parkinsonian lymphocytes, the enzyme may be an endogenous factor in the pathogenesis of Parkinson's disease.

The metabolism of L-DOPA and L-threo-3,4-dihydroxyphenylserine and their effects on monoamines in the human brain: analysis of the intraventricular fluid from parkinsonian patients.

The monoamines and their metabolites were analyzed in the intraventricular fluid of parkinsonian patients treated with L-DOPA alone or together with L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS), the precursor amino acids of dopamine and noradrenaline, respectively. In the intraventricular fluid of the patients administered with L-DOPA, the level of dopamine metabolites were higher than control, suggesting enhanced turnover of dopamine in the brain. However, L-DOPA administration increased free noradrenaline only slightly, and did not affect serotonin and its metabolite. On the other hand, by administration of L-DOPA combined with L-threo-DOPS, the levels of monoamines increased in general, whereas the monoamine metabolites by catechol-O-methyltransferase were reduced compared with those in the patients treated with L-DOPA alone. Only a minor part of L-threo-DOPS was metabolized into noradrenaline by aromatic L-amino acid decarboxylase, and it was metabolized mainly by two other enzymes, catechol-O-methyltransferase and DOPS-aldolase in the brain. An overview of the metabolism of neurotransmitters in the brain proved to be useful to evaluate the therapeutic effects of these precursor amino acids.

N-methylation of dopamine-derived 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, (R)-salsolinol, in rat brains: in vivo microdialysis study.

N-Methylation of (R)-1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [(R)-salsolinol] derived from dopamine was proved by in vivo microdialysis study in the rat brain. The striatum was perfused with (R)-salsolinol and N-methylated compound was identified in the dialysate using HPLC and electrochemical detection with multichanneled electrodes. N-Methylation of (R)-salsolinol was confirmed in three other regions of the brain, the substantia nigra, hypothalamus, and hippocampus. In the substantia nigra, the amount of N-methylated (R)-salsolinol was significantly larger than in the other three regions. These results indicate that around dopaminergic neurons, particularly in the substantia nigra, (R)-salsolinol was methylated into N-methyl-(R)-salsolinol, which has a chemical structure similar to that of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, the selective dopaminergic neurotoxin. N-Methylation of tetrahydroisoquinolines and beta-carbolines have already been proven to increase their toxicity to dopaminergic neurons and N-methylation might be an essential step for these alkaloids to increase their toxicity. On the other hand, after perfusion of (R)-salsolinol, release of dopamine and 5-hydroxytryptamine was observed and inhibition of monoamine oxidase was indicated. (R)-Salsolinol and its derivatives may be candidates for being dopaminergic neurotoxins.

[Combination of transarterial chemoembolization and endocrine therapy for liver metastases of breast cancer].

Nine patients with multiple metastases including liver from breast cancer were treated with transarterial chemoembolization through hepatic artery using 40-50 mg of 4'-epi-adriamycin and Lipiodol, followed by 800-1,200 mg/day of medroxyprogesterone acetate. Of 9 patients thus treated, there were 4 partial response (44%), 2 no change and 3 progressive disease. Duration of disease control ranged from 4 to 46 months (mean 24.5 months). Seven out of 9 patients died within 6 to 37 months (mean 15.3 months) after diagnosis of liver metastases. The 3- and 5-year survival rates were 45% and 11%, respectively. We conclude that this therapy is a useful treatment modality for controlling liver metastases of breast cancer.

Reduction of enzymatic activity of tyrosine hydroxylase by a heterocyclic amine, 3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole (Trp-P-1), was due to reduced affinity to a cofactor biopterin.

A carcinogenic, food-derived heterocyclic amine, 3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole (Trp-P-1) was found to reduce the enzymatic activity of tyrosine hydroxylase in clonal rat pheochromocytoma PC12h cells, by its supplement to the culture medium. The reduction was observed with 10 microM Trp-P-1, and at this concentration the amount of cell protein and the activity of a non-specific enzyme, beta-galactosidase, were not affected. The mechanism of the reduction of the enzyme activity was clarified by kinetical studies. The amine reduced the affinity of tyrosine hydroxylase to a cofactor, tetrahydrobiopterin. The alteration of the enzymatic properties by Trp-P-1 was discussed in relation to the possible effect on catecholamine metabolism in the brain.

Effects of morphine administration on catecholamine levels in rat brain; specific reduction of epinephrine concentration in hypothalamus.

The effects of morphine administration on concentrations of epinephrine, norepinephrine and dopamine were examined in the rat brain. Morphine injection reduced the epinephrine level only in the hypothalamus, while the norepinephrine level was reduced in the hypothalamus, medulla, and locus coeruleus. The dopamine concentration was elevated in all regions examined. These changes were blocked by administration of naloxone. Repeated injection of morphine for 14 days did not affect any catecholamine level. In naloxone-induced withdrawal, epinephrine was most markedly depleted in hypothalamus. These observations suggest that the epinephrine level in hypothalamus is affected by morphine acting on opioid receptors.

[A case of remarkable regression of a colonic cancer involving metastasis to the liver as a result of FT-207 treatment].

In mid-August, 1986, a 50-year-old man underwent a detailed examination following the finding of a tumor in the upper abdominal region. The tumor was revealed to be a sigmoid colon cancer with multiple metastasis to both halves of the liver. Subsequent administration of FT-207 suppositories (750 mg X 2/day) resulted in a recognizable shrinkage of the metastatic lesions in the liver after one month, and a barium enema a month later indicated a decrease in the size of the original tumor. The pre-operative CEA value was 2,317 ng/ml, but this has reduced to 46.7 ng/ml to date March, 1987. In this report of single chemotherapy treatment with FT-207 of a sigmoid colon cancer involving metastasis to the liver, the prognosis obtained for the original and hepatic lesions has been good, and the patient's course to date healthy.

Laparoscopic-assisted serial biopsy of the bovine kidney.

A serial renal biopsy with endoscopy was done, using 10 calves and a cow. In 8 of the calves, biopsy materials were collected 3 to 5 times over a period of 15 to 41 days. A laparoscope was inserted into the peritoneal cavity from the center of the right paralumbar fossa through the outer cannula of the trocar. Under laparoscopic observation, the renal parenchyma was collected with the cutting prong of a biopsy needle. Of 34 biopsy attempts, 32 were successful; in 2, there was incomplete penetration of the trocar assembly into the peritoneal cavity. In one instance, the trocar was misguided to the small intestine which was closely adherent to the peritoneum. The error may have been the result of the presence of a persistent blood clot resulting from the preceding biopsy. An immediate saline rinse of the blood clot attached to kidney and the surrounding tissues was effective in preventing such adhesions. The size of the average sample obtained was 1.5 mm in diameter and 16 mm (2 to 40 mm) long. The tissues were collected in 61 times from the 72 insertions of the biopsy needle to the renal tissue. The 11 unsuccessful attempts were caused by bluntness of the cutting parts of the needle. Adverse clinical signs were no observed after the serial biopsy of kidney, except for the presence of blood in he urine persisting for 1 to 5 days. Although a dehydrated blood clot was found in the renal pelvis of one animal at necropsy, any complication such as obstruction of urinary flow was not observed.