A review on the development of Kallikrein (Kallidinogenase)

This article briefly summarizes the historical events particularly these in Japan, in the kallikrein-kinin research and progress of the development of kallidinogenase (INN), enzyme with circulatory action. In 1926, E. K. Frey observed a drop in blood pressure in dogs following intravenous injection of the urine of human and other mammals into dogs. Intensive research showed that the urine contained a high-molecular active substance which dilated the peripheral arterial vessels. The substance was later called kallikrein after the Greek synonym for pancreas, as it occurred there at such a high concentration (Kraut et al., 1930) that this gland was thought to be its cite of origin. In 1930, kallikrein was commercially available as Padutin from Bayer, Germany. The product was introduced into Japan a few years later under the trade name of Kallikrein and was used for the treatment of circulatory disorders even during the Second World War. Kallikrein was again imported by Yoshitomi Pharmaceutical Industries, Ltd. in 1952. However, Kallikrein introduced after the War did not contain substance derived from the urine but from porcine pancreatic kallikrein as the active ingredient. It grew rapidly with its active promotion of the product in such fields as internal medicine, ophthalmology, otology etc. Domestic manufacturers increasingly entered this market and the number of the manufacturing license holders of similar products reached 26 in 1975 when kallidinogenase preparations were designated to undergo drug re-evaluation by the health authorities. Since June 1988 when the re-evaluation for kallidinogenase preparations was completed, all the relevant manufacturers have supplied new formulations containing higher quality substances and labeling their potencies expressed in International Units based on the kallidinogenase reference standards which had since been established.     

Analysis of C-myc messenger-RNA expression in primary breast carcinomas with clinical follow-up

The level of c-myc messenger RNA was measured in 105 primary breast carcinoma samples and matched normal breast tissue from the same patients. Only tumors showing a greater than 2-fold increase in c-myc levels were considered to be overexpressed. Overexpression of c-myc mRNA was identified in 27.6% of tumor samples analysed and was significantly correlated with mitotic grade (p=0.05) and intense lymphocytic infiltrate (p=0.026) but not with other clinical and pathological variables such as size, necrosis, lymph node involvement, estrogen or progesterone receptor status, menopausal status, age or staging of the patients and increased risk of relapse or overall survival. Approximately 25% of the tumors contained overexpression of c-erbB-2 mRNA and simultaneous overexpression of the two oncogenes was seen in only five samples. Disease-free survival was significantly shorter in these patients (p=0.02) and this reduction remained significant after adjustment for nodal status. However, simultaneous overexpression of c-myc and c-erbB-2 did not improve significantly the prediction of risk of death.     

A short history of patient package insert in the EU

In recent years the Japanese general public has become increasingly aware of health matters, and many people wish to know more about the medicines they receive from doctors. This means that Japanese patients have not been given medicinal product information fully by medical professionals, whereas many European countries have already introduced patient package inserts (PPIs) with near full disclosure leaflets in understandable language in all packages of dispensed medications. This article describes a short history of PPIs in European countries, centering on the development of PPIs in Germany and Belgium. It is expected that these European experiences contribute to our country in terms of providing patients with pharmaceutical information.     

Breast parenchymal activity on scintimammography: Comparison between bone-seeking agents and99mTc-sestamibi

The aim of this study was to evaluate breast parenchymal activity on scintimammography with bone-seeking agents and 99mTc-MIBI. Scintimammography was performed with bone-seeking agents in 61 patients and with 99mTc-MIBI in 33 patients. Activity in the breast parenchyma contralateral to the suspected lesion was visually assessed by two independent observers. Increased breast parenchymal activity was shown in 19 of 61 patients examined with bone-seeking agents, while it was demonstrated in only two of 33 patients examined with 99mTc-MIBI. Breast parenchymal activity of bone-seeking agents was higher in patients aged 50 years or younger than in those older than 50. Increased parenchymal activity of bone-seeking agents may disturb visualization of primary breast cancer especially in relatively young patients. Low parenchymal activity is suggested to be a favorable characteristic of 99mTc-MIBI as a scintimammographic agent.     

A case of retroperitoneal hemangiopericytoma

We report a case of a huge retroperitoneal tumor in a 67-year-old woman. When the patient was taken to another hospital by ambulance, she had lost consciousness because of hypertension and hypoglycemia and abdominal CT revealed a huge retroperitoneal tumor with deviation of the right kidney and inferior vena cava. After further examinations including ultrasonography, MRI and angiography in our hospital, the tumor was extirpated. The tumor, 22 x 17 x 10 cm in size and 2,580 g in weight was diagnosed as hemangiopericytoma histologically. She has remained well with no evidence of recurrence for 9 months since the operation.     

Absorption and distribution of lycopene in rat colon.

Colonic absorption and distribution of lycopene, which inhibited rat colon carcinogenesis in our previous studies, were investigated in Sprague-Dawley rats. Three groups of six rats each with or without a single-barreled colostomy at the mid colon were given a single intragastric or intracolonic dose of 0.2 mL of corn oil containing 12 mg of lycopene. Twenty-four hours later, all rats were sacrificed and the blood and some tissues were collected. The contents of lycopene in the samples were assayed by HPLC. Lycopene was detected in an appreciable amount in the liver, but only in trace amount in the serum of all rats treated with an intracolonic dose of lycopene and in rats with an intragastric dose. After an intragastric lycopene treatment, lycopene was detected in the mucosa of the proximal colon and of the distal colon of the colostomized rats, whose distal colon had been excluded from the fecal stream. A large amount of lycopene was recovered in the feces. None was detected in any sample from the control rats treated with an intragastric or intracolonic dose of plain corn oil. The results suggest that lycopene is absorbed from the colon and also from the small intestine. It might be concluded that both ways of absorption contribute to a comparative amount of lycopene accumulation in the colon mucosa after ingestion of this carotenoid.     

In Vitro Contraction of the Canine Corpus Cavernosum Penis by Direct Perfusion with Prolactin or Growth Hormone

Purpose

It is well established that hyperprolactinemia, most typically seen in prolactinoma patients, causes hypogonadism and impotence. There seem to be a good possibility that hyperprolactinemia causes impotence, at least partially via some intrinsic property of prolactin (PRL), rather than through its suppressive effects on the hypothalamic-pituitary-gonadal testosterone dynamics. In the present investigation, we used an in vitro canine model to attempt to clarify whether direct action of PRL on the corpus cavernosum penis may lead to erectile insufficiency. Growth hormone (GH) and placental lactogen (PL), both having close structural and functional homologies to PRL, were also studied.

Materials and Methods

Isometric tension measurement with cavernous strips was performed in the presence or absence of 10 sup -5 to 10 sup -9 M. PRL, GH, or PL in the perfusion medium. The tension change induced by the test substances was normalized relative to that induced by 120 mEq KCl.

Results

Both PRL and GH produced dose-related elevations (p less than 0.01) of the cavernous tension, whereas PL and thiol-cleaved PRL in comparable doses were without effect (p greater than 0.05). When the tension rise produced by 120 mEq KCl was taken as 100 percent, the maximum contractions produced by PRL and GH were 80 percent and 110 percent. The minimum effective concentration was 10 sup -8 to 10 sup -7 M. for both PRL and GH. Pretreatment with indomethacin (10 sup -5 M.), but not tetrodotoxin (10 sup -5 M.), partially suppressed (p less than 0.05) the effects of PRL.

Conclusion

These results suggest that PRL and GH directly and specifically produced contraction of the corpus cavernosum penis, resulting in erectile insufficiency, and that the effect of PRL is partially mediated by prostaglandin.     

The effect of cadmium on vitamin A metabolism

It has been reported that a number of toxic agents impair normal vitamin A (VA) metabolism (A. D. Bruin, 1976, In Biochemical Toxicology of Environmental Agents, pp. 937–980. Elsevier, Amsterdam). A study was conducted to explore the effect of cadmium chloride (CdCl₂) on VA metabolism. Female rats of the Wistar strain were given drinking water containing 50 ppm of cadmium (Cd) for 237 days. Cadmium ingestion did not affect the food intake and body weight, but a significant decrease in serum VA was observed, concurrently with an increase in liver VA. In studying ingestion of tritiated VA alcohol (all trans-[15-³H]retinol), it was found that the absorption of VA alcohol from the intestine, the release of newly absorbed VA from the liver to serum, and the conversion of VA to water-soluble metabolites in the liver were not influenced by Cd. These findings suggest that Cd interfered with the release of VA, especially stored VA, to serum.