[50 years of the Institute for Research in Pharmacy and Biochemistry]. / Padesát let Výzkumného ústavu pro farmacii a biochemii.

After the nationalization of pharmaceutical industry and establishment of the United Pharmaceutical Enterprises in 1946, the Research and Control Institute (VKU) was established in Prague in 1947 to support the development of research, manufacture, and control of drugs. After other measures of nationalization and unification of research, in 1951 the research sections of the VKU and the pharmaceutical sections of the Research Institute of CCHZ were fused to form the Research Institute for Pharmacy and Biochemistry (VUFB). The section the VUFB taking care of the quality of production was transformed into the Pharmaceutical Control Institute (KUF). Each of the institutes had its own farm for breeding experimental animals outside Prague. In 1958, KUF was transformed into the Research Institute of Medicinal Plants (VULERO) and later, in 1960, into the Research Institute of Natural Substances (VUPL), which eventually fused with VUFB in 1967. During the years of increasing activities of VUFB, a chemical pilot plant was established in Olomouc, and a department of clinical pharmacology in Plzen. Research activities of VUFB were aimed to search for original drugs and to develop non-proprietary medicines in the field of the central and vegetative nervous systems, blood circulation, inflammatory processes, microbial infections, carcinostatic drugs, etc. In natural substances, the greatest attention was paid to ergot alkaloids, but the extent of research also included the constituents of the poppy, periwinkle, and other plants. An important part of the programme was also the breeding and cultivation of selected medicinal plants. The results of research were continuously published in both inland and foreign scholarly journals and at conferences and congresses. Every year, usually more than 100 papers were published and 40-50 for patents applications were submitted. The activity of the Institute resulted in the production of 30 original substances which were introduced into therapeutic practice. Twenty of them are still commonly prescribed. Some of these original substances got into foreign markets, particularly Prothiaden and Trimepranol represented important exports. In addition, 83 non-proprietary drugs were introduced into the inland market.

[Pharmacology of a new antihypertensive agent, metazosin (Kenosin)]. / Farmakologie nového antihypertenzíva metazosinu (Kenosin).

Metazosin (KENOSIN) displaces 3H-prazosin from its bond to alpha-1 receptors of the cerebral cortex, antagonizes the effects of phenylephrin on spinal rats and on perfused peripheral vascular regions, which demonstrates that it is a blocker of alpha-1 adrenergic receptors. It does not affect the central alpha-2 adrenergic receptors. No peripheral antiserotonin effect was found. Metazosin decreases the blood pressure in normotensive and hypertensive animals. On intravenous administration, the decrease commences very rapidly after the onset of administration. In dogs, systolic and diastolic blood pressure, cardiac output, peripheral resistance and pressure in the pulmonary artery are decreased. In animals with experimentally increased pressure in the lesser circulation it produces a decrease in pressure. On the basis of hypotensively active doses in experimental animals, the administration of 5 mg was proposed as the clinica pose. Results of the 1st stage of clinical trials have demonstrated that this dose is effective in persons with the systolic pressure higher than 120 mm Hg. At present the effect of metazosin is tested on hypertonic patients.

QSAR analysis and data extrapolation among mammals in a series of aliphatic alcohols.

Concepts of QSAR analysis and biological similarity models are combined for use in extrapolation of LD50 values after IP application of a series of aliphatic alcohols (C1-C5) to mouse, hamster, rat, and guinea pig and rabbit. It has been found that although close correlation exists between LD50 values after IP and IV applications for mouse and rat, the QSARs obtained with LD50 after IV application are not suitable for a prediction of LD50 values after IP application for rabbit. Different transformation or distribution processes in mouse, rat, and rabbit after the two types of applications might be the reason. The LD50 values (expressed in mmole/m2 of body surface) seem to be independent of mammalian species used (at least within the mouse, rat, hamster, and probably guinea pig series). This fact makes it possible to predict reasonable values of LD50 after IP application for rabbit. Expression of toxicity in mmole/m2 of body surface may be useful in toxicological studies. The model of quantitative structure-activity-species relationships (QSASR) for the system of alcohols and animals chosen is proposed: log BAij = kj + lj log Xi log BAij = aj + bi log Zj where i denotes an alcohol, j an animal, BA being LD50 (mmole/m2) after IP application, X molecular connectivity 1 chi and Z body surface: body weight ratio. The model is based on the assumption that bi is independent of chemical structure (being zero or close to zero), ai is a function of molecular connectivity 1 chi, kj and lj being independent of animal species. These assumptions resulted from the statistical analysis of QSARs and allometric equations obtained under various conditions.