Identification of transplanted pancreatic islet cells by radioactive Dithizone-[131I]-Histamine conjugate. Preliminary report

Background: The unique mechanism of dithizone action in the interior of the viable pancreatic islet suggests the possible development of a specific radiopharmaceutical that may have a potential clinical application in the diagnosis of the pancreatic organ allografts or islets rejection. The radiodiagnostic properties of the newly developed radioactive analogue of dithizone, i.e. Dithizone-[131I]-Histamine conjugate have been evaluated in the present study. METHODS: The four islet cells transplantation models were chosen for this purpose. The most important feature of the Dithizone-[131I]-Histamine conjugate is its possessed ability of zinc chelation. As was presented in the recent study, the conjugate stains pink-reddish the isolated pancreatic islets in vitro. Among the studied transplantation models, only the islets grafting under testis capsule enabled determination of the pancreatic islets in rats by radioactive Dithizone-[131I]-Histamine conjugate. The level of the radioactivity in the recipient testis (right) was almost two times higher compared to the controls (0.24 vs. 0.13% ID/g, respectively). CONCLUSIONS:These preliminary data demonstrate the ability of the developed radioactive analogue of dithizone for in vivo identification of transplanted pancreatic islets, and suggests a potential clinical application of the radiodithizone in the diagnosis of the pancreatic islet rejection

Mass-spectrometric studies of new 6-nitroquipazines—serotonin transporter inhibitors

Six synthesized 6-nitroquipazine derivatives were examined by electron ionization (EI) and electrospray ionization (ESI) mass spectrometry in positive and negative ion mode. The compounds exhibit high affinity for the serotonin transporter (SERT) and belong to a new class of SERT inhibitors. The EI mass spectra registered in negative ion mode showed prominent molecular ions for all the compounds studied. All EI mass spectra and all ESI mass spectra showed similar fragmentation pathways of molecular ions, but the pathways differed between EI and ESI. The differences were explained with the aid of theoretical evaluation of the stability of the respective radical ions (EI MS) and protonated ions (ESI MS)

A Molecular Reactivity Template for Cannabinoid Activity

Methods of theoretical chemistry are used to characterize the molecular structure and some reactivity properties of the major psychopharmacologically active component of cannabis, (—)-trans-Δ9-tetrahydrocannabinol (Δ9-THC). This characterization is part of an exploration of the molecular parameters that could serve to unify considerations of structure-activity relationships in disparate classes of cannabinoids. Our hypothesis is that there are two components of the Δ9-THC structure that confer upon the molecule reactivity characteristics crucial to activity: the lone pairs of electrons of the phenol oxygen, and the orientation of the carbocyclic ring. The conformation of Δ9-THC is calculated using molecular mechanics. Since the position of the phenolic OH is central to the working hypothesis, the rotational energy behavior of the phenolic OH is studied. Results from the calculations identify two minimum energy conformations of the OH in Δ9-THC. Results from ab-initio calculations of the OH rotation on a model fragment of Δ9-THC agree well with the molecular mechanics results. The molecular electrostatic potential (MEP) of Δ9-THC is calculated for the energetically optimal conformations. The results indicate that the two faces of the Δ9-THC molecule are distinguishable. The MEP of the bottom face of Δ9-THC (in each of the two minimum energy conformations of the phenolic OH), along with the conformational results for the orientation of the carbocyclic ring relative to the phenol group form a reactivity template to be used in comparisons with properties of active and inactive cannabinoids

A Molecular Reactivity Template for Cannabinoid Analgesic Activity

The methods of theoretical chemistry were used to characterize the molecular structure and some reactivity properties of (–)-9-nor-9β-hydroxyhexahydrocannabinol (9-nor-9β-OH-HHC), our template molecule for cannabinoid analgesia. This characterization is part of a project whose ultimate goal is the design of cannabinoid analgesics with reduced psychoactive liabilities. Our working hypothesis is that the analgesic activity of 9-nor-9β-OH-HHC is due to the presence and relative location of two regions of negative potential in the top half of the molecule. A complete conformational study of the fused ring structure of 9-nor-9β-OH-HHC was performed using the technique of molecular mechanics as encoded in the MMP2(85) program. This study revealed six accessible conformers of 9-nor-9β-OH-HHC. All six conformers were found to have the same fused ring conformation, but to differ in the position of the phenol and 9β-hydroxyl groups. Molecular electrostatic potential (MEP) maps of each accessible conformer were calculated from molecular wave functions obtained with the LP-3G basis set implemented into the Gaussian 80 program. The MEP maps calculated at distances of 1.5 and 3.3 Å from the molecular plane defined by the aromatic ring serve as a discriminative factor for the conformers of the studied compound. In order to quantiate the spatial relationship of the potential minima in the MEPs of each accessible conformer, points of minimum potential associated with the 9β-hydroxyl oxygen (X1 at –1.5 Å and X2 at –3.3 Å) and with the phenol oxygen (Y1 at 1.5 Å and Y2 at –1.5 Å) were identified in the MEP maps of each conformer. The distances, |;XnYn|, and the nonbonded torsion angles, Yn–O–C9–Xn, were then measured for all conformers. The accessible conformations of 9-nor-9β-OH-HHC along with their MEPs and the measurements |XnYn| and Yn–O–C9–Xn form our preliminary template for cannabinoid analgesia. Future comparisons of this template with the properties of active and inactive cannabinoid analgesics should permit the identification of the relevant conformer at the site of action of these compounds and permit the formulation of an interaction site model for the cannabinoid analgesics

METHODS OF CHROMATOGRAPHIC DETERMINATION OF MEDICINES DECREASING THE LEVEL OF CHOLESTEROL

Polish Pharmaceutical Society Hyperlipidemia (HLP) is a group of disorders in the lipid balance of various pathogenesis, which demonstrate an increase in the cholesterol concentration, mostly the level of lipoprotein fractions of low density (LDL) and/or the concentration of triglycerides in blood. The increase in the total cholesterol and LDL concentration is closely connected with an increase in the risk of appearance of the cardiac ischemia and disorders in the cerebral, coronary and peripheral circulation. In May 2001, the National Cholesterol Education Program issued the third edition of the guidelines of Adult Treatment Panel (ATP III). The most important parameter of the lipid profile is the cholesterol concentration LDL ñ the proper level shall be below 130 mg/dL, though, the optimum concentration LDL has been assumed as below 100 mg/dL. The level for the cholesterol HDL has been also increased ñ the correct number shall be at the level of more than 40 mg/dL for men and more than 50 mg/dL for women and the risk factor ñ the concentration below 40 mg/dL. The third most important parameter is the concentration of triglycerides ñ the correct number shall constitute the concentration not exceeding 150 mg/dL. The selected medicines applied in the treatment of hyperlipidemia, particularily leading to a decrease in the level of cholesterol, have been apart from statins, the derivatives of aryloxyalkyl-carboxylic acids ñ so called fibrates. Fibrates inhibit the synthesis of lipoproteins VLDL in the liver and they accelerate catabolism by an increase in the activity of lipoprotein lipase. They increase the removal of fractions of the cholesterol LDL from the organism and they change their structure by means of increasing their sizes and decreasing density. Moreover, the compounds from this group influence the increase of the HDL fraction and the reverse transportation of cholesterol. The specific mechanism of action of fibrates relies on their interaction with nuclear receptors, so called PPAR (peroxisome proliferator activated receptors), which are crucial transmitters of stimuli for the genes controlling the metabolism of lipids. As a result of their action, there is a decrease in the level of triglycerides by 20ñ50%, the increase of cholesterol HDL by 10ñ15% and a decrease in the LDL fraction. Apart from the significant influence on the profile of lipids and lipoproteins, this group of com- Abstract: With reference to common application of HPLC to routine analytical tests on medicinal products decreasing the level of cholesterol, including three compounds from this group ñ fenofibrate, bezafibrate and etofibrate, we developed a new method for determining two other compounds ñ ciprofibrate and gemfibrozil. The developed HPLC method may be used for identification and qualitative determination of selected compounds ñ derivatives of aryloxyalkylcarboxylic acids as well as it may be used for simultaneous separation and determination of all compounds from the group of fibrates using one column and the same methodology. The results and statistical data indicate good sensitivity and precision. The RSD value presented is equivalent to the newly developed method of determinination of ciprofibrate and gemfibrozil in the substances and medicinal products ñ capsules and coated tablets. ANALYSIS METHODS OF CHROMATOGRAPHIC DETERMINATION OF MEDICINE

Synthesis and study of substituted amides of some 5-membered isocyclic and heterocyclic acids as potential anticonvulsants

A series of substituted amides of isocyclic and heterocyclic acids have been synthesized. All obtained compounds were evaluated qualitatively for their anticonvulsant activity in the maximal electroshock seizure test (MES test) and psychomotor seizure test (6 Hz test) in mice after intraperitoneal administration. The neurological toxicity was determined in the rotorod neurotoxicity test (Tox test). Two of these compounds appeared most promising: 3-oxo-1-cyklopentanecarboxylic acid 2-fluorobenzylamide (5), 1-cyclopentenecarboxylic acid 2-(trifluoromethyl)benzylamide (8) and were tested quantitatively in MES test in mice after oral administration (o.p.) and in 6 Hz test in mice after intraperitoneal administration(i.p.). Compound (5) showed MES ED50 =82.65 mg/kg and compound (8) showed 6 Hz ED50=84.13 mg/kg