Aminoguanidine inhibits albuminuria, but not the formation of advanced glycation end-products in skin collagen of diabetic rats.

Aminoguanidine, an inhibitor of advanced glycation reactions in vitro, inhibits the development of diabetic complications in animal models of diabetes, suggesting that it acts by inhibition of advanced glycation reactions in vivo. However, effects of aminoguanidine on the formation of specific advanced glycation end-products (AGEs) in vivo have not been rigorously examined. Therefore, we studied the effects of aminoguanidine on the formation of pentosidine and N(epsilon)-(carboxymethyl)lysine (CML), measured by analytical chemical methods, in collagen of streptozotocin-diabetic Lewis rats at doses which ameliorated urinary albumin excretion, an index of diabetic nephropathy. At 12 weeks, diabetic animals had fivefold higher blood glucose, threefold higher glycated hemoglobin and fivefold higher collagen glycation, compared to metabolically healthy controls; pentosidine and CML in skin collagen were increased by approximately 30 and 150%, respectively. Administration of aminoguanidine, 50 mg/kg by daily intraperitoneal injection, significantly inhibited the development of albuminuria (approximately 60%, P < 0.01) in diabetic rats, without an effect on blood glucose or glycation of hemoglobin or collagen. Surprisingly, aminoguanidine failed to inhibit the increase in pentosidine and CML in diabetic rat skin collagen. Similar results were obtained in an independent experiment in which aminoguanidine was administered in drinking water at a dose of 0.5 g/l. We conclude that the therapeutic benefits of aminoguanidine on albuminuria may not be the result of inhibition of AGE formation.

Potent free radical scavenging activity of propol isolated from Brazilian propolis.

We evaluated free radical scavenging activity of the water, methanol and chloroform extracts of propolis in 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical and xanthine-xanthine oxidase (XOD) generated superoxide anion assay systems. The free radical scavenging activity guided fractionation and chemical analysis led to the isolation of a new compound, propol (3-[4-hydroxy-3-(3-oxo-but-1-enyl)-phenyl]-acrylic acid) from the water extract, which was more potent than most common antioxidants such as vitamin C and vitamin E (alpha-tocopherol) in these assay systems.

Nucleosides 5(15): synthesis of novel 1,2,4-triazolo[3,4-c]-1,2,4-triazole nucleosides.

Ribosylation of 3-methylthio-5-phenyl-1,2,4-triazole (1) with ribose derivative 2 gave the protected 1,2,4-triazole-nucleoside 3, which reacted with hydrazine hydrate to afford the 3-hydrazino-1,2,4-triazole derivative 5. Reaction of 5 with aromatic aldehydes yielded the corresponding hydrazones 6, which cyclized under bromination in acetic acid to give 8. Debenzoylation of 8 afforded novel 1,2,4-triazolo[3,4-c]-1,2,4-triazole nucleosides 9.

[Biotransformation and pharmacokinetics of bamipine in rats. 1. biotransformation]. / Biotransformation und Pharmakokinetik von Bamipin an Ratten. 1. Mitteilung: Untersuchungen zur Biotransformation.

Biotransformation and Pharmacokinetics of Bamipine in Rats/1st Communication: Biotransformation studies. The metabolism of the antihistaminic N-phenyl-N-benzyl-4-amino-1-methylpiperidine (bamipine) was investigated after oral application in Wistar rats. The major metabolites in the urine were the ether glucuronides of N-p-hydroxy-phenyl-N-benzyl-4-amino-1-methylpiperidine and of N-p-hydroxyphenyl-N-benzyl-4-amino-piperidine. Unchanged drug was not detected. In vitro studies showed, in good correlation with in vivo studies, a oxidative demethylation of bamipin.

[Biotransformation and pharmacokinetics of bamipine in rats. 2. Pharmacokinetics (P 2)]. / Biotransformation und Pharmakokinetik von Bamipin an Ratten. 2. Mitteilung: Untersuchungen zur Pharmakokinetik (2. Teil).

After oral application pharmacokinetic parameters of N-phenyl-N-benzyl-4-amino-1-methylpiperidin (bamipine) were investigated. The curve of the plasma level is characterized by two maxima. If the first maximum is neglected, the calculated elimination half-life is 9.52 h, the invasion half-life 1.03 h. The first maximum is calculated as a lag-time (1.62 h). By whole-body radiography of the animal an accumulation of activity was determined in the glandular tissues behind the eye--beside the usual accumulation of activity in liver, spleen, kidney and lung.

[Biotransformation und pharmacokinetics of beta-methyl[1,1'-biphenyl]-4-propanenitrile (LU 20884) in rats. Studies on biotransformation]. / Biotransformation und Pharmakokinetik von beta-Methyl[1,1'-biphenyl]-4-propannitril (LU 20884) an Ratten. Untersuchungen zur Biotransformation.

The metabolism of the antiphlogistic beta-methyl[1,1'-biphenyl]-4-propanenitrile (LU 20884) was investigated in urine after oral application in male Wistar-rats. Metabolite with the major share was alpha-hydroxy-4'-methoxy-alpha-methyl[1,1'-biphenyl]- 4-aceticacidmethylester, which could be identified by mass and 1H-NMR spectroscopy as derivative of diazomethane. Furthermore the following metabolites could be detected as 4'-methoxy-beta-methyl[1,1'-biphenyl]-4-propanoicmethylester and propanenitrile.

[Biotransformation and pharmacokinetics of beta-methyl-(1,1'-biphenyl)-4-propanenitrile (LU 20,884) in rats. Spectroscopic studies]. / Biotransformation und Pharmakokinetik von beta-Methyl-[1,1'-biphenyl]-4-propannitril (LU 20,884) an Ratten. Spektroskopische Untersuchungen.

Several compounds of comparison have been examined by their spectroscopic behavior in mass-, 1H-NMR- and IR-spectra of the antiphlogistic active beta-methyl[1,1'-biphenyl]-4-propanenitrile (LU 20,884). Characteristic fragments of alkyl-substituted biphenyls could be determined as well as the localisation of hydroxylated products in 1H-NMR-spectra.

[Biotransformation and pharmacokinetics of mesoionic didehydro-4-methyl-5-phenyl-1,3,4-thiadiazolidine-2-thione (LU 2443). Studies on its biotransformation in rats]. / Biotransformation und Pharmakokinetik von mesoionischem Didehydro-4-methyl-5-phenyl-1,3,4-thiadiazolidin-2-thion (LU 2443). Untersuchungen zur Biotransformation an Ratten.

The metabolism of the antiepileptic mesoionic didehydro-4-methyl-5-phenyl-1,3,4-thiadiazolidine-2-thione (LU 2443) was investigated after p.o. application in rats. The main metabolite was benzoic acid, besides the unchanged material and hippuric acid the spasmodically compounds N-methyl-benzamide and mesionic didehydro-4-methyl-5-phenyl-1,3,4-thiadiazolidine-2-one were detectable. In-vitro experiments could be demonstrated that LU 2443 was not demethylated by biochemical oxidation, and LU 2443 was also very stable against metabolizing influences by enteric bacteria.

[Biotransformation and pharmacokinetics of mesionic didehydro-4-methyl-5-phenyl-1,3,4-thiadiazolidine-2-thione (LU 2443). Studies on the pharmacokinetics in rats]. / Biotransformation und Pharmakokinetik von mesoionischem Didehydro-4-methyl-5-phenyl-1,3,4-thiadiazolidin-2-thion (LU 2443). Untersuchungen zur Pharmakokinetik an Ratten.

After p.o. application in rats the pharmacokinetic properties of the mesionic dihydro-4-methyl-5-phenyl-1,3,4-thiadiazolidine-2-thione (LU 2443) were examined. The compound is extensively absorbed, in the maximum 18% are eliminated unabsorbed. The half-time of the activity in plasma is 13.17 h, the highest concentration in plasma after p.o. application as a solution of polyethyleneglycol is reached after 5.09 h. The elimination is mainly renal--namely 61.9%, 28.7% are eliminated with the faeces. After 96 h 90.6% of the applicated activity was eliminated. The distribution of LU 2443 was in the whole organism; entrance of the compound into liquor was proven. By radiography of the total animal a transient accumulation of LU 2443 and its metabolites in liver and kidney was determined; besides, a considerable concentration of activity in the suprarenal medulla was found.

[Biotransformation and pharmacokinetics of beta-methyl-(1,1'-biphenyl)-4-propanenitrile (LU 20884) in rats. Studies on pharmacokinetics]. / Biotransformation und Pharmakokinetik von beta-Methyl-[1,1'-biphenyl]-4-propannitril (LU 20884) an Ratten. Untersuchungen zur Pharmakokinetik.

After oral application in Wistar rats the pharmacokinetic properties of beta-methyl[1,1'-biphenyl]-4-propanenitrile (LU 20884) were investigated. The compound is extensively absorbed, a maximum amount of 8.9% being eliminated as unchanged drug. The half-life in plasma is 22.7 h; the highest concentration in plasma is reached after 6.85 h. The maximum of the primary product is achieved after 4 h which substantiates its intensive and fast rate of metabolism. The distribution of LU 20884 is to be seen in the whole organism. An enrichment of activity is to be found in liver and kidney. The lowest concentration can be detected in brain. The elimination takes place almost equally in urine (44.7%) and feces (41.3%). The total excretion of the administered activity is 86.0% after 96 h; 1.8% of the activity still remains in the organism.

[Biotransformation and pharmacokinetics of grandiflorenic acid [kauradiene-9(11),16-oic acid-18] / 1st communication (author's transl)]. / Biotransformation und Pharmakokinetik von Grandiflorensäure [Kauradien-9(11),16-säure-18] 1. Mitt.: Spektroskopische Untersuchungen

Grandiflorenic acid is oxidized by several partial-synthetic ways. The spectroscopic properties of the resulting compounds are compared in mass-, IR- and 1H-NMR-spectrometer.

[Biotransformation and pharmacokinetics of grandiflorenic acid [kauradien-9(11),16-oic acid-18] / 2nd communication (author's transl)]. / Biotransformation und Pharmakokinetik von Grandiflorensäure [Kauradien-9(11),16-säure-18] 2. Mitteilung: Untersuchungen zur Biotransformation an Ratten.

6 metabolites are formed by incubation of grandiflorenic acid (GFA) with rat liver microsomes. 79% of GFA are metabolized after i.p. application to rats; 11 biotransformation products are found in faeces, the main excretion way. They are conjugated to glucuronic acid. Gut microflora is involved in these metabolic reactions. The structure of three metabolites is proved by IR-, MS- and NMR-spectroscopies.

[Biotransformation and pharmacokinetics of grandiflorenic acid [kauradien-9(11),16-oic acid-18]. 3rd communication (author's transl)]. / Biotransformation und Pharmakokinetik von Grandiflorensäure [Kauradien-9(11),16-säure-18] 3. Mitteilung: Untersuchungen zur Pharmakokinetik an Ratten.

Absorption, metabolism and excretion of 14C-GFA following i.v., i.p. and oral application are investigated in rats. After i.p. administration GFA is completely absorbed, after oral dosage about 83% are absorbed. GFA is excreted by 100% via bile and undergoes extensive enterohepatic circulation. After administration of 20 mg/kg 14C-GFA nearly all radioactivity is eliminated after 96 h, more than 80% via the faeces.

In vitro studies of poorly absorbed drugs using porcine intestine in the ring model RIMO.

Two compounds, an aminobisphosphonate (A) and a steroid (B), showing a very large difference in lipophilicity (log PC (A) = O, log PC (B) > 8) but both revealing very poorly absorption in vivo of less than 1% were tested in respect of in vitro absorption and mucoadhesion using a model with porcine intestine named RIMO (ring model). Explanations for the poor absorption of the two compounds were investigated in order to propose methods for absorption enhancement. Moreover, absorption and mucoadhesion were measured for different parts of intestine with radiolabelled substances. Last but not least the inhibiting effect of calcium ions was investigated as well as enhancement by DTT (dithiothreitol), EDTA and bile. Results showed that mucus plays an important role in oral bioavailability. The aminobisphosphonate formed a complex with calcium ions which was insoluble in the mucus and resulted in a smaller amount of substance being absorbed. The very lipophilic steroid was kept back from the mucosa by the hydrophilic mucus, but addition of the solubilizer bile increased the absorption. The results were in good agreement with in vivo bioavailability data. Therefore, simplicity of the model and easy access of porcine intestine by slaughter houses make RIMO a valuable tool for investigations concerning the role of mucus and influences of diverse additives on absorption.

Biotransformation of the organic nitrate trans-N-(4-nitroxycyclohexyl)acetamide in dogs.

The biotransformation of BM 12.1307 (trans-N-(4-nitroxycyclohexyl)acetamide, CAS 137291-91-3) in the dog was examined after oral and intravenous administration. For that purpose, the organic nitrate was synthesized as radioactive [14C]- and as [13C]-labeled compounds. The defined isotopic mixture was administered to the dogs. Within the examined period of 168 h, the elimination of BM 12.1307 and its metabolites via urine and feces amounted to 76.5% after oral application, and to 80.7% of the applied dose after intravenous application. The major amount of radioactivity was eliminated via urine (69.4% and 73.6% of the dose, respectively), whereas the fecal elimination was found to be negligible. Investigations of the urinary samples showed that the drug is metabolized to a high percentage trans-N-(4-Hydroxycyclohexyl) acetamide is the main metabolite; 73% of the radioactive compounds (after p.o.-administration and 69% after intravenous application could be identified as the alcohol of BM 12.1307; the amounts of the drug totalled 9% and 13%, respectively. The quantitative determination of BM 12.1307 in urine and plasma was performed by gas chromatography; the amount of the main metabolite excreted in urine was determined by high-pressure liquid chromatography. Trans-N-(4-hydroxycyclohexyl)-acetamide, N-(4-oxocyclohexyl)acetamide, and 3-acetamido-7-oxa-bicyclo [4.1.0]heptane were formed as metabolites. For the identification and characterization of the possible metabolic structures, these compounds were synthesized and used in comparison with the detected drugs.

[Pharmacokinetics of 4-oxa-5-exo-(N-methylcarbamoyloxy)-tricyclo- [5.2.1.0. 2,6-endo] dec-8-en-3-one in the rat]. / Pharmakokinetik von 4-Oxa-5-exo-(N-methylcarbamoyloxy)-tricyclo- [5.2.1.0. 2,6endo]dec-8-en-3on an der Ratte.

Pharmacokinetics of 4-Oxa-5-exo-(N-methylcarbamoyloxy)-tricyclo- [5.2.1.0. 2,6endo]dec-8-en-3one in the Rat The pharmacokinetics of 4-oxa-5-exo-(N-methylcarbamoyloxy)-tricyclo- [5.2.1.0. 2,6endo]dec-8-en-3one (Lu 253) were investigated after oral application in male Wistar rats. The compound is extensively absorbed and mainly renally eliminated. Within 60 h, 63% of the activity is recovered in urine and faeces. After 12 h 27% of the activity is eliminated (application in polyethylene glycol). The highest total concentration of the activity in the plasma is found after 2 h, the highest of the unchanged drug is found after 1 h. The half-life is 2.9 h. The concentration in plasma is mathematically characterized by the parameters of a two-compartiment model and also independent of a model. Lu 253 is distributed in the whole organism, a maximum of activity is achieved 2 h after application. By whole-body autoradiography the entrance of the compound into liquor and an enduring accumulation in the frontal cavity is detected.

Biotransformation and pharmacokinetics of the nitrate trans-2-amino-2-methyl-N-(4-nitroxycyclohexyl)-propionamide in dogs.

The biotransformation and the pharmacokinetic behavior of the organic nitrate trans-2-Amino-2-methyl-N-(4-nitroxycyclohexyl)-propionamide (BM 12.1179, CAS 129795-96-6) were examined in dogs. BM 12.1179 was predominantly eliminated by urinary excretion, and the unchanged molecule prevailed in urine as well as in plasma. By means of various mass spectroscopic methods, the chemical structures of the metabolites were elucidated. As metabolites trans-2-amino-2-methyl-N-(4-hydroxycyclohexyl)-propionamide and trans-2-amino-2-methyl-N-(4-oxocyclohexyl)-propionamide were formed. Urine levels of the main metabolite were determined by high-pressure liquid chromatography; plasma and urine levels of BM 12.1179 were determined by capillary gas chromatography. The absolute bioavailability of BM 12.1179 was 80-100%. The plasma protein binding was about 34% which is high in comparison to other organic nitrates. BM 12.1179 represents a long-acting organic nitrate in that it shows a slow reductive denitration, and a long elimination half-life of about 10 h.

[Biotransformation of 4-oxa-5-exo-(N-methylcarbamoyloxy)-tricyclo-[5.2.1.0-2, 6endo] dec-8-en-3one in the rat]. / Biotransformation von 4-Oxa-5-exo-(N-methylcarbamoyloxy)-tricyclo-[5.2.1.0-2,6endo]dec-8-en -3on an der Ratte.

The metabolism of the analgesic compound 4-oxa-5-exo-(N-methylcarbamoyloxy)-tricyclo-[5.2.1.0-2. 6endo]dec-8-en-3one (Lu 253) was investigated after oral application in male Wistar rats. From urine, faeces, bile, and plasma epoxidized, rearranged, and N-desmethylated metabolites were isolated. The main reaction was the epoxidation of the double bond. The structure of most of the biotransformation products was proved by synthetic compounds.