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Biomedical subjects

G Lubec

Publications and source records attributed to G Lubec.

At least 199 records · Page 11Linked to original sources
PubMed1995

Thiazolidine prodrugs of cysteamine and cysteine as radioprotective agents.

The need for protection against the toxic effects of ionizing radiation comes from many different directions: occupational exposure, nuclear accidents, environmental sources and protection of normal tissue during the therapeutic irradiation of cancer. Sulfhydryl-containing compounds, including cysteamine and L-cysteine, have long been known to possess radioprotective properties, but their therapeutic utility is limited by their side effects at radioprotective doses. To avoid this drawback, thiazolidine prodrugs of cysteamine and L-cysteine were prepared by the condensation of each thioalmine with the aldose monosaccharides, D-ribose and D-glucose, producing RibCyst, GlcCyst, RibCys and GlcCys. The prodrugs were designed to liberate the parent thiolamine nonenzymatically, after ring opening and hydrolysis, which is then available to function as a radioprotective agent. Cysteamine's inherent toxicity, measured using Chinese hamster V79 cells growing in culture, was completely eliminated, even at concentrations as high as 25 mM, by providing the thiolamine in the form of a prodrug. Good protection against radiation-induced lethality was demonstrated by the cysteamine prodrugs using a clonogenic assay. Protection against radiation-induced DNA single-strand breaks, as measured by alkaline elution, was also shown by both RibCyst and GlcCyst; this activity was higher than that exhibited by either cysteamine or WR-1065. The L-cysteine prodrugs, RibCys and GlcCys, also possessed radioprotective abilities under most of the conditions studied. Protection against DNA damage was comparable between L-cysteine, WR-1065 and RibCys.

Animals↗
PubMed1994

Low-dose dietary L-arginine increases plasma interleukin 1 alpha but not interleukin 1 beta in patients with diabetes mellitus.

Oral high-dose arginine supplementation is used for the experimental immunotherapy of tissue trauma and sepsis. Yet the adequate dosage required for immunomodulation has to be established and the toxicity of high-dose arginine has not been fully elucidated. Following a protocol for the treatment of diabetic long-term complications (oral daily doses of 30 mg/kg BW; blind, placebo-controlled prospective study with crossing-over design) we studied plasma levels of interleukins 1 alpha (IL-1 alpha) and 1 beta reflecting immunostimulation. Arginine supplementation in 29 patients with diabetes mellitus prompted a 2-fold increase of IL-1 alpha from baseline levels (P < 0.001) while IL-1 beta was unaffected. Implications for the treated panel of diabetic patients could be a reduction of collagen accumulation by enhanced collagenolysis and clearance of advanced-stage non-enzymatic glycosylation products. Based upon our data, low-dose arginine protocols for further immunotherapeutical studies should be discussed.

Aged↗
PubMed1994

L-arginine reduces kidney collagen accumulation and N-epsilon-(carboxymethyl)lysine in the aging NMRI-mouse.

BACKGROUND: The aging process leads to glomerular basement membrane (GBM) thickening due to increased collagen accumulation. This mechanism can be explained by the nonenzymatic glycosylation hypothesis of collagen aging. We have published the positive effect of L-arginine on glucose-mediated cross-linking, and if the nonenzymatic glycosylation hypothesis of aging holds, the pharmacological effect of L-arginine on glucose-mediated cross-links in the aging Hannover NMRI mouse can be expected. METHODS: Animals were given L-arginine 50 mg/kg body weight/day orally and compared to a control group without treatment. RESULTS: Electron microscopical measurement of the GBM thickness showed significant differences between controls (4920 +/- 1680 A) and the experimental group (2345 +/- 815 A). Determination of the total kidney collagen content based upon 4-trans hydroxyproline revealed 13.9 +/- 3.9 mg/100 mg kidney weight (kw) in the untreated group versus 7.9 +/- 4.2 mg/100 mg kw in the treated group. For solubility studies based upon hydroxyproline determination, collagen was eluted by pepsin digestion. This revealed 18.7 +/- 3.9 mg/100 mg kw in the controls versus 7.8 +/- 4.8 mg/100 mg kw in the treated group. HPLC analysis of N-epsilon-(carboxymethyl)lysine (CML) showed in the treated group (1.847 +/- 0.247 nM/microM hydroxyproline) significantly lower concentrations than in the untreated group (3.399 +/- 0.349 nM/microM hydroxyproline). On sodium dodecyl sulfate (SDS) polyacrylamidegel electrophoresis, the eluates of the treated animals showed less high molecular weight material than their untreated mates. CONCLUSIONS: We cannot discriminate between the probable mechanisms of cross-linking but we clearly can state that L-arginine reduces cross-linking and collagen accumulation in aging collagen type IV accompanied and strongly associated with decreased CML content.

Aging↗
PubMed1994

Racemization and oxidation studies of hair protein in the Homo tirolensis.

Amino acids contained in fossil materials show an increasing extent of racemization with age, postulating time and temperature as the two major variables. The recent discovery of the Homo tirolensis made possible a comparison between racemization rates of the amino acids found in hair at identical ages (5200 years of age) but at different diagenetic temperatures ("Ginger," found in the hot, dry sand of Egypt; H. tirolensis, found on a glacier of the Otztaler Alps). The rate of racemization was higher in the H. tirolensis, which is surprising and in contrast to current concepts. Ortho-tyrosine and di-tyrosine, parameters for OH-radical attack, were also higher in the H. tirolensis, suggesting a role for free OH-radical involvement in the racemization process.

Amino Acids↗
PubMed1994

Thiaproline reduces glomerular basement membrane thickness and collagen accumulation in the db/db mouse.

Glomerular basement membrane thickening and mesangial expansion are the main pathological features in diabetic nephropathy--glomerulosclerosis with the biochemical correlate of increased collagen accumulation. We studied a new principle to reduce collagen accumulation in the glomerulus: thiaproline, known to inhibit protein synthesis by blocking the elongation, led in our studies to a morphological reduction of the glomerular basement membrane thickening and to a decreased collagen content. As the thiaproline analogue is incorporated into collagen, the mechanism of increased degradation of the modified collagen is being discussed.

Animals↗
PubMed1994

Creatine reduces collagen accumulation in the kidneys of diabetic db/db mice.

In the present study, we tested the hypothesis whether creatine, a metabolite of arginine metabolism, shares the pharmacological activities of arginine reducing collagen accumulation in the diabetic kidney. Ten db/db mice were given, for 3 months, a solution containing a daily dosage of creatine of 50 mg/kg body weight. Eleven db/db mice served as controls. At the end of the 3-month study period, the mean N-carboxymethyllysine concentration in the untreated group was significantly higher than in the treated group (0.163 +/- 0.18 versus 0.096 +/- 0.017 nmol/mumol hydroxyproline, p < 0.001). Collagen accumulation was also significantly higher in the untreated than in the treated group (2.21 +/- 0.24 versus 1.68 +/- 0.22 mumol hydroxyproline/100 mg kidney weight, p < 0.001). We conclude that creatine led to a significant reduction in collagen type IV accumulation resembling arginine or aminoguanidine action. We do suggest that the guanidino group common to both compounds is able to block reactive carbonyls.

Animals↗
PubMed1994

L-arginine reduces heart collagen accumulation in the diabetic db/db mouse.

BACKGROUND: Diabetic cardiomyopathy presents with significant collagen accumulation; decreased solubility, increased glucose-mediated abnormal cross-linking, free radical cross-linking, or glucose-induced increased transcription of collagen is incriminated. In a previous study, we reduced collagen accumulation in the kidneys of diabetic mice by treatment with oral arginine. This observation led us to examine the effect of arginine on cardial fibrosis. METHODS AND RESULTS: Twenty-nine db/db spontaneously diabetic mice were used in the experiments. Sixteen were given L-arginine (free base, in tap water, 50 mg/kg body wt per day) for 4 months. At the end of the experiment, we determined total collagen content of total ventricular tissue, acid solubility, carboxymethyllysine, O-tyrosine, glutathione, blood glucose, and fructosamine as parameters for glycemic control. Heart collagen level was significantly (P = .0001) reduced in the experimental group (mean, 0.24 +/- 0.05) compared with the control group (mean, 0.49 +/- 0.10 mumol hydroxyproline per 100 mg heart tissue). Significantly more collagen could be eluted from heart samples of the experimental group (P = .02). Carboxymethyllysine and O-tyrosine did not differ when related to heart weight. Glutathione level was significantly higher in the untreated group (P = .003). Parameters of glycemic control did not differ between the groups. CONCLUSIONS: Our findings clearly indicate that L-arginine reduced total heart collagen and increased acid solubility of heart collagen. Both findings are compatible with the cross-linking hypothesis. The data for carboxymethyllysine, O-tyrosine, and glutathione would rule out the glycoxidation hypothesis and, therefore, free radical cross-linking. The postulated mechanism of action is most likely the blocking of reactive carbonyl functions by L-arginine in analogy to aminoguanidine activity. Correlations of collagen with glycemic control, however, point to an association of glucose with collagen metabolism, a phenomenon documented in cell cultures at the transcriptional level.

Animals↗
PubMed1992

L-arginine reduces glomerular basement membrane collagen N epsilon-carboxymethyllysine in the diabetic db/db mouse.

The present study was carried out to examine the effect of L-arginine on advanced stage nonenzymatic glycosylation end products in glomerular basement membrane (GBM) as represented by carboxymethyllysine (CML). Twelve db/db mice were given a solution containing a daily dosage of L-arginine of 50 mg/kg body weight orally. Twelve db/db mice served as controls. At the end of the 4-months study period treated animals had significantly lower concentrations of CML (0.084 +/- 0.008, 0.071-0.098 nmol/mumol OH-proline; mean +/- SD, range, p less than 0.01) compared to untreated controls (0.11 +/- 0.018, 0.095-0.152 nmol/mumol OH-proline). In addition, there was a significant positive correlation between GBM thickness and concentrations of CML (r = 0.86, p less than 0.001). We conclude that reduction of CML concentrations in treated db/db mice possibly reflects a beneficial effect of L-arginine on advanced stage nonenzymatic glycosylation end-products in GBM. In addition, measuring CML concentrations might have future clinical implications as a noninvasive parameter for basement membrane thickening.

Administration, Oral↗
PubMed1991

Urinary 3-hydroxyproline excretion in Alport's syndrome: a non-invasive screening test?

Alport's syndrome is characterised by morphological and structural changes of the renal basement membranes. As the hydroxyproline content of isolated glomerular basement membranes is reduced in patients with Alport's syndrome, it is possible that the renal excretion of 3-hydroxproline (3-OHP), a key substrate of basement membrane collagen, may be altered in such patients. The urinary excretion of 3-OHP was determined by thin layer chromatography in 20 patients with Alport's syndrome, in healthy control subjects, and in patients with other renal diseases. These included patients with poststreptococcal glomerulonephritis, lower urinary tract infection, severe reflux nephropathy, lithium induced nephropathy, polycystic kidney disease, familiar benign haematuria, and renal graft rejection. Urinary excretion of 3-OHP was significantly higher in patients with Alport's syndrome compared with the patients with other renal diseases and the healthy control subjects. All other renal diseases investigated had 3-OHP values within the normal range. Urinary 3-OHP determination detected patients with Alport's syndrome with a high sensitivity (95.2%) and specificity (97.2%). We therefore suggest using urinary 3-OHP determinations as a simple non-invasive screening test for Alport's syndrome.

Adolescent↗
PubMed1990

[Clomiphene citrate ointment in the local treatment of condylomata acuminata].

The hypothesis underlying local treatment of Condylomata acuminata with clomiphene citrate is based on the assumption that susceptibility to this disease in women depends on the relative amount of oestrogen receptors in the affected, as opposed to the unaffected areas. We postulate blockade of these skin receptors after local application of clomiphene citrate ointment. A pilot study was conducted in 15 patients aged 20-33 with Condylomata acuminata. After only 2 months a complete remission was recorded in 12 patients (= 80%).

Administration, Topical↗
PubMed1990

The effect of substance L on glucose-mediated cross-links of collagen in the diabetic db/db mouse.

Genetically diabetic mice (db/db) were given 50 mg/kg body weight/day substance L, a nontoxic basic amino acid and compared to control diabetic mice without treatment. The oral administration of the compound was started at the age of 3 months and the animals were sacrificed at the age of 7 months. No adverse effects were observed in animals given the substance L. Total food consumption, drinking water intake and body weight were comparable between the groups. Nonenzymatic glycosylation of serum proteins and hemoglobin was not significantly different in the groups. Renal pathological lesions in the control diabetic mice showed glomerular mesangial expansion and on electron microscopy thickened glomerular basement membranes with a mean thickness of 3,204 +/- 186 A. Treated animals showed significantly less mesangial crescents and thinner glomerular basement membrane thickness of 2,520 +/- 252 A (p less than 0.01). The experimental animals showed in addition a lower mean kidney weight. Glomerular but not tubular proteinuria was reduced in the treated group. Basement membrane collagen type IV isolated from kidneys of experimental animals was more soluble in acidity and showed a lower degree of cross-linking as evaluated by SDS-polyacrylamide gel electrophoresis. We conclude that substance L is beneficial to diabetic renal changes. We suggest that this positive effect could be due to the inhibition of glucose-mediated abnormal cross-linking of collagenous structures by the interaction of substance L with reactive carbonyl residues of glycosylation adducts of collagen. Other possible mechanisms are discussed.

Administration, Oral↗
PubMed1990

[Paracetamol hepatotoxicity].

A potential side effect of paracetamol is its hepatotoxicity. This side effect can be found in excessive overdosages exceeding the therapeutical dosage significantly. There is a specific antidot: N-acetyl-cysteine. Liver diseases are not absolute contraindication against paracetamol medication.

Acetaminophen↗
PubMed1990

A species and organ specific glomerular basement membrane antigen.

By the use of a monoclonal antibody reacting with the human glomerular basement membrane exclusively we have been isolating a specific glomerular antigen. The antibody failed to react with other renal structures and other basement membranes and extracellular matrix constituents of other organs or plasma proteins. It did not react with glomerular basement membranes of other species as mice and rats. For the isolation of the antigen we applied affinity chromatography, on Sepharose beads coupled to the monoclonal antibody PM II 34 G3. From this column the antigen was eluted under acid conditions. In 8% polyacrylamide gel electrophoresis the approximate molecular weight was estimated with 14400 daltons, which was confirmed on high pressure liquid chromatography using the Bio-Sil TSK method. The antigen was temperature sensitive in that at high temperatures (60 degrees C) several bands on SDS-PAGE and several peaks on HPLC could be noted. This could be responsible for the crystal formation after treatment/concentration on the rotary vacuum pump at 60 degrees C. Preliminary data of amino acid analysis showed a high glycine content pointing towards a collageneous molecule. But cross reactivity with many connective tissue proteins could be ruled out by immuno-histochemical techniques and affinity chromatography. A major point of interest is that this antigen can be detected in human urine under physiological conditions. We are herewith reporting the first species and organ specific glomerular basement membrane antigen.

Amino Acids↗