Hepatorenal tyrosinaemia (HT1) is an autosomal recessive disorder of tyrosine degradation resulting in hepatic and renal dysfunction, neurological sequelae may occur in some patients. The use of nitisinone (NTBC) has revolutionised treatment and outcome of this disorder. NTBC has to be combined with a low protein diet. While NTBC modulates the disease course in HT1 patients, several issues are open. Optimal dosage, doses per day, therapeutic range of NTBC concentration, mode of protein restriction and biomarkers are not well defined. HCC and neurocognitive deficits are long-term sequelae. Early diagnosis and treatment are essential to minimise the risk for these complications. Clinical guidance for management of HT1-patients is required. Randomised clinical studies are difficult in the presence of therapeutic options. We discussed these issues in a consensus group of 10 paediatricians, 1 adult hepatologist, 1 geneticist, 2 dieticians, 2 newborn screening specialists with experience in HT1, 1 psychologist and 2 representatives of a patient group from the German-speaking countries (DACH). Recommendations were based on scientific literature and expert opinion, also taking into account recent experience with newborn screening. There was strong consensus that newborn screening using succinylacetone (SA) and early treatment are essential for a good outcome. The dose of NTBC should be as low as possible without losing metabolic control. This has to be accompanied by a low protein diet, in some patients a simplified diet without calculation of protein intake. Specific education and psychosocial support are recommended. Indications for liver transplantation were defined. Monitoring shall include clinical findings, levels of SA, tyrosine, phenylalanine and NTBC in (dried) blood.

• MeSH
• Cyclohexanones * therapeutic use   MeSH
• Heptanoates MeSH
• Consensus MeSH
• Humans MeSH
• Nitrobenzoates * therapeutic use   MeSH
• Diet, Protein-Restricted MeSH
• Infant, Newborn MeSH
• Neonatal Screening * methods   MeSH
• Liver Transplantation MeSH
• Tyrosinemias * diagnosis   therapy   MeSH
• Check Tag
• Humans MeSH
• Infant, Newborn MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Geographicals
• Germany MeSH

Úvod: Cílem práce je ovlivnit růst a histologické změny ve stěně experimentálně navozeného aneuryzmatu břišní aorty u velkého laboratorního zvířete (prase domácí) podáváním atorvastatinu (inhibitoru 3-hydroxy-3-methyl-glutaryl-koenzym A reduktázy). Materiál a metodika: V uvedené experimentální práci srovnáváme rychlost růstu experimentálního aneuryzmatu u prasete ve skupině ovlivňované podáváním statinu (n=14) a ve skupině farmakologicky neovlivněné (n=13). Srovnáváme i histologické změny ve stavbě aortální stěny v obou skupinách a v aortální stěně bez aneuryzmatu (n=6). Výsledky: Během 4týdenního sledování jsme neprokázali statisticky významný rozdíl v rychlosti růstu aneuryzmat mezi uváděnými skupinami. Histologická skladba stěny aneuryzmatu se v obou skupinách lišila. Ve skupině zvířat farmakologicky ovlivněné se složení stěny blížilo složení stěny aorty bez aneuryzmatu. Závěr: Předložené výsledky dokazují, že statiny ovlivňují skladbu aortální stěny. Navozené změny mohou vést ke stabilizaci stěny aneuryzmatu. Domníváme se, že pacienti s menšími aneuryzmaty, kteří nejsou indikováni k chirurgické nebo endovaskulární léčbě, by mohli být léčeni statiny. Tato léčba by mohla stabilizovat stěnu aneuryzmatu, což by mohlo zpomalovat růst a předcházet ruptuře aneuryzmatu.

Introduction: The aim of our work was to influence growth and histological changes in the wall of an experimentally induced aneurysm of the abdominal aorta in a large laboratory animal (domestic pig) by administering atorvastatin (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor). Material and methods: Within the scope of the above mentioned experimental work, we compared the growth rate of the aneurysm between the group influenced by statin administration (n=14) and the group without any pharmacological treatment (n=13). We also compared histological changes in the structure of the aortic wall in both groups with aneurysm and the wall of the aorta without aneurysm (n=6). Results: During the 4-week follow-up, we did not prove a statistically significant difference in the growth rate of aneurysms between the above mentioned groups. The histological structure of the aneurysm walls, however, differed between the two groups. The structure of the wall in the group of animals influenced by statin administration resembled the structure of the aortic wall without aneurysm. Conclusion: The results presented demonstrate that statins do influence the composition of the aortic wall. In our opinion, the administration of statins could lead to changes resulting in a more stable aneurysmatic wall. We believe that patients with smaller aneurysms who are not indicated for surgery or endovascular treatment could be treated with statins. Stabilization of the aneurysmal wall could slow down the growth of the aneurysm and prevent its rupture.

• Keywords
• aneuryzma, experimentální model,
• MeSH
• Aortic Aneurysm, Abdominal * drug therapy   pathology   MeSH
• Heptanoates * administration & dosage   pharmacology   MeSH
• Immunohistochemistry methods   utilization   MeSH
• Disease Models, Animal MeSH
• Pyrroles * administration & dosage   pharmacology   MeSH
• Hydroxymethylglutaryl-CoA Reductase Inhibitors * administration & dosage   MeSH
• Sus scrofa MeSH
• Tunica Intima cytology   drug effects   MeSH

• MeSH
• Amlodipine administration & dosage   therapeutic use   MeSH
• Drug Combinations MeSH
• Heptanoates therapeutic use   MeSH
• Drug Evaluation statistics & numerical data   MeSH
• Risk Assessment statistics & numerical data   MeSH
• Hypercholesterolemia drug therapy   complications   MeSH
• Hypertension drug therapy   complications   MeSH
• Humans MeSH
• Check Tag
• Humans MeSH
• Publication type
• Clinical Trial MeSH

Dosažení dostatečné adherence k léčbě nemocných s arteriální hypertenzí a dyslipidemií představuje i v dnešní době stále vážný medicínský problém. Proto jsou soustavně vyvíjeny a zdokonalovány nástroje k jejímu zvyšování. Jedním z nich je zavedení fixní kombinace dvou různých léků s antihypertenzním a hypolipidemickým účinkem. Právě volba amlodipinu a atorvastatinu díky svému synergickému efektu se zdá být v tomto směru logická. V článku je kromě jiného podán rozbor studie popisující až dvojnásobné dosažení optimální adherence k léčbě (tedy >= 80 %) při podávaní obou léků ve fixní kombinaci na rozdíl od podávání ve dvou samostatných tabletách.

• Keywords
• adherence k léčbě, arterial wall compliance, arteriální hypertenze,
• MeSH
• Patient Compliance MeSH
• Amlodipine therapeutic use   MeSH
• Atorvastatin MeSH
• Dyslipidemias drug therapy   MeSH
• Drug Combinations MeSH
• Heptanoates therapeutic use   MeSH
• Drug Evaluation MeSH
• Hypertension drug therapy   MeSH
• Clinical Trials as Topic MeSH
• Drug Therapy, Combination MeSH
• Humans MeSH
• Pyrroles therapeutic use   MeSH
• Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use   MeSH
• Drug Synergism MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH

Succinylacetone (SA) is an inhibitor of heme synthesis that acts on the enzyme delta-aminolevulinic acid dehydratase. When reticulocytes are incubated with 59Fe-transferrin (59Fe-Tf) in the presence of SA, there is an accumulation of 59Fe in the mitochondrion and in a cytosolic non-heme intermediate that has been described as a putative Fe transporter (Adams et al, Biochim Biophys Acta 1012:243, 1989). Considering these observations, the present study was designed to examine the intermediates of Fe metabolism in control and SA-treated reticulocytes. This investigation showed that in the cytosol of control cells, most 59Fe was incorporated into hemoglobin (Hb) with a minor amount entering ferritin. In addition, a previously unrecognized cytosolic intermediate was identified (band X) that was absent when heme synthesis was inhibited with SA. Upon reincubation of SA-treated reticulocytes with protoporphyrin IX, band X initially increased in intensity and then decreased later in the incubation. In contrast, when 59Fe-labeled control cells were reincubated in the presence of SA and unlabeled diferric Tf, there was a marked decrease in the intensity of band X. These experiments suggest that component X may be an intermediate involved in the transfer of heme in the cytosol. Alternatively, these data could also be interpreted as indicating that band X may be a short-lived hemoprotein. We have confirmed the presence of an 59Fe-containing molecule in the cytosol of SA-treated reticulocytes (band Y) that is not present in control cells. However, when cells were incubated with 59Fe-Tf plus SA and then chased in the presence of SA and unlabeled diferric Tf, there was no decrease in this cytosolic pool of Fe, suggesting that it was not a intermediate supplying Fe for either ferritin or heme synthesis. Finally, there is little low molecular weight (Mr) Fe in reticulocytes, and our studies suggest that the low-Mr Fe present does not behave as an intermediate. Moreover, after inhibition of heme synthesis with SA, 59Fe in the low-Mr compartment was markedly decreased, suggesting that this component may be heme or a low-Mr heme-containing molecule. Considering the apparent lack of a cytosolic Fe transporter in rabbit reticulocytes, an alternative model of intracellular Fe transport is proposed that does not implicate a potentially toxic intermediate pool of low-Mr Fe complexes.

• MeSH
• Models, Biological MeSH
• Iron Chelating Agents pharmacology   MeSH
• Cytosol metabolism   MeSH
• Deferoxamine pharmacology   MeSH
• Heme biosynthesis   MeSH
• Hemoglobins biosynthesis   MeSH
• Heptanoates pharmacology   MeSH
• Enzyme Inhibitors pharmacology   MeSH
• Cell Compartmentation MeSH
• Rabbits MeSH
• Blood Proteins metabolism   MeSH
• Membrane Proteins metabolism   MeSH
• Mitochondria metabolism   MeSH
• Porphobilinogen Synthase antagonists & inhibitors   metabolism   MeSH
• Protoporphyrins metabolism   MeSH
• Reticulocytes chemistry   drug effects   ultrastructure   MeSH
• Transferrin metabolism   MeSH
• Iron analysis   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rabbits MeSH
• Animals MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH