Huntington's Disease — Imbalance of free amino acids in the cerebrospinal fluid of patients and offspring at-risk

Summary A total of 27 different amino acids were determined in the fasting, morning lumbar CSF of 12 patients with Huntington's Disease (HD), 8 at-risk offspring and 16 non-choreic control patients. A significant (P<0.001) decrease was observed for asparagine, isoleucine, leucine, phenylalanine, histidine, arginine, -aminoadipic acid and homocarnosine in patients with HD compared to the non-choreic controls. Only tyrosine was increased in HD. These alterations were to an extent more pronounced in 5 neurophysiologically conspicuous offspring. The alterations suggest that amino acid imbalance is an early metabolic disturbance in HD.

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Zusammenfassung Bei 12 Patienten mit manifester Huntingtonscher Krankheit (HD), 8 nicht erkrankten Nachkommen und 16 nicht choreatischen Kontrollpatienten wurden 27 verschiedene Aminosäuren im Liquor cerebrospinalis (nüchterner Lumballiquor) untersucht. Asparagin, Isoleucin, Leucin, Phenylalanin, Histidin, Arginin, -Aminoadipinsäure und Homocarnosin waren signifikant (P<0.001) erniedrigt bei Patienten gegenüber den Kontrollen. Diese Veränderungen waren bei 5 neurophysiologisch auffälligen Nachkommen teilweise ausgeprägter, was für eine frühzeitige metabolische Störung spricht. Tyrosin war als einzige Aminosäure erhöht. Die Veränderungen sprechen für eine Aminosäurenimbalanz bei Huntingtonscher Krankheit, deren Bedeutung besprochen wird.

     

Swimming capacity of mice after prolonged treatment with psychostimulants

Swimming endurance and availability of metabolic substrates (blood glucose and nonesterified fatty acids [NEFA], liver and muscle glycogen, body fat) were studied in mice treated with 10 g/g methamphetamine/day for 6 weeks. At the end of the 6-week treatment, motor coordination of the methamphetamine-treated animals was much better than that of controls, and swimming capacity tended to increase. While swimming, mice treated with methamphetamine mobilized more glycogen from the hepatic stores and utilized glucose more effectively. Their NEFA levels in blood were higher than those of controls. There was no difference in the muscular glycogen content.     

Swimming capacity of mice after prolonged treatment with psychostimulants

The effect of long-term treatment with fencamfamine on swimming endurance and availability of metabolic substrates was investigated in mice. Fencamfamine (14 g/g per day orally for 6 weeks) reduced maximum swimming capacity by more than 40%. This effect could not be attributed to motor incoordination or a diminution of pre-swimming levels of metabolic substrates such as liver and muscle glycogen or blood glucose and non-esterified fatty acids. However, during swimming the hepatic and muscular glycogen stores were depleted more rapidly in the fencamfamine-treated animals. Thus it appears that fencamfamine leads more rapidly to a shortage of combustible substrates in the swimming animals.     

Diazepam metabolism in human foetal and adult liver

Summary Diazepam was metabolized by human foetal liver microsomes to N-desmethyldiazepam and N-methyloxazepam as early as the 13th week of gestation. The metabolic activity was lower than that of microsomes from adult human liver. Diazepam was shown mainly to be hydroxylated to N-methyloxazepam at substrate concentrations higher than 0.1 mM. Diazepam levels above 1.0 mM were inhibitory to the overall metabolic reaction. SKF 525-A inhibited diazepam metabolism by foetal liver microsomes at a concentration of 0.1 mM. The addition of diazepam to foetal and adult human liver microsomes resulted in a type II spectral change. Its inhibition by carbon monoxide indicated that biotransformation of diazepam was performed by the cytochrome P-450-linked mono-oxygenase system.     

Disposition and placental transfer of etidocaine in pregnancy

Summary Following epidural administration of etidocaine hydrochloride to non-pregnant and pregnant patients, a similar rate of absorption was observed and there was no significant difference in total systemic blood clearance (Cl_sb) of etidocaine in the two groups. There were no major differences in the urinary excretion of etidocaine and metabolites in 48 h urine in both groups. The ability of pregnant women to form the N-glucuronide of the metabolite ABX (2-amino-2-butyroxylidide) was similar to that of non-pregnant individuals. In vitro experiments showed that the blood/plasma concentration ratio () of etidocaine was significantly higher in pregnant females than in males, presumably due to the lower haematocrit in females. The fraction unbound in plasma (f_p) of etidocaine was low in control subjects (mean 0.057) and was not significantly different in pregnant women of 35 to 37 weeks gestation. A marked increase in f_p was observed in pregnant women during delivery (mean 0.264). This finding has potentially serious clinical implications because it is the unbound drug in blood which is pharmacologically important. Placental transfer of etidocaine was rapid and the cord/maternal venous blood concentration ratio at delivery (CM_b) was, with one exception, always less than unity (mean 0.342). Following epidural administration of etidocaine to pregnant women in labour, measurable concentrations of mono-dealkylated metabolites of etidocaine, PABX (2-N-propylamino-2-butyroxylidide) and EABX (2-N-ethylamino-2-butyroxylidide) were detectable in maternal blood within 5 min and cord blood within 30 min. The CM_b for PABX and EABX was 0.401 and 0.658 respectively.List of Abbreviations Used ABX 2-Amino-2-butyroxylidide - EABX 2-N-Ethylamino-2-butyroxylidide - PABX 2-N-Propylamino-2-butyroxylidide - Cl_sb Total systemic blood clearance - Cl_sp Total systemic plasma clearance - Blood/plasma concentration ratio - f_p Fraction of unbound drug in plasma - f_pw Fraction of free drug in plasma water in blood - C_mb Cord/maternal venous blood concentration ratio at delivery - C_mp Cord/maternal venous plasma concentration ratio at delivery - t_1/2 Terminal phase half-life - t_p Time of attainment of peak plasma concentration - E Mean hepatic extraction ratio - Q Liver blood flow     

Pharmacokinetics of methyldopa in healthy man

Summary The pharmacokinetics of 2-¹⁴C-L--methyldopa have been investigated in five healthy volunteers following intravenous and oral administration. In the intravenous study a bi-phasic plasma concentration curve was found both for chemically determined -methyldopa and for radioactivity. The plasma level of radioactivity differed significantly from chemically determined drug, a pattern which was also found in urine. This suggests the presence of unidentified metabolite(s). The difference between plasma disappearance and urine recovery of -methyldopa and radioactivity during the first 4 h after injection suggests distribution to an extravascular compartment. Plasma half-lives of total radioactivity and of unchanged drug were calculated. In three subjects, pharmacokinetic parameters for a two-compartment open body model were calculated from urine and plasma data. Urinary recovery of radioactivity was almost complete within 48 h after intravenous administration. After oral administration, however, only about 40 per cent of the radioactive dose was recovered in the urine, and it contained approximately equal amounts of unconjugated methyldopa, acid-labile conjugated methyldopa and unidentified metabolite(s). The acid-labile conjugate was found only after oral administration, which supports the theory of a mucosal conjugation process. The lack of acid-labile conjugated drug either in the plasma or urine after intravenous injection indicates that there is no enterohepatic circulation of this drug.     

家兔急性缺氧后左心室舒张功能和心肌细胞内钙转运及能量代谢的研究

为探讨急性缺氧对家兔左心室舒张功能、心肌细胞内钙转运和能量代谢的影响。将２３只家兔分为对照组（６只）、吸入５％低氧混合气的缺氧１组（Ｈ１）（１２只）、吸入１０％低氧混合气的缺氧２组（Ｈ２）（５只），用心导管法测定左心室压力下降最大速率（ＬＶｄｐ／ｄｔｍａｘ）和压力下降时间常数（Ｔ值）；测定心肌肌浆网（ＳＲ）钙ＡＴＰ酶活性、心肌ＳＲ摄钙量、心肌组织ＡＴＰ和磷酸肌酸（ＣｒＰ）。结果，缺氧后ＬＶｄｐ／ｄｔｍａｘ下降，Ｔ值延长；缺氧组心肌ＳＲ钙ＡＴＰ酶活性及摄钙量下降；心肌线粒体钙含量升高；心肌组织ＡＴＰ和ＣｒＰ下降，心肌组织ＡＴＰ与线粒体钙含量呈负相关。提示，急性缺氧可引起左心室舒张功能障碍并影响心肌ＳＲ钙转运和心肌能量代谢。     

PATHOLOGY OF LONG-CHAIN 3-HYDROXYACYL-COA DEHYDROGENASE DEFICIENCY CAUSED BY THE G1528C MUTATION

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency is a recently discovered disorder affecting the mitochondrial-oxidation of fatty acids. There have been few reports of the pathologic findings in-oxidation defects. We examined pathologic specimens from 16 patients with this disorder (11 patients were homozygous for the common mutation G1528C, 5 patients were siblings with a similar clinical presentation). Autopsies were performed on all 15 patients who died, and liver biopsy specimens were available from 8 patients. Hepatomegaly and steatosis of the liver, found in every patient, were often combined with fibrosis or cirrhosis. Cardiomegaly and accumulation of fat in the myocardium, renal tubules, and skeletal muscle were found in many patients. A detailed neuropathologic examination was performed on six patients, and brain specimens obtained at autopsy were examined in four others. In general, neuropathologic findings were mild and unspecific, but vacuolization was detected in the deep gray matter and in the cerebellum and brain stem nuclei of five patients. In one patient the vacuolization was prominent; in the other four it was milder and more focal. The vacuoles seemed to be either in the neuropil or associated with swollen hydropic cells. The uniform pattern of histopathologic changes facilitates the diagnostics in this severe disorder, allowing opportunities for therapy and prenatal diagnosis.     

A new case of malonyl coenzyme A decarboxylase deficiency presenting with cardiomyopathy

A new case of mitochondrial malonyl coenzyme A decarboxylase deficiency is described. The patient presented with an initial episode of metabolic acidosis, seizures, hypoglycemia, and cardiac failure at 2 months of age which slowly resolved. Subsequent evaluations at 4 years of age for developmental delay revealed a prominent elevation of malonic acid in urine. Malonyl carnitine was also elevated. The activity of malonyl CoA decarboxylase in cultured fibroblasts was 7% of normal. Conclusion Malonyl CoA decarboxylase deficiency may result in inhibition of fatty acid oxidation, which may account for the cardiomyopathy. Received: 12 April 1996 / Accepted: 24 September 1996     

突发性聋与铁代谢障碍疾病关系的临床调查

对１９７９年７月至１９９６年６月的突发性聋发病情况进行前瞻性研究与回顾性分析，探讨突聋与铁代谢障碍疾病的关系，前瞻性研究的对象分为铁代谢障碍疾病组２１８例，血液病组２１５例和正常对照组４８５０例；回顾性分析为１７年间资料完整的４２９例突聋患者史的代谢障碍疾病及其他血液病的发病情况。结果表明，铁代谢障碍疾病组的突聋调整年发病率显著高于血液病组以及正常对照组，４２９例突聋患者的无贫血缺铁，缺铁性人同血