S-adenosylmethionine and S-adenosylhomocysteine in plasma and cerebrospinal fluid in Rett syndrome and the effect of folinic acid supplementation

Rett syndrome is a neurodevelopmental disorder characterized by cognitive and locomotor regression and stereotypic hand movements. The disorder is caused by mutations in the X chromosomal MECP2 a gene encoding methyl CpG-binding protein. It has been associated with disturbances of cerebral folate homeostasis, as well as with speculations on a compromised DNA-methylation. Folinic acid is the stable form of folate. Its derived intermediate 5-MTHF supports the conversion of homocysteine to methionine, the precursor of S-adenosylmethionine (SAM). This in turn donates its methyl group to various acceptors, including DNA, thereby being converted to S-adenosylhomocysteine (SAH). The SAM/SAH ratio reflects the methylation potential. The goal of our study was to influence DNA methylation processes and ameliorate the clinical symptoms in Rett syndrome. Therefore we examined the hypothesis that folinic acid supplementation, besides increasing cerebrospinal fluid (CSF) 5-MTHF (p?=?0.003), influences SAM and SAH and their ratio. In our randomized, double-blind crossover study on folinic acid supplementation, ten female Rett patients received both folinic acid and placebo for 1 year each. It was shown that both SAM and SAH levels in the CSF remained unchanged following folinic acid administration (p?=?0.202 and p?=?0.097, respectively) in spite of a rise of plasma SAM and SAH (p?=?0.007; p?=?0.009). There was no significant change in the SAM/SAH ratio either in plasma or CSF. The apparent inability of Rett patients to upregulate SAM and SAH levels in the CSF may contribute to the biochemical anomalies of the Rett syndrome. Our studies warrant further attempts to promote DNA methylation in the true region of interest, i.e. the brain.     

Effect of folic acid and folinic acid on zinc absorption]

We have investigated the effect of folic and folinic acids on intestinal zinc absorption in humans, using zinc tolerance tests. Zinc (30 mg) as the gluconate was given by mouth to 10 healthy subjects, alone (1), with 200 mg of folic acid (2) or with 200 mg of folinic acid (3). The zinc/folate molar ratio was 1:1. These three oral loading doses were given after overnight fasting to each of the 10 subjects, at weekly intervals. Serum zinc was measured at 0, 1, 2, 3, 6, 12 and 24 h. Zinc was also determined in urine collected for a 6-hour period following the ingestion of oral loading dose. The results do not indicated any inhibition of zinc absorption and urinary zinc excretion by folates. The areas under the curves varied from 48.2 +/- 20.0 mumol/6 h (1) to 57.0 +/- 10.3 mumol/6 h (3), peak zinc concentration from 28.8 +/- 7.3 mumol/l (1) to 32.1 +/- 4.1 mumol/l (3), half-life from 3.12 +/- 1.12 h (3) to 3.42 +/- 1.48 h (1), elimination rate constant from 0.22 +/- 0.08 (1) to 0.24 +/- 0.07 (3), mean urinary zinc excretion from 58.1 mumol/6 h (2) to 98.7 mumol/6 h (1) and mean zinc clearance from 1.15 l/h (3) to 3.26 l/h (1). All these indices were not statistically significantly different among the three different loading doses.     

Protective effect of folinic acid on low-dose methotrexate genotoxicity

Introduction Methotrexate (MTX) is an antineoplastic agent widely used in low dose to treat patients with rheumatoid arthritis (RA). Its side effects can partly be explained by folate antagonism. Folinic acid (Leucovorin) is generally administered with MTX to decrease MTX-induced toxicity. However information regarding the inhibitory effect of folinic acid against cytogenetic damage caused by MTX is limited. The aim of this study was to assess the protective effect of folinic acid against MTX-genotoxicity. Methods This study was done on Wistar albino rats and in patients with RA. Forty rats of both sexes were randomized into four equal groups and dosed in the following way: Group-I, distilled water vehicle; Group-II, 0.5mg/kg folinic acid; Group-III, 0.5 mg/kg MTX; Group-IV, 0.5mg/kg folinic acid plus 0.5mg/kg MTX. Doses were given i.p., once daily for 8 consecutive days. A bone marrow chromosomal study and a micronucleus test were performed for each rat.    Twenty patients with RA (5males and 15 females) on a 10mg weekly dose of MTX, i.m., for one month, were administered the same dose of MTX in addition to 10mg of folinic acid as a single dose 4 hours after MTX administration, i.m., every week for another 4 weeks. Chromosomal studies as well as a micronucleus test were evaluated for each patient. Results MTX produced a significant genetic injury as proved by the increased incidence of chromosomal aberration and micronuclei formation in Group-III animals. Inversely, folinic acid (group IV) produced a significant protection against genetic damages induced by MTX. In RA patients, folinic acid provides satisfactory improvement of MTX-induced genetic damage. Conclusion Folinic acid has a protective affect against MTX genotoxicity in human as well as in animal models.     

Protective effect of folinic acid on low-dose methotrexate genotoxicity

Summary Introduction Methotrexate (MTX) is an antineoplastic agent widely used in low dose to treat patients with rheumatoid arthritis (RA). Its side effects can partly be explained by folate antagonism. Folinic acid (Leucovorin) is generally administered with MTX to decrease MTX-induced toxicity. However information regarding the inhibitory effect of folinic acid against cytogenetic damage caused by MTX is limited. The aim of this study was to assess the protective effect of folinic acid against MTX-genotoxicity. Methods This study was done on Wistar albino rats and in patients with RA. Forty rats of both sexes were randomized into four equal groups and dosed in the following way: Group-I, distilled water vehicle; Group-II, 0.5mg/kg folinic acid; Group-III, 0.5 mg/kg MTX; Group-IV, 0.5mg/kg folinic acid plus 0.5mg/kg MTX. Doses were given i.p., once daily for 8 consecutive days. A bone marrow chromosomal study and a micronucleus test were performed for each rat.    Twenty patients with RA (5males and 15 females) on a 10mg weekly dose of MTX, i.m., for one month, were administered the same dose of MTX in addition to 10mg of folinic acid as a single dose 4 hours after MTX administration, i.m., every week for another 4 weeks. Chromosomal studies as well as a micronucleus test were evaluated for each patient. Results MTX produced a significant genetic injury as proved by the increased incidence of chromosomal aberration and micronuclei formation in Group-III animals. Inversely, folinic acid (group IV) produced a significant protection against genetic damages induced by MTX. In RA patients, folinic acid provides satisfactory improvement of MTX-induced genetic damage. Conclusion Folinic acid has a protective affect against MTX genotoxicity in human as well as in animal models. Received: 6 September 2000 Accepted: 24 November 2000     

Capillary blood flow to the skin of forearm in cirrhosis.

In liver cirrhosis a hyperkinetic circulatory state is frequently observed as a consequence of an arterial or even a venous peripheral vasodilatation with secondary increase in cardiac output. Indirect evidence suggests that, in liver disease, the manifestation of warm hands, capillary pulsation, or palmar erythema may also relate to such a state by way of an increased skin blood flow. The purpose of the present study has been to directly assess capillary skin blood flow in liver disease through the clearance of a locally injected radioactive substance. The study was performed in 24 patients with different liver diseases, including 14 Child class II cirrhotics, and in 9 control subjects. A small volume of Na 131I solution was injected at the volar surface of the forearm, and radioactive counts were recorded continuously for ten seconds every minute for up to twenty minutes. The best fit line of the disappearance rate was determined by the least square method, and both its T/2 and an estimated blood flow parameter were calculated. The T/2 of isotope disappearance rate was 4.54 +/- 0.71 and 4.38 +/- 0.68 minutes in cirrhotics and controls, respectively. Similarly, estimates of skin blood flow (mL/min/100 g tissue) were 7.82 +/- 1.28 in the cirrhotic patients, not significantly different from those in both patients with mixed liver diseases (7.6 +/- 2.86) and control subjects (8.06 +/- 1.04). Parameters of skin blood flow were also invariant in respect to the various etiologies of liver disease. Thus, the present findings indicate that capillary skin blood flow is not affected by the hyperdynamic circulatory changes occurring in liver cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Capillary blood flow in the genital tracts of conscious ewes: cyclic changes and the effect of ovarian hormones

The indicator fractionation technique with [86Rb]rubidium chloride as the indicator was used in conscious animals to determine the relative blood flow (RBF) as a measure of capillary blood flow in regions of the genital tract of cyclic ewes and of hormonally treated ovariectomized ewes. The RBF values in the ampulla, isthmus, uterus and cervix of cyclic ewes were markedly raised at pro-oestrus and declined thereafter to low levels during the remainder of the oestrous cycle. On Day 4 a small secondary rise in flow occurred in the ampulla and isthmus. In ovariectomized ewes, oestradiol induced high levels of RBF in the ampulla, isthmus, uterus and cervix whether the animals had been treated previously with progesterone or given concurrent small doses of progesterone. Though progesterone given alone caused a significant rise in RBF in the uterus, this effect appeared to be one occurring only during active re-growth of regressed tracts. The findings are discussed in relation to oestradiol inducing a stimulatory effect on RBF in the genital tract of the ewe around oestrus but not at Days 3-4 of the oestrous cycle.     

The effect of folic acid and folinic acid supplements on purine metabolism in methotrexate-treated rheumatoid arthritis

OBJECTIVE: To determine if folinic acid supplementation during methotrexate (MTX) therapy for rheumatoid arthritis (RA) reduces both urinary 5-aminoimidazole-4-carboxamide (AICA) and urinary adenosine excretion more than does folic acid supplementation. AICA and adenosine are markers for MTX interference with purine metabolism. METHODS: Forty patients with RA who received MTX for 6 weeks were randomized to receive either daily folic acid or folinic acid supplements during an additional week of MTX therapy. Colorimetric and radioimmunocompetition assays were used to measure 24-hour urinary AICA and adenosine excretion levels, respectively. RESULTS: At the end of 6 weeks, 24-hour urinary levels of AICA, but not adenosine, were elevated as compared with baseline levels (i.e., prior to MTX therapy). Folinic acid, but not folic acid, supplementation normalized urinary AICA levels during MTX therapy. Relatively high urinary levels of AICA were correlated with reduced disease activity. No similar correlations were seen with urinary adenosine levels. CONCLUSION: The blockade of purine nucleotide biosynthesis by MTX at the AICA ribonucleotide transformylase-catalyzed step may be related to the efficacy of MTX, and this blockade is effectively relieved by folinic acid, but not by folic acid, supplementation.     

Comparison of oral folic acid and folinic acid on blood homocysteine level of patients on hemodialysis

INTRODUCTION. Hyperhomocysteinemia is common in patients with chronic kidney disease. There is a direct relationship between cardiovascular mortality and increase of blood homocysteine. Folic acid is used as common treatment in such patients. Folinic acid, a shortened form of folic acid, is not affected by inhibitors of dihydrofolate reductase enzyme such as methoterxate. This study was performed to evaluate the effect of oral folinic acid on the blood homocysteine level of hemodialysis patients, in comparison with folic acid. MATERIALS AND METHODS. This clinical trial was performed on 60 hemodialysis patients. The participants were divided into 2 groups to receive either 15 mg of oral folic acid or 15 mg of oral folinic acid, daily. Blood homocysteine levels were measured before dialysis and after the study period. RESULTS. Folic acid and folinic acid decreased the blood homocysteine levels by 33.0% and 28.7%, respectively (P < .001). However, only 3 patients (6.5%) enjoyed a normalized homocysteine level. CONCLUSIONS. Our study showed that both folic and folinic acid decreased the blood homocysteine level and no meaningful difference was observed between them; therefore, we suggest they can be used interchangeably.     

Cholic acid synthesis as an index of the severity of liver disease in man

Bile acid pool size and kinetics were determined in 17 patients with cirrhosis and 11 patients without liver disease and correlated with the severity of liver disease as determined by the usual clinical and laboratory criteria. In order to assess the severity of liver disease, a grading system was devised which assigned numerical values to various clinical signs and laboratory results. The total clinical score and the patients were divided into two groups of advanced (7-18 points) or mild (1-6 points) cirrhosis. The clinical rating was then correlated with the various aspects of bile acid metabolism. Cholic acid synthesis was markedly reduced in the early stages of cirrhosis and continued to decrease with the advancement of the liver disease. There was an inverse correlation between synthesis of cholic acid and the severity of cirrhosis. Nine of the 10 patients with advanced cirrhosis and a very low cholic acid synthetic rate (average 68 mg per day) died within one to 13 months from the start of the study. Patients with mild cirrhosis also had significantly reduced cholic acid synthesis (average 152 mg per day) but they all were well and alive three to 23 months after the study. In contrast, chenodeoxycholic acid synthesis was not markedly affected in either patients with mild or advanced cirrhosis. There was also a high degree of correlation between the fractional daily turnover rate of cholic acid and the severity of liver disease. The fractional daily turnover rate of cholic acid was greatly reduced (50%) in patients with advanced cirrhosis. Deoxycholic acid was reduced in patients with mild cirrhosis and virtually absent from the bile of patients with advanced cirrhosis. The findings of the present report provide evidence that cholic acid synthesis is a sensitive indicator of the hepatocellular damage, whereas chenodeoxycholic acid synthesis is relatively unaffected by cirrhosis. The selective alteration in cholic acid synthesis probably resides in a deficiency of one or more enzymes regulating the formation of the 3-keto, 7 alpha, 12 alpha-dihydroxy precursor of cholic acid.     

Intravascular ultrasound appearance of scattered necrotic core as an index for deterioration of coronary flow during intervention in acute coronary syndrome

In acute coronary syndrome (ACS) patients with deterioration of coronary flow during percutaneous coronary intervention (PCI), a scattered necrotic core pattern (SNC) is observed by intravascular ultrasound virtual histology (VH-IVUS). The purpose of this study was to evaluate the impact of SNC on deterioration of coronary flow during PCI in ACS. A total of 38 ACS patients were imaged using VH-IVUS before PCI. In addition to conventional definitions of thin-cap fibroatheroma by VH-IVUS (ID-TCFA), the SNC was defined as necrotic core foci with a maximum diameter of <14 pixels on a 400 × 400 VH-IVUS image in the presence of >50% plaque burden except in the ID-TCFA frame. Patients were divided into deterioration of coronary flow group (n = 15) and normal-reflow group (n = 23). The incidence of residual thrombus and plaque rupture, the external elastic membrane, plaque and fibrous volumes, the incidence of ID-TCFA and the average number of SNC per frame was significantly greater in deterioration of coronary flow group than in normal-reflow group (all parameters P < 0.05). Multivariate analysis revealed that the average number of SNC per frame was independently associated with deterioration of coronary flow in ACS patients (odds ratio 1.18, P < 0.05). In conclusion, an increased number of SNC is associated with deterioration of coronary flow during PCI in ACS patients.