The N314D polymorphism was found in two different alleles of the galactose-1-phosphate uridyltransferase (GALT) gene, Duarte-1 (D1) and Duarte-2 (D2). Although both variants have identical electrophoretic mobility and isoelectro-focusing points, the galactose-1-phosphate uridyltransferase (GALT) activity varies: D1 alleles showed 110-130% of the normal RBC activity, but D2 alleles only 40-50%. We found that D1 alleles also carried a silent mutation in exon 7 (L218L) in addition to N314D. In contrast, besides N314D, D2 alleles carried two regulatory mutations, G1105C and G1391A, in introns D and E, respectively. In normal and Q188R alleles none of the above four mutations coexisted. However, some galactosaemia alleles with mutations other than Q188R, such as W316X and E340X of exon 10, also carried the N314D mutation. The W316X alleles existed in cis with the intron mutations (G1105C and G1391A), whereas those with E340X are in cis with L218L. In all cases examined, the intron mutations were not found in D1 alleles and no D2 alleles had the silent mutation of L218L. These results suggest that the decrease in the GALT activity in D2 may be due to regulation of the GALT gene expression. The G1105C site may be critical to the function of erythroid transcription factor NF-E1, since it flanks the core consensus sequence for one of its binding sites. The G1391A mutation may affect another cis-acting regulatory sequence. Alternatively, both mutations may be involved in an aberrant splice processing, which possibly results in a low level of correctly spliced mRNA.

Candesartan cilexetil is the prodrug of candesartan, an angiotensin II receptor antagonist. Candesartan binds selectively and non-competitively to the angiotensin II receptor type 1, thus preventing the actions of angiotensin II. Clinical trials have demonstrated its efficacy at a dose range of 2 to 32 mg once daily in hypertension of all grades, heart failure, in reducing urinary albumin excretion in diabetes mellitus and in coexisting hypertension and renal failure. Pharmacokinetic properties of candesartan cilexetil in elderly patients are not significantly different from those in younger individuals. Hepatic impairment does not change pharmacokinetics of candesartan cilexetil at doses up to 12 mg/day. No dose adjustment is necessary in patients with mild or moderate renal impairment. Tolerability of candesartan cilexetil is not much different from that of placebo. All adverse events are usually of mild to moderate severity and not dose-related. The most common adverse events were headache, upper respiratory tract infection, back pain, and dizziness. The incidence of these adverse effects, as well as of cough, was similar in patients treated with candesartan cilexetil or placebo. The incidence of adverse events in long-term trials was not different from that in short-term trials. Tolerability of candesartan cilexetil does not differ with either age or gender.

The paper addresses the safety of febuxostat and summarizes reports on side effects and interactions of febuxostat published by the cut-off date (last day of literature search) of 20 March 2018. Publications on side effects and the interactions of febuxostat were considered. Information concerning the occurrence of side effects and interactions in association with the treatment with febuxostat was collected and summarized in the review. The incidence of severe side effects was much less frequent than mild side effects (1.2–3.8% to 20.1–38.7%). The rate and range of febuxostat side effects are low at doses of up to 120 mg and only increase with a daily dose of over 120 mg. The publications reveal no age-dependent increase in side effects for febuxostat. In patients with impaired renal function, no increase in adverse events is described with a dose of up to 120 mg of febuxostat per day. Patients with impaired liver function had no elevated risk for severe side effects. A known allopurinol intolerance increases the risk of skin reactions during treatment with febuxostat by a factor of 3.6. No correlation between treatment with febuxostat and agranulocytosis has been confirmed. Possible interactions with very few medications (principally azathioprine) are known for febuxostat. Febuxostat is well tolerated and a modern and safe alternative to allopurinol therapy.

BackgroundOur review of the scientific literature focused on an analysis of studies describing instances of methylphenidate treatment leading (or not) to behavioral changes in the pediatric, adolescent, and adult populations.Materials and methodsWe conducted a literature search in PubMed, Medline, and Google using the keywords “methylphenidate”, “behavioral changes”, “adverse effects”, and “side effects”. A total of 44 studies were identified as reporting on the effects and adverse effects of methylphenidate administration, and were included in the analysis.ResultsFive studies specifically set out to study, record, and discuss changes in behavior. Eight studies did not set out to study behavioral effects, but record and discuss them. A total of 28 studies recorded behavioral effects, but failed to discuss these further. Three studies did not include behavioral effects.ConclusionThis review records what data have been published in respect of changes in behavior in association with the use of methylphenidate. While there is some evidence to suggest that methylphenidate causes changes in behavior, the majority of the studies reviewed paid little or no attention to this issue. Based on the available data, it is impossible to determine the point at which such behavioral effects occur. The frequency of occurrence of behavioral effects is also impossible to determine with certainty. Based on the available data, it is not possible to rule out whether behavioral effects may persist or not persist once treatment is discontinued. In conclusion, despite countless publications and extensive administration, especially to children, we have insufficient data to judge the long-term effects and risks of methylphenidate taking.

Classical galactosemia, which is caused by deficiency of galactose-1-phosphate uridyltransferase, is characterized by acute problems of hepatocellular dysfunction, sepsis, cataracts and failure to thrive. Galactose limitation reverses these symptoms immediately; however, the long-term complications, such as mental retardation and ovarian failures are major problems in most of these patients. In order to investigate the molecular basis for phenotype variation in galactosemia, we have screened the most common mutation in the GALT gene, Q188R. We have further examined those patients who are heterozygous for Q188R or negative for this mutation by SSCP analysis and direct sequencing. In three male patients, we have identified, for the first time, two stop-codon mutations in the GALT gene, G212X (exon 7) and E340X (exon 10). Two patients of 8 and 28 years of age, respectively, who are compound heterozygotes for Q188R and G212X, have severe mental retardation and their general clinical condition is more severe than that of patients with missense mutations. The third patient, who is 8 years of age and who is homozygous for E340X, the N314D polymorphism and a silent substitution L218L, presents with a relatively normal physical and mental condition to date.