Synthesis and characterisation of a new class of stable S-adenosyl-L-methionine salts

S-adenosyl-L-methionine (SAM) is an important metabolic intermediate that serves as a donor of methyl and aminopropyl groups to a variety of acceptor molecules. The molecule in vitro is unstable both in solution and in crystalline form undergoing irreversible conversion to 5'-methyltioadenosine (MTA) and homoserine lactone. Since this form of instability seems to be prevented in the cell of the living organism by bonds with macromolecules, we designed and developed a novel class of salts of SAM with large size anions to improve the stability of the sulfonium compound outside the cell. For this purpose we synthesised and characterised by NMR and IR spectroscopy anions consisting of amidic derivatives of taurine with fatty acids. Stability studies performed with the new SAM salts indicate that SAM becomes much more stable when it interacts with large size anions and in fact, more than 84% of the SAM is recovered after 36 months in lyophilized samples. The high stability of the new products widens the possibility of new therapeutic applications of SAM in human therapy.     

MRI of focal nodular hyperplasia (FNH) with gadobenate dimeglumine (Gd-BOPTA) and SPIO (ferumoxides): an intra-individual comparison

PURPOSE: To compare the efficacy of two different MR contrast agents for the detection and diagnosis of focal nodular hyperplasia (FNH). MATERIALS AND METHODS: Fifty patients with 83 FNH lesions detected on spiral CT were studied in two different MRI sessions with Gd-BOPTA (MultiHance) and ferumoxides (Endorem). MRI with Gd-BOPTA was performed precontrast (T1wGRE and T2wTSE sequences) and during the dynamic and late (1-3 hours) phases after injection (T1wGRE sequences only). MRI with ferumoxides (T1wGRE and T2wTSE sequences) was performed before and at least 30 minutes after injection. Hyper- or isointensity of FNH in the late phase was considered typical for Gd-BOPTA, while isointensity or lesion hypointensity was considered typical for ferumoxides. RESULTS: With Gd-BOPTA, 83 FNH lesions (100%) appeared hyperintense during the arterial phase of dynamic MRI. All but one lesion was iso- or slightly hyperintense in the portal-venous and equilibrium phases. In the late phase, 81 FNH lesions were hyper- or isointense to the surrounding parenchyma, with two lesions appearing slightly hypointense. With ferumoxides, a significant (P < 0.001) number (21/83, 25.3%) of FNH lesions (mean diameter = 16.8 +/- 6.6 mm) were not visible. Of the visible FNH lesions, 38/62 were slightly hyperintense, and 24/62 were isointense to the surrounding parenchyma on the T2wTSE images. On the T1wGRE images, 42/62 lesions were isointense, 19/62 were slightly hyperintense, and one lesion was slightly hypointense. Seventeen lesions in 12 patients with previous neoplasia were all detected after Gd-BOPTA administration, whereas only nine of these 17 lesions (52.9%) were detected after ferumoxide administration. Two of these nine lesions showed atypical enhancement features. CONCLUSION: Gd-BOPTA-enhanced MRI is significantly better than ferumoxide-enhanced MRI for the identification and characterization of FNH.     

High frequency of psoriasis in relatives is associated with early onset in an Italian multiple sclerosis cohort

OBJECTIVES: An exploratory study has been carried out to assess the association of autoimmune diseases in multiple sclerosis (MS) families with clinical features and disability of MS patients. MATERIAL AND METHODS: Age at onset, symptoms and signs at onset, and disability were assessed in 177 patients with definite MS and 178 age- and sex-matched control patients with autoimmune diseases (78 with endocrine and 100 with rheumatological diseases) and correlated with the most frequent autoimmune diseases recorded in the families. RESULTS: Psoriasis was found in 30 relatives of 177 (16.9%) MS patients, thyroid disorders in 17 (9.6%) and allergies in 17 (9.6%). In the control group, psoriasis was found in 22 relatives of 178 (12%) patients, thyroid diseases in 19 (10.7%) and allergies in seven (3.9%). Of the 30 relatives with psoriasis in the MS group, 16 (53.3%) were fathers (P < 0.0001). There was a significant association of high frequency of family psoriasis with early age of MS onset (P = 0.025) but not with onset of symptoms or severe disability. CONCLUSION: In this Italian MS cohort, a subgroup of patients with a first- or second-degree relative with psoriasis had early onset of MS.     

S-adenosyl- -methionine N-ole-1-oyltaurate: pharmacokinetic of the orally administered salt in rats

A pharmacokinetic study based on the distribution of radioactivity from the double labelled S-adenosyl- -methionine (SAM) has been carried out by oral administration of the liposoluble stable salt [methyl-¹⁴C, 8-³H]SAM N-ole-1-oyltaurate to rats. The SAM sulfate p-toluensulfonate salt, the only SAM salt at present commercialized as drug, was chosen as reference compound to have a comparative pharmacokinetic analysis. The metabolism of the SAM is characterised by a differential use of the two labelled moieties by the various organs, liver being the most active in metabolizing the sulfonium compound with a preferential uptake of the methyl-¹⁴C fragment. The radioactivity detected after the administration of [methyl-¹⁴C, 8-³H]SAM N-ole-1-oyltaurate is, in all the organs examined, two times higher than the [methyl-¹⁴C, 8-³H]SAM sulfate p-toluensulfonate compound, attesting that the liposoluble [methyl-¹⁴C, 8-³H]SAM N-ole-1-oyltaurate is provided with better bioavailability.     

Anti-glutamic Acid decarboxylase limbic encephalitis without epilepsy evolving into dementia with cerebellar ataxia

OBJECTIVES To expand the spectrum of the clinical presentation of anti-glutamic acid decarboxylase antibodies-related limbic encephalitis and to improve the recognition of this entity. DESIGN Case study. SETTING University hospital. PATIENT An 11-year-old-girl with progressive mood and behavioral disorder, speech impairment, and short-term memory impairment who manifested cerebellar ataxia with nystagmus during the disease course. INTERVENTIONS Blood and cerebrospinal fluid analysis including autoantibodies, electroencephalography, brain and spinal magnetic resonance imaging, and cognitive and neuropsychological assessment were performed. High-dose methylprednisolone sodium succinate pulses, cycles of intravenous immunoglobulins, mycophenolate mofetil, and rituximab as well as antipsychotics and benzodiazepine were administered. RESULTS Diagnosis of anti-glutamic acid decarboxylase antibodies-related limbic encephalitis was made. The clinical features during the first months of disease included only mood, behavioral, and memory impairment. After 5 months, despite immunotherapies, cerebellar ataxia with nystagmus appeared with brain magnetic resonance imaging evidence of cerebral atrophy. No clinical or infraclinical seizures were recorded during follow-up. CONCLUSIONS Anti-glutamic acid decarboxylase antibodies-related limbic encephalitis can present with only behavioral or neuropsychological symptoms without any epileptic disorder. Moreover, cerebellar ataxia related to anti-glutamic acid decarboxylase antibodies can be observed in patients with limbic encephalitis during the disease course.     

Evaluation of a novel time-efficient protocol for gadobenate dimeglumine (Gd-BOPTA)-enhanced liver magnetic resonance imaging

OBJECTIVE: We sought to evaluate gadobenate dimeglumine for the detection and characterization of focal liver lesions in the unenhanced and already pre-enhanced liver. MATERIALS AND METHODS: Sixty patients were evaluated prospectively. Unenhanced T1-weighted gradient echo (T1wGRE) and T2-weighted turbo spin echo (T2wTSE) images were acquired followed by contrast-enhanced T1wGRE images during the dynamic, equilibrium, and delayed phases after the bolus injection of 0.05 mmol/kg gadobenate dimeglumine. An identical series of dynamic images was then acquired after the delayed scan following a second 0.05 mmol/kg bolus of gadobenate dimeglumine. Images were evaluated randomly in 2 sessions by 3 independent blinded readers. Evaluated images in the first session comprised the unenhanced images, the first or second set of dynamic images, and the delayed images. The second session included the unenhanced images, the dynamic images not yet evaluated in the first session, and the delayed images. The 2 reading sessions were compared for lesion characterization and diagnosis, and kappa (kappa) values for interobserver agreement were determined. Quantitative evaluation of lesion contrast enhancement was also performed. RESULTS: The enhancement behavior in the second dynamic series was similar to that in the first series, although pre-enhancement of the normal liver resulted in reduced lesion-liver contrast-to-noise ratios and the visualization of some lesions only on arterial phase images. Typical imaging features for the lesions included in the study were visualized clearly in both series. Strong agreement (kappa=0.56-0.89; all evaluations) between the 2 images sets was noted by all readers for differentiation of benign from malignant lesions and for definition of specific diagnosis, and between readers for diagnoses established based on images acquired in the unenhanced and pre-enhanced liver. CONCLUSION: Dynamic imaging in the hepatobiliary phase gives similar information as dynamic imaging of the unenhanced liver. This might prove advantageous for screening protocols involving same session imaging of primary extrahepatic tumors and liver.     

Antihypertensive Drugs in Croatia: What Changes the Drug Usage Patterns?

Purpose: Possible factors that could influence changes in patterns of prescribing antihypertensives could be identified by monitoring national trends in hypertension treatment. The choice of pharmacologic treatment in people with hypertension has important therapeutic and financial implications, due to the fact that the financial costs associated with hypertension continue to increase. The aims of our study were to identify and analyze changes in the usage of antihypertensive drugs in Croatia from 2000 to 2016 and to identify the changes in prescribing patterns as well as mean prices per defined daily dose (DDD).Methods: Data on consumption in Croatia were obtained from the International Medical Statistics database. According to the World Health Organization's Collaborating Center for Drugs Statistics Methodology, per-annum volumes of drugs are presented in DDD per 1000 population per day (DDD/1000), while data on financial expenditure are presented in euros.Findings: The consumption of drugs for cardiovascular disease in Croatia during the period from 2000 to 2016 increased 150.81%, while financial expenditure in the same period increased 47.32%. The most frequently prescribed subgroup was agents acting on the renin-angiotensin system (RAS). Their share among antihypertensives increased from 39.13% (2000) to 53.39% (2016). The share of diuretics in the same period decreased from 20.16% in 2000 to 12.73% in 2016.Implications: The prescribing patterns of antihypertensive drugs in Croatia have changed, which could be a result of a combination of different factors, such as changes in laws, pharmaceutical marketing, and guidelines on hypertension therapy. The most prescribed subgroup in all of the investigated years was agents acting on the RAS, mainly because of the increased prescribing of combinations of RAS agents plus diuretics. The financial implications of legal changes and the introduction of new generic drugs led to decreased cost per DDD of antihypertensives during the investigated period, but the total expenditure on antihypertensives in Croatia increased due to increased consumption.