Hyperinsulinism hyperammonaemia (HI/HA) syndrome due to GLUD1 mutation: phenotypic variations ranging from late presentation to spontaneous resolution.

Background The hyperinsulinism/hyperammonaemia (HI/HA) syndrome is the second most common cause of hyperinsulinaemic hypoglycaemia, caused by activating mutations in GLUD1. In this article, we report a series of three unrelated patients with HI/HA syndrome who demonstrated variable phenotypes, ranging from delayed presentation to spontaneous resolution of hypoglycaemia, thereby expanding the current knowledge and understanding of GLUD1 mutations. Case presentation This paper is a retrospective analysis of patients with HI/HA syndrome who demonstrated a variable disease course. Patient 1 presented with hypoglycaemic seizures at the age of 7 months and was diagnosed with HI/HA syndrome. Patient 2, a 5-year-old boy, on anti-convulsants since 8 months of age, was diagnosed with HI/HA at the age of 4 years. Patient 3, an 11-year-old girl with a history of transient neonatal hypoglycaemia, was diagnosed with HI/HA at the age of 12 months following evaluation for absence seizures. Patients 1 and 2 had raised ammonia levels, whilst patient 3 had normal ammonia level. The genetic analysis in all three patients confirmed GLUD1 mutation. Good glycaemic control was observed in all following diazoxide treatment. All patients have learning difficulties. Patient 1 demonstrated spontaneous resolution of hypoglycaemia at the age of 8 years, enabling discontinuation of diazoxide. Conclusions The cases highlight the diagnostic challenges in HI/HA syndrome due to a highly variable presentation. Knowledge of variable phenotypes would enable early diagnosis, thereby decreasing the risk of long-term neurological damage. Spontaneous resolution of hyperinsulinism could occur, and it is important to consider a trial off diazoxide therapy especially if the patients are on a small dose of diazoxide.

Coupling of micro-solid-phase extraction and internal extractive electrospray ionization mass spectrometry for ultra-sensitive detection of 1-hydroxypyrene and papaverine in human urine samples.

Quantification of ultra-trace analytes in complex biological samples using micro-solid-phase extraction followed by direct detection with internal extractive electrospray ionization mass spectrometry (µSPE-iEESI-MS) was demonstrated. 1-Hydroxypyrene (1-OHP) and papaverine at attomole levels in human raw urine samples were analyzed under negative and positive ion detection mode, respectively. The µSPE was simply prepared by packing a disposable syringe filter with octadecyl carbon chain (C18)-bonded micro silica particles, which were then treated as the "bulk sample" after the analytes were efficiently enriched by the C18 particles. Under the optimized experimental conditions, the analytes were readily eluted by isopropanol/water (80/20, V/V) at a high voltage of ± 4.0 kV, producing analyte ions under ambient conditions. The limit of detection (LOD) was 0.02 pg/L (9.2 amol) for 1-hydroxypyrene and 0.02 pg/L (5.9 amol) for papaverine. The acceptable linearity (R2 > 0.99), signal stability (RSD ≤ 10.7%), spike recoveries (91-95%), and comparable results for real urine samples were also achieved, opening up possibilities for quantitative analysis of trace compounds (at attomole levels) in complex bio-samples. Graphical abstract.

Lomerizine, trimetazidine and bis-(4-fluorophenyl)-methylpiperazine in human urine after oral administration of lomerizine dihydrochloride: analysis by liquid chromatography-high resolution-tandem mass spectrometry.

In sports drugs testing, the differentiation between the abuse of the prohibited substance trimetazidine and that of the permitted drug lomerizine is required because trimetazidine is one of the metabolites of lomerizine. Therefore, it is important to identify a lomerizine-specific metabolite in urine that allows making the distinction. In this study, a simple dilute-and-shoot method employing liquid chromatography-high resolution-tandem mass spectrometry for the quantification of trimetazidine, lomerizine and the specific metabolite bis-(4-fluorophenyl)-methylpiperazine (M6) in urine was developed. An oral dose of 15 mg was administered to 10 male volunteers, after which urine samples collected during the following 276 hours were analyzed using the developed method, allowing for examination of the target analytes' excretion profile. The limit of detection of all target analytes was <0.02 ng/mL. In all volunteers, the metabolite M6 was detected up to 276 hours after administration. After more than 12 hours, all volunteers were found to have higher concentrations of the metabolite M6 than of trimetazidine. The concentrations of trimetazidine, lomerizine, M6, and the M6/trimetazidine ratio in the final sample collected after 276 hours were 0.2-0.9 ng/mL, <0.05-0.1 ng/mL, 14.1-38.3 ng/mL, and 28.8-122.9, respectively. The urinary excretion of trimetazidine, unchanged lomerizine, and the metabolite M6 within the first 276 hours was 0.64%, 0.006%, and 6.1%, respectively. Consequently, the absence of the metabolite M6 in doping control urine samples corroborates the conclusion that lomerizine is unlikely to be the source of trimetazidine. The results confirm that the M6 metabolite is the longest-lasting urinary metabolite of lomerizine currently known.

SWATH acquisition mode for drug metabolism and metabolomics investigations.

AIM: Sequential window acquisition of all theoretical fragment-ion spectra (SWATH) has recently emerged as a powerful high resolution mass spectrometric data independent acquisition technique. In the present work, the potential and challenges of an integrated strategy based on LC-SWATH/MS for simultaneous drug metabolism and metabolomics studies was investigated. METHODOLOGY: The richness of SWATH data allows numerous data analysis approaches, including: detection of metabolites by prediction; metabolite detection by mass defect filtering; quantification from high-resolution MS precursor chromatograms or fragment chromatograms. Multivariate analysis can be applied to the data from the full scan or SWATH windows and allows changes in endogenous metabolites as well as xenobiotic metabolites, to be detected. Principal component variable grouping detects intersample variable correlation and groups variables with similar profiles which simplifies interpretation and highlights related ions and fragments. Principal component variable grouping can extract product ion spectra from the data collected by fragmenting a wide precursor ion window. CONCLUSION: It was possible to characterize 28 vinpocetine metabolites in urine, mostly mono- and di-hydroxylated forms, and detect endogenous metabolite expression changes in urine after the administration of a single dose of a model drug (vinpocetine) to rats.

Analytical detection of trimetazidine produced by metabolic conversion of lomerizine in doping control analysis.

The identification of trimetazidine in urine samples might result from administration of the permitted drug lomerizine. Laboratories are therefore urged to carefully investigate suspicious cases where trimetazidine is detected. Differentiation of abuse of the banned substance trimetazidine from use of the permitted drug lomerizine would be supported by analysis of the intact drug lomerizine and/or specific metabolites. Copyright © 2015 John Wiley & Sons, Ltd.

The prevalence of trimetazidine use in athletes in Poland: excretion study after oral drug administration.

Stimulants, together with anabolic androgenic steroids, are regarded as one of the most popular doping substances in sport. Owing to a great variety of these substances and new designer drugs being introduced to the market, each year the World Anti-Doping Agency (WADA) updates the list of substances and methods prohibited in sport. On 1 January 2014, a new doping agent - trimetazidine (TMZ) - was added to the WADA Prohibited List. TMZ, a substance prohibited in competition, is classified in the S6b Specified Stimulant Group. TMZ is used as a well-known cardiologic drug with confirmed biochemical and clinical activity. According to knowledge of the pharmacology and mechanism of TMZ action, TMZ can be used by athletes to improve physical efficiency, especially in the case of endurance sports. This study presents the phenomena of TMZ use by Polish athletes involved in anti-doping control in the WADA-accredited laboratory in Warsaw (Poland) between 2008 and 2013. Samples were taken from the athletes of such disciplines as cycling, athletics, and triathlon. Moreover, the elimination study of TMZ has been conducted to establish the change of TMZ concentration in urine sample after oral administration of a single or double (during the long-term therapy) dose. TMZ was monitored in urine samples by gas chromatography-mass spectrometry-nitrogen phosphorus detection (GC-MS-NPD).

Doping control analysis of trimetazidine and characterization of major metabolites using mass spectrometric approaches.

Since January 2014, the anti-anginal drug trimetazidine [1-(2,3,4-trimethoxybenzyl)-piperazine] has been classified as prohibited substance by the World Anti-Doping Agency (WADA), necessitating specific and robust detection methods in sports drug testing laboratories. In the present study, the implementation of the intact therapeutic agent into two different initial testing procedures based on gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) is reported, along with the characterization of urinary metabolites by electrospray ionization-high resolution/high accuracy (tandem) mass spectrometry. For GC-MS analyses, urine samples were subjected to liquid-liquid extraction sample preparation, while LC-MS/MS analyses were conducted by established 'dilute-and-inject' approaches. Both screening methods were validated for trimetazidine concerning specificity, limits of detection (0.5-50 ng/mL), intra-day and inter-day imprecision (<20%), and recovery (41%) in case of the GC-MS-based method. In addition, major metabolites such as the desmethylated trimetazidine and the corresponding sulfoconjugate, oxo-trimetazidine, and trimetazidine-N-oxide as identified in doping control samples were used to complement the LC-MS/MS-based assay, although intact trimetazidine was found at highest abundance of the relevant trimetazidine-related analytes in all tested sports drug testing samples. Retrospective data mining regarding doping control analyses conducted between 1999 and 2013 at the Cologne Doping Control Laboratory concerning trimetazidine revealed a considerable prevalence of the drug particularly in endurance and strength sports accounting for up to 39 findings per year.

Quantitative LC-MS/MS method in urine for the detection of drugs used to reverse the effects of chemical castration.

The chemical castration law, which targets child molesters with recidivism, was introduced in Korea in 2011. For this, leuprolide, a gonadotropin-releasing hormone agonist, is used to decrease testosterone production and suppress libido. In order to achieve efficient law enforcement, it is necessary to monitor intentional ingestion of drugs that antagonize the effect of leuprolide. Therefore, an analytical method for the simultaneous detection of mirodenafil, sildenafil, tadalafil, udenafil, vardenafil, icariin, alprostadil, and yohimbine, which are the major impotence treatment drugs, legitimately or otherwise, in Korea, as well as their selected metabolites, in human urine was established and validated using liquid chromatography-tandem mass spectrometry (LC-MS/MS). First, different sample preparation methods, two solid-phase extractions with different cartridges and protein precipitation, were compared and protein precipitation was chosen for the entire study because it showed better matrix effects and recoveries. Thus, the drugs and metabolites in urine were extracted by protein precipitation and then filtered and analyzed by LC-MS/MS with polarity switching electrospray ionization. The validation results of selectivity, matrix effect, recovery, linearity, intra- and inter-assay precision and accuracy were satisfactory. The limits of detection ranged from 0.25 to 10 ng/mL, and the limits of quantification were 2.5 to 50 ng/mL. The drugs and metabolites in urine did not show any degradation under storage for 7 and 15 days at 4 and -20 °C as well as after three freeze-thaw cycles. The developed method will be very useful for monitoring the illegal use of impotence treatment drugs.

A validated HPLC method for the simultaneous determination of naftidrofuryl oxalate and its degradation product (metabolite), naftidrofuryl acid: applications to pharmaceutical tablets and biological samples.

A simple, sensitive, and selective reverse phase-high performance liquid chromatography (RP-HPLC) method was developed and validated for the simultaneous determination of naftidrofuryl oxalate (NF) and its hydrolytic degradation product (metabolite), naftidrofuryl acid (NFA). Chromatographic separation was achieved on Spheri-5 RP-C8 (5 µm) (220 × 4.6 mm i.d.) column using a mobile phase composed of acetonitrile, 0.05 M sodium acetate and triethylamine (40 : 60 : 0.1, by volume) adjusted to pH 5.5 using glacial acetic acid. The mobile phase was pumped at flow rate 1.5 ml/min. The UV detector was set at 225 nm and quantification of the analytes was based on measuring the peak areas. The method was proved to be accurate and precise with linearity ranges of 0.1-25 and 0.2-25 µg ml(-1) for NF and NFA, respectively. The limits of detection were 0.03 and 0.04 µg ml(-1) for NF and NFA, respectively. The method was applied to serve three goals: (1) stability-indicating assay of the parent drug NF in its pharmaceutical formulation, (2) determination of the degradation product NFA down to a level of 0.005% in the presence of large excess of the parent drug, and (3) drug monitoring of naftidrofuryl and its metabolite, naftidrofuryl acid, in human plasma/urine samples taken from a healthy volunteer treated with 200 mg oral dose of naftidrofuryl oxalate. The proposed method proved to be accurate, precise, and reliable in all these application fields.

Automated flow system for sildenafil enrichment using surfactant coated solid-phase with fluorescence detection.

In this work, Amberlite XAD-1180 resin is used for on-line surfactant-mediated pre-concentration of sildenafil as a prior step for its fluorescent detection. In order to activate the column for sildenafil pre-concentration, the cationic surfactant (hexadecyltrimethylammoniunm bromide, HTAB) is adsorbed onto the resin. In these conditions, sildenafil is retained by HTAB-resin and then it is eluted with ethanol and analyzed by spectrofluorimetry. Drug-surfactant association produces a considerable fluorescence enhancement, increasing considerably the sensitivity of detection. Therefore, sildenafil can be pre-concentrated and quantitatively determined, with a detection limit of 0.2 ng mL(-1). The proposed method was successfully applied to the analysis of bulk drug, human urine, tablets, and local herbal medicine. Validation processes were performed by recovering studies and statistical analysis with satisfactory results.

Identification and characterization of urinary prenylamine metabolites by means of liquid chromatography-tandem mass spectrometry.

Prenylamine is a vasodilator of phenylalkylamine structure and was used for the treatment of angina pectoris, until reports of undesirable effects including ventricular tachycardia led to a decreasing use of the drug in the 1980s. Metabolic N-dealkylation of orally ingested prenylamine can liberate amphetamine in humans and cause positive findings for amphetamine in doping and forensic analysis. In 2010, the World Anti-Doping Agency (WADA) classified prenylamine as a non-specified stimulant according to the 2010 Prohibited List, thus banning its use in sports in-competition. Supporting the development of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) based detection method, a post-administration urine sample following a single oral prenylamine ingestion (Segontin(®) 60 mg) was analyzed for urinary metabolites. The LC-separated analytes were ionized in positive electrospray ionization (ESI) mode and detected as protonated ions using an AB Sciex TripleTOF 5600 quadrupole-time-of-flight hybrid mass spectrometer. Over 40 phase I metabolites were detected, including previously unknown mono- bis-, tris- and tetra-hydroxylated prenylamine, several hydroxylated and methoxylated prenylamine metabolites and (hydroxylated) diphenylpropylamine. Investigation of the collision-induced dissociation behaviours of the metabolites by high resolution/high accuracy mass spectrometry allowed for the assignment of the nature and the site of observed metabolic transformations. The most abundant phase I metabolite was confirmed as p-hydroxy-prenlyamine by chemical synthesis and stable isotope labelling of reference material. An existing routine screening assay based on direct injection and LC-MS/MS analysis of urine was modified and validated according to common guidelines, in order to allow for the detection of p-hydroxy-prenylamine in sports drug testing. The assay demonstrated the ability to detect the target metabolite at 0.1 ng/ml at intra- and inter-day imprecisions below 10%.

Effects of furosemide and the combination of furosemide and the labeled dosage of pimobendan on the circulating renin-angiotensin-aldosterone system in clinically normal dogs.

OBJECTIVE: To evaluate the effect of administration of the labeled dosage of pimobendan to dogs with furosemide-induced activation of the renin-angiotensin-aldosterone system (RAAS). ANIMALS: 12 healthy hound-type dogs. PROCEDURES: Dogs were allocated into 2 groups (6 dogs/group). One group received furosemide (2 mg/kg, PO, q 12 h) for 10 days (days 1 to 10). The second group received a combination of furosemide (2 mg/kg, PO, q 12 h) and pimobendan (0.25 mg/kg, PO, q 12 h) for 10 days (days 1 to 10). To determine the effect of the medications on the RAAS, 2 urine samples/d were obtained for determination of the urinary aldosterone-to-creatinine ratio (A:C) on days 0 (baseline), 5, and 10. RESULTS: Mean ± SD urinary A:C increased significantly after administration of furosemide (baseline, 0.37 ± 0.14 µg/g; day 5, 0.89 ± 0.23 µg/g) or the combination of furosemide and pimobendan (baseline, 0.36 ± 0.22 µg/g; day 5, 0.88 ± 0.55 µg/g). Mean urinary A:C on day 10 was 0.95 ± 0.63 µg/g for furosemide alone and 0.85 ± 0.21 µg/g for the combination of furosemide and pimobendan. CONCLUSIONS AND CLINICAL RELEVANCE: Furosemide-induced RAAS activation appeared to plateau by day 5. Administration of pimobendan at a standard dosage did not enhance or suppress furosemide-induced RAAS activation. These results in clinically normal dogs suggested that furosemide, administered with or without pimobendan, should be accompanied by RAAS-suppressive treatment.

The stereochemical configuration of flavanols influences the level and metabolism of flavanols in humans and their biological activity in vivo.

Extensive epidemiological and clinical evidence associates diets high in flavanol-containing foods with cardiovascular health benefits in humans. Catechin and epicatechin, the most common flavanols in foods, are present in the diet in different enantiomeric forms. This study investigated the influence of the stereochemical configuration of flavanols on their absorption, metabolism, and biological activity. Healthy adult males were asked to consume equal amounts of the stereochemically pure flavanols (-)-epicatechin, (-)-catechin, (+)-catechin, and (+)-epicatechin (1.5mg/kg bw) in a well-defined cocoa-based, dairy-containing drink matrix, and flavanol levels were subsequently determined in plasma and 24-h urine. The results obtained show that the stereochemical configuration of flavanols has a profound influence on their uptake and metabolism in humans. In addition, we assessed the vasodilatory activity of each flavanol stereoisomer in vivo and found (-)-epicatechin to be the single stereoisomer capable of mediating a significant arterial dilation response. Importantly, this effect was independent of the classic antioxidant properties of flavanols. Overall, these results indicate that the proposed beneficial health effects associated with the consumption of flavanol-containing foods will significantly depend on the stereochemical configuration of the flavanols ingested.

Direct injection liquid chromatography/electrospray ionization mass spectrometric horse urine analysis for the quantification and confirmation of threshold substances for doping control. II. Determination of theobromine.

In equine sport, theobromine is prohibited with a threshold level of 2 microg mL(-1) in urine, hence doping control laboratories have to establish quantitative and qualitative methods for its determination. Two simple liquid chromatography/mass spectrometry (LC/MS) methods for the identification and quantification of theobromine were developed and validated using the same sample preparation procedure but different mass spectrometric systems: ion trap mass spectrometry (ITMS) and time-of-flight mass spectrometry (TOFMS). Particle-free diluted urine samples were directly injected into the LC/MS systems, avoiding the time-consuming extraction step. 3-Propylxanthine was used as the internal standard. The tested linear range was 0.75-15 microg mL(-1). Matrix effects were evaluated analyzing calibration curves in water and different fortified horse urine samples. A great variation in the signal of theobromine and the internal standard was observed in different matrices. To overcome matrix effects, a standard additions calibration method was applied. The relative standard deviations of intra- and inter-day analysis were lower than 8.6 and 7.2%, respectively, for the LC/ITMS method and lower than 5.7 and 5.8%, respectively, for the LC/TOFMS method. The bias was less than 8.7% for both methods. The methods were applied to two case samples, demonstrating simplicity, accuracy and selectivity.

Determination of trapidil in human serum and urine by derivative UV spectrophotometry after selective solid-phase extraction.

A novel analytical technique able to determine the anti-ischemic drug trapidil in human serum and urine is proposed. In order to achieve satisfactory sensitivity and selectivity, an extraction procedure was required to isolate the drug from complex matrixes such as serum and urine. A solid-phase extraction procedure was investigated to both increase the analyte concentration and eliminate the interfering molecules present in large amounts in both matrixes. Optimization of the extraction step was realized by selecting a new polymeric sorbent based on a surface-modified styrene-divinylbenzene polymer which provided fast and efficient drug extraction. Drug quantification was performed by using the third-order derivative spectra of the SPE eluates. Absorbance specific signals at (3)D(335,316) and (3)D(316) nm for urine and serum, respectively, were demonstrated to be directly proportional to drug concentration and barely affected by residual matrix interferences. Under the optimized experimental conditions the calibration plots were linear over the concentration range 0.2-50 microg mL(-1). The method was validated by analysis of a series of spiked samples. Accuracy (recovery of 95 and 94% for serum and urine, respectively) and precision (RSD below 4%) were good.

[Detection of dipiridamol in biological fluids].

Acetone is proposed as an isolating agent for dipiridamol isolation from biological fluids. Purification of the isolates was performed with liquid-liquid extraction and colon chromatography with silasorb C-18 sorbent. The technique of dipiridamol detection in the blood and urine is described. The assays results are presented.

Pharmacokinetic, tissue distribution, and excretion of puerarin and puerarin-phospholipid complex in rats.

Puerarin is a potential therapeutic agent for cardiovascular diseases. But its poor oral bioavailability restricts its clinical application. In present study, as an evaluation of a formulation to improve the bioavailability of the drug, puerarin and its phospholipid complex were given to rats by intragastrically (i.g.) administration to compare pharmacokinetic, tissue distribution, and excretion. Serum samples were obtained at designated times after a single oral dose of 400 mg/kg puerarin or its complex. Tissue samples (heart, liver, spleen, kidney, lung, and brain), urine, and feces were collected and analyzed by a sensitive and specific high performance liquid chromatography (HPLC) method after i.g. administration of puerarin or its phospholipid complex. Compartmental and non-compartmental analyses were applied to the serum concentration versus time data. Pharmacokinetic parameters were calculated using the 3P97 pharmacokinetic software package. An open two-compartment, first-order model was selected for pharmacokinetic modeling. The results showed that after i.g. administration of 400 mg/kg puerarin and its phospholipid complex (equivalent to 400 mg/kg of puerarin), the pharmacokinetic parameters of the two formulations were different. The serum concentrations reached peaks at 0.894+/-0.521 h and 0.435+/-0.261 h, respectively, indicating the complex was more readily absorbed in serum than puerarin. The maximum concentrations for puerarin and its complex were 1.367+/-0.586 mg.L(-1) and 2.202+/-1.28 mg.L(-1) and AUC were 5.779+/-1.662 mg.h. L(-1) and 8.456+/-0.44 mg.h L(-1), respectively, indicating a higher bioavailability for the complex. The widely distribution characteristics of puerarin and its complex in tissues post-i.g. administration was identical and in a descending order as follows: lung, kidney, liver, heart, spleen, and brain. However, the amount was different. Puerarin distribution was higher in heart, lung, and brain after administering the complex. The cumulative 72 h urinary excretion of puerarin after i.g. administration of puerarin and its complex accounted for 1.05%, 1.11% of the administered dose, respectively. The cumulative feces excretion of puerarin was 32.3% and 25.5%. To sum up, oral administration of puerarin phospholipid complex modified the pharmacokinetics and tissue distribution of puerarin and it could be an effective oral formulation for puerarin.

Fatores clínicos, etiológicos e evolutivos da audição na surdez súbita / Clinical, etiological and progression factors of hearing in sudden deafness

Existem várias terapias preconizadas para o tratamento da surdez súbita, algumas apresentam riscos significativos necessitando inclusive de internação hospitalar. OBJETIVO: Este estudo prospectivo analisa aspectos clínicos, etiológicos e evolutivos nos casos de surdez súbita (SS) em pacientes tratados ambulatorialmente com medicação oral. FORMA DE ESTUDO: clínico com coorte transversal. MATERIAL E MÉTODO: 40 pacientes com perda súbita da audição submeteram inicialmente a avaliação clínica otorrinolaringológica, testes audiométricos, análise hematológica e ressonância magnética. Confirmado o diagnóstico de SS, todos os pacientes receberam inicialmente prednisona e pentoxifilina sendo acompanhados por pelo menos um ano. RESULTADO: 45 por cento (n=18) apresentaram normalização dos limiares auditivos, 40 por cento (n=16) apresentaram melhoras auditivas, 15 por cento (n=6) mantiveram os mesmos limiares iniciais. Nove casos (22,5 por cento) apresentaram manifestações clínicas que justificaram a perda auditiva (infecção viral, fatores imunomediados, alterações vasculares e outros), três (7,5 por cento) apresentaram tumores na região do ângulo ponto-cerebelar. A evolução auditiva nestes 12 casos com etiologia presumida não apresentou diferença estatística significante em relação aos 28 casos sem etiologia definida. O tratamento clínico instituído nos primeiros sete dias de instalação da perda auditiva, nos pacientes que obtiveram melhora, foi o único parâmetro estatisticamente significante dos fatores prognóstico avaliado. CONCLUSÃO: A pesquisa exaustiva etiológica deve ser realizada em qualquer caso de perda auditiva neurossensorial aguda. A presença de 7,5 por cento de tumores localizados na região do ângulo ponto-cerebelar nos casos de SS juntamente com outras causas tratáveis justifica a investigação clínica nestes pacientes. Nossos pacientes apresentaram uma boa melhora auditiva em 67,5 por cento dos casos, independentemente da etiologia. O início da terapia nos primeiros sete dias de instalação da perda auditiva foi o único fator de melhora significante dos limiares auditivos.

Clinical, etiological and progression factors of hearing in sudden deafness.

UNLABELLED: Out of the many forms of therapy for sudden deafness, some require hospitalization and present significant risks. AIM: This prospective study analyzes etiology and evolution in cases of sudden deafness (SD) where outpatient oral treatment was used. STUDY DESIGN: Clinical with transversal cohort. MATERIAL AND METHOD: Forty cases of sudden hearing loss were followed for at least one year. All were submitted to initial clinical evaluation, auditory tests, routine blood analysis, and magnetic resonance imaging. All received initial treatment with pentoxifylline and prednisone. RESULTS: 45% (n=18) presented normal auditory thresholds, 40% (n=16) showed some improvement in hearing, 15% (n=6) maintained initial hearing level. Nine cases (22.5%) presented clinical conditions possibly implicated in hearing loss (viral infection, immunomediated hearing loss, vascular disorders, and so on); three (7.5%) had cerebellopontine tumors. Evolution of hearing in these 12 cases with presumed etiology presented no differences from hearing in the 28 cases without any known etiological factor. Clinical treatment within the first seven days was the only statistically significantly different condition in patients who improved hearing. CONCLUSIONS: An objective search for etiological bases should be conducted in any case of acute sensorineural hearing loss. The presence of cerebellopontine tumors in 7.5% of cases of SD, among other treated causes, justifies a thorough clinical investigation in these patients. Overall good evolution of hearing was observed in 67.5% of cases of SD, regardless of its etiology. Therapy within the first seven days of SD was significantly related to better outcomes in hearing.

Urinary methylxanthine and autistic disorder: absence of previously reported correlation.

We were unable to reveal significant difference in the levels of xanthine and methylxanthines in the urine samples from 59 patients diagnosed with autistic symptoms and 64 age- and sex-matched normal volunteers. Our data suggest that abnormalities in xanthine and methylxanthine excretion (US Patent 20020019406 A1, Feb. 12, 2002) represent distincly uncommon symptoms in autism.