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1.
Clin Chem Lab Med ; 62(6): 1109-1117, 2024 May 27.
Article in English | MEDLINE | ID: mdl-38290722

ABSTRACT

OBJECTIVES: Seizures (SZ) are one of the main complications occurring in infants undergoing therapeutic hypothermia (TH) due to perinatal asphyxia (PA) and hypoxic ischemic encephalopathy (HIE). Phenobarbital (PB) is the first-line therapeutic strategy, although data on its potential side-effects need elucidation. We investigated whether: i) PB administration in PA-HIE TH-treated infants affects S100B urine levels, and ii) S100B could be a reliable early predictor of SZ. METHODS: We performed a prospective case-control study in 88 PA-HIE TH infants, complicated (n=44) or not (n=44) by SZ requiring PB treatment. S100B urine levels were measured at 11 predetermined monitoring time-points from first void up to 96-h from birth. Standard-of-care monitoring parameters were also recorded. RESULTS: S100B significantly increased in the first 24-h independently from HIE severity in the cases who later developed SZ and requested PB treatment. ROC curve analysis showed that S100B, as SZ predictor, at a cut-off of 2.78 µg/L achieved a sensitivity/specificity of 63 and 84 %, positive/negative predictive values of 83 and 64 %. CONCLUSIONS: The present results offer additional support to the usefulness of S100B as a trustable diagnostic tool in the clinical daily monitoring of therapeutic and pharmacological procedures in infants complicated by PA-HIE.


Subject(s)
Asphyxia Neonatorum , Hypothermia, Induced , S100 Calcium Binding Protein beta Subunit , Seizures , Humans , S100 Calcium Binding Protein beta Subunit/urine , Seizures/urine , Seizures/diagnosis , Seizures/drug therapy , Male , Infant, Newborn , Female , Case-Control Studies , Prospective Studies , Asphyxia Neonatorum/urine , Asphyxia Neonatorum/therapy , Asphyxia Neonatorum/complications , ROC Curve , Hypoxia-Ischemia, Brain/urine , Hypoxia-Ischemia, Brain/therapy , Hypoxia-Ischemia, Brain/diagnosis , Phenobarbital/therapeutic use , Infant , Biomarkers/urine
3.
BMC Med Genet ; 19(1): 193, 2018 11 06.
Article in English | MEDLINE | ID: mdl-30400883

ABSTRACT

BACKGROUND: X-linked creatine transporter deficiency (OMIM#300036,CRTR-D) is characterized by cerebral creatine deficiency, intellectual disabilities, severe speech impairment, seizures and behavioral problems. Mutations in the creatine transporter gene SLC6A8, a member of the solute-carrier family 6 mapped to Xq28, have been reported to cause the creatine transporter deficiency. CASE PRESENTATION: The proband presented at 5 yrs. 1 month of age with delays in intellectual and development, seizures and behavioral problems. A novel missense mutation, c.1181C > A (p.Thr394Lys), in the SLC6A8 gene (NM_005629.3) was detected via targeted exome sequencing, and then validated by Sanger sequencing. Multiple in silico variant effect analysis methods, including SIFT, PolyPhen2, PROVEAN, and Mutation Taster predicted that this variant was likely damaging or diseasing-causing. This hemizygous variation was also identified in the affected brother with the same clinical condition and inherited from the heterozygous carrier mother. The diagnosis was suggested by increased urinary creatine/creatinine (Cr:Crn) ratio and markedly reduced creatine content peak by brain proton magnetic resonance spectroscopy (MRS). The proband's mother became pregnant with a 3rd sibling, in whom the Sanger sequencing result of c.1181C > A was negative. CONCLUSION: The novel mutation c.1181C > A in the SLC6A8 gene reported in a Chinese family has expanded the mutation spectrum of CRTR-D. The combination of powerful new technologies such as targeted exome sequencing with thorough systematic clinical evaluation of patients will improve the diagnostic yield, and assist in genetic counselling and prenatal diagnosis for suspected genetic disorders.


Subject(s)
Brain Diseases, Metabolic, Inborn/genetics , Creatine/deficiency , Intellectual Disability/genetics , Mental Retardation, X-Linked/genetics , Mutation, Missense , Nerve Tissue Proteins/genetics , Plasma Membrane Neurotransmitter Transport Proteins/deficiency , Seizures/genetics , Asian People , Base Sequence , Brain Diseases, Metabolic, Inborn/ethnology , Brain Diseases, Metabolic, Inborn/physiopathology , Brain Diseases, Metabolic, Inborn/urine , Child, Preschool , Chromosomes, Human, Pair 10/chemistry , Creatine/genetics , Creatine/urine , Creatinine/urine , DNA Mutational Analysis , Exome , Gene Expression , Humans , Intellectual Disability/ethnology , Intellectual Disability/physiopathology , Intellectual Disability/urine , Maternal Inheritance , Mental Retardation, X-Linked/ethnology , Mental Retardation, X-Linked/physiopathology , Mental Retardation, X-Linked/urine , Pedigree , Plasma Membrane Neurotransmitter Transport Proteins/genetics , Plasma Membrane Neurotransmitter Transport Proteins/urine , Seizures/ethnology , Seizures/physiopathology , Seizures/urine , Siblings
4.
Appl Environ Microbiol ; 84(21)2018 11 01.
Article in English | MEDLINE | ID: mdl-30217846

ABSTRACT

The experimental pathophysiology of organophosphorus (OP) chemical exposure has been extensively reported. Here, we describe an altered fecal bacterial biota and urine metabolome following intoxication with soman, a lipophilic G class chemical warfare nerve agent. Nonanesthetized Sprague-Dawley male rats were subcutaneously administered soman at 0.8 (subseizurogenic) or 1.0 (seizurogenic) of the 50% lethal dose (LD50) and evaluated for signs of toxicity. Animals were stratified based on seizing activity to evaluate effects of soman exposure on fecal bacterial biota and urine metabolites. Soman exposure reshaped fecal bacterial biota by altering Facklamia, Rhizobium, Bilophila, Enterobacter, and Morganella genera of the Firmicutes and Proteobacteria phyla, some of which are known to hydrolyze OP chemicals. However, analogous changes were not observed in the bacterial biota of the ileum, which remained the same irrespective of dose or seizing status of animals after soman intoxication. However, at 75 days after soman exposure, the bacterial biota stabilized and no differences were observed between groups. Interestingly, in considering just the seizing status of animals, we found that the urine metabolomes were markedly different. Leukotriene C4, kynurenic acid, 5-hydroxyindoleacetic acid, norepinephrine, and aldosterone were excreted at much higher rates at 72 h in seizing animals, consistent with early multiorgan involvement during soman poisoning. These findings demonstrate the feasibility of using the dysbiosis of fecal bacterial biota in combination with urine metabolome alterations as forensic evidence for presymptomatic OP exposure temporally to enable administration of neuroprotective therapies of the future.IMPORTANCE The paucity of assays to determine physiologically relevant OP exposure presents an opportunity to explore the use of fecal bacteria as sentinels in combination with urine to assess changes in the exposed host. Recent advances in sequencing technologies and computational approaches have enabled researchers to survey large community-level changes of gut bacterial biota and metabolomic changes in various biospecimens. Here, we profiled changes in fecal bacterial biota and urine metabolome following a chemical warfare nerve agent exposure. The significance of this work is a proof of concept that the fecal bacterial biota and urine metabolites are two separate biospecimens rich in surrogate indicators suitable for monitoring OP exposure. The larger value of such an approach is that assays developed on the basis of these observations can be deployed in any setting with moderate clinical chemistry and microbiology capability. This can enable estimation of the affected radius as well as screening, triage, or ruling out of suspected cases of exposures in mass casualty scenarios, transportation accidents involving hazardous materials, refugee movements, humanitarian missions, and training settings when coupled to an established and validated decision tree with clinical features.


Subject(s)
Bacteria/drug effects , Biota/drug effects , Feces/microbiology , Nerve Agents/poisoning , Seizures/metabolism , Soman/poisoning , Animals , Bacteria/classification , Bacteria/genetics , Bacteria/isolation & purification , Humans , Male , Rats , Rats, Sprague-Dawley , Seizures/etiology , Seizures/microbiology , Seizures/urine , Soman/administration & dosage , Urine/chemistry
5.
Seizure ; 60: 132-138, 2018 Aug.
Article in English | MEDLINE | ID: mdl-29960852

ABSTRACT

PURPOSE: To determine whether use of a ketogenic formula during the first month of the modified Atkins diet (MAD) in adults with drug-resistant epilepsy (DRE) improves seizure reduction and compliance compared to MAD alone. METHODS: Eighty adults (age ≥18 years) with DRE and ≥4 reliably quantifiable seizures/month were enrolled. All participants were trained to follow a 20 g/day net carbohydrate limit MAD. Patients were randomized to receive one 8-ounce (237 mL) tetrapak of KetoCal®, a 4:1 ketogenic ratio formula, daily in combination with MAD during the first month (treatment arm) or second month (control/cross-over arm). Patients recorded urine ketones, weight, and seizure frequency and followed up at 1 and 2 months. RESULTS: By 1 month, 84% of patients achieved ketosis (median of 4-4.5 days). At 1 month, the treatment arm had a significantly higher ketogenic ratio and more patients with a ≥1:1 ketogenic ratio compared to the control arm. There was no difference in median seizure frequency, proportion of responders (≥50% seizure reduction), or median seizure reduction from baseline between groups. However, patients treated with KetoCal® during the first month were significantly more likely to continue MAD for 6 months or more. CONCLUSION: Although supplementing MAD with a ketogenic formula in the first month did not increase the likelihood of reducing seizures compared to MAD alone, significantly more adults remained on MAD long-term with this approach. This suggests a potential strategy for encouraging compliance with MAD in adults with DRE.


Subject(s)
Diet, High-Protein Low-Carbohydrate/methods , Drug Resistant Epilepsy/diet therapy , Patient Compliance , Adult , Body Weight , Cross-Over Studies , Diet, High-Protein Low-Carbohydrate/adverse effects , Diet, Ketogenic/adverse effects , Diet, Ketogenic/methods , Drug Resistant Epilepsy/urine , Female , Follow-Up Studies , Humans , Ketosis/diet therapy , Ketosis/urine , Male , Seizures/diet therapy , Seizures/urine , Time Factors , Treatment Outcome
6.
J Child Neurol ; 29(3): 331-5, 2014 Mar.
Article in English | MEDLINE | ID: mdl-23271755

ABSTRACT

Rotavirus infection disturbs cellular Ca(2+) homeostasis by triggering an increase in Ca(2+) permeation. A theoretical link between Ca(2+) dysregulation and seizures in patients with rotavirus gastroenteritis has been suggested, but no prior studies have investigated this relationship. To test our hypothesis that patients with rotavirus-associated seizures have greater Ca(2+) homeostasis disruption than those without seizures, we compared clinical and laboratory data--including corrected total serum Ca(2+) levels--between the 2 groups. Age, gender, maximum body temperature, day of admission, levels of electrolytes except Ca(2+), blood pH, and urine ketone levels were not related to seizure occurrence. Significantly lower Ca(2+) levels were found among the seizure (+) group (9.22 ± 0.50 vs 9.66 ± 0.46 mg/dL, P = .01). Although Ca(2+) levels were within normal ranges and did not directly cause the seizures, our results provide preliminary evidence for a relationship between Ca(2+) homeostasis disruption and seizures in rotavirus patients.


Subject(s)
Calcium/blood , Rotavirus Infections/blood , Rotavirus Infections/complications , Seizures/blood , Seizures/etiology , Aging , Blood Chemical Analysis , Body Temperature , Child , Child, Preschool , Female , Homeostasis , Humans , Infant , Infant, Newborn , Ketones/urine , Male , Patient Admission , Retrospective Studies , Rotavirus Infections/urine , Seizures/urine , Sex Characteristics
7.
J Child Neurol ; 27(7): 917-21, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22190498

ABSTRACT

Acute intermittent porphyria is a metabolic disorder rarely seen in prepubertal children. A delay in diagnosis of acute intermittent porphyria is common because of variable and nonspecific symptoms. We report an 8-year-old boy with right hemimegalencephaly and intractable seizures, who presented with dark-colored urine, hypertension, increasing lethargy, fluctuating seizures, and poor oral intake. He subsequently developed hyponatremia secondary to syndrome of inappropriate antidiuretic hormone secretion. His urinalysis was negative for red blood cells, and a random urine porphobilinogen level was elevated. Further biochemical and molecular testing confirmed the diagnosis of acute intermittent porphyria. His antiepileptic medications were discontinued and hemin administered, with dramatic clinical improvement. The diagnosis of acute intermittent porphyria was challenging because of his underlying neurologic condition. This case highlights the variable presentation of acute intermittent porphyria and emphasizes the importance of considering the diagnosis even in young patients with underlying neurologic conditions when they present with nonspecific neurovisceral symptoms or with unexplained neurologic deterioration.


Subject(s)
Porphyria, Acute Intermittent/diagnosis , Brain/pathology , Child , Complement C3/metabolism , Electroencephalography , Humans , Hypertension/etiology , Magnetic Resonance Imaging , Male , Porphobilinogen/urine , Porphyria, Acute Intermittent/complications , Porphyria, Acute Intermittent/urine , Seizures/blood , Seizures/etiology , Seizures/urine
8.
Clin Toxicol (Phila) ; 49(8): 760-4, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21970775

ABSTRACT

OBJECTIVE: To report a case of seizures and supraventricular tachycardia (SVT) following confirmed synthetic cannabinoid ingestion. BACKGROUND: Despite widespread use of legal synthetic cannabinoids, reports of serious toxicity following confirmed use of synthetic cannabinoids are rare. We report severe toxicity including seizures following intentional ingestion of the synthetic cannabinoid JWH-018 and detail confirmation by laboratory analysis. CASE REPORT: A healthy 48 year old man had a generalized seizure within thirty minutes of ingesting an ethanol mixture containing a white powder he purchased from the Internet in an attempt to get high. Seizures recurred and abated with lorazepam. Initial vital signs were: pulse, 106/min; BP, 140/88 mmHg; respirations, 22/min; temperature, 37.7 °C. A noncontrast computed tomography of the brain and EEG were negative, and serum chemistry values were normal. The blood ethanol concentration was 3.8 mg/dL and the CPK 2,649 U/L. Urine drug screening by EMIT was negative for common drugs of abuse, including tetrahydrocannabinol. On hospital day 1, he developed medically refractory SVT. The patient had no further complications and was discharged in his normal state of health 10 days after admission. The original powder was confirmed by gas chromatography mass spectrometry to be JWH-018, and a primary JWH-018 metabolite was detected in the patient's urine (200 nM) using liquid chromatography tandem mass spectrometry. DISCUSSION: Synthetic cannabinoids are legal in many parts of the world and easily obtained over the Internet. Data on human toxicity are limited and real-time confirmatory testing is unavailable to clinicians. The potential for toxicity exists for users mistakenly associating the dose and side effect profiles of synthetic cannabinoids to those of marijuana. CONCLUSION: Ingestion of JWH-018 can produce seizures and tachyarrhythmias. Clinicians, lawmakers, and the general public need to be aware of the potential for toxicity associated with synthetic cannabinoid use.


Subject(s)
Cannabinoids/toxicity , Ethanol/toxicity , Indoles/toxicity , Naphthalenes/toxicity , Seizures/chemically induced , Tachycardia, Supraventricular/chemically induced , Cannabinoids/blood , Cannabinoids/urine , Ethanol/blood , Gas Chromatography-Mass Spectrometry , Humans , Indoles/blood , Indoles/urine , Male , Middle Aged , Naphthalenes/blood , Naphthalenes/urine , Seizures/blood , Seizures/therapy , Seizures/urine , Severity of Illness Index , Tachycardia, Supraventricular/blood , Tachycardia, Supraventricular/therapy , Tachycardia, Supraventricular/urine , Treatment Outcome
10.
J Popul Ther Clin Pharmacol ; 17(2): e256-61, 2010.
Article in English | MEDLINE | ID: mdl-20664118

ABSTRACT

BACKGROUND: Historically, physicians have been reluctant to maintain infants on phenytoin (PHT) following initial stabilization with intravenous loading doses, as therapeutic blood levels are difficult to achieve with conventional oral doses, and there is concern that high doses will result in toxicity. OBJECTIVES: To determine the oral dose of PHT required to achieve therapeutic blood concentrations, without clinical toxicity, in the first weeks of life. METHODS: Eight infants with seizures were treated with phenytoin from 2 weeks to 3 months of age. Total and free phenytoin concentrations, and urine phenytoin metabolite (p-hydroxyphenytoin) were measured every 2 weeks. Parents were asked to note seizure frequency and complete a questionnaire about possible side effects every 2 weeks. RESULTS: No infants had seizures and no clinical side effects were noted. Doses required to achieve therapeutic serum concentrations ranged from 10-20mg/kg/day, considerably higher than doses required in adults. Free phenytoin levels were 8-13% of total serum concentrations, similar to ratios reported in adults. CONCLUSION: To achieve therapeutic serum phenytoin levels in infants, doses of 10-20 mg/kg/day are required. These higher doses can be safely administered without clinical toxicity.


Subject(s)
Phenytoin/administration & dosage , Administration, Oral , Age Factors , Dose-Response Relationship, Drug , Humans , Infant , Infant, Newborn , Phenytoin/blood , Phenytoin/urine , Prospective Studies , Random Allocation , Seizures/blood , Seizures/drug therapy , Seizures/urine
11.
J Med Toxicol ; 6(4): 424-6, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20411370

ABSTRACT

Reports of toxicity secondary to Kratom are rare and lack of diagnostic testing in human specimens has prevented confirmatory explanation of observed clinical effects. We present a novel case of serious human toxicity following Kratom use confirmed via quantitative analysis of urine by high performance liquid chromatography coupled to electrospray tandem mass spectrometry. A 64 year-old male was witnessed to have a seizure at home following kratom consumption. Upon arrival to the emergency department (ED), the patient was unresponsive. While in the ED, the patient sustained a second seizure. He was intubated to protect his airway. The remainder of his hospital course was uneventful. A urine specimen was collected shortly after admission and sent for analysis. The mitragynine concentration in the urine was 167 ± 15 ng/ml. We report a rare case of Kratom toxicity characterized by a seizure and coma confirmed by urinary analysis of mitragynine by high performance liquid chromatography coupled to electrospray tandem mass spectrometry. The proposed mechanism for this reaction is unclear but suggested mechanisms include adenosine binding or stimulation of adrenergic and/or serotonergic receptors similar to tramadol.


Subject(s)
Coma/chemically induced , Mitragyna/chemistry , Poisoning/etiology , Secologanin Tryptamine Alkaloids/poisoning , Seizures/chemically induced , Anticonvulsants/therapeutic use , Chromatography, High Pressure Liquid , Coma/urine , Glasgow Coma Scale , Humans , Intubation, Intratracheal , Male , Middle Aged , Phenytoin/therapeutic use , Plant Extracts/poisoning , Poisoning/therapy , Poisoning/urine , Secologanin Tryptamine Alkaloids/urine , Seizures/urine , Spectrometry, Mass, Electrospray Ionization , Treatment Outcome
12.
Seizure ; 19(1): 36-9, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19962324

ABSTRACT

PURPOSE: To investigate whether it is better to use blood beta-hydroxybutyrate (BHB) or urinary ketones to monitor ketogenic diet (KD). METHOD: In 33 patients on KD we measured ketosis in two different ways. At the 3-monthly visits to the clinic we measured BHB in capillary blood obtained by finger-prick and the level of ketones in the urine using a urine dipstick. If the patient was able to collect urine, the urinary ketones were also measured every day at home. We compared the degree of ketosis with seizure reduction. RESULTS: BHB measured during the 3-monthly visits correlated with seizure reduction at 3 and 6 months (p=0.037 and 0.019, respectively). Urinary ketones measured at the same time did not correlate at any visit. The averaged values of the daily measured ketones in the urine did not correlate either. CONCLUSIONS: BHB correlates better with seizure reduction than do ketones in urine. It is, therefore, better to use BHB to monitor KD even if BHB is measured less frequently than urinary ketones.


Subject(s)
3-Hydroxybutyric Acid/blood , Diet, Ketogenic , Ketones/urine , Seizures , Adolescent , Adult , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Infant , Male , Retrospective Studies , Seizures/blood , Seizures/diet therapy , Seizures/urine , Statistics as Topic , Time Factors , Treatment Outcome , Young Adult
14.
J Child Neurol ; 25(1): 98-101, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19461121

ABSTRACT

For the first time, the use of urine [(1)H] magnetic resonance spectroscopy has allowed the detection of 1 case of guanidinoacetate methyl transferase in a database sample of 1500 pediatric patients with a diagnosis of central nervous system impairment of unknown origin. The urine [(1)H] magnetic resonance spectroscopy of a 9-year-old child, having severe epilepsy and nonprogressive mental and motor retardation with no apparent cause, revealed a possible guanidinoacetic acid increase. The definitive assignment of guanidinoacetic acid was checked by addition of pure substance to the urine sample and by measuring [(1)H]-[(1)H] correlation spectroscopy. Diagnosis of guanidinoacetate methyl transferase deficiency was further confirmed by liquid chromatography-mass spectrometry, brain [(1)H] magnetic resonance spectroscopy, and mutational analysis of the guanidinoacetate methyl transferase gene. The replacement therapy was promptly started and, after 1 year, the child was seizure free. We conclude that for this case, urine [(1)H] magnetic resonance spectroscopy screening was able to diagnose guanidinoacetate methyl transferase deficiency.


Subject(s)
Deficiency Diseases/diagnosis , Deficiency Diseases/urine , Guanidinoacetate N-Methyltransferase/deficiency , Brain/metabolism , Child , Chromatography, Liquid , DNA Mutational Analysis , Deficiency Diseases/therapy , Diagnosis, Differential , Epilepsy/diagnosis , Epilepsy/therapy , Epilepsy/urine , Guanidinoacetate N-Methyltransferase/genetics , Guanidinoacetate N-Methyltransferase/therapeutic use , Humans , Intellectual Disability/diagnosis , Intellectual Disability/therapy , Intellectual Disability/urine , Magnetic Resonance Spectroscopy/methods , Male , Mass Spectrometry , Movement Disorders/diagnosis , Movement Disorders/therapy , Movement Disorders/urine , Protons , Seizures/diagnosis , Seizures/therapy , Seizures/urine , Treatment Outcome
15.
J Child Neurol ; 24(10): 1268-72, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19687389

ABSTRACT

A pilot prospective follow-up study of the role of the branched chain amino acids as additional therapy to the ketogenic diet was carried out in 17 children, aged between 2 and 7 years, with refractory epilepsy. All of these patients were on the ketogenic diet; none of them was seizure free, while only 13 had more or less benefited from the diet. The addition of branched chain amino acids induced a 100% seizure reduction in 3 patients, while a 50% to 90% reduction was noticed in 5. Moreover, in all of the patients, no reduction in ketosis was recorded despite the change in the fat-to-protein ratio from 4:1 to 2.5:1. Although our data are preliminary, we suggest that branched chain amino acids may increase the effectiveness of the ketogenic diet and the diet could be more easily tolerated by the patients because of the change in the ratio of fat to protein.


Subject(s)
Amino Acids, Branched-Chain/therapeutic use , Diet, Ketogenic , Epilepsy/diet therapy , Amino Acids, Branched-Chain/adverse effects , Anticonvulsants/therapeutic use , Child , Child, Preschool , Epilepsy/drug therapy , Epilepsy/urine , Follow-Up Studies , Humans , Ketosis/urine , Models, Biological , Pilot Projects , Prospective Studies , Seizures/diet therapy , Seizures/drug therapy , Seizures/urine , Treatment Outcome
16.
Arch Dis Child ; 92(8): 687-9, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17088338

ABSTRACT

BACKGROUND: Pyridoxine-dependent seizures (PDS) is a rare, autosomal recessively inherited disorder. Recently alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase deficiency was identified as a major cause of PDS, which causes accumulation of both alpha-AASA and pipecolic acid (PA) in body fluids. METHODS: We studied urinary and plasma alpha-AASA and PA levels in 12 Dutch clinically diagnosed patients with PDS. RESULTS: Alpha-AASA was elevated in both urine and plasma in 10 patients. In these patients plasma PA levels were also elevated but urinary PA levels were normal. DISCUSSION: In all patients with clinically definite PDS, and in most patients with probable or possible PDS, the clinical diagnosis of PDS could be confirmed at the metabolite level. Non-invasive urinary screening for alpha-AASA accumulation provides a reliable tool to diagnose PDS and can save these patients from the classical and potentially dangerous pyridoxine withdrawal test to prove PDS.


Subject(s)
Hyperlysinemias/diagnosis , Pipecolic Acids , Seizures/diagnosis , Aldehyde Dehydrogenase/blood , Aldehyde Dehydrogenase/urine , Biomarkers/blood , Biomarkers/urine , Female , Humans , Netherlands , Pipecolic Acids/blood , Pipecolic Acids/urine , Pyridoxine/therapeutic use , Seizures/blood , Seizures/urine , Vitamin B Complex/therapeutic use
17.
Biopharm Drug Dispos ; 27(2): 77-84, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16308884

ABSTRACT

The relationship between free phenytoin concentrations and clinical responses, and the factors influencing protein binding of phenytoin were investigated. A total of 119 plasma samples from 70 patients treated orally with phenytoin were analysed. The mean free phenytoin concentration was significantly higher in the patients who received phenytoin monotherapy and were classified as having a complete response (1.25 +/- 1.09 microg/ml) than that in the partial response group (0.59 +/- 0.07 microg/ml), whereas the mean total concentrations were not significantly different between the two groups. Samples were divided into three groups based on the free fraction of phenytoin, i.e. low, <5%; medium, 5%-10%; high, > 10%. The mean age (55.3 +/- 10.9 years) was significantly higher in the high group than in the low (42.7 +/- 21.2 years) and medium (42.8 +/- 16.0 years) groups. The mean creatinine clearance (CLcr) (55.3 +/- 10.9 ml/min) and serum albumin concentration (3.30 +/- 1.25 g/dl) were significantly lower in the high group than the low (88.3 +/- 29.0 ml/min and 4.08 +/- 0.50 g/dl, respectively) and medium (95.0 +/- 32.8 ml/min and 3.95 +/- 0.92 g/dl, respectively) groups. These results suggest that the free phenytoin concentration, rather than the total concentration, is more useful for monitoring antiepileptic effects in patients receiving phenytoin monotherapy. It was also found that the free phenytoin fraction was significantly influenced by aging, CLcr and serum albumin levels.


Subject(s)
Anticonvulsants/pharmacokinetics , Phenytoin/pharmacokinetics , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Anticonvulsants/blood , Anticonvulsants/therapeutic use , Child , Creatinine/urine , Drug Monitoring , Female , Humans , Male , Middle Aged , Phenytoin/blood , Phenytoin/therapeutic use , Protein Binding , Retrospective Studies , Seizures/blood , Seizures/prevention & control , Seizures/urine , Serum Albumin/metabolism
18.
Forensic Sci Int ; 135(1): 16-26, 2003 Jul 29.
Article in English | MEDLINE | ID: mdl-12893131

ABSTRACT

A GC-MS method has been developed for the detection of amphetamine, methamphetamine, and the ephedrines, in seizures and the urine, based on on-GC condensation (derivatization) with cyclohexanone. The method is simple: the dried seizure material or the urine extract was mixed with cyclohexanone and injected into the GC-MS. The method was found to be superior to the methods based on acyl and trimethylsilyl (TMS) derivatization. Unlike for the acyl and TMS derivatives, the molecular and fragment ions of the cyclohexanone condensation products (cyclohexanone derivatives) were of substantial abundance, a useful property in unambiguous compound characterization. Furthermore, the high stability of the "derivatizing" reagent, cyclohexanone, compared with acyl and TMS derivatizing reagents, is a useful property in method development. The present method has proved selective and, tentatively, sensitive enough in the following areas (where methods based on acyl and TMS derivatization, as tested in this laboratory, have failed): (a) detection of amphetamine as a metabolite of methamphetamine; (b) detection of norpseudoephedrine as a metabolite of pseudoephedrine; (c) detection of amphetamine as an impurity of methamphetamine; (d) detection of cathine (norephedrine) as a constituent of Khat leaves; and (e) differentiation of Khat use from phenylpropanolamine use.


Subject(s)
Amphetamines/urine , Central Nervous System Stimulants/urine , Cyclohexanones , Ephedrine/urine , Forensic Medicine/methods , Gas Chromatography-Mass Spectrometry/methods , Seizures/urine , Amphetamines/chemistry , Catha , Central Nervous System Stimulants/chemistry , Ephedrine/chemistry , Humans , Methamphetamine/chemistry , Methamphetamine/urine
19.
Forensic Sci Int ; 115(3): 183-8, 2001 Jan 15.
Article in English | MEDLINE | ID: mdl-11074173

ABSTRACT

To evaluate pathophysiological significance of post-mortem urinary myoglobin levels in determining the cause of death, we investigated 210 forensic autopsy cases, partially in comparison with serum levels. Post-mortem serum myoglobin levels were extraordinary high in most cases possibly due to post-mortem change. Urinary myoglobin levels did not correlate with the serum levels, showing possible post-mortem elevation in cases of a prolonged post-mortem period over 48h. A high (>1000 ng/ml), moderate (100-1000 ng/ml), slight (50-100 ng/ml) and not significant (<50 ng/ml) elevation of urinary myoglobin were observed in 26, 43, 31 and 110 cases, respectively. Half the highly elevated cases were those with a survival time over 24h. In cases of minor muscle injury such as head trauma, elevation of urinary myoglobin level was closely related to longer survival. In acute/subacute deaths with a post-mortem interval within 48h, a significant difference was observed in relation to the blood carboxyhemoglobin (COHb) levels of fire victims: myoglobinuria over 100 ng/ml was more frequently and markedly observed in cases with COHb below 60% than over 60%, suggesting muscle damage in fatal burns. Similar elevation was observed in heat stroke victims, and also in some cases of acute and subacute death from polytrauma, asphyxiation, drowning, electricity and spontaneous cerebral bleeding, but not in myocardial infarction. Thus, it was suggested that high post-mortem urinary myoglobin levels in acute and subacute death cases may be a possible indicator of antemortem massive skeletal muscle damage as well as exertional muscle hyperactivity or convulsive disorders associated with hypoxia.


Subject(s)
Autopsy/methods , Cause of Death , Myoglobinuria/urine , Postmortem Changes , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Biomarkers/urine , Burns/blood , Burns/urine , Carboxyhemoglobin/metabolism , Child , Child, Preschool , Female , Heat Stroke/blood , Heat Stroke/urine , Humans , Hypoxia/blood , Hypoxia/urine , Infant , Infant, Newborn , Male , Middle Aged , Myoglobinuria/blood , Seizures/blood , Seizures/urine , Time Factors , Wounds and Injuries/blood , Wounds and Injuries/urine
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