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Background Given the limited treatment options for younger children with attention-deficit/hyperactivity disorder (ADHD), a clinical study for SHP465 treatment was warranted. Objectives We aimed to evaluate the pharmacokinetics, safety, and tolerability of SHP465 mixed amphetamine salts (MAS) 6.25 mg after multiple once-daily doses in children aged 4-5 years with ADHD. Methods In this open-label multicenter study, SHP465 MAS 6.25 mg once daily was administered for 28 days to children aged 4-5 years with ADHD; baseline ADHD Rating Scale-5 total score ≥ 28 (boys) or ≥ 24 (girls) and Clinical Global Impression-Severity scale score ≥ 4. Blood samples were collected in the pharmacokinetic-rich group predose on day 1 week 1 and day 7 week 4 (predose, postdose at 2, 5, 8, 12, 16, 24, and 48 hours); and in the pharmacokinetic-sparse group predose on day 1 weeks 1, 2, and 3 and 24 hours postdose on day 7 week 4 . Key pharmacokinetic parameters included maximum plasma drug concentration (Cmax), plasma trough drug concentration, time to Cmax during a dosing interval (tmax), area under the concentration-time curve from time 0 to time of last collected sample, area under the concentration-time curve over the dosing interval (24 h) at steady state (AUCtau,ss), first-order rate constant associated with the terminal phase of elimination, terminal half-life (t1/2), total clearance of drug from plasma after oral administration, and apparent volume of distribution at steady state. Safety endpoints included treatment-emergent adverse events and vital signs. Results Mean ± standard deviation age and body mass index of 24 participants (66.7% male) were 4.8 ± 0.41 years and 17.2 ± 3.18 kg/m2, respectively. The most common ADHD was the combined presentation (91.7%); ratings were 50% markedly ill and 45.8% moderately ill on the Clinical Global Impression-Severity scale. Plasma d-amphetamine and l-amphetamine steady state was attained by predose on treatment day 8, consistent with the half-life. Peak steady-state plasma concentration (median tmax) for both d-amphetamine and l-amphetamine occurred at 7.92 h postdose on day 7 week 4 and thereafter declined monoexponentially, with a geometric mean t1/2 of 10.4 and 12.3 h for d-amphetamine and l-amphetamine, respectively. For both d-amphetamine and l-amphetamine, Cmax and AUCtau,ss were comparable between children aged 4 years (n = 3) and children aged 5 years (n = 8) regardless of sex. In total, 14 treatment-emergent adverse events were reported by 45.8% (11/24) of participants. Five treatment-emergent adverse events, reported for four (16.7%) participants, were considered treatment related; affect lability occurred in two (8.3%) participants, and insomnia, accidental overdose, and increased blood pressure each occurred in one (4.2%) participant. Conclusions In children aged 4-5 years with ADHD, following multiple once-daily administrations of SHP465 MAS 6.25 mg, the pharmacokinetic profile of plasma d-amphetamine and l-amphetamine was generally consistent among participants. Between-individual variability of plasma d-amphetamine and l-amphetamine steady-state exposure was low to moderate. SHP465 MAS was generally well tolerated in this study. Trial registration ClinicalTrials.gov, NCT03327402 (31 October, 2017).

Lanabecestat, a novel β-site amyloid precursor protein-cleaving enzyme 1 inhibitor evaluated for Alzheimer treatment, inhibits P-glycoprotein (P-gp) activity in vitro. After oral 50-mg lanabecestat administration, gastric fluid lanabecestat concentrations exceed half-maximal inhibitory concentration (IC50 ), suggesting P-gp inhibition at the intestinal wall. Plasma drug concentrations following 50 mg lanabecestat administered once daily are

Background In Japan, intravenous (IV) administration of antiepileptic drugs in a healthcare setting is the preferred treatment option that is both licensed and recommended for initial treatment of status epilepticus (SE). However, prompt conveyance to a healthcare institution and IV access may be difficult in patients experiencing a seizure and so delay treatment. Thus, there is an unmet need for an alternative effective antiepileptic drug with an easier and more rapid mode of administration. In this study we evaluated a midazolam hydrochloride oromucosal solution (MHOS) that can be simply and rapidly administered to patients in SE. Methods A Phase 3, interventional, multicenter, nonrandomized study was conducted in 28 clinical centers in Japan. Pediatric subjects in convulsive SE received treatment with buccal MHOS with dosage based on their age. The primary efficacy outcome was the percentage of subjects with seizure termination within 10 min and a 30-min absence of visible seizure activity from time of administration. Safety evaluations included respiratory depression and the frequency of treatment-emergent adverse events (TEAEs). Pharmacokinetic (PK) profile was also assessed. Results The study population comprised 25 subjects with a median age of 2.8 years and median bodyweight of 13.4 kg. The primary efficacy outcome was achieved in 80 % of subjects; 84 % of subjects had seizure resolution within 10 min. Nine subjects experienced a total of 13 TEAEs, and protocol-defined respiratory depression occurred in one subject. Mean maximum plasma midazolam concentration was 78.0 ng/mL, and mean time to peak concentration was 20.5 min, demonstrating that achieving maximum plasma midazolam concentration is not required for seizure cessation. Conclusions The efficacy, safety and pharmacokinetic profile of MHOS in pediatric Japanese subjects was consistent with that observed in non-Japanese populations. Compared to IV treatments, MHOS offers easier administration which may reduce the time to treatment and thereby minimize the sequelae of prolonged seizures.

Lanabecestat (AZD3293; LY3314814) is an orally active potent inhibitor of human β-secretase 1 in clinical development for the treatment of Alzheimer disease. In this first Japanese clinical study for an Alzheimer disease intervention to include cerebrospinal fluid (CSF) sampling in Japanese elderly healthy subjects, we report the pharmacokinetics and effects on plasma and CSF amyloid-β (Aβ) peptides of lanabecestat in a phase 1 study involving 40 healthy Japanese subjects (NCT02005211). No safety and tolerability concerns were identified in healthy Japanese subjects exposed to lanabecestat up to the highest doses given, which is consistent with observations in a US phase 1 study of lanabecestat. Exposure to lanabecestat was similar for young and elderly subjects and increased in a dose-dependent manner. For elderly subjects, plasma lanabecestat half-life after multiple dosing was 12 to 17 hours (on days 10 and 14). Robust plasma and CSF Aβ peptide reductions were also seen at all doses, with CSF Aβ42 concentrations reduced by 63% and 79% in the 15- and 50-mg lanabecestat groups, respectively. CSF soluble amyloid-β precursor protein β also decreased following lanabecestat treatment. Suppression of CSF Aβ peptides was similar in elderly healthy Japanese subjects and US patients with mild to moderate Alzheimer disease. Lanabecestat is a promising potentially disease-modifying treatment in phase 3 development for patients with early Alzheimer disease.

Aim: AZD3293 is a novel BACE1 inhibitor in Phase III development for Alzheimer's disease. Sensitive and robust bioanalytical methods were required to quantitate AZD3293 and its metabolite AZ13569724 in human biological matrices. Methodology/results: Human plasma was prepared by protein precipitation. Linearity for both analytes was in the range of 0.5–500 ng/ml with up to 100-fold dilution. Plasma ultrafiltrate samples were prepared using Centrifree® ultrafiltration device. Urine and CSF samples were analyzed directly after dilution. A 27% decrease in AZD3293 concentrations in the CSF collection apparati was found due to nonspecific binding. Incurred sample reanalysis was acceptable. Conclusion: Methods for simultaneous quantitation of AZD3293 and its metabolite AZ13569724 in human biological matrices have been validated and successfully applied to clinical studies.

A growing body of pathological, biomarker, genetic, and mechanistic data suggests that amyloid accumulation, as a result of changes in production, processing, and/or clearance of brain amyloid-β peptide (Aβ) concentrations, plays a key role in the pathogenesis of Alzheimer’s disease (AD). Beta-secretase 1 (BACE1) mediates the first step in the processing of amyloid-β protein precursor (AβPP) to Aβ peptides, with the soluble N terminal fragment of AβPP (sAβPPβ) as a direct product, and BACE1 inhibition is an attractive target for therapeutic intervention to reduce the production of Aβ. Here, we report the in vitro and in vivo pharmacological profile of AZD3293, a potent, highly permeable, orally active, blood-brain barrier (BBB) penetrating, BACE1 inhibitor with unique slow off-rate kinetics. The in vitro potency of AZD3293 was demonstrated in several cellular models, including primary cortical neurons. In vivo in mice, guinea pigs, and dogs, AZD3293 displayed significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Aβ40, Aβ42, and sAβPPβ. The in vitro potency of AZD3293 in mouse and guinea pig primary cortical neuronal cells was correlated to the in vivo potency expressed as free AZD3293 concentrations in mouse and guinea pig brains. In mice and dogs, the slow off-rate from BACE1 may have translated into a prolongation of the observed effect beyond the turnover rate of Aβ. The preclinical data strongly support the clinical development of AZD3293, and patients with AD are currently being recruited into a combined Phase 2/3 study to test the disease-modifying properties of AZD3293.

Impaired mitochondrial function, oxidative stress and formation of excessive levels of reactive oxygen species play a key role in neurodegeneration in Parkinson’s disease. Myeloperoxidase is a reactive oxygen generating enzyme and is expressed by microglia. The novel compound AZD3241 is a selective and irreversible inhibitor of myeloperoxidase. The hypothesized mechanism of action of AZD3241 involves reduction of oxidative stress leading to reduction of sustained neuroinflammation. The purpose of this phase 2a randomized placebo controlled multicentre positron emission tomography study was to examine the effect of 8 weeks treatment with AZD3241 on microglia in patients with Parkinson’s disease. Parkinson patients received either AZD3241 600 mg orally twice a day or placebo (in 3:1 ratio) for 8 weeks. The binding of 11C-PBR28 to the microglia marker 18 kDa translocator protein, was examined using positron emission tomography at baseline, 4 weeks and 8 weeks. The outcome measure was the total distribution volume, estimated with the invasive Logan graphical analysis. The primary statistical analysis examined changes in total distribution volume after treatment with AZD3241 compared to baseline. Assessments of safety and tolerability of AZD3241 included records of adverse events, vital signs, electrocardiogram, and laboratory tests. The patients had a mean age of 62 (standard deviation = 6) years; 21 were male, three female and mean Unified Parkinson’s Disease Rating Scale III score (motor examination) ranged between 6 and 29. In the AD3241 treatment group ( n = 18) the total distribution volume of 11C-PBR28 binding to translocator protein was significantly reduced compared to baseline both at 4 and 8 weeks ( P < 0.05). The distribution volume reduction across nigrostriatal regions at 8 weeks ranged from 13–16%, with an effect size equal to 0.5–0.6. There was no overall change in total distribution volume in the placebo group ( n = 6). AZD3241 was safe and well tolerated. The reduction of 11C-PBR28 binding to translocator protein in the brain of patients with Parkinson’s disease after treatment with AZD3241 supports the hypothesis that inhibition of myeloperoxidase has an effect on microglia. The results of the present study provide support for proof of mechanism of AZD3241 and warrant extended studies on the efficacy of AZD3241 in neurodegenerative disorders. * Abbreviations : 11C-PBR28 : carbon-11 labelled PBR28 [ N -acetyl- N -(2-[11C]methoxybenzyl)-2-phenoxy-5-pyridinamine] 18F-FE-PE2I : fluorine-18 labelled FE-PE2I [(E)- N -(3-iodoprop-2-enyl)-2beta-carbo(2-[18F]fluoroethoxy)-3beta-(4-methylphenyl)nortropane] 11C-(R)PK11195 : carbon-11 labelled (R)-PK11195 [(R)-1-(2-chlorophenyl)- N -[11C]methyl- N -(1-methylpropyl)-3-isoquinolinecarboxamide] and general notation 11C-PK11195 is used, when stereoisomerization is ambiguous DAT : dopamine transporter VT : total distribution volume

Background: AZD3293 (also known as LY3314814) is a novel, potent, non-selective BACE1/BACE2 inhibitor currently in Phase 3 clinical development for the treatment of Alzheimer’s disease. Objectives: The purpose of these studies was to characterize the effects, putative mechanism, and reversibility of hypopigmentation following treatment with AZD3293 in pigmented Long-Evans rats, Beagle dogs, human cell cultures, and humans. Design: Nonclinical studies were conducted in Long-Evans pigmented rats, and both young and older Beagle dogs using a variety of oral dose levels of AZD3293 or AZD3839 (BACE inhibition reference compound; used in older dogs only) for dosing durations of 13 to 26 weeks. In vitro studies of normal human epidermal melanocytes and reconstituted human epidermis were also conducted. Skin biopsy data from a multiple-dose Phase 1 clinical study of AZD3293 (NCT01795339) are also reported. Setting: Nonclinical in vivo and in vitro studies were conducted in laboratory settings in the US, Canada, and France; the multiple dose clinical study was conducted in a specialized inpatient setting in the US. Participants: Beagle dogs: 13-week study N=36 young (8-10 mo) animals; 39-week study N=64 young animals; and a second 13-week study N=32 older (30-32 mo) animals. Long-Evans rats: N=68 animals. Multiple-dose clinical study: only data for subjects enrolled in Part 2 of this study are included in this report (N=16). Interventions: AZD3293 was the primary intervention used in these studies. AZD3839, a relatively BACE1-selective reference inhibitor compound was used in one group in the 13 week study in older Beagle dogs and one in vitro assessment. Finally, AZ1340, another relatively BACE1-selective reference inhibitor compound was used only in one in vitro assessment. Measurements: Measurements for the nonclinical studies in dogs and rats included macroscopic observation and assessment of skin biopsies via histopathology, immunochemistry, and electron microscopy. Measurements for the in vitro studies included melanocyte premelanosome protein (PMEL) processing, cytotoxicity, melanin synthesis, Pmel17 labeling, and melanocyte dendricity. Measurements in the clinical study included scoring of melanin content in skin biopsies taken before and after dosing with AZD3293 over 14 days at dose levels up to 150 mg. Results: Depigmentation in rats and dogs was limited to skin, hair, and mucosa with no effects on other pigmented tissues. At a cellular level depigmentation was observed within a week of treatment, whereas the appearance of depigmentation in skin and hair did not become apparent until, at earliest, 4 weeks of treatment. The depigmentation effects were reversible, not associated with degenerative or inflammatory changes, and were dose- and species-dependent in severity. Full recovery of melanization was observed at the microscopic (cellular) level and at least partial recovery was seen in the macroscopic appearance of animals by the end of the 12-week recovery period in both rats and dogs. Interestingly, no changes in melanin production or melanocyte morphology were seen in human primary melanocytes or reconstituted human epidermis in vitro. Finally, there were no changes in melanization level in skin biopsies following 12 days of daily AZD3293 treatment at doses of AZD3293 up to 150 mg/day in human subjects. Conclusions: AZD3293, a novel, potent, non-selective BACE1/BACE2 inhibitor is in development as a potentially disease-modifying treatment for Alzheimer’s disease. Chronic nonclinical studies in Beagle dogs and pigmented rats showed macroscopic and microscopic hypopigmentation effects of AZD3293 that were limited to skin, hair, and mucosa. These effects were shown to be reversible in both species. Analysis of data from nonclinical and in vitro studies suggests that hypopigmentation is caused by BACE2 inhibition resulting in accumulation of a premelanosome protein fragment, which interrupts the normal production of melanin. No macroscopic or microscopic reports of hypopigmentation were observed in a Phase 1 clinical study following 13 doses of AZD3293 over 14 days at dose levels up to 150 mg/day. These data suggest that hypopigmentation is species-specific and humans appear to be least sensitive to the depigmentation effect caused by BACE2 inhibition.

Lanabecestat (AZD3293; LY3314814) is an orally active potent inhibitor of human β-secretase 1 in clinical development for the treatment of Alzheimer disease. In this first Japanese clinical study for an Alzheimer disease intervention to include cerebrospinal fluid (CSF) sampling in Japanese elderly healthy subjects, we report the pharmacokinetics and effects on plasma and CSF amyloid-β (Aβ) peptides of lanabecestat in a phase 1 study involving 40 healthy Japanese subjects (NCT02005211). No safety and tolerability concerns were identified in healthy Japanese subjects exposed to lanabecestat up to the highest doses given, which is consistent with observations in a US phase 1 study of lanabecestat. Exposure to lanabecestat was similar for young and elderly subjects and increased in a dose-dependent manner. For elderly subjects, plasma lanabecestat half-life after multiple dosing was 12 to 17 hours (on days 10 and 14). Robust plasma and CSF Aβ peptide reductions were also seen at all doses, with CSF Aβ

The relative bioavailability of lanabecestat administered as 2 tablet formulations versus an oral solution was investigated. This phase 1 single‐center, open‐label, randomized, 3‐period crossover study involved healthy male and nonfertile female subjects aged 18–55 years (NCT02039180). Subjects received a single 50‐mg lanabecestat dose as solution, tablet A, or tablet B on day 1 of each crossover period; 14 of 16 subjects completed the study. Relative bioavailability based on plasma lanabecestat AUC0–∞ (area under the plasma drug concentration–time curve from zero to infinity) geometric mean ratio versus oral solution (primary variable) was: tablet A, 1.052 (90% confidence interval [CI], 1.001–1.106); tablet B, 1.040 (0.989–1.093). These 90%CIs for geometric mean ratios are within accepted standard bioequivalence boundaries for all other pharmacokinetic (PK) parameters for both lanabecestat and metabolite (AZ13569724). All 3 formulations had similar plasma lanabecestat concentration–time profiles. Six adverse events were reported by 6 subjects (37.5%, all mild). GastroPlus modeling predicted a negligible impact of gastric pH changes on systemic PK (up to pH 7.4). Both tablet formulations fall within standard accepted bioequivalence criteria versus the oral solution. A single 50‐mg lanabecestat dose was well tolerated as a solution or tablet formulation in this population.

AZD3293 (LY3314814) is a promising new potentially disease-modifying BACE1 (β-secretase) inhibitor in Phase III clinical development for the treatment of Alzheimer's disease. Reported here are the first two Phase I studies: (1) a single ascending dose study evaluating doses of 1-750 mg with a food-effect component (n = 72), and (2) a 2-week multiple ascending dose study evaluating doses of 15 or 50 mg once daily (QD) or 70 mg once weekly (QW) in elderly subjects (Part 1, n = 31), and 15, 50, or 150 mg QD in patients with mild to moderate Alzheimer's disease (Part 2, n = 16). AZD3293 was generally well tolerated up to the highest doses given. No notable food effects were observed. PK following multiple doses (Part 2) were tmax of 1 to 3 h and mean t1/2 of 16 to 21 h across the 15 to 150 mg dose range. For single doses of ≥5 mg, a ≥70% reduction was observed in mean plasma Aβ40 and Aβ42 concentrations, with prolonged suppression for up to 3 weeks at the highest dose level studied. Following multiple doses, robust reductions in plasma (≥64% at 15 mg and ≥78% at ≥50 mg) and cerebrospinal fluid (≥51% at 15 mg and ≥76% at ≥50 mg) Aβ peptides were seen, including prolonged suppression even with a QW dosing regimen. AZD3293 is the only BACE1 inhibitor for which prolonged suppression of plasma Aβ with a QW dosing schedule has been reported. Two Phase III studies of AZD3293 (AMARANTH, NCT02245737; and DAYBREAK-ALZ, NCT02783573) are now ongoing.

Objectives Amphotericin B inhalation powder (ABIP) is a novel dry-powder amphotericin B formulation that is directly delivered to the lung, resulting in elevated lung tissue drug concentrations of this polyene. We evaluated the prophylactic efficacy of single dose administration of ABIP in a guinea pig model of invasive pulmonary aspergillosis. Methods Guinea pigs were immunosuppressed with cyclophosphamide and cortisone acetate and challenged with Aspergillus fumigatus conidia in an aerosol chamber. Guinea pigs received prophylaxis with a single inhaled dose of ABIP at 0.05, 0.5, 4 or 10 mg/kg administered 24 h prior to infection. Treatment with oral voriconazole at doses of 5 or 10 mg/kg twice daily beginning 24 h post-challenge served as the positive control. Results Improvements in survival were observed with ABIP prophylaxis. A single inhaled dose of 4 mg/kg ABIP and treatment with 5 mg/kg voriconazole both improved median and percentage survival compared with untreated controls. In addition, pulmonary fungal burden, as assessed by cfu, quantitative PCR and galactomannan, was also reduced in a dose-dependent fashion with ABIP prophylaxis as well as with both doses of voriconazole treatment. Conclusions Single-dose prophylaxis with inhaled ABIP as prophylaxis demonstrated a significant survival advantage and reductions in pulmonary fungal burden in this model of invasive pulmonary aspergillosis. Optimization of the dose and dosing frequency of ABIP dose may help to further enhance the anti-Aspergillus activity of this novel amphotericin B formulation.

We report on the investigation of a Salmonella enteritidis outbreak in hospitals and nursing homes in the district Oberallgaeu, Bavaria, in July 2004. Affected by this outbreak were hospital patients, inhabitants of nursing homes, kitchen coworkers and maintenance personnel. Within this outbreak six deaths were observed. A forensic medical investigation of four deaths revealed two cases of Salmonella enteritis as the primary cause of death, another cause of death was due to other causes and one cause of death remained unclear. The microbiological investigation of stool samples linked all positive samples to an outbreak during this period. The epidemiological outbreak curve pointed towards a foodborne transmission of the pathogen. The infection period could be limited to the weekend of the 3./4.7.2004. All affected institutions were supplied by a catering service with several sites. All tested food samples were negative for Salmonella enteritis. Epidemiological investigations revealed that a contaminated pudding was probably responsible for the outbreak.

Cefdinir (Omnicef; Abbott Laboratories) is a cephalosporin antibiotic primarily eliminated by the kidney. Nonlinear renal elimination of cefdinir has been previously reported. Cefdinir renal transport mechanisms were studied in the erythrocyte-free isolated perfused rat kidney. Studies were performed with drug-free perfusate and perfusate containing cefdinir alone to establish the baseline physiology and investigate cefdinir renal elimination characteristics. To investigate cefdinir renal transport mechanisms, inhibition studies were conducted by coperfusing cefdinir with inhibitors of the renal organic anion (probenecid), organic cation (tetraethylammonium), or dipeptide (glycylsarcosine) transport system. Cefdinir concentrations in biological samples were determined using reversed-phase high-performance liquid chromatography. Differences between treatments and controls were evaluated using analysis of variance and Dunnett's test. The excretion ratio (ER; the renal clearance corrected for the fraction unbound and glomerular filtration rate) for cefdinir was 5.94, a value indicating net renal tubular secretion. Anionic, cationic, and dipeptide transport inhibitors all significantly affected the cefdinir ER. With probenecid, the ER was reduced to 0.59, clearly demonstrating a significant reabsorptive component to cefdinir renal disposition. This finding was confirmed by glycylsarcosine studies, in which the ER was elevated to 7.95, indicating that reabsorption was mediated, at least in part, by the dipeptide transporter system. The effects of the organic cation tetraethylammonium, in which the ER was elevated to 7.53, were likely secondary in nature. The anionic secretory pathway was found to be the predominant mechanism for cefdinir renal excretion.

Opioid-induced constipation (OIC) is the most common and often a treatment-limiting adverse event (AE) of opioid therapy for chronic pain. Naloxegol (previously NKTR-118), a PEGylated derivative of naloxone that has minimal penetration of the central nervous system, has received regulatory approval as an oral therapy for OIC. This randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation study was performed to assess safety, tolerability, and pharmacokinetics of multiple doses of naloxegol in healthy volunteers. Four cohorts, each with 4 male and 4 female volunteers, were randomized 3:1 to a twice-daily naloxegol solution (25, 60, 125, and 250 mg) or matching placebo solution. Doses were given every 12 hours for 7 days, with a single final dose on the morning of day 8. All 32 subjects completed the study. The incidence of most AEs was similar in the naloxegol and placebo groups; no AE led to study discontinuation. Naloxegol was rapidly absorbed. Plasma naloxegol pharmacokinetics showed dose proportionality, negligible accumulation at steady state, and no sex differences. Naloxegol in doses up to 250 mg every 12 hours was generally safe and well tolerated in this healthy volunteer population.

This randomized, double-blind, placebo-controlled, ascending-dose, crossover study evaluated single oral doses of naloxegol (NKTR-118; 8, 15, 30, 60, 125, 250, 500, and 1000 mg), a PEGylated derivative of naloxone, for safety and tolerability, antagonism of peripheral and central nervous system (CNS) effects of intravenous morphine, and pharmacokinetics. Healthy men were randomized 1:1 to naloxegol or naloxegol-matching placebo administered with morphine and lactulose in a 2-period crossover design. Periods were separated by a 5- to 7-day washout. Assessments included safety, tolerability, orocecal transit time (OCTT), pupillary miosis, and pharmacokinetics. The study was completed by 46 subjects. The most common adverse events were somnolence, dizziness, headache, and nausea. Greater reversal of morphine-induced delay in OCTT occurred with increasing naloxegol dose, demonstrating dose-ordered antagonism of morphine's peripheral gastrointestinal effects. Forty-four subjects showed no reversal of pupillary miosis; 2 showed potential partial reversal at 250 and 1000 mg, indicating negligible antagonism of morphine's CNS effects at doses ≤ 125 mg. Rapid absorption, linear pharmacokinetics up to 1000 mg, and low to moderate between-subject pharmacokinetic variability was observed. The pharmacokinetics of morphine or its glucuronide metabolites were unaltered by concurrent naloxegol administration. Naloxegol was generally safe and well tolerated at single doses up to 1000 mg.

Subjects Completing Month 12, n (%) 28(77.8) 27(73) 30(83.3) 29(78.4) Male, n (%) 13(36.1) 18(48.6) 19(52.8) 12(32.4) Mean Age (SD) 73.3(8.79) 73.5(8.34) 74.1(9.26) 70.5(8.68) ApoE *e4 Carriers, n (%) 22(61.1) 22(59.5) 22(61.1) 22(59.5) Symptomatic AD Treatment 29(80.6) 30(81.1) 34(94.4) 30(81.1) Mean Florbetapir PET GCA SUVR (SD) 1.74(0.294) 1.75(0.313) 1.87(0.299) 1.85(0.316) Mean MMSE Total Score (SD) 22.3(2.84) 22.3(2.78) 21.5(2.47) 21.9(2.99) Mean ADAS-Cog/11 Total Score (SD) 18.3(6.70) 19.6(9.47) 20.9(7.66) 18.4(8.34) Mean DAD Total Score (SD) 86.5(15.31) 81.7(17.41) 86.1(12.92) 85.2(13.25) Florbetapir PET GCA SUVR Change From Baseline at Month 12 Within-treatment LS Mean 0.000 -0.014 -0.066 -0.021 (95% CI) (-0.062, .063) (-0.078, .050) (-0.129, -0.004) (-0.084, 0.004) p-value 0.991 0.661 0.038 0.492 Florbetapir PET GCA SUVR Change From Baseline at Month 12 Between-treatment Difference of LS Means -0.015 -0.067 -0.022 (95% CI) (-0.103, 0.074) (-0.155, 0.022) (-0.109, 0.066) p-value 0.747 0.138 0.627 Poster Presentations: P1 P447

Objectives Endometrial polyps (EPs) are among the common cases of abnormal uterine bleeding. Hormonal factors may be involved in the pathogenesis as indicated by endometrial abnormalities in patients treated with tamoxifen. This study was designed to analyse the patient characteristics which may be associated with polyp occurrence and assess the diagnostic and therapeutic difficulties. Group of 245 patients was formed to 152 postmenopausal and 93 premenopausal women with EP diagnosed hysteroscopically and confirmed histologically. Evaluated factors were as follows: 1) patient characteristics: age, body mass, systemic hypertension, diabetes mellitus, nulliparity, late menopause, estrogen replacement therapy, and tamoxifen treatment; 2) clinical features of EPs, and 3) the number of curettage's (D & C) and hysteroscopies. Results Hypertension associated with obesity appears to be an important factor in combination which may play role in the pathogenesis of EPs like the late menopause which was noted in 30% of examined postmenopausal women. An association between EPs and tamoxifen was found in 8% patients with breast cancer. 2. Postmenopausal uterine bleeding and menstrual disorders were prominent clinical symptoms in 44% post- and in 82% of premenopausal women. The other 56% post- and 18% premenopausal patients were asymptomatic. 3. The multiple EPs were present in 26% of postmenopausal and in 15% premenopausal women. 4. Transvaginal ultrasonography supplemented by sonohysterography in cases with abnormal ultrasonographic findings should be the main diagnostic method. 5 Hysteroscopical polypectomy is regarded as the optimal therapy and the removal of the endometrial basalis in the EP origin area prevents persistence or recurrence of EP.

Im ersten Halbjahr 1997 wurden 414 Stuhlproben von 58 EHEC-infizierten Personen mit verschiedenen diagnostischen Methoden untersucht. Zum EHEC-Toxinnachweis wurde ein ELISA und der Verozelltest eingesetzt, Toxingene wurden mit der PCR nachgewiesen. Mit der IMS wurden die Stuhlproben aufE. coli der Serogruppe O157 untersucht. Bei insgesamt 272 Proben wurden phanotypisch und/oder genotypisch Shigatoxin nachgewiesen. Die Nachweisverfahren fur Toxin und Toxingene ergaben in 60 % der Falle ein ubereinstimmendes positives Ergebnis, wahrend bei den restlichen Proben meist der ELISA und/oder der Verozelltest negativ ausfielen. Bei 61 Proben war nur mit der PCR der Nachweis einer EHEC-Infektion moglich. Durch Untersuchung von mehrerenE. coli-Einzelkolonien konnten bei 51 Personen EHEC-Stamme isoliert und einer Serotypisierung zugefuhrt werden. Die Stamme gehorten zu 22 verschiedenen O-Gruppen. EHEC der Serogruppe O157 wurden dabei dreimal isoliert. Von den O157-positiven Personen wurden nur sieben Stuhlproben untersucht, so das ein aussagekraftiger Vergleich der IMS mit anderen Nachweisverfahren nicht moglich war.

The cross-reactivity of fosphenytoin, a phosphate ester prodrug of phenytoin, was investigated in the Abbott phenytoin TDx®/TDxFLxTM fluorescence polarization immunoassay (TDx) and the Behring Diagnostics phenytoin Emit® 2000 enzyme-multiplied immunoassay (Emit). The first part of our study investigating cross-reactivity utilized in vitro correlation of the two immunoassays with a validated and specific phenytoin HPLC method used to assay plasma samples prepared in several phenytoin and fosphenytoin concentration combinations. Fosphenytoin cross-reacted with both immunoassays, but to a greater extent with TDx. In the second part of the study, empirically-derived models that best explained the in vitro data were used to predict “immunoassay-derived” phenytoin concentrations in plasma samples collected from actual patients after intravenous (IV) or intramuscular (IM) fosphenytoin dosing. The greatest degree of phenytoin concentration overestimation occurred at times when fosphenytoin concentrations were highest: within 1 to 2 h after IV infusion or during the first 2 to 4 h after IM injection. It is recommended that phenytoin concentrations not be monitored using these or other potentially nonspecific immunoanalytical methods for at least 2 h after IV fosphenytoin infusion or 4 h after IM fosphenytoin injection.

Objective The results of past research have identified changes in brain structure in anorexia nervosa. We observed previously unreported MRI alterations in two cases of anorexia nervosa. Method: For both cases, we reviewed the clinical history, MRI scans and conducted a pertinent literature review. Results: The MRI brain scans of two patients with the diagnosis of anorexia nervosa revealed evidence of subcortical hyperintense changes on T2-weighted images. Discussion: No previous reports of these findings have been described in the literature on anorexia nervosa to date. Clinical and pathologic correlates associated with these brain observations in anorexia nervosa are discussed. © 1997 by John Wiley & Sons, Inc. Int J Eat Disord 21: 391–394, 1997.

Fosphenytoin sodium, a phosphate ester prodrug of phenytoin, was developed as a replacement for parenteral phenytoin sodium. Unlike phenytoin, fosphenytoin is freely soluble in aqueous solutions, including standard i.v. solutions, and is rapidly absorbed by the i.m. route. Fosphenytoin is metabolized (conversion half-life of 8 to 15 min) to phenytoin by endogenous phosphatases. Therapeutic free (unbound) and total plasma phenytoin concentrations are consistently attained after i.m. or i.v. administration of fosphenytoin loading doses. Fosphenytoin has fewer local adverse effects (e.g., pain, burning, and itching at the injection site) after i.m. or i.v. administration than parenteral phenytoin. Systemic effects related to the CNS are similar for both preparations, but transient paresthesias are more common with fosphenytoin.

The tubular uptake and esterolysis of quinapril and quinaprilat were studied in male Sprague‐Dawley rats using an in vivo micropuncture technique. [ 3 H]Quinapril or [ 3 H]quinaprilat was injected with [ 14 C]inulin into either proximal or distal segments of the renal tubules, and urine was collected over 30 min. Urine and perfusate were assayed for [ 14 C]inulin using dual label spectrometry. [ 3 H]Quinapril and [ 3 H]quinaprilat concentrations were determined in urine and perfusate using a reversed‐phase HPLC procedure with radiochemical detection, coupled to liquid scintillation spectrometry. These studies demonstrated that quinapril could access the esterase enzyme from tubular fluid and be metabolized to quinaprilat in both proximal and to a lesser extent distal segments of the kidney tubule. Quinapril, but not quinaprilat, was extensively reabsorbed. Its reabsorption along the proximal tubule and/or the loop of Henle could account for as much as 45–50% of the available dose of quinapril. Further, the urinary recovery of quinapril and quinaprilat (after dosing quinapril into proximal segments) was urine flow rate dependent.

Quinapril and quinaprilat concentrations were determined in perfusate, urine, and perfusate ultrafiltrate using a specific and sensitive reversed-phase high-performance liquid chromatographic procedure with radiochemical detection, coupled to liquid scintillation counting spectrometry. Quinapril and quinaprilat were measured in perfusate and urine after pretreatment with acetonitrile and subsequent centrifugation. Perfusate ultrafiltrate was used as collected. Two quinapril diketopiperazine metabolites, PD 109488 and PD 113413, were separated chromatographically from quinapril, quinaprilat, and from each other. Assay performance for quinapril and quinaprilat was assessed by examining precision and accuracy of the assay over four days. Using a 100-microliters sample volume, the limit of quantitation for both 3H-quinapril and 3H-quinaprilat (sp. act. approximately 2.0 muCi/micrograms) was 1 ng/ml.

Describes an automated laser cutting cell used in the automotive industry. The cell has the benefits of fast throughput because of high cutting speeds, adaptability of height sensing, safety of crash protection and flexibility of part modifications via robot path and program modifications. Outlines the feature of the cell which consists of two Nd:YAG lasers with fibre‐optic delivery and two five‐axis robots with trepanning heads, and describes their performance characteristics. Concludes with a summary of the advantages of using a laser cutting cell.

The interaction of quasi-one-dimensional electrons and longitudinal-optical (LO) phonons is calculated. Results are presented for the polaron correction to the electric subbands and the polaron effective mass. Using improved Wigner-Brillouin perturbation theory, we have investigated in detail the energy-momentum relation for quasi-one-dimensional polarons. It is shown that the dispersion curves of all subbands bend over and are pinned at the phonon continuum above the renormalized ground state. This should result in a spatial oscillation of the electron group velocity in real quantum-well wires.

Gabapentin (l-(aminomethyl)cyclohexaneacetic acid) is a neuroprotective agent with antiepileptic properties. The structure is small (molecular weight less than 200), is zwitterionic, and resembles an amino acid with the exception that it does not contain a chiral carbon and the amino group is not alpha to the carboxylate functionality. Gabapentin is not metabolized by humans, and thus, the amount of gabapentin excreted by the renal route represents the fraction of dose absorbed. Clinical trials have reported dose-dependent bioavailabilities ranging from 73.8 ± 18.3 to 35.7 ± 18.3% when the dose was increased from 100 to 1600 mg. The permeability of gabapentin in the rat intestinal perfusion system was consistent with carrier-mediated absorption, i.e., a 75 to 80% decrease in permeability when the drug concentration was increased from 0.01 to 50 mM (0.46 ± 0.05 to 0.12 ± 0.04). Excellent agreement was obtained between the actual clinical values and the predicted values from in situ results for the fraction of dose absorbed calculated using the theoretically derived correlation, Fabs = 1 - exp(−2Peff) by Ami-don et al. (Pharm. Res. 5:651–654, 1988). The permeability values obtained for gabapentin correspond to 67.4 and 30.2% of the dose absorbed at the low and high concentrations, respectively. In the everted rat intestinal ring system, gabapentin shared an inhibition profile similar to that of L-phenylalanine. Characteristics of gabapentin uptake included cross-inhibition with L-Phe, sensitivity to inhibition by L-Leu, stereoselectivity as evidenced by incomplete inhibition by D-Phe, and lack of effect by Gly. Our findings support absorption of gabapentin by a saturable pathway, system L, shared by the large hydrophobic amino acids, L-Phe and L-Leu. The saturable absorption pathway makes a major contribution to the lack of proportionality in plasma levels of drug with increasing dose ob-served in the clinic.

New drug development is best conceptualized as occurring in three phases: exploratory, registration, and commercialization. The most important initial goals in the exploratory phase of a new antiepileptic drug (AED) are to reliably determine efficacy and safety across the full dose range. Because of variability and the placebo effect, large randomized, controlled trials are necessary and are increasingly being employed early. When successful, such trials can shorten clinical development time by simultaneously meeting the goals of both the exploratory and registration phases of new drug development.

The design of most add-on registration trials for anti epileptic drugs (AEDs) usually results in a calculated compromise regarding size, scope, cost, and duration. Appropriate trial duration incorporates issues such as efficacy, safety, and regulatory constraints and is dependent on sample size, titration usage, time to onset, and magnitude of treatment effect. Two phases are usually evaluated in these trials: baseline and treatment. Typical duration for add-on epilepsy registration trials range from 4 to 12 weeks of baseline evaluation followed by 12 to 18 weeks of double-blind treatment. Trials with shorter baseline and/or shorter double-blind periods would likely be less costly, more timely, and result in improved enrollment and retention rates. Data from large dose-response trial of 3 AEDs were retrospectively analyzed previously (Sahlroot and Pledger, 1998) to examine the effect of trial duration on the primary efficacy parameter. 2. Methods

The tubular uptake and esterolysis of quinapril and quinaprilat were studied in male Sprague‐Dawley rats using an in vivo micropuncture technique. [ 3 H]Quinapril or [ 3 H]quinaprilat was injected with [ 14 C]inulin into either proximal or distal segments of the renal tubules, and urine was collected over 30 min. Urine and perfusate were assayed for [ 14 C]inulin using dual label spectrometry. [ 3 H]Quinapril and [ 3 H]quinaprilat concentrations were determined in urine and perfusate using a reversed‐phase HPLC procedure with radiochemical detection, coupled to liquid scintillation spectrometry. These studies demonstrated that quinapril could access the esterase enzyme from tubular fluid and be metabolized to quinaprilat in both proximal and to a lesser extent distal segments of the kidney tubule. Quinapril, but not quinaprilat, was extensively reabsorbed. Its reabsorption along the proximal tubule and/or the loop of Henle could account for as much as 45–50% of the available dose of quinapril. Further, the urinary recovery of quinapril and quinaprilat (after dosing quinapril into proximal segments) was urine flow rate dependent.

Off-the-shelf beam analysis systems work very well in investigating and measuring collimated laser beam spatial profiles, focus spot spatial profiles, and the waist caustic. These standard systems have some shortcomings, however, related to viewing very small focus spot sizes at any wavelength, but especially at 10.6um. Another problem that these beam analysis systems can solve is alignment of optics and other components that can be damaged by high power beams if improperly set-up. This presentation will investigate the use of novel but simple imaging systems to allow in-depth analysis and real-time imaging of focus spot sizes from ∼10um to 100um at any laser wavelength, including 10.6um, allowing resolution of features as small as 0.25um. It will also investigate the use of low power pointing laser beams and artificial incoherent light to produce fine alignment and registration of optics and opto-mechanical components to high power laser beams. Examples will also employ ray-tracing information to validate the optical systems.Off-the-shelf beam analysis systems work very well in investigating and measuring collimated laser beam spatial profiles, focus spot spatial profiles, and the waist caustic. These standard systems have some shortcomings, however, related to viewing very small focus spot sizes at any wavelength, but especially at 10.6um. Another problem that these beam analysis systems can solve is alignment of optics and other components that can be damaged by high power beams if improperly set-up. This presentation will investigate the use of novel but simple imaging systems to allow in-depth analysis and real-time imaging of focus spot sizes from ∼10um to 100um at any laser wavelength, including 10.6um, allowing resolution of features as small as 0.25um. It will also investigate the use of low power pointing laser beams and artificial incoherent light to produce fine alignment and registration of optics and opto-mechanical components to high power laser beams. Examples will also employ ray-tracing information to validat...

Colloidal gold nanoparticles are investigated as a potential scaffold for the assisted immobilisation of probe oligonucleotides on silicon surfaces. A preliminary study is devoted to the examination of the immobilisation of DNA-modified gold nanoparticles as a function of time, concentration, salt and pH. The DNA-modified nanoparticles self-assembled onto solid surfaces in a three-dimensional self-assembled architecture. The functionalised surfaces are evaluated in diagnostic assays, where their potential to improve the efficiency of the hybridisation reaction is tested. The system utilising DNA-modified nanoparticles produced an enhancement in the hybridisation efficiency and the sensitivity limit by a factor 10 to 100 as compared to a conventional DNA immobilisation system on a planar surface.

We report on the investigation of a Salmonella enteritidis outbreak in hospitals and nursing homes in the district Oberallgaeu, Bavaria, in July 2004. Affected by this outbreak were hospital patients, inhabitants of nursing homes, kitchen coworkers and maintenance personnel. Within this outbreak six deaths were observed. A forensic medical investigation of four deaths revealed two cases of Salmonella enteritis as the primary cause of death, another cause of death was due to other causes and one cause of death remained unclear. The microbiological investigation of stool samples linked all positive samples to an outbreak during this period. The epidemiological outbreak curve pointed towards a foodborne transmission of the pathogen. The infection period could be limited to the weekend of the 3./4.7.2004. All affected institutions were supplied by a catering service with several sites. All tested food samples were negative for Salmonella enteritis. Epidemiological investigations revealed that a contaminated pudding was probably responsible for the outbreak.

Objective: To evaluate the efficacy, tolerability, and safety of two pregabalin regimens administered as adjunctive therapy to that of placebo in patients with medically refractory partial epilepsy. Methods: A multicenter, double-blind, randomized, parallel-group, placebo-controlled trial was performed. Following a prospective 8-week baseline phase, patients were randomized to 12 weeks of double-blind treatment with placebo or pregabalin 600 mg/day administered twice daily (BID) or three times daily (TID). Primary efficacy was measured as change in seizure frequency from baseline of either pregabalin regimen compared with placebo. Secondary efficacy comparisons included the proportion of patients experiencing ≥50% reduction in seizure frequency (responder rate) and median percentage change from baseline in seizure frequency. Safety/tolerability assessments included adverse events (AEs), physical and neurologic examinations, and clinical laboratory evaluation. Efficacy and safety analyses were performed on the intent-to-treat (ITT) population. Results: Pregabalin treatment resulted in seizure frequency reductions: 53% for pregabalin TID ( p ≤ 0.0001) and 44% for pregabalin BID ( p ≤ 0.0001) compared with a 1% increase for placebo. Responder rates were 49% for pregabalin TID and 43% for pregabalin BID compared with 9% for placebo ( p ≤ 0.001). Both pregabalin regimens were similar in efficacy and tolerability. The most common AEs were dizziness, somnolence, and ataxia. Conclusions: Pregabalin administered at 600 mg/day is safe, generally well tolerated, and efficacious as adjunctive therapy for the treatment of patients with partial seizures, with or without secondary generalizations. This dose can be administered on a twice daily or three times daily schedule with similar efficacy and tolerability results.

Summary: Purpose: To evaluate pregabalin (PGB), 150 mg/day, and PGB, 600 mg/day, as an add-on treatment for patients with refractory partial seizures concurrently treated with one to three anticonvulsants (AEDs). Methods: An international (13 countries), multicenter (45 centers), 12-week, double-blind, randomized study in which patients with partial seizures received placebo (n = 96); PGB, 150 mg/day (n = 99); or PGB, 600 mg/day (n = 92); given 3 times a day (t.i.d.). The primary efficacy criterion was reduction in seizure frequency during treatment as compared with baseline, as measured by RRatio, the symmetrical percentage change in seizure rates determined from daily seizure diaries. The RRatio between the 8-week baseline (pretreatment phase) and the 12-week treatment period were compared between each of the PGB groups and the placebo group by using an analysis of variance analysis of the intent-to-treat population. Results: PGB, 150 mg/day and 600 mg/day, were both significantly more effective than placebo in reducing the RRatio [–11.5 (p = 0.0007) and –31.4 (p ≤ 0.0001), respectively, vs. 0.9]. These RRatio values correspond to seizure-frequency reductions from baseline of –1.8, 20.6, and 47.8% for placebo, 150 mg/day, and 600 mg/day, respectively. PGB efficacy was significantly dose related (p ≤ 0.0001). Secondary efficacy variables corroborated the findings of the primary analysis. Significantly more patients were responders (≥50% reduction in seizure frequency) in the PGB, 600 mg/day (43.5%), group than in the placebo group (6.2%) (p ≤ 0.001). PGB was well tolerated. Dose-related, treatment-emergent adverse events (≥10%), mostly mild or moderate in intensity, were somnolence, dizziness, ataxia, diplopia, and weight gain. The withdrawal rate due to adverse events was 10% of patients at 150 mg/day and 18.5% of patients at 600 mg/day, compared with 6.2% of patients receiving placebo. Conclusions: PGB, 150 mg/day and 600 mg/day, is highly effective and well-tolerated add-on therapy in patients with partial seizures.

Background: Pregabalin is an α2-δ ligand that has anxiolytic, analgesic, and anticonvulsant properties. Objective: To establish the efficacy, safety, and tolerability of pregabalin administered twice-daily (BID) without dose titration as adjunctive treatment in patients with partial seizures and to confirm the dose-response relationship. Methods: This 76-center, double-blind, randomized, placebo-controlled, parallel-group study consisted of an 8-week baseline and a 12-week double-blind phase. Patients with refractory partial seizures on one to three antiepileptic drugs were randomly assigned to one of five treatment groups (placebo or 50, 150, 300, and 600 mg/d pregabalin, all administered BID). Efficacy was assessed using seizure frequency reduction and responder rate (≥50% seizure reduction from baseline). Pharmacokinetic parameters were estimated. Results: A total of 453 patients were included in the intent-to-treat analysis. The median baseline seizure rate was 10 per month. Seizure frequency reductions from baseline were 7% (placebo; n = 100), 12% (50 mg/d; n = 88), 34% (150 mg/d; n = 86), 44% (300 mg/d; n = 90), and 54% (600 mg/d; n = 89). Responder rates (≥50% seizure reduction) were 14% (placebo), 15% (50 mg/d), 31% (150 mg/d), 40% (300 mg/d), and 51% (600 mg/d). Discontinuation rates due to adverse events were 5% (placebo), 7% (50 mg/d), 1% (150 mg/d), 14% (300 mg/d), and 24% (600 mg/d). The 150-, 300-, and 600-mg/d pregabalin groups were associated with greater reductions in seizures (p ≤ 0.0001) and greater responder rates compared with the placebo group (p ≤ 0.006). There was a favorable dose-response trend for both seizure reductions (p ≤ 0.0001) and responder rate (p ≤ 0.001). Conclusion: Adjunctive therapy with pregabalin 150, 300, and 600 mg/d, given in twice-daily doses without titration, is significantly effective and well tolerated in the treatment of patients with partial seizures as demonstrated in patients with refractory partial seizures.

Endometrial polyps (EPs) are among the common cases of abnormal uterine bleeding. Hormonal factors may be involved in the pathogenesis as indicated by endometrial abnormalities in patients treated with tamoxifen. This study was designed to analyse the patient characteristics which may be associated with polyp occurrence and assess the diagnostic and therapeutic difficulties. Group of 245 patients was formed to 152 postmenopausal and 93 premenopausal women with EP diagnosed hysteroscopically and confirmed histologically. Evaluated factors were as follows: 1) patient characteristics: age, body mass, systemic hypertension, diabetes mellitus, nulliparity, late menopause, estrogen replacement therapy, and tamoxifen treatment; 2) clinical features of EPs, and 3) the number of curettage's (DC) and hysteroscopies.Hypertension associated with obesity appears to be an important factor in combination which may play role in the pathogenesis of EPs like the late menopause which was noted in 30% of examined postmenopausal women. An association between EPs and tamoxifen was found in 8% patients with breast cancer. 2. Postmenopausal uterine bleeding and menstrual disorders were prominent clinical symptoms in 44% post- and in 82% of premenopausal women. The other 56% post- and 18% premenopausal patients were asymptomatic. 3. The multiple EPs were present in 26% of postmenopausal and in 15% premenopausal women. 4. Transvaginal ultrasonography supplemented by sonohysterography in cases with abnormal ultrasonographic findings should be the main diagnostic method. 5 Hysteroscopical polypectomy is regarded as the optimal therapy and the removal of the endometrial basalis in the EP origin area prevents persistence or recurrence of EP.

Fosphenytoin, a prodrug of phenytoin, is rapidly and completely converted to phenytoin in adults after intravenous or intramuscular administration and is significantly better tolerated than parenteral phenytoin. Fosphenytoin is highly plasma-protein bound and, when present in sufficient concentration, will displace phenytoin from plasma proteins. The clinical utility is that fosphenytoin may be used to achieve therapeutic phenytoin concentrations more rapidly than intravenous phenytoin infused at its maximum recommended rate. In a clinical study of generalized convulsive status epilepticus, fosphenytoin, with or without benzodiazepine pretreatment, controlled seizures in 76 (93.8%) of 81 patients. In other studies, fosphenytoin maintained seizure control when substituted for oral phenytoin and for seizure prophylaxis in neurosurgery and trauma patients. Adverse events associated with fosphenytoin generally were related to the central nervous system and were similar to those associated with phenytoin, except for a higher incidence of transient pruritus with fosphenytoin. Intravenous fosphenytoin has significant advantages over intravenous phenytoin: It requires a shorter infusion time and fewer intravenous disruptions, causes less pain and burning at the infusion site and minimal consequences in case of intravenous infiltration, allows longer maintenance of intravenous sites, and has better intravenous fluid compatibility and stability. In contrast to intramuscular phenytoin, intramuscular fosphenytoin is well tolerated in both large loading doses and maintenance doses. (J Child Neurol 1998;13(Suppl 1):S15-S18).

The cross-reactivity of fosphenytoin, a phosphate ester prodrug of phenytoin, was investigated in the Abbott phenytoin TDx/TDxFLx fluorescence polarization immunoassay (TDx) and the Behring Diagnostics phenytoin Emit 2000 enzyme-multiplied immunoassay (Emit). The first part of our study investigating cross-reactivity utilized in vitro correlation of the two immunoassays with a validated and specific phenytoin HPLC method used to assay plasma samples prepared in several phenytoin and fosphenytoin concentration combinations. Fosphenytoin cross-reacted with both immunoassays, but to a greater extent with TDx. In the second part of the study, empirically-derived models that best explained the in vitro data were used to predict "immunoassay-derived" phenytoin concentrations in plasma samples collected from actual patients after intravenous (i.v.) or intramuscular (i.m.) fosphenytoin dosing. The greatest degree of phenytoin concentration overestimation occurred at times when fosphenytoin concentrations were highest: within 1 to 2 h after i.v. infusion or during the first 2 to 4 h after i.m. injection. It is recommended that phenytoin concentrations not be monitored using these or other potentially nonspecific immunoanalytical methods for at least 2 h after i.v. fosphenytoin infusion or 4 h after i.m. fosphenytoin injection.

Using a report system of the Bavarian Public Health services 300 EHEC infections were registered within one year (Apr 1, 1996, to Mar 31, 1997) in Bavaria. These consisted of 22 cases of haemolytic uraemic syndrome (HUS) (mean age, 2.8 yr), 6 cases of incomplete HUS (1.3 yr), 188 cases of enteritis (3.3 yr) and 84 asymptomatic infections (12.9 yr), respectively. From this follows an incidence rate for all infections of approximately 2.5 per 100,000 inhabitants and for HUS in the age group of children and juveniles up to 18 years of approximately 0.8, respectively. Possible sources (paths) of infection registered in relevant frequencies were: raw milk consumption (18% of the infected), farm-animal associated contact (43%), and contact with patients suffering from diarrhoea (36%).

The results of past research have identified changes in brain structure in anorexia nervosa. We observed previously unreported MRI alterations in two cases of anorexia nervosa.For both cases, we reviewed the clinical history, MRI scans and conducted a pertinent literature review.The MRI brain scans of two patients with the diagnosis of anorexia nervosa revealed evidence of subcortical hyperintense changes on T2-weighted images.No previous reports of these findings have been described in the literature on anorexia nervosa to date. Clinical and pathologic correlates associated with these brain observations in anorexia nervosa are discussed.

Positron emission tomography (PET) studies in Parkinson’s’ disease (PD) using the radioligand [11C]PK11195 have demonstrated increased binding to TSPO, in particular in the nigrostriatal system. However, due to high non-specific binding [11C]PK11195 is not ideal for quantitative analysis. In the present study we used the new radioligand [11C]PBR28 in 24 patients with PD, following confirmation of the diagnosis by PET imaging of the dopamine transporter ([18F]FE-PE2I). [11C]PBR28 data was quantified by linear graphic analysis, using an arterial input function and wavelet aided parametric imaging. DNA polymorphism for TSPO (A147T) was controlled for by genetic analysis. The total distribution volume, VT, was similar across brain regions with slightly higher levels in the thalamus. The mean VT values ranged from 2.60 in the substantia nigra to 3.54 in the thalamus. The inter-subject variability in VT was high and could be related to TSPO genotype. There were no correlations between [11C]PBR28 and [18F]FE-PE2I binding. The radioligand [11C]PBR28 shows suitable characteristics for quantitative imaging of TSPO binding in brain. For clinical applications, i.e. studies on disease pathophysiology, TSPO genotyping is needed. Preliminary analysis suggests that patients with PD may not have conspicuous upregulation of TSPO in the nigrostriatal system. Note: The data presented are a subset of results from a double-blind, placebo-controlled study to assess the effect of treatment with AZD3241 on microglia activation using PET.

Background: Safety, tolerability, and pharmacokinetics of fosphenytoin sodium, a water-soluble phenytoin prodrug, were investigated after a temporary substitution of intramuscular fosphenytoin for oral phenytoin sodium in 240 epileptic or neurosurgical patients taking oral phenytoin sodium (100-500 mg/d). Methods: Patients were randomly assigned to 1 of 2 parallel groups. During screening and follow-up, patients were maintained on a regimen of oral phenytoin at an individualized dose. During treatment, the phenytoin-treated patients received intramuscular placebo and their prescribed dose of oral phenytoin; the fosphenytoin-treated patients received oral placebo and intramuscular fosphenytoin equimolar to their phenytoin dose. Results: Both groups had similar types and frequencies of mild to moderate adverse events. Fosphenytoin was as well tolerated as intramuscular placebo at the injection site. Intramuscular fosphenytoin equimolar to a patient's oral phenytoin dose produced equal or greater plasma phenytoin concentrations. Conclusions: Dosing adjustments are not required when intramuscular fosphenytoin is temporarily substituted or oral phenytoin therapy is resumed. Intramuscular fosphenytoin is a safe and well-tolerated alternative to oral phenytoin when oral administration is not feasible.