ABSTRACT
Cervical dystonia (CD) is a neurological movement disorder causing the neck to move involuntarily away from the neutral position. CD is a network disorder, involving multiple brain areas and, therefore, may impair movement in parts of the body other than the neck. This study used clinical assessments to investigate walking, balance and upper limb function (UL) in people with CD; the reliability of scoring these assessments and examined for relationship between CD severity, usual exercise and clinical assessments. We conducted a prospective observational cohort study of participants with isolated, focal, idiopathic CD. Participants were assessed by experienced physiotherapists and completed three questionnaires and eight clinical assessments of fear of falling, balance confidence, walking, balance, UL function and usual exercise. Results were compared to published data from healthy adults and other neurological populations. Twenty-two people with mild to moderate CD participated. Fear of falling, gross UL function and usual exercise were worse in people with CD compared with healthy adults, while walking, balance and distal UL function were similar to healthy populations. All assessments were reliably performed by physiotherapists, and we found no correlations between the severity of dystonia or usual exercise and performance on the physical assessments. Routine performance of clinical assessment of walking and balance are likely not required in people with mild to moderate CD; however, fear of falling and gross upper limb function should be assessed to determine any problems which may be amenable to therapy.
Subject(s)
Torticollis , Walking , Accidental Falls , Adult , Cross-Sectional Studies , Fear , Humans , Postural Balance , Prospective Studies , Reproducibility of Results , Upper ExtremityABSTRACT
BACKGROUND AND PURPOSE: Falls are problematic for people living with neurological disorders and a fear of falling can impact on actual falls. Fear of falling is commonly assessed using the Falls Self-Efficacy Scale International (FES-I) or the Activities-specific Balance Confidence (ABC) Scale. These scales can predict risk of falling. We aimed to validate the FES-I and the ABC in persons with dystonia. METHODS: We conducted an online survey of people with dystonia, collecting information on demographics, 6-month falls history, dystonia disability, and the FES-I and ABC scales. Scales were validated for structural validity and internal consistency. We also examined goodness-of-fit, convergent validity, and predictive validity, and determined cutoff scores for predicting falls risk. RESULTS: Survey responses (n = 122) showed that both FES-I and ABC scales have high internal validity and convergent validity with the Functional Disability Questionnaire in persons with dystonia. Each scale examines a single factor, fear of falling (FES-I) and balance confidence (ABC). At least one fall was reported by 39% of participants; the cutoff value for falls risk was found to be 29.5 and 71.3 for the FES-I and the ABC respectively. DISCUSSION AND CONCLUSIONS: The FES-I and the ABC scales are valid scales to examine fear of falling and balance confidence in persons with dystonia. Fear of falling is high and balance confidence is low and both are worse in those with dystonia who have previously fallen.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A182).
Subject(s)
Accidental Falls , Dystonia/psychology , Fear/psychology , Postural Balance , Psychometrics/standards , Self Efficacy , Adult , Aged , Female , Humans , Male , Middle Aged , Reproducibility of Results , Young AdultABSTRACT
PURPOSE: To explore, in a microdose (phase-0) study, the pharmacokinetics, bioavailability and concentrations in key compartments of the lung, of AR-709, a novel diaminopyrimidine antibiotic for the treatment of respiratory infection. METHODS: Four healthy men each received two single, 100 µg microdoses of ¹4C-AR-709, 7 days apart: the first was administered intravenously (IV), the second orally. Plasma pharmacokinetics of ¹4C and unchanged AR-709 were obtained by high-performance liquid chromatography and accelerator mass spectrometry (AMS). Next, 15 healthy men received a single, 100 µg microdose of ¹4C-AR-709 IV. Plasma, bronchoalveolar lavage fluid, alveolar macrophages and bronchial mucosal biopsy samples were analysed by AMS. RESULTS: After IV administration, clearance of AR-709 was 496 mL/min, volume of distribution was 1,700 L and the absolute oral bioavailability was 2.5 %. Excretion in urine was negligible. At 8-12 h after IV dosing, ¹4C concentrations in lung samples were 15- (bronchial mucosa) to 200- (alveolar macrophages) fold higher than in plasma. In alveolar macrophages, ¹4C was still mostly associated with AR-709 at 12 h after dosing. CONCLUSIONS: The results of this microdose study indicate that AR-709 attains concentrations appreciably higher within the lung than in plasma. Its low oral bioavailability however, precludes oral administration. Although IV administration would appear to be an effective route of administration, this would limit the use of AR-709 to a clinical setting and would therefore be economically unsustainable. If further clinical development were to be undertaken, therefore, an alternative route of administration would be necessary.
Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Indoles/pharmacokinetics , Pyrimidines/pharmacokinetics , Adult , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/blood , Anti-Bacterial Agents/urine , Biological Availability , Bronchi/metabolism , Bronchoalveolar Lavage Fluid/chemistry , Carbon Radioisotopes , Cross-Over Studies , Humans , Indoles/administration & dosage , Indoles/blood , Indoles/urine , Macrophages, Alveolar/metabolism , Male , Pyrimidines/administration & dosage , Pyrimidines/blood , Pyrimidines/urine , Respiratory Mucosa/metabolism , Young AdultABSTRACT
BACKGROUND: beta-Tryptase is a multifunctional mast cell serine protease released during mast cell degranulation and tryptase/trypsin inhibitors are a novel potential therapeutic approach for allergic inflammatory diseases. OBJECTIVES: This study was performed to assess the effects of RWJ-58643 on nasal symptoms, eosinophil influx, and cytokine and chemokine release following nasal allergen challenge (NAC). METHODS: Male patients with grass pollen allergic rhinitis (n=16) out of season received single doses of RWJ-58643 (100, 300, 600 microg) or matched placebo given 30 min before NAC in a double-blind, randomized crossover design. A single dose of 200 microg budesonide was studied in an open-label extension phase. NAC was performed with Timothy grass pollen (ALK) via a nasal device, and nasal lavage was performed at times 0 (pre-drug, pre-allergen), 0.5 (30 min post-drug, pre-NAC) 1.5, 2.5, 4.5, 6.5, 8.5, and 24 h after drug administration. Nasal lavage mediators were analysed using a sensitive multiplexed bead immunoassay system. RESULTS: Low-dose RWJ-58643 (100 microg) and budesonide (200 microg) significantly reduced symptoms, eosinophils and levels of IL-5 following NAC. However, higher doses of RWJ-58643 (300 and 600 microg) caused a late eosinophilia and preceding increases in IL-5 compared with placebo. CONCLUSIONS: This study suggests that combined beta-tryptase and trypsin inhibition has therapeutic potential in allergic inflammation, however, this property is dose responsive and higher doses are ineffective and may cause eosinophilia.
Subject(s)
Pyrrolidines/immunology , Rhinitis, Allergic, Seasonal/immunology , Serine Endopeptidases/immunology , Thiazoles/immunology , Trypsin Inhibitors/immunology , Administration, Intranasal , Adult , Allergens/immunology , Benzothiazoles , Budesonide/administration & dosage , Budesonide/immunology , Chemokine CCL11 , Chemokine CCL2/analysis , Chemokines, CC/analysis , Chemotactic Factors, Eosinophil/immunology , Cross-Over Studies , Double-Blind Method , Eosinophils/immunology , Female , Humans , Inflammation Mediators/immunology , Interleukin-5/analysis , Interleukin-8/analysis , Leukocyte Count , Male , Mast Cells/immunology , Middle Aged , Pyrrolidines/administration & dosage , Thiazoles/administration & dosage , Trypsin Inhibitors/administration & dosage , Tryptases , Tumor Necrosis Factor-alpha/analysisABSTRACT
BACKGROUND: Nasal lavage is a noninvasive method of obtaining inflammatory exudates following nasal allergen challenge (NAC), and permits cells and released mediators to be evaluated. OBJECTIVE: To determine the effects of a single dose of topical steroid on eosinophils and levels of chemokines and cytokines in nasal lavage fluid following NAC in patients with allergic rhinitis. METHODS: Patients with grass pollen seasonal allergic rhinitis (n = 32) out of the allergy season received either nasal budesonide (100 microg per nostril) or matched placebo before allergen challenge in a double blind two-way crossover design. A semi-automated mixed bead array system was employed to measure multiple chemokines and cytokines in small volumes (50 microl) of nasal lavage supernatants. RESULTS: Following NAC there was a rapid onset of nasal symptoms together with nasal eosinophilia, and the appearance of IL-5 and IL-13 in lavages between 4 and 8 h. Elevated levels of eotaxin, RANTES, IL-8 and MCP-1 were also detected following allergen challenge. A single dose of nasal budesonide caused a decrease in symptoms (P < 0.05) and nasal eosinophils (P < 0.05) with selective abrogation of IL-5 and IL-13 responses (P < 0.05), but a lack of effect on levels of eotaxin, RANTES, IL-8 and MCP-1. CONCLUSION: This study suggests that a single dose of nasal steroid has the capacity to selectively abolish IL-5 and IL-13 responses following NAC. This model should be convenient for testing novel anti-inflammatory and immunoregulatory agents intended for the treatment of allergic rhinitis.
Subject(s)
Anti-Inflammatory Agents/administration & dosage , Budesonide/administration & dosage , Interleukin-13/antagonists & inhibitors , Interleukin-5/antagonists & inhibitors , Phleum/immunology , Pollen/immunology , Rhinitis, Allergic, Seasonal/drug therapy , Administration, Intranasal , Adult , Allergens/adverse effects , Allergens/immunology , Anti-Inflammatory Agents/therapeutic use , Budesonide/therapeutic use , Female , Humans , Interleukin-13/metabolism , Interleukin-5/metabolism , Male , Middle Aged , Nasal Lavage Fluid/immunology , Nasal Provocation Tests , Phleum/adverse effects , Pollen/adverse effects , Rhinitis, Allergic, Seasonal/etiology , Rhinitis, Allergic, Seasonal/metabolism , Rhinitis, Allergic, Seasonal/physiopathology , Treatment OutcomeABSTRACT
We used a randomised, double-blind, crossover design to evaluate the pharmacokinetics, safety and tolerability of three doses of buccal adhesive testosterone tablets (BATT). Twenty-four healthy men, whose endogenous testosterone was suppressed to =5.38 nmol/l with leuprorelin acetate, took BATT (10, 20 or 30 mg) daily for 10 days. There was a 4-day washout between treatments. Substantial testosterone absorption occurred from BATT, and mean serum testosterone, free testosterone and dihydrotestosterone (DHT) concentrations over 24 h showed circadian variation. Steady state was reached by day 5. Average 24-h concentrations for the three BATT doses were within the normal range for eugonadal men: testosterone 11.67-14.57 nmol/l, free testosterone 0.026-0.33 nmol/l and DHT 1.66-2.03 nmol/l. On all three doses, peak testosterone and free testosterone was reached 8-9 h after tablet application; DHT peaked about 1-2 h later, and declined more slowly. Hormone concentrations increased with BATT dose, but increases were less than dose-proportional. There was no evidence of testosterone accumulation. BATT was well tolerated.
Subject(s)
Testosterone/administration & dosage , Administration, Buccal , Adult , Aged , Analysis of Variance , Area Under Curve , Cheek , Circadian Rhythm , Cross-Over Studies , Dihydrotestosterone/blood , Double-Blind Method , Drug Administration Schedule , Electrocardiography , Gingiva , Hormone Antagonists/pharmacology , Humans , Leuprolide/pharmacology , Lip , Male , Middle Aged , Mouth Mucosa/drug effects , Patient Satisfaction , Testosterone/blood , Testosterone/pharmacokineticsABSTRACT
BACKGROUND: Interleukin-12 (IL-12) is a macrophage-derived cytokine that modulates T lymphocyte responses and has the capacity to suppress allergic and eosinophilic inflammation. METHODS: We carried out a double-blind, randomised, parallel group clinical study, in which patients with mild allergic asthma were given subcutaneous recombinant human IL-12 at increasing weekly injections of 0.1, 0.25, 0.5 microg/kg (n=19), or placebo (n=20). We compared responses to inhaled allergen challenge 24 h before the first injection and 24 h after the final injection. Airways hyper-responsiveness and concentrations of peripheral blood eosinophils and sputum eosinophils were also assessed. FINDINGS: IL-12 caused a significant decrease from baseline in the main peripheral blood eosinophil count 24 h after the fourth injection compared with placebo (p=0.0001). Sputum eosinophils were also significantly decreased 24 h after allergen challenge when treated with IL-12 compared with placebo (p=0.024). IL-12 caused a non-significant trend towards improvement in airway hyper-responsiveness to histamine, but had no significant effect on the late asthmatic reaction after inhaled allergen challenge. After administration of IL-12, four of 19 patients withdrew prematurely; two with cardiac arrhythmias, one with abnormal liver function, and a single patient with severe flu-like symptoms. INTERPRETATION: We have shown that IL-12 lowers numbers of blood and sputum eosinophils, but without any significant effects on airway hyper-responsiveness or the late asthmatic reaction. This questions the role of eosinophils in mediating these reactions, and has important implications for development of new anti-inflammatory treatments.
Subject(s)
Adjuvants, Immunologic/therapeutic use , Asthma/drug therapy , Eosinophils/metabolism , Interleukin-12/therapeutic use , Recombinant Proteins/therapeutic use , Adult , Analysis of Variance , Bronchial Provocation Tests , Double-Blind Method , Eosinophils/drug effects , Female , Histamine/blood , Humans , Leukocyte Count , Male , Sputum/cytology , T-Lymphocytes, Helper-Inducer/drug effectsABSTRACT
PCR DNA amplification of a region of the himA gene of Salmonella typhimurium specifically detected Salmonella spp. In oysters, 1 to 10 cells of Salmonella spp. were rapidly detected by the PCR following a pre-enrichment step to increase sensitivity and to ensure that detection was based on the presence of viable Salmonella spp.
Subject(s)
Food Microbiology , Ostreidae/microbiology , Polymerase Chain Reaction/methods , Salmonella/genetics , Salmonella/isolation & purification , Animals , Base Sequence , DNA, Bacterial/genetics , Evaluation Studies as Topic , Molecular Sequence Data , Polymerase Chain Reaction/statistics & numerical data , Sensitivity and SpecificityABSTRACT
The pharmacokinetics of xamoterol, a beta-adrenoceptor partial agonist under clinical evaluation for the treatment of mild to moderate heart failure, have been studied in 12 healthy male subjects. They received 14 mg i.v. and oral doses of 50 and 200 mg as a tablet and 200 mg as a solution in a 4 way cross-over design. After i.v. dosing the elimination half-life was 7.7 h, the total body clearance was 224 ml.min-1 and the volume of distribution at steady-state (Vss) was 48 l. Sixty-two percent of the dose was recovered unchanged in urine. After oral doses, the absolute bioavailability of xamoterol was shown to be 5% irrespective of whether the dose was administered as a tablet or solution. Peak plasma concentrations occurred at about 2 h for the tablet dose and slightly earlier (1.4 h) for the solution. Peak plasma concentration, AUC and urinary recovery of unchanged drug increased in proportion to dose. The apparent elimination half-life after oral doses (16 h) was significantly longer than that observed after an intravenous dose. Despite the low bioavailability, the degree of inter-subject variability of oral bioavailability was small probably indicating that the controlling factor is the hydrophilic nature of the molecule rather than extensive first pass metabolism or poor dissolution of xamoterol from the tablet formulation.
Subject(s)
Adrenergic beta-Agonists/pharmacokinetics , Propanolamines/pharmacokinetics , Administration, Oral , Adrenergic beta-Agonists/administration & dosage , Adrenergic beta-Agonists/pharmacology , Adult , Biological Availability , Blood Pressure/drug effects , Heart Rate/drug effects , Humans , Injections, Intravenous , Male , Middle Aged , Propanolamines/administration & dosage , Propanolamines/pharmacology , Protein Binding , XamoterolABSTRACT
In 5 normal adult men, histamine was infused i.v. for 5 min at 20 micrograms/kg/h and at 80 micrograms/kg/h on two occasions one week apart. Diastolic blood pressure fell and heart rate, plasma adrenaline and noradrenaline all rose in a dose-dependent manner, but plasma methionine-enkephalin (Met-Enk) concentrations were unchanged. These results indicate that while Met-Enk may be co-stored with catecholamines (CAs) in the adrenal medulla in at least this paradigm, circulating concentrations of CAs may be altered without similar changes in plasma Met-Enk immunoreactivity.
Subject(s)
Enkephalin, Methionine/blood , Epinephrine/blood , Histamine/pharmacology , Norepinephrine/blood , Adrenal Medulla/metabolism , Adult , Blood Pressure/drug effects , Dose-Response Relationship, Drug , Heart Rate/drug effects , Humans , Infusions, Parenteral , Male , RadioimmunoassayABSTRACT
Data from pharmacological studies carried out in healthy subjects using systemic histamine or impromidine and their antagonists are reviewed. Exogenous histamine by rapid injection appears to stimulate only H1-receptors. Chlorpheniramine alone antagonised the responses to histamine. The effects of cardiovascular H2-receptor stimulation are demonstrated best by a sustained and large dose of histamine given by infusion. If it be considered desirable to antagonise all the cardiovascular responses to endogenous histamine, the available pharmacological data in man suggest this would be achieved best by a combination of an H1-and H2-receptor antagonist.
Subject(s)
Cardiovascular System/drug effects , Histamine/analogs & derivatives , Imidazoles/pharmacology , Receptors, Histamine H1/drug effects , Receptors, Histamine/drug effects , Chlorpheniramine/pharmacology , Cimetidine/pharmacology , Hemodynamics/drug effects , Histamine/administration & dosage , Histamine/pharmacology , Humans , Imidazoles/administration & dosage , Impromidine , Receptors, Histamine H2/drug effectsABSTRACT
Experiments have been made in anaesthetised cats and dogs and in healthy, human volunteers to compare the changes in blood pressure and heart rate during systemic administration of histamine. Histamine, 1 x 10(-9) to 1 x 10(-7) mol/kg/min, lowered blood pressure in a similar dose-dependent fashion in all three species. In man and the cat this was accompanied by clear dose-dependent tachycardia whereas in the dog heart rate changes were minimal. Pharmacological analysis of the depressor responses to histamine in all three species and the reduction in total peripheral resistance in the cat and dog showed that the immediate responses to histamine in all three species involved H1-receptors and that sustained responses involved H2-receptors. Abolition of responses to histamine throughout infusions required H1-and H2-receptor blockade. Histamine antagonists, used in doses which cause abolition of cardiovascular responses to large doses of histamine, do not cause any significant change in the resting cardiovascular system.
Subject(s)
Cardiovascular System/drug effects , Histamine/pharmacology , Animals , Cats , Chlorpheniramine/pharmacology , Cimetidine/pharmacology , Dogs , Hemodynamics/drug effects , Humans , Pyrilamine/pharmacology , Time FactorsSubject(s)
Adrenergic beta-Antagonists , Hydrazines/pharmacology , Pyridazines , Vasodilator Agents , HumansSubject(s)
Diarrhea, Infantile/pathology , Intestinal Mucosa/pathology , Intestine, Small/pathology , Animals , Biopsy , Body Weight , Carbohydrate Metabolism , Child, Preschool , Disaccharidases/metabolism , Epithelial Cells , Epithelium/ultrastructure , Humans , Infant , Intestinal Mucosa/metabolism , Intestine, Small/metabolism , Milk , Nutrition Disorders/pathology , Tympanic Membrane/pathologySubject(s)
Cysts/complications , Duodenal Ulcer/complications , Gastrointestinal Hemorrhage/complications , Intestinal Perforation/complications , Omentum , Duodenal Ulcer/diagnostic imaging , Duodenal Ulcer/surgery , Humans , Infant , Male , Mesocolon , Peritoneal Diseases/complications , RadiographySubject(s)
Herpesvirus 4, Human/isolation & purification , Polyradiculopathy/microbiology , Adult , Humans , MaleSubject(s)
Blister/etiology , Brain Injuries/complications , Coma/chemically induced , Adult , Female , Humans , PressureABSTRACT
A further example of the rare disorder of embryonic development known as ;foetus in foetu' is described. Extensive blood group determinations, using a new autoanalytical technique, were combined with chromosome studies to show that the chance of the foetus in foetu and its host being of monozygotic origin was 0.947.