Isoniazid urine spectrophotometry for prediction of serum pharmacokinetics in adults with TB.

BACKGROUND: Isoniazid (INH) is an important drug in many TB regimens, and unfavorable treatment outcomes can be caused by suboptimal pharmacokinetics. Dose adjustment can be personalized by measuring peak serum concentrations; however, the process involves cold-chain preservation and laboratory techniques such as liquid chromatography (LC)/mass spectrometry (MS), which are unavailable in many high-burden settings. Urine spectrophotometry could provide a low-cost alternative with simple sampling and quantification methods. METHODS: We enrolled 56 adult patients on treatment for active TB. Serum was collected at 0, 1, 2, 4, 6, and 8 h for measurement of INH concentrations using validated LC-MS/MS methods. Urine was collected at 0-4, 4-8, and 8-24 h intervals, with INH concentrations measured using colorimetric methods. RESULTS: The median peak serum concentration and total serum exposure over 24 h were 4.8 mg/L and 16.4 mg*hour/L, respectively. Area under the receiver operator characteristic curves for urine values predicting a subtherapeutic serum concentration (peak <3.0 mg/L) were as follows: 0-4 h interval (AUC 0.85, 95% CI 0.7-0.96), 0-8 h interval (AUC 0.85, 95% CI 0.71-0.96), and 0-24 h urine collection interval (AUC 0.84, 95% CI 0.68-0.96). CONCLUSION: Urine spectrophotometry may improve feasibility of personalized dosing in high TB burden regions but requires further study of target attainment following dose adjustment based on a urine threshold.

CONTEXTE: L'isoniazide (INH) est un médicament important dans de nombreux schémas thérapeutiques contre la TB, et des résultats thérapeutiques défavorables peuvent être dus à une pharmacocinétique sous-optimale. L'ajustement de la dose peut être personnalisé en mesurant les concentrations sériques maximales ; cependant, le processus implique la conservation de la chaîne du froid et des techniques de laboratoire telles que la chromatographie liquide (LC)/spectrométrie de masse (MS), qui ne sont pas disponibles dans de nombreuses régions à forte charge de morbidité. La spec-trophotométrie urinaire pourrait constituer une alternative peu coûteuse avec des méthodes d'échantillonnage et de quantification simples. MÉTHODES: Nous avons recruté 56 patients adultes sous traitement pour une TB active. Le sérum a été prélevé à 0, 1, 2, 4, 6 et 8 h pour mesurer les concentrations d'INH à l'aide de méthodes LC-MS/MS validées. L'urine a été prélevée à des intervalles de 0­4, 4­8 et 8­24 h, et les concentrations d'INH ont été mesurées à l'aide de méthodes colorimétriques. RÉSULTATS: La concentration sérique maximale médiane et l'exposition sérique totale sur 24 h étaient respectivement de 4,8 mg/L et de 16,4 mg*heure/L. L'aire sous les courbes caractéristiques de l'opérateur récepteur a été mesurée à l'aide de méthodes color-imétriques. Les aires sous les courbes caractéristiques des récepteurs pour les valeurs urinaires prédisant une concentration sérique sous-thérapeutique (pic <3,0 mg/L) étaient les suivantes : intervalle 0­4 h (AUC 0,85 ; IC 95% 0,7­0,96), intervalle 0­8 h (AUC 0,85 ; IC 95% 0,71­0,96), et intervalle de collecte d'urine 0­24 h (AUC 0,84 ; IC 95% 0,68­0,96). CONCLUSION: La spectrophotométrie urinaire peut améliorer la faisabilité d'un dosage personnalisé dans les régions à forte charge de TB, mais nécessite une étude plus approfondie de l'atteinte de la cible après l'ajustement de la dose sur la base d'un seuil urinaire.

A study of the pharmacokinetics and pharmacodynamics of oxytocin at elective caesarean delivery.

Oxytocin is widely used to prevent atonic postpartum haemorrhage after caesarean delivery. Initial treatment failure rates are high and inadequate dosing may contribute. Excessive doses, however, are associated with serious adverse effects. The pharmacokinetic data from this context are sparse and there is a lack of data in the immediate postpartum minutes after an initiating bolus. The pharmacodynamic data from this context are exclusively from dose-effect studies, with some suggesting that higher doses of oxytocin are required to provide adequate uterine tone in obese compared with non-obese women. We aimed to perform a pharmacokinetic and pharmacodynamic study that would facilitate more precise weight-based oxytocin dosing. We measured arterial oxytocin concentration, uterine tone and haemodynamic parameters in 25 women in the first 40 min after exogenous oxytocin administration at elective caesarean delivery. Serum oxytocin concentrations varied considerably between individuals. We constructed a one-compartment pharmacokinetic model of exogenous oxytocin deposition, after its administration with an initiating bolus and a maintenance infusion, at elective caesarean delivery. Body weight was evaluated as a potential covariate but was not included in the model due to lack of statistically significant reduction in the objective function. We calculated the volume of distribution and clearance (mean [coefficient of variation]) as 156.1 l [18%] and 83 ml.s-1 [32%] but found no within-individual correlation between serum oxytocin concentration and uterine tone or haemodynamic parameters. In conclusion, we observed a large variation in serum oxytocin concentrations between individuals receiving similar doses of oxytocin and were unable to establish weight-based dosing of exogenous oxytocin at caesarean delivery. Our findings suggest that future studies on oxytocin pharmacokinetics would need large sample sizes. In the absence of such data, oxytocin dosing should continue to be guided by uterine tone assessments and adjusted according to a strategy based on the best evidence from dose-effect studies.

Acetylsalicylic Acid Produces Different Effects on the Production of Active Oxygen Species by Activated Platelets in Different Inflammatory Diseases.

We studied the effect of acetylsalicylic acid on ROS generation by platelets in patients after surgical interventions and in patients with bronchial asthma was studied. Platelets stimulated with platelet-activating factor are characterized by weak luminol-enhanced chemiluminescence in healthy people and patients after operations with laparoscopic incisions. Addition of platelet activation factor to platelet samples from patients after open abdominal surgery caused intensive chemiluminescence that was suppressed after platelet incubation with acetylsalicylic acid. At the same time, platelets of patients with aspirin-sensitive asthma did not respond to addition of platelet activating factor, but after incubation with acetylsalicylic acid, an intensive burst of chemiluminescence was detected with a maximum in 5-10 sec after the addition of a platelet-activating factor. In patients with bronchial asthma tolerant to aspirin, platelet activation factor did not induce chemiluminescence irrespective of incubation with acetylsalicylic acid.

EXPERIMENTAL SUBSTANTIATION AND CLINICAL APPLICATION OF MICROSURGICAL ANTIREFLUX GASTROINTESTINAL ANASTOMOSES IN GASTRIC RESECTION.

AIM: An improvement of the stomach through the development of reconstructive operations results of anatomical - the experimentally study and clinical testing of a series of new microsurgical areflux gastrointestinal anastomosis with sphincter properties. MATERIALS AND METHODS: The study was performed on 60 animals (dogs) and 52 organocomplexes people dead. 4 A series of experiments, developed new ways to 4 gastro-intestinal anastomosis with sphincter properties gastroduodenostomii way to "end to end" (patent number 2,197,903); pilorosohranyayuschey gastrectomy method (patent number 2,201,714); gastronesteostomy way to "end to side" (patent number 2,201,716); gastroduodenostomii way to the formation of artificial pyloric sphincter (patent number 2,212,195). RESULTS: Anatomical studies on cadaveric organocomplexes installed, but that the use of the formation of the gastro-intestinal anastomosis of microsurgical techniques and a separate cross-linking methods of internal and external casings of hollow organs without entrainment into the joint mucosa anastomosis gives high.impermeability and durability, retains histotopography linkable tissues. Gastric resection methods developed to form microsurgical gastrojejunal anastomosis and gastro used in clinical practice in 20 patients. Operated patients were examined after 1-6 years after surgery. When gastroscopia they celebrated, good function Form-balanced, the sphincter, the absence of duodenal reflux. CONCLUSION: The use of microsurgical techniques with gastric resection with the formation of functionally active gastroduodenal and gastrojejunal anastomosis can create gastrointes.inal anastomosis with anti-reflux properties and save the porter, without violating its contractile function, ensures minimum trauma to the tissues, the exact adaptation of the histologic homogeneous layers of the walls of bound bodies.

Enhanced antinociceptive efficacy of epidural compared with i.v. methadone in a rat model of thermal nociception.

BACKGROUND: The properties of methadone suggest a potential advantage for epidural over i.v. administration for pain relief, but little supportive evidence exists. METHODS: To investigate the pharmacokinetic and the pharmacodynamic properties of epidural and i.v. methadone, four doses of methadone (0.1, 0.25, 0.5, and 0.75 mg kg(-1)) were investigated by each route in a rat model. The tail-flick and hot water tail immersion test were used for thermal nociception. The magnitude of antinociceptive efficacy was expressed as per cent maximal possible effect (%MPE) of tail withdrawal latency, and the area under the %MPE vs time curve indicated the cumulative antinociceptive effect. A pharmacokinetic model describing the disposition and elimination of methadone was established. RESULTS: The pharmacokinetic profiles of methadone were not significantly different after epidural and i.v. administration. A two-compartment model with saturable elimination provided a good fit of the experimental data. At equivalent doses, epidural methadone produced higher cumulative antinociceptive effect in both thermal models. Supraspinal opioid effect, assessed by pinna reflex presence, was significantly lower with epidural methadone at equivalent doses. The duration of antinociceptive effect was longer with epidural administration of 0.5 and 0.75 mg kg(-1) doses. CONCLUSIONS: Epidural administration of methadone in rats resulted in systemic exposure similar to that after i.v. administration, but improved thermal antinociceptive efficacy, and reduced supraspinal undesired effects. The findings suggest the presence of local effect at the spinal cord level, in addition to the systemic effect produced by epidural methadone.

Combustion waves in hydraulically resisted systems.

The effects of hydraulic resistance on the burning of confined/obstacle-laden gaseous and gas-permeable solid explosives are discussed on the basis of recent research. Hydraulic resistance is found to induce a new powerful mechanism for the reaction spread (diffusion of pressure) allowing for both fast subsonic as well as supersonic propagation. Hydraulic resistance appears to be of relevance also for the multiplicity of detonation regimes as well as for the transitions from slow conductive to fast convective, choked or detonative burning. A quasi-one-dimensional Fanno-type model for premixed gas combustion in an obstructed channel open at the ignition end is discussed. It is shown that, similar to the closed-end case studied earlier, the hydraulic resistance causes a gradual precompression and preheating of the unburned gas adjacent to the advancing deflagration, which leads (after an extended induction period) to a localized autoignition that triggers an abrupt transition from deflagrative to detonative combustion. In line with the experimental observations, the ignition at the open end greatly encumbers the transition (compared with the closed-end case), and the deflagration practically does not accelerate up to the very transition point. Shchelkin's effect, that ignition at a small distance from the closed end of a tube facilitates the transition, is described.

Novel gastroretentive controlled-release drug delivery system for amoxicillin therapy in veterinary medicine.

Beta-lactam antimicrobials, commonly used in both veterinary and human medicine, generally present short biologic half-lives, whereas their activity is enhanced as pathogen exposure is prolonged. These properties necessitate multiple-dose regimens of standard dosage forms, thereby hampering pet owner adherence, frequently resulting in therapeutic failure. This study presents a novel controlled-release gastroretentive oral drug delivery system for beta-lactams with which single-dose administration provides an effective antimicrobial course, optimizing pharmacokinetic (PK)-pharmacodynamic (PD) profiles, minimizing adverse effects and emergence of antimicrobial resistance and facilitating adherence. Our prototype sustained-delivery swelling-tablet (SDST), based on a degradable hydrophilic polymeric matrix, was designed to enable continuous input of these drugs to their absorption sites over several days. Several SDST formulations of the beta-lactam amoxicillin were evaluated in in vitro dissolution studies. Two formulations were selected for further in vivo canine studies, for determination of gastric retention and PK-PD profiling. Prolonged gastric retention times maintaining allowed for maintained effective drug concentrations against many clinically relevant pathogens for more than 48 h for one formulation and more than 5 days for the other. Both SDST formulations offer significant advantages over standard immediate-release therapy in achieving PK-PD goals and enhancing adherence. The prototypical formulations represent a novel platform which may be modified to meet various clinical requirements.

A novel subcutaneous controlled-release amoxicillin degradable implant for extended-interval administration in veterinary medicine.

Dosage forms of antimicrobials play a critical role in facilitating the attainment of pharmacokinetic-pharmacodynamic (PK-PD) targets as well as adherence in both veterinary and human medicine. The purpose of this study was to develop and evaluate a controlled-release subcutaneous amoxicillin implant for single-dose therapy of large ruminants such as goats, sheep, and deer. The degradable implant, designed to attain PK-PD targets following single administration, was evaluated for amoxicillin release rate and time-concentration profile. In vitro release studies demonstrated constant-rate release of approximately 40% of amoxicillin content within 96 h. In an in vivo study in goats, serving as a model for target animals, a serum concentration of approximately 0.4 mg/L was achieved within 8 h of implant insertion and maintained for >6 days. In comparison, in control goats given a standard single intramuscular amoxicillin dose of 15 mg/kg, amoxicillin peaked at 1.2 mg/L after 1 h, rapidly dropping to below detection level at 8 h. These results suggest that the proposed implant offers a unique modality for animal caregivers to conveniently administer a full antimicrobial course following a single dose of an efficient PK-PD-optimized dosage form. Furthermore, modifications of implant composition may allow for tailoring of its characteristics to various PK, PD, microbiological, and clinical requirements.

[A comparative in vitro analysis of primary and immortalized keratocytes]. / Vergleichende In-vitro-Analyse von primären und immortalisierten Keratozyten.

BACKGROUND: The cultivation of primary keratocytes (HCKp) is difficult and influenced by a multitude of factors. In this study it was examined if immortalized keratocytes (HCKi) can replace HCKp in experiments and be useful in the development of a cornea construct. METHODS: HCKp and HCKi were cultivated and incubated for 72 h with benzalkonium chloride (BAC) or cetrimide at concentrations of 40-0.1 microg/ml or 100-0.01 microg/ml. The vitality and the doubling time (tv) were measured. RESULTS: Treatment with 40 or 4 microg/ml BAC as well as 100 or 10 microg/ml cetrimide led to cell death. The tv was shortened in HCKi especially in cells that were treated with BAC, but only HCKp showed a significant loss of vitality. In cells treated with cetrimide the tv increased significantly in both cell lines and no loss of vitality was detected from 0.1 microg/ml onwards in both cell lines. CONCLUSION: HCKi are more resistant and proliferative than HCKp but they can be used in preliminary experiments as an alternative to primary cells in for example toxicity studies if the detectable differences between the two cell lines, such as the capacity for proliferation and reaction to agents are taken into consideration.

Sexually inappropriate behaviour in demented elderly people.

AIM: To determine the prevalence, aetiology, and treatment profile of abnormal sexual behaviour in subjects with dementia in psychogeriatric practices. METHODS: A retrospective cross sectional study was conducted in a long term care psychiatry consultation service, community based geriatric psychiatry service, and an inpatient dementia behavioural unit in Edmonton, Canada. RESULTS: Forty one subjects (1.8%) had sexually inappropriate behaviour. Of those cognitively impaired subjects with sexually inappropriate behaviour, 20 (48.8%) were living in nursing homes and the rest, 21 (51.2%) in the community. Of these subjects, 53.7% had vascular dementia, 22% had Alzheimer's, and 9.8% had mild cognitive impairment. History of alcohol misuse and psychosis were reported in 14.6% and 9.8% of subjects respectively. Twenty seven (65.7%) had verbally inappropriate behaviour and 36 (87.8%) had physically inappropriate behaviour. In this study, verbally inappropriate behaviour was more commonly seen in the community sample (81%) than in the nursing home sample (50%) (p = 0.04). Behavioural treatment was also more commonly seen in the community sample (81%) than in the nursing home sample (45%) (p = 0.01). CONCLUSION: In this study sexually inappropriate behaviour was seen in all stages of dementia, more commonly associated with subjects of vascular aetiology, and is as commonly seen in community dwelling subjects with dementia as in nursing home subjects.

Observation of radio-wave-induced red hydroxyl emission at low altitude in the ionosphere.

We report the discovery of radio-wave-induced red emission of OH Meinel rotation-vibrational bands at 629.79 nm. These are the first measurements of artificial aurora below 100 km. We believe that the 629.79-nm OH emission was due to radio-wave focusing by sporadic ionization clouds near 80-85 km altitude, thus giving a technique to visualize the low-altitude sporadic ionization and providing insight into ionospheric interactions at these low altitudes.

Children's compliance to dialysis.

Relationships among physiologic measures of compliance to dialysis therapy and selected parent and child variables were investigated. Child's age and length of time receiving dialysis related significantly to compliance.

l-Ascorbic Acid Biosynthesis in Ochromonas danica.

Ochromonas danica Pringsheim, a freshwater chrysomonad, converts d-glucose into l-ascorbic acid over a metabolic pathway that ;inverts' the carbon chain of the sugar. In this respect, l-ascorbic acid formation resembles that found in ascorbic acid-synthesizing animals. It differs from this process in that d-galacturonate and l-galactono-1,4-lactone, rather than d-glucuronate and l-gulono-1,4-lactone, enhance production of ascorbic acid and repress the incorporation of (14)C from d-[1-(14)C]glucose into ascorbic acid.

Myoglobinemia in inflammatory myopathies.

Myoglobin was detected in the sera of patients with dermatomyositis, polymyositis, scleroderma, and systemic lupus erythematosus (LE) with active myopathy. Overall, myoglobinemia was detected in 74.1% of sera taken from patients with active myositis before therapy, with slightly greater frequency in the groups with dermatomyositis and polymositis. With steroid therapy, this frequency fell to 43.4% and to 9.5% in patients in clinical remission not requiring therapy. Serum enzyme (creatine phosphokinase, lactic dehydrogenase, and SGOT) activity was higher in samples containing myoglobin, but there was considerable overlap between those with and without myoglobinemia. Sequential serum determinations in six patients demonstrated rapid reduction in the levels of serum myoglobin with therapy, usually before enzyme values had returned to normal. In one patient followed up for 30 months, myoglobinemia correlated with clinically observed exacerbations of rash and weakness to a greater degree than did enzyme determinations.