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Selected AbstractsPositive photocontact responses are not elicited to sunscreen ingredients exposed to UVA prior to application onto the skinCONTACT DERMATITIS, Issue 4 2007Shyamal Wahie Photocontact allergic reactions to sunscreen chemicals are investigated by photopatch testing. It has generally been assumed that for photocontact allergy to be shown, the putative pro-allergen must be in the skin at the time of ultraviolet A (UVA) exposure. However, this assumption has not, to our knowledge, been tested. The objective of this study was to determine whether positive photocontact responses can still be elicited when sunscreen chemicals are exposed to UVA prior to application onto the skin. 3 patients known to have positive photocontact reactions to a total of 6 sunscreen chemicals were studied. For conventional photopatch testing, patch test strips were applied onto the back and removed 1 D later, and the area was irradiated with UVA (5 J/cm2). For pre-irradiated testing, patches were exposed to the same dose of UVA immediately before application onto the back and then removed 1 D later. Skin responses were visually assessed by a blinded investigator 1 and 2 D after patch test removal. The same photocontact responses of the same magnitude, as previously documented for each patient, were seen at each of the conventional UVA-exposed patch test sites. However, in no patient was a positive response elicited at any of the sites where pre-irradiated patches had been applied. This study shows that positive photocontact responses to sunscreen chemicals do not occur when the putative pro-allergen is irradiated prior to application onto the skin. This suggests that for a photoallergic reaction to occur, the sunscreen chemical needs to be within the skin when activated by UVA. [source] Dose per unit area , a study of elicitation of nickel allergyCONTACT DERMATITIS, Issue 5 2007Louise Arup Fischer Background:, Experimental sensitization depends upon the amount of allergen per unit skin area and is largely independent of the area size. Objectives:, This study aimed at testing if this also applies for elicitation of nickel allergy. Patients/methods:, 20 nickel allergic individuals were tested with a patch test and a repeated open application test (ROAT). Nickel was applied on small and large areas. The varying parameters were area, total dose and dose per unit area. Results:, In the patch test, at a low concentration [15 ,g nickel (,gNi)/cm2], there were significantly higher scores on the large area with the same dose per area as the small area. At higher concentrations of nickel, no significant differences were found. In the ROAT at low concentration (6.64 ,gNi/cm2), it was found that the latency period until a reaction appeared was significantly shorter on the large area compared to the small area. It was also found that the ROAT threshold (per application) was lower than the patch test threshold. Conclusion:, For elicitation of nickel allergy, the size of the exposed area and therefore the total amount of applied nickel, influence the elicitation reaction at some concentrations, even though the same dose per unit area is applied. [source] Involvement of BMP-4/msx-1 and FGF pathways in neural induction in the Xenopus embryoDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 4 2000Akihiko Ishimura The msx homeodomain protein is a downstream transcription factor of the bone morphogenetic protein (BMP)-4 signal and a key regulator for neural tissue differentiation. Xmsx-1 antagonizes the dorsal expression of noggin and cerberus, as revealed by in situ hybridization and reverse transcription,polymerase chain reaction assays. In animal cap explants, Xmsx-1 and BMP-4 inhibit the neural tissue differentiation induced by noggin or cerberus. A loss-of-function study using the Xmsx-1/VP-16 fusion construct indicated that neural tissue formation was directly induced by the injection of fusion ribonucleic acid, although the expression of neural cell adhesion molecule (N-CAM) in the cap was less than that in the cap injected with tBR or noggin. In contrast to the single cap assay, unexpectedly, both BMP-4 and Xmsx-1 failed to inhibit neurulation in the ectodermal explants to which the organizer mesoderm was attached. The results of cell-lineage tracing experiments indicated that the neural cells were differentiated from the animal pole tissue where the excess RNA of either BMP-4 or Xmsx-1 was injected, whereas notochord was differentiated from the organizer mesoderm. Neural tissue differentiated from BMP-4 -injected ectodermal cells strongly expressed posterior neural markers, such as hoxB9 and krox20, suggesting that the posterior neural cells differentiated regardless of the existence of the BMP signal. The introduction of a dominant-negative form of the fibroblast growth factor (FGF) receptor (XFD) into the ectodermal cells drastically reduced the expression of pan and posterior neural markers (N-CAM and hoxB-9) if co-injected with BMP-4 RNA, although XFD alone at the same dose did not shut down the expression of N-CAM in the combination explants. Therefore, it is proposed that an FGF-related molecule was involved in the direct induction of posterior neural tissue in the inducing signals from the organizer mesoderm in vivo. [source] Early adolescents show enhanced acute cocaine-induced locomotor activity in comparison to late adolescent and adult ratsDEVELOPMENTAL PSYCHOBIOLOGY, Issue 2 2008Kimberly A. Badanich Abstract Initiation of drug use during adolescence is associated with an increased probability to develop a drug addiction. The present study examined dose,response effects of cocaine (0, 5, 10, or 20 mg/kg, i.p.) on locomotor activity in early adolescent (postnatal day (PND) 35), late adolescent (PND 45), and young adults (PND 60) by measuring total distance moved (TDM) and frequency of start,stops. In response to 20 mg/kg cocaine, early adolescents showed the greatest cocaine-induced increase in TDM in comparison to late adolescent and adult rats. At this same dose, early adolescents showed the greatest cocaine-induced attenuation of start,stops relative to older rats. Results suggest that early adolescents engage in more cocaine-induced locomotor activity and less stationary behavior indicating that early adolescents are more sensitive to locomotor activating effects of high dose cocaine than older rats. © 2008 Wiley Periodicals, Inc. Dev Psychobiol 50: 127,133, 2008. [source] A 75% insulin lispro/25% NPL mixture provides a longer duration of insulin activity compared with insulin lispro alone in patients with Type 1 diabetesDIABETIC MEDICINE, Issue 11 2003P. Roach Abstract Aims To compare a new insulin formulation, high mix (HM) [75% lispro (LP) and 25% neutral protamine lispro (NPL)], to regular human insulin (HR) and LP with respect to glucose response and pharmacokinetics following a test meal in patients with Type 1 diabetes. Methods After fasting overnight, patients received an intravenous insulin infusion to standardize blood glucose (BG) to 7.5 mmol/l (135 mg/dl). In a randomised, three-way crossover study, HR was injected 30 min before, and LP or HM was injected immediately before the test meal on three separate occasions. For each patient, LP and HR were administered at identical doses; the HM dose was one and one third times that of HR and LP to maintain the same dose of short or rapid-acting insulin. The insulin infusion was stopped 15 min after the insulin injection. Free insulin and BG concentrations were measured frequently for 7 h following the test meal. Results HM and LP resulted in better glycaemic control than HR during the observation period. BG concentrations during the first 4,5 h did not differ between HM and LP. However, HM exhibited prolonged insulin activity relative to LP beyond 5 h, extending the duration of action by approximately 1 h, and resulting in lower overall BG concentrations when the 0,6- and 0,7-h intervals were considered. Conclusions Compared with LP, HM provided similar glycaemic control for up to 5 h and superior glycaemic control from 5 to 7 h following a standard test meal [source] Post-prandial glucose excursions following four methods of bolus insulin administration in subjects with Type 1 diabetesDIABETIC MEDICINE, Issue 4 2002H. P. Chase Abstract Aims To determine if one method of short-acting insulin bolus administration is superior to other methods in managing a meal high in carbohydrates, calories and fat. Methods Nine subjects receiving continuous subcutaneous insulin infusion using insulin lispro (Humalog®) agreed to consume the same meal high in carbohydrates, calories and fat on four occasions 1 week apart. They received the same dose of bolus insulin on each of the four occasions randomly assigned and beginning 10 min prior to the meal as either a single bolus, two separate boluses of one-half the same total dose (the second after 90 min), the entire bolus given as a square-wave (over 2 h) or a dual-wave (70% as a bolus and 30% as a square-wave over 2 h). Blood glucose levels were measured at ,60 and ,30 min and at zero time, and then every half-hour for 6 h using the Hemacue® in the out-patient clinic. Results Changes in blood glucose values from fasting were the lowest after 90 and 120 min (P < 0.01) when the dual wave was administered. When the dual or square-wave methods of insulin administration were used, subjects had significantly lower glucose levels after 4 h in comparison with when the single or double boluses were used (P = 0.04). Conclusions We conclude that the dual wave provided the most effective method of insulin administration for this meal. The dual- and square-wave therapies resulted in lower glucose levels 4 h after the meal in comparison with the single and double-bolus treatments. [source] Development of Amygdaloid Kindling in Histidine Decarboxylase,deficient and Histamine H1 Receptor,deficient MiceEPILEPSIA, Issue 4 2004Tadashi Hirai Summary: Purpose: This study attempted to clarify the role of histamine or histamine H1 receptors in the development of amygdaloid kindling by using histidine decarboxylase (HDC)-deficient and histamine H1 receptor (H1R)-deficient mice. Methods: Under pentobarbital anesthesia, mice were fixed to a stereotaxic apparatus, and bipolar electrodes were implanted into the right amygdala. Electrodes were connected to a miniature receptacle, which was embedded in the skull with dental cement. A bipolar electroencephalogram was recorded; bipolar stimulation of the amygdala was applied every day with a constant-current stimulator and continued until a generalized convulsion was obtained. Results: The development of amygdaloid kindling in HDC-deficient and H1R-deficient mice was significantly accelerated compared with that in their respective wild-type mice. In addition, the afterdischarge (AD) duration and generalized seizure duration in HDC-deficient and H1R-deficient mice were prolonged. Intraperitoneal injection of histidine resulted in an inhibition of amygdaloid kindled seizures in wild-type mice at doses that caused an increase in the histamine contents of the brain. However, no significant effect was observed with histidine in H1R-deficient mice at the same dose. Conclusions: These findings suggest that histaminergic mechanisms through H1 receptors play a crucial role not only in amygdaloid kindled seizures but also in the development of amygdaloid kindling. [source] Comparison of cardiovascular function and quality of recovery in isoflurane-anaesthetised horses administered a constant rate infusion of lidocaine or lidocaine and medetomidine during elective surgeryEQUINE VETERINARY JOURNAL, Issue 3 2010A. VALVERDE Summary Reasons for performing study: The effects of lidocaine combined with medetomidine or lidocaine alone on cardiovascular function during anaesthesia and their effects on recovery have not been thoroughly investigated in isoflurane-anaesthetised horses. Objectives: To determine the effects of an intraoperative i.v. constant rate infusion of lidocaine combined with medetomidine (Group 1) or lidocaine (Group 2) alone on cardiovascular function and on the quality of recovery in 12 isoflurane-anaesthetised horses undergoing arthroscopy. Hypothesis: The combination would depress cardiovascular function but improve the quality of recovery when compared to lidocaine alone in isoflurane-anaesthetised horses. Methods: Lidocaine (2 mg/kg bwt i.v. bolus followed by 50 µg/kg bwt/min i.v.) or lidocaine (same dose) and medetomidine (5 µg/kg bwt/h i.v.) was started 30 min after induction of anaesthesia. Lidocaine administration was discontinued 30 min before the end of surgery in both groups, whereas medetomidine administration was continued until the end of surgery. Cardiovascular function and quality of recovery were assessed. Results: Horses in Group 1 had longer recoveries, which were of better quality due to better strength and overall attitude during the recovery phase than those in Group 2. Arterial blood pressure was significantly higher in Group 1 than in Group 2 and this effect was associated with medetomidine. No significant differences in cardiac output, arterial blood gases, electrolytes and acid-base status were detected between the 2 groups. Conclusions and potential relevance: The combination of an intraoperative constant rate infusion of lidocaine and medetomidine did not adversely affect cardiovascular function in isoflurane-anaesthetised horses and improved the quality of recovery when compared to an intraoperative infusion of lidocaine alone. [source] Pharmacokinetics of detomidine administered to horses at rest and after maximal exerciseEQUINE VETERINARY JOURNAL, Issue 5 2009J. A. E. HUBBELL Summary Reason for performing study: Increased doses of detomidine are required to produce sedation in horses after maximal exercise compared to calm or resting horses. Objectives: To determine if the pharmacokinetics of detomidine in Thoroughbred horses are different when the drug is given during recuperation from a brief period of maximal exercise compared to administration at rest. Methods: Six Thoroughbred horses were preconditioned by exercising them on a treadmill. Each horse ran a simulated race at a treadmill speed that caused it to exercise at 120% of its maximal oxygen consumption. One minute after the end of exercise, horses were treated with detomidine. Each horse was treated with the same dose of detomidine on a second occasion a minimum of 14 days later while standing in a stocks. Samples of heparinised blood were obtained at various time points on both occasions. Plasma detomidine concentrations were determined by liquid chromatographymass spectrometry. The plasma concentration vs. time data were analysed by nonlinear regression analysis. Results: Median back-extrapolated time zero plasma concentration was significantly lower and median plasma half-life and median mean residence time were significantly longer when detomidine was administered after exercise compared to administration at rest. Median volume of distribution was significantly higher after exercise but median plasma clearance was not different between the 2 administrations. Conclusions and potential relevance: Detomidine i.v. is more widely distributed when administered to horses immediately after exercise compared to administration at rest resulting in lower peak plasma concentrations and a slower rate of elimination. The dose requirement to produce an equivalent effect may be higher in horses after exercise than in resting horses and less frequent subsequent doses may be required to produce a sustained effect. [source] Efficacy of tropisetron in patients with advanced non-small-cell lung cancer receiving adjuvant chemotherapy with carboplatin and taxanesEUROPEAN JOURNAL OF CANCER CARE, Issue 2 2008N. TSAVARIS md Even though significant progress has been made, chemotherapy-induced emesis remains a challenging problem. Few studies focus on emesis in patients treated with carboplatin and the observation period is limited to the initial 24 h following chemotherapy. Thus, we investigated if tropisetron (T) monotherapy can adequately prevent acute and delayed emesis in non-small-cell lung cancer (NSCLC) patients receiving a moderately emetogenic chemotherapy (MEC) (carboplatin-containing) regimen. Furthermore, we explored the merits of adding dexamethasone (D) or alprazolam (A) to T, especially in the setting of a pre-existing high level of stress. We studied 60 patients with advanced NSCLC receiving carboplatin and taxanes in three consecutive cycles. During the first cycle, patients received 5 mg of T intravenously before chemotherapy and the same dose per os on each of the following 3 days. In the second cycle, T was co-administered with 8 mg of D once a day, while, during the third cycle, T was combined with per os A 0.25 mg every 12 h and continued over the following 3 days. Finally, we evaluated the impact of stress on the anti-emetic response achieved with the previously described regimens. The combination of T + A was superior to T monotherapy and the combination of T + D, regarding the prevention of acute and delayed emesis. Both T + A and T + D combinations led to appetite improvement, while patients receiving T + A experienced sedation more frequently. Interestingly, subgroup analysis revealed that patients without underlying stress obtained no further benefit by the addition of A or D, while both T + A and T + D combinations led to a better anti-emetic response in patients with stress. In conclusion, T monotherapy provides a satisfactory result in controlling nausea and emesis caused by a MEC regimen in patients without stress. However, the addition of D and, mainly, A improves its anti-emetic effect in patients with obvious stress. [source] PRECLINICAL STUDY: Different effects of chronic phencyclidine on brain-derived neurotrophic factor in neonatal and adult rat brainsADDICTION BIOLOGY, Issue 2 2006Jun'ichi Semba ABSTRACT The N-methyl-D-aspartate (NMDA) receptor and brain-derived neurotrophic factor (BDNF) are both known to play major roles in the normal development of the brain. We have hypothesized that the chronic blockade of NMDA with phencyclidine (PCP) may have a different effect on BDNF synthesis at different stages of development. In an acute experiment, rat pups and adult rats were injected with PCP (2.5, 5 or 10 mg/kg) at postnatal day (PD) 15 or 49, respectively. In a chronic experiment, rat pups were injected daily from PD 5 to PD 14 with PCP (2.5, 5 or 10 mg/kg), while adult rats were injected daily with the same dose from PD 39 to PD 48. BDNF levels in the hippocampus, striatum and frontal cortex were determined by ELISA assay 24 hours after the last injection. Chronic PCP treatment of neonatal rats induced a dose-dependent decrease in BDNF in the hippocampus but not in the frontal cortex and striatum. Single injection of PCP to rat pups showed a slight reduction of BDNF in the hippocampus but only at higher doses. In contrast to neonatal brain, neither acute nor chronic injection of PCP influenced BDNF in adult brain. These findings suggest that chronic blockade of NMDA receptor in the early neonatal period has an inhibitory effect on BDNF synthesis in the hippocampus and may impair normal neurodevelopment in rat pups. [source] Cocaine increases medial prefrontal cortical glutamate overflow in cocaine-sensitized rats: a time course studyEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2004Jason M. Williams Abstract Excitatory amino acid transmission within mesocorticolimbic brain pathways is thought to play an important role in behavioural sensitization to psychomotor stimulants. The current studies evaluated a time course of the effects of cocaine on extracellular glutamate levels within the medial prefrontal cortex (mPFC) following increasing periods of withdrawal from repeated cocaine exposure. Male Sprague,Dawley rats underwent stereotaxic surgeries and were pretreated daily with saline (1 mL/kg/day × 4 days, i.p.) or cocaine (15 mg/kg/day × 4 days, i.p.) and withdrawn for 1, 7 or 30 days. After withdrawal rats were challenged with the same dose of saline or cocaine and in vivo microdialysis of the mPFC was conducted with concurrent analysis of locomotor activity. Animals that were withdrawn from repeated daily cocaine for 1 day and 7 days displayed an augmentation in cocaine-induced mPFC glutamate levels compared to saline and acute control subjects, which were similarly unaffected by cocaine challenge. At the 7 day time point, a subset of animals that received repeated cocaine did not express behavioural sensitization, nor did these animals exhibit the enhancement in mPFC glutamate in response to cocaine challenge. In contrast to these early effects, 30 days of withdrawal resulted in no significant changes in cocaine-induced mPFC glutamate levels regardless of the pretreatment or behavioural response. These data suggest that repeated cocaine administration transiently increases cocaine-induced glutamate levels in the mPFC during the first week of withdrawal, which may play an important role in the development of behavioural sensitization to cocaine. [source] Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2002Annick Rousseau Abstract Over the last 10 years, proofs of the clinical interest of therapeutic drug monitoring (TDM) of certain anticancer drugs have been established. Numerous studies have shown that TDM is an efficient tool for controlling the toxicity of therapeutic drugs, and a few trials have even demonstrated that it can improve their efficacy. This article critically reviews TDM tools based on pharmacokinetic modelling of anticancer drugs. The administered dose of anticancer drugs is sometimes adjusted individually using either a priori or a posteriori methods. The most frequent clinical application of a priori formulae concerns carboplatin and allows the computation of the first dose based on biometrical and biological data such as weight, age, gender, creatinine clearance and glomerular filtration rate. A posteriori methods use drug plasma concentrations to adjust the subsequent dose(s). Thus, nomograms allowing dose adjustment on the basis of blood concentration are routinely used for 5-fluorouracil given as long continuous infusions. Multilinear regression models have been developed, for example for etoposide, doxorubicin, carboplatin, cyclophosphamide and irinotecan, to predict a single exposure variable [such as area under concentration,time curve (AUC)] from a small number of plasma concentrations obtained at predetermined times after a standard dose. These models can only be applied by using the same dose and schedule as the original study. Bayesian estimation offers more flexibility in blood sampling times and, owing to its precision and to the amount of information provided, is the method of choice for ensuring that a given patient benefits from the desired systemic exposure. Unlike the other a posteriori methods, Bayesian estimation is based on population pharmacokinetic studies and can take into account the effects of different individual factors on the pharmacokinetics of the drug. Bayesian estimators have been used to determine maximum tolerated systemic exposure thresholds (e.g. for topotecan or teniposide) as well as for the routine monitoring of drugs characterized by a very high interindividual pharmacokinetic variability such as methotrexate or carboplatin. The development of these methods has contributed to improving cancer chemotherapy in terms of patient outcome and survival and should be pursued. [source] Induction of an antitumour adaptive immune response elicited by tumour cells expressing de novo B7-1 mainly depends on the anatomical site of their delivery: the dose applied regulates the expansion of the responseIMMUNOLOGY, Issue 4 2003Silvia Sartoris Summary De novo expression of costimulatory molecules in tumours generally increases their immunogenicity, but does not always induce a protective response against the parental tumour. This issue was addressed in the mouse Sp6 hybridoma model, comparing different immunization routes (subcutaneous, intraperitoneal and intravenous) and doses (0·5 × 106 and 5 × 106 cells) of Sp6 cells expressing de novo B7-1 (Sp6/B7). The results can be summarized as follows. First, de novo expression of B7-1 rendered Sp6 immunogenic, as it significantly reduced the tumour incidence to ,15% with all delivery routes and doses tested, whereas wild-type Sp6 was invariably tumorigenic (100% tumour incidence). Second, long-lasting protection against wild-type Sp6 was mainly achieved when immunization with Sp6/B7 was subcutaneous: a dose of 0·5 × 106 Sp6/B7 cells elicited protection that was confined to sites in the same anatomical quarter as the immunizing injection. Repeated injections of the same dose extended protection against wild-type Sp6 to other anatomical districts, as well as a single injection of a 10-fold higher dose (5 × 106 cells). Finally, Sp6-specific cytotoxic T-lymphocyte activity was detected in draining lymph nodes, and the splenic expansion of Sp6-specific cytotoxic T-lymphocyte precursors quantitatively correlated with the dose of antigen. We conclude that activation of a protective immune response against Sp6 depends on the local environment where the immunogenic form of the ,whole tumour cell antigen' is delivered. The antigen dose regulates the anatomical extent of the protective response. [source] Cooperative antitumor effects of vitamin D3 derivatives and rosemary preparations in a mouse model of myeloid leukemiaINTERNATIONAL JOURNAL OF CANCER, Issue 12 2006Hagar Sharabani Abstract 1,,25-dihydroxyvitamin D3 (1,25D3) is a powerful differentiation agent, which has potential for treatment of myeloid leukemias and other types of cancer, but the calcemia produced by pharmacologically active doses precludes the use of this agent in the clinic. We have shown that carnosic acid, the major rosemary polyphenol, enhances the differentiating and antiproliferative effects of low concentrations of 1,25D3 in human myeloid leukemia cell lines (HL60, U937). Here we translated these findings to in vivo conditions using a syngeneic mouse leukemia tumor model. To this end, we first demonstrated that as in HL60 cells, differentiation of WEHI-3B D, murine myelomonocytic leukemia cells induced by 1 nM 1,25D3 or its low-calcemic analog, 1,25-dihydroxy-16-ene-5,6-trans-cholecalciferol (Ro25-4020), can be synergistically potentiated by carnosic acid (10 ,M) or the carnosic acid-rich ethanolic extract of rosemary leaves. This effect was accompanied by cell cycle arrest in G0+G1 phase and a marked inhibition of cell growth. In the in vivo studies, i.p. injections of 2 ,g Ro25-4020 in Balb/c mice bearing WEHI-3B D, tumors produced a significant delay in tumor appearance and reduction in tumor size, without significant toxicity. Another analog, 1,25-dihydroxy-16,23Z-diene-20-epi-26,27-hexafluoro-19-nor-cholecalciferol (Ro26-3884) administered at the same dose was less effective than Ro25-4020 and profoundly toxic. Importantly, combined treatment with 1% dry rosemary extract (mixed with food) and 1 ,g Ro25-4020 resulted in a strong cooperative antitumor effect, without inducing hypercalcemia. These results indicate for the first time that a plant polyphenolic preparation and a vitamin D derivative can cooperate not only in inducing leukemia cell differentiation in vitro, but also in the antileukemic activity in vivo. These data may suggest novel protocols for chemoprevention or differentiation therapy of myeloid leukemia. © 2006 Wiley-Liss, Inc. [source] Isolation and identification of 1,-hydroxy-3-epi-vitamin D3, a potent suppressor of parathyroid hormone secretionJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2005Alex J. Brown Abstract Since our original demonstration of the metabolism of 1,,25(OH)2D3 into 1,,25(OH)2 -3-epi-D3 in human keratinocytes, there have been several reports indicating that epimerization of the 3 hydroxyl group of vitamin D compounds is a common metabolic process. Recent studies reported the metabolism of 25OHD3 and 24(R),25(OH)2D3 into their respective C-3 epimers, indicating that the presence of 1, hydroxyl group is not necessary for the 3-epimerization of vitamin D compounds. To determine whether the presence of a 25 hydroxyl group is required for 3-epimerization of vitamin D compounds, we investigated the metabolism of 1,OHD3, a non-25 hydroxylated vitamin D compound, in rat osteosarcoma cells (ROS 17/2.8). We noted metabolism of 1,OHD3 into a less polar metabolite which was unequivocally identified as 1,OH-3-epi-D3 using the techniques of HPLC, GC/MS, and 1H-NMR analysis. We also identified 1,OH-3-epi-D3 as a circulating metabolite in rats treated with pharmacological concentrations of 1,OHD3. Thus, these results indicated that the presence of a 25 hydroxyl group is not required for 3-epimerization of vitamin D compounds. Furthermore, the results from the same studies also provided evidence to indicate that 1,OH-3-epi-D3, like 1,OHD3, is hydroxylated at C-25. We then evaluated the biological activities of 1,OH-3-epi-D3. Treatment of normal rats every other day for 7 days with 2.5 nmol/kg of 1,OH-3-epi-D3 did not raise serum calcium, while the same dose of 1,OHD3 increased serum calcium by 3.39,±,0.52 mg/dl. Interestingly, in the same rats which received 1,OH-3-epi-D3 we also noted a reduction in circulating PTH levels by 65,±,7%. This ability of 1,OH-3-epi-D3 to suppress PTH levels in normal rats without altering serum calcium was further tested in rats with reduced renal function. The results indicated that the ED50 of 1,OH-3-epi-D3 for suppression of PTH was only slightly higher than that of 1,,25(OH)2D3, but that the threshold dose of the development of hypercalcemia (total serum Ca >,10.5 mg/dl) was nearly 80 times higher. These findings indicate that 1,OH-3-epi-D3 is a highly selective vitamin D analog with tremendous potential for treatment of secondary hyperparathyroidism in chronic renal failure patients. © 2005 Wiley-Liss, Inc. [source] Influence of therapy on the antioxidant status in patients with melanomaJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 2 2008V. Gadjeva DSc Summary Background and objective:, Some anticancer drugs can result in increased production of reactive oxygen species (ROS). Alkylating agents are the most frequently used drugs in chemotherapeutic regimens for the treatment of malignant melanoma. It is known that triazenes exhibit in vivo activity by alkylation of nucleic acids and proteins, but there is no data about ROS formation during oxidative metabolism. Single agents of most interest for treatment of malignant melanomas include 5-(3,3-dimethyltriazene-1-yl)-imidazole-4-carboxamide (DTIC) and nitrosoureas such as 1-(2-chloroethyl) -3-cyclohexyl-1-nitrosourea (CCNU), but complete response to these drugs is rare. The present study aimed to determine whether an oxidative stress occurs during the clinical course of melanoma and the influence of therapy on the antioxidant status of patients with melanoma. For this purpose, we investigated plasma concentrations of MDA as indices of the levels of lipid peroxidation products. In addition, we studied the activities of the antioxidant enzymes superoxide dismutases (SOD) and catalase (CAT) in patients with melanoma before any treatment, after surgical removal of melanoma, and after chemotherapy with DTIC or in combination with CCNU of the operated patients. Methods:, Twenty one patients with melanoma were studied. Patients were operated prior to chemotherapy. After recovery for 10,20 days postoperatively, they were studied again for MDA, SOD and CAT activity. The patients were divided into two groups according to the chemotherapy (3,7 treatment cycles): with DTIC , given orally daily for 5 days, every 3 weeks as a single 2200 mg/kg dose and with the combination , DTIC (the same dose) + CCNU , administered orally at a dosage of 120 mg/m2 once every 40 days in accordance with protocols, approved by the Bulgarian Ministry of Health. The total amount of lipid peroxidation products in plasma was assayed. Results and discussion:, Plasma levels of MDA and CAT activity were significantly higher, and erythrocyte SOD activity significantly lower, in patients with melanoma, than in control healthy volunteers (P < 0·0001). Ten to twenty days after surgery, oxidative stress decreased but levels of MDA increased as a result of therapy. Important sources of increased ROS production may be the monocytes, phagocytosis of tumour cells and the cancer tissues. Plasma MDA in patients treated with DTIC + CCNU were significantly higher (P < 0·001), but erythrocyte SOD statistically lower (P < 0·00001), compared with patients treated with DTIC only. However, a combination of DTIC + CCNU did not attenuate oxidative stress, or reduced antioxidant status. Patients treated with this combination are at bigger risk of oxidative injury. Therefore, this disturbance might be due to augmented generation of toxic ROS, possibly from the metabolism of CCNU. Conclusion:, Increased oxidative stress follows an imbalance in antioxidant defence in non-treated patients with melanoma. The impaired antioxidant system favours accumulation of ROS, which may promote the cancer process. After complete removal of melanoma tissues, oxidative stress decreased. The antioxidant status of melanoma patients operated on was influenced by the different chemotherapeutic regimens used and may play an important role in the response. Patients on DTIC + CCNU are at higher risk of oxidative injury. This drug combination probably exerts its toxic activity by ROS, which could be products of the metabolism of CCNU. [source] Assessing the accuracy of a computerized decision support system for digoxin dosing in primary care: an observational studyJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2005W. L. G. Kroese Drs Summary Background:, This study was carried out as part of a European Union funded project (PharmDIS-e+), to develop and evaluate software aimed at assisting physicians with drug dosing. A drug that causes particular problems with drug dosing in primary care is digoxin because of its narrow therapeutic range and low therapeutic index. Objectives:, To determine (i) accuracy of the PharmDIS-e+ software for predicting serum digoxin levels in patients who are taking this drug regularly; (ii) whether there are statistically significant differences between predicted digoxin levels and those measured by a laboratory and (iii) whether there are differences between doses prescribed by general practitioners and those suggested by the program. Methods:, We needed 45 patients to have 95% Power to reject the null hypothesis that the mean serum digoxin concentration was within 10% of the mean predicted digoxin concentration. Patients were recruited from two general practices and had been taking digoxin for at least 4 months. Exclusion criteria were dementia, low adherence to digoxin and use of other medications known to interact to a clinically important extent with digoxin. Results:, Forty-five patients were recruited. There was a correlation of 0·65 between measured and predicted digoxin concentrations (P < 0·001). The mean difference was 0·12 ,g/L (SD 0·26; 95% CI 0·04, 0·19, P = 0·005). Forty-seven per cent of the patients were prescribed the same dose as recommended by the software, 44% were prescribed a higher dose and 9% a lower dose than recommended. Conclusion:, PharmDIS-e+ software was able to predict serum digoxin levels with acceptable accuracy in most patients. [source] Interindividual variation of serum haloperidol concentrations in Japanese patients , clinical considerations on steady-state serum level,dose ratiosJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 2 2003E. Yukawa Summary Objective:, Marked interpatient variability in haloperidol (HAL) level,dose (L/D) ratios makes it difficult to use the administered dose for predicting serum concentrations. Objective:, To investigate the effect of dose, age, total body weight and co-medication on steady-state HAL L/D ratios. Method:, Retrospective analysis of dose and HAL blood level data from 168 patients. Results:, The HAL L/D ratio decreased curvilinearly with increasing daily dose of HAL. The patients treated with concomitant antiparkinsonian drugs showed a mean HAL L/D ratio that was 24·9% higher than those without antiparkinsonian drugs. The patients treated with concomitant antiepileptic drugs showed a mean HAL L/D ratio that was 27·2% lower than those without antiepileptic drugs. The mean HAL L/D ratio of patients treated with concomitant CYP2D6 substrates was not significantly different from those without CYP2D6 substrates. Conclusion:, There is a wide interindividual variability in blood levels of HAL in patients given the same dose. Routine monitoring of HAL serum level is useful, especially in patients who require associated antiepileptic and/or antiparkinsonian medication. [source] Effect of dexmedetomidine on the characteristics of bupivacaine in a caudal block in pediatricsACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 2 2009I. SAADAWY Background: Dexmedetomidine (DEX) is a highly selective ,2 -adrenoceptor agonist that has been used increasingly in children. However, the effect of caudal DEX has not been evaluated before in children. This prospective randomized double-blinded study was designed to evaluate the analgesic efficacy of caudal DEX with bupivacaine in providing pain relief over a 24-h period. Methods: Sixty children (ASA status I) aged 1,6 years undergoing unilateral inguinal hernia repair/orchidopexy were allocated randomly to two groups (n=30 each). Group B received a caudal injection of bupivacaine 2.5 mg/ml, 1 ml/kg; Group BD received the same dose of bupivacaine mixed with DEX 1 ,g/kg during sevoflurane anesthesia. Processed electroencephalogram (bispectral index score), heart rate, blood pressure, pulse oximetry and end-tidal sevoflurane were recorded every 5 min. The characteristics of emergence, objective pain score, sedation score and quality of sleep were recorded post-operatively. Duration of analgesia and requirement for additional analgesics were noted. Results: The end-tidal sevoflurane concentration and the incidence of agitation were significantly lower in the BD group (P<0.05). The duration of analgesia was significantly longer (P<0.001) and the total consumption of rescue analgesic was significantly lower in Group BD compared with Group B (P<0.01). There was no statistically significant difference in hemodynamics between both groups. However, group BD had better quality of sleep and a prolonged duration of sedation (P<0.05). Conclusion: Caudal DEX seems to be a promising adjunct to provide excellent analgesia without side effects over a 24-h period. It has the advantage of keeping the patients calm for a prolonged time. Implications statement: Caudally administered DEX (1 ,g/kg), combined with bupivacaine, was associated with an extended duration of post-operative pain relief. [source] Comparative bioavailability study in dogs of a self-emulsifying formulation of progesterone presented in a pellet and liquid form compared with an aqueous suspension of progesteroneJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2004Catherine Tuleu Abstract A pellet formulation of progesterone in a self-emulsifying system (SES) was prepared by the process of extrusion/spheronization to provide a good in vitro drug release (100% within 30 min, T50% at 13 min). A three-way randomized crossover study was performed in six fasted male beagle dogs with these pellets and the same SES liquid formulation, both contained in a hard shell capsule, and an aqueous suspension. The same dose of progesterone (16 mg) in pellets and in the SES liquid formulation resulted in similar AUC, Cmax and Tmax values, estimated from progesterone plasma levels by 125I radioimmunoassay. Although the maximum absorption was slightly retarded (0.5 to 1 h) by SES (pellets and liquid), AUC and Cmax were approximately seven and nine times greater then those obtained when an aqueous suspension formulation of the same dose of progesterone was administered to the same dogs. These results showed that it was possible to improve the bioavailability of the poorly soluble, poorly permeable progesterone when administered in SES. Moreover, presenting the progesterone in the form of a pellet did not prevent the release of the drug in vivo. These data demonstrate the utility of extrusion/spheronization in delivering a nonaqueous system in a novel solid dosage form. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1495,1502, 2004 [source] Impact of formulation excipients on human intestinal transitJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2006Julia D. R. Schulze The accelerating effect of polyethylene glycol 400 on small intestinal transit has been previously reported. The aim of this study was to investigate the influence of other solubility-enhancing excipient, propylene glycol, D-,-tocopheryl-polyethylene glycol-1000 succinate (VitE-TPGS) and Capmul MCM, on human intestinal transit. A 5-g dose of each excipient was administered to seven healthy male subjects. Propylene glycol and VitE-TPGS were administered dissolved in 150 mL water. Capmul MCM was administered in the form of four 000 hard gelatin capsules to mask its taste and then given with 150 mL water. On a separate occasion, 150 mL water was administered as the control. Each formulation was radiolabelled with technetium-99 m to follow its transit using a gamma camera. The mean small intestinal transit times were 234, 207, 241 and 209 min for the control, propylene glycol, VitE-TPGS and Capmul MCM treatments, respectively. Although there were differences in the small intestinal transit times for the excipients investigated compared with the control, none of the results were statistically significant. Unlike polyethylene glycol 400 at the same dose of 5g, the excipients tested (propylene glycol, VitE-TPGS and Capmul MCM) had little or no impact on small intestinal transit. [source] Tetanus toxoid-loaded transfersomes for topical immunizationJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2005Prem N. Gupta Topical immunization is a novel immunization strategy by which antigens and adjuvants are applied topically to intact skin to induce potent antibody and cell-mediated responses. Among various approaches for topical immunization, the vesicular approach is gaining wide attention. Proteineous antigen alone or in combination with conventional bioactive carriers could not penetrate through the intact skin. Hence, specially designed, deformable lipid vesicles called transfersomes were used in this study for the non-invasive delivery of tetanus toxoid (TT). Transfersomes were prepared and characterized for shape, size, entrapment efficiency and deformability index. Fluorescence microscopy was used to investigate the mechanism of vesicle penetration through the skin. The immune stimulating activity of these vesicles was studied by measuring the serum anti-tetanus toxoid IgG titre following topical immunization. The immune response was compared with the same dose of alum adsorbed tetanus toxoid (AATT) given intramuscularly, topically administered plain tetanus toxoid solution, and a physical mixture of tetanus toxoid and transfersomes again given topically. The results indicated that the optimal transfersomal formulation had a soya phosphatidylcholine and sodium deoxycholate ratio of 85:15%, w/w. This formulation showed maximum entrapment efficiency (87.34±3.81%) and deformability index (121.5±4.21). An in-vivo study revealed that topically administered tetanus toxoid-loaded transfersomes, after secondary immunization, elicited an immune response (anti-TT-IgG) comparable with that produced by intramuscular AATT. Fluorescence microscopy revealed the penetration of transfersomes through the skin to deliver the antigen to the immunocompetent Langerhans cells. [source] Characterization of Histamine Release Induced by Fluoroquinolone Antibacterial Agents In-vivo and In-vitroJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2000KAZUHIKO MORI Characterization of histamine release induced by fluoroquinolone antibacterial agents, levofloxacin and ciprofloxacin, was investigated in-vivo and in-vitro. Intravenous injection of levofloxacin and ciprofloxacin at 1,10 mg kg,1 produced dose-related elevations in plasma histamine level in anaesthetized dogs. In contrast, levofloxacin was devoid of plasma histamine increment in anaesthetized rats at 100 mg kg,1, whereas ciprofloxacin at the same dose caused endogenous histamine release. Levofloxacin and ciprofloxacin induced non-cytotoxic secretion of histamine from all mast cells tested in a concentration-dependent manner, whereas rat skin and peritoneal mast cells were thirty- to one-hundred-times less sensitive to the effect of fluoroquinolones as compared with the canine skin mast cells. These results suggest that the functional heterogeneity of mast cells from different species in histamine releasing activity of fluoroquinolones may exist, and that mast cells from the dog appear to be particularly sensitive to the effect of the fluoroquinolones. [source] SIAM-Like Phenomenon Caused by Low Doses of AlcoholALCOHOLISM, Issue 2010Akiko Shimamoto Background:, Swift increase in alcohol metabolism (SIAM) is usually evoked by a large dose of ethanol, which is often demonstrated by an abrupt increase in oxygen uptake. SIAM was induced by low doses of ethanol and evaluated by pharmacokinetic analyses of ethanol and its metabolites. Methods:, Rabbits were initially administered 1.0 g/kg of ethanol solution and the same dose was given to the bolus group 6 hours after the first injection. The infusion group was administered 0.25 g/kg/h of ethanol 2 hours after the first injection. Blood concentrations of ethanol, acetaldehyde, and acetate were then determined and comparisons were made using pharmacokinetic parameters. Results:, A significantly higher ethanol elimination rate was observed after re-administration of ethanol to the bolus group. Other pharmacokinetic parameters were unaffected. The concentration at steady state (Css) for the infusion group was stable. A significantly higher level of mean residence time (MRT) in blood acetaldehyde was observed for the bolus group, whereas no MRT changes were observed for the infusion group. A significantly higher level of blood acetate Css was observed after re-administration of ethanol to the bolus group, following the changes in area under concentration and MRT. No Css changes were observed for the infusion group. The Css of acetate at stage 2 was significantly higher for the bolus group, compared to the infusion group. Conclusion:, Low doses of ethanol enhanced alcohol metabolism in rabbits, according to a pharmacokinetic analysis of circulating ethanol concentrations. Simultaneous analyses of its metabolites followed the kinetic of ethanol. [source] Aldehyde Dehydrogenase 2 Gene Targeting Mouse Lacking Enzyme Activity Shows High Acetaldehyde Level in Blood, Brain, and Liver after Ethanol GavagesALCOHOLISM, Issue 11 2005Toyohi Isse Abstract: Background: Previously, we created an aldehyde dehydrogenase 2 gene transgenic (Aldh2,/,) mouse as an aldehyde dehydrogenase (ALDH) 2 inactive human model and demonstrated low alcohol preference. In addition, after a free-choice drinking test, no difference in the acetaldehyde level was observed between the Aldh2,/, and wild type (Aldh2+/+) mice. The actual amounts of free-choice drinking were so low that it is uncertain whether these levels are pharmacologically and/or behaviorally relevant in either strain. To elucidate this uncertainty, we compared the ethanol and acetaldehyde concentration in the blood, brain, and liver between the Aldh2,/, and Aldh2+/+ mice after ethanol gavages at the same dose and time. Method: We measured differences in the ethanol and acetaldehyde levels between the Aldh2,/, and Aldh2+/+ mice by headspace gas chromatography-mass spectrometry (GC-MS) after ethanol gavages at the same dose and time. Results: Significantly higher blood acetaldehyde concentrations were found in the Aldh2,/, mice than in the Aldh2+/+ mice 1 hr after the administration of ethanol gavages at doses of 0.5, 1.0, 2.0, and 5.0 g/kg. The blood acetaldehyde concentrations in the two strains were 2.4 vs. 0.5, 17.8 vs. 1.9, 108.3 vs. 4.3, and 247.2 vs. 14.0 (,M), respectively. In contrast, no significant difference was observed in the blood ethanol concentrations between the Aldh2+/+ and Aldh2,/, mice. The aldehyde dehydrogenase 2 enzyme metabolized 94% of the acetaldehyde produced from the ethanol as calculated from the area under the curve (AUC) of acetaldehyde when ethanol was administered at a dose of 5.0 g/kg. Conclusions: These data indicate that mouse ALDH2 is a major enzyme for acetaldehyde metabolism, and the Aldh2,/, mice have significantly high acetaldehyde levels after ethanol gavages. [source] Pharmacokinetics of total thyroxine in dogs after administration of an oral solution of levothyroxine sodiumJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2008G. LE TRAON Oral l -thyroxine (l -T4) supplementation is used to replace thyroid hormone concentrations in dogs with hypothyroidism. The pharmacokinetics of l -T4 following administration of a solution (Leventa®) was investigated in healthy dogs. l -T4 was absorbed fairly rapidly (tmax 3 h). A mean bioavailability of 22% was calculated following a single oral administration of 40 ,g l -T4/kg body weight. Repeated oral administration at the same dose for 14 consecutive days did not lead to any accumulation of T4 in serum. After intravenous administration of l -T4, a serum half-life of 11.6 h was calculated. Food intake concomitant with l -T4 oral administration delayed l -T4 absorption and decreased its rate and extent by about 45%. The relative bioavailability of l -T4 following administration of a tablet formulation was about 50% of that of the l -T4 solution. The pharmacokinetic properties of liquid l -T4 after oral administration support the use of a dose rate of 20 ,g/kg once daily, as a starting dose for replacement therapy in dogs with hypothyroidism. [source] Efficacy of a short-term ribavirin plus interferon alpha combination therapy followed by interferon alpha alone in previously untreated patients with chronic hepatitis C: a randomized multicenter trialLIVER INTERNATIONAL, Issue 6 2000Thomas Berg Abstract:Background: Combination therapy with interferon alpha (IFN,) plus ribavirin has been shown to improve the sustained response rate in patients with chronic hepatitis C but there is little information regarding the lengths of time for this therapeutic regimen. In this study we therefore tried to evaluate whether the analysis of different virological parameters could provide new clues with respect to the early determination of the efficacy of this form of combination therapy. Furthermore, we also examined whether short-term induction combination therapy followed by IFN, alone is more effective than monotherapy in mounting an initial as well as a sustained virological response. Methods: 185 patients with histologically proven chronic hepatitis C (mean age 42 years (range 19,65 years); 110 males, 75 females) were enrolled in the study. The patients were randomly assigned to receive, over the first 12 weeks, either interferon alpha 2a 6 million units (MU) three times weekly plus ribavirin 14 mg/kg per day (n=93) or the same dose of IFN, alone (n=92). Patients with a virological response (serum HCV RNA undetectable) after 12 weeks were subsequently treated with 3 MU IFN, alone thrice weekly for a further 40 weeks. Otherwise, treatment was discontinued. After the end of treatment, patients were followed up for 24 weeks. Results: Patient characteristics at baseline were not significantly different in the two treatment groups. An initial virological response at week 12 was seen in 61 (66%) patients receiving IFN, plus ribavirin and in 44 (48%) being treated with IFN, alone (p=0.015) and this improvement in the response rate was mainly restricted to HCV genotype 1-infected patients (58% vs. 38%). In contrast, end-of-treatment (week 52) and sustained virological response rates were similar in both groups (37% vs. 29% and 26% vs. 17% [p=0.1], respectively). Interestingly, patients with HCV genotype 3, however, clearly benefited from short-term combination therapy. Thus, sustained virological response rates in these patients significantly increased from 25% (IFN, monotherapy) to 59% (combination therapy) (p=0.05). Conclusions: Short-term combined therapy for 12 weeks is more effective than the monotherapy with respect to the induction of an initial virological response but this effect applies only to genotype 1-infected patients. However, there is no significant difference between both therapeutic schedules with regard to the induction of sustained response. Although HCV genotype 3-infected patients seem to benefit from this short-term combined therapy, prolonged combined therapy may be necessary in HCV genotype 1-infected patients. [source] Two different doses of caudal neostigmine co-administered with levobupivacaine produces analgesia in childrenPEDIATRIC ANESTHESIA, Issue 5 2009KAZIM KARAASLAN MD Summary Background:, This study was aimed to evaluate the analgesic efficacy, duration of analgesia, and side effects of two different doses of caudal neostigmine used with levobupivacaine in children. Methods:, Sixty boys, between 5 months and 5 years, undergoing genito-urinary surgery were allocated randomly to one of three groups (n = 20 each). Group I patients received caudal 0.25% levobupivacaine (1 ml·kg,1) alone. Groups II and III patients received neostigmine (2 and 4 ,g·kg,1 respectively) together with levobupivacaine used in the same dose as Group I. Pain scores were assessed using Children's and Infant's Postoperative Pain Scale (CHIPPS) at 15th (t1) min after arrival to postanesthetic care unit, and 1st (t2), 2nd (t3), 3rd (t4), 4th (t5), 8th (t6), 16th (t7), and 24th (t8) hour postoperatively. Duration of analgesia, amount of additional analgesic (paracetamol), score of motor blockade and complications were recorded for 24 h postoperatively, and compared between groups. Results:, CHIPPS scores were higher during t2, t3, t6, t7 and t8 periods, duration of analgesia was shorter, and total analgesic consumption was higher in Group I compare to neostigmine groups (P < 0.05). Duration of postoperative analgesia and total analgesic consumption were similar in Groups II and III (P > 0.05). Adverse effects were not different between three groups. Conclusions:, Caudal neostigmine in doses of 2 and 4 ,g·kg,1 with levobupivacaine extends the duration of analgesia without increasing the incidence of adverse effects, and 2 ,g·kg,1 seems to be the optimal dose, as higher dose has no further advantages. [source] Effect of an intravenous single dose of ketamine on postoperative pain in tonsillectomy patientsPEDIATRIC ANESTHESIA, Issue 9 2006MARIO JOSE DA CONCEIÇÃO MSC MD TSA Summary Background:, Tonsillectomy has a high incidence of postoperative pain. The aim of the present study was to determine whether the use of low-dose IV ketamine, before the start of surgery or after the end of the operation, would lead to significantly improved pain control after tonsillectomy in pediatric patients. Methods:, Ninety children, 5,7 years old, scheduled for elective tonsillectomy were randomly assigned to one of three groups of 30 patients each; groups I, II and III. Patients in group I received no ketamine. Patients in group II received 0.5 mg·kg,1 of ketamine before the surgical start and for group III the same dose was given after the operation ended. Postoperative pain was scored by the Oucher scale. Systolic and diastolic pressures and heart rate were recorded perioperatively. Unwanted side effects were recorded by the ward staff personnel on a 24-h study-specific questionnaire. Statistical tests consisted of Student's t -test, chi-square and anova as appropriated. Results:, The number of patients complaining of pain was greater in group I compared with patients in groups II and III with a significative statistical difference (P < 0.05). The degree of postoperative pain was significantly higher in patients of group I compared with groups II and III (P < 0.05). Eight patients in group I needed rescue doses of morphine, three for group II and none for group III. In group I, three of eight patients required two doses of morphine during the first 249h postoperatively. No unwanted side effects were noted. Conclusions:, The use of a single small dose of ketamine in a pediatric population undergoing tonsillectomy could reduce the frequency or even avoid the use of rescue analgesia in the postoperative period independent of whether used before or after the surgical procedure. [source] | |||||||||||||||||||||||||||||||||||||