Optimal Effective Dose Research Articles

Select the optimized effective dose to reduce nuclear radiations in pediatric nuclear medicine.

Many techniques and research models on calculating and reducing the nuclear radiation dose on pediatric nuclear medicine procedure have been developed and reported in recent years. However, most those models either utilized simple shapes to present the organs or used more realistic models to estimate the nuclear dose applied on pediatric patients. The former are too simple to provide accurate estimation results, and the latter are too complicated to intensively involve complex calculations. In this study, a simple but practical model is developed to enable physicians to easily and quickly calculate and select the average optimal effective nuclear dose for the given age and body-size of the pediatric patients. This model is built based on one research result reported by Frederic Fahey, et al and it can be easily implemented in most common pediatric nuclear medicine procedures. This is the first research of using fuzzy inference system to calculate the optimal effective dose applied in the nuclear medicine for pediatric patients.

Analgesic and hypnotic activities of Laghupanchamula: A preclinical study.

Background:In Ayurvedic classics, two types of Laghupanchamula -five plant roots (LP) have been mentioned containing four common plants viz. Kantakari, Brihati, Shalaparni, and Prinshniparni and the fifth plant is either Gokshura (LPG) or Eranda (LPE). LP has been documented to have Shothahara (anti-inflammatory), Shulanashka (analgesic), Jvarahara (antipyretic), and Rasayana (rejuvenator) activities.Aim:To evaluate the acute toxicity (in mice), analgesic and hypnotic activity (in rats) of 50% ethanolic extract of LPG (LPGE) and LPE (LPEE).Materials and Methods:LPEG and LPEE were prepared separately by using 50% ethanol following the standard procedures. A graded dose (250, 500 and 1000 mg/kg) response study for both LPEE and LPGE was carried out for analgesic activity against rat tail flick response which indicated 500 mg/kg as the optimal effective analgesic dose. Hence, 500 mg/kg dose of LPEE and LPGE was used for hot plate test and acetic acid induced writhing model in analgesic activity and for evaluation of hypnotic activity.Results:Both the extracts did not produce any acute toxicity in mice at single oral dose of 2.0 g/kg. Both LPGE and LPEE (250, 500, and 1000 mg/kg) showed dose-dependent elevation in pain threshold and peak analgesic effect at 60 min as evidenced by increased latency period in tail-flick method by 25.1-62.4% and 38.2-79.0% respectively. LPGE and LPEE (500 mg/kg) increased reaction time in hot-plate test at peak 60 min analgesic effect by 63.2 and 85.8% and reduction in the number of acetic acid-induced writhes by 55.9 and 65.8% respectively. Both potentiated pentobarbitone-induced hypnosis as indicated by increased duration of sleep in treated rats.Conclusion:The analgesic and hypnotic effects of LP formulations authenticate their uses in Ayurvedic system of Medicine for painful conditions.

Studies on Laxative Effect of Extract of Dried Fruit Pulp of Cassia fistula

Cassia fistula (CF) is known as Aragvadha (disease killer) in Ayurvedic classics and its sun-dried (SD) fruit pulp has been advocated for the treatment of constipation, fever, leprosy, diabetes, intestinal disorders and wounds. Present study includes the evaluation of SD and non-sun dried (NSD) fruit pulp of CF for purgative action in rat and acute toxicity in mouse. Aqueous suspension of SD and NSD were administered orally 60 min before experiment in rats and SD just before toxicity study in mice. Both SD and NSD in the dose of 1.0 g/kg showed an increase in the number of defecations and fecal output during 4 hour after treatment but stool was semisolid with SD and semisolid and watery with NSD. Both SD and NSD treated rats showed increase in the intestinal intraluminal fluid (ILF) accumulation and motility but the accumulation of ILF was less marked in SD group compared to NSD group. The stimulatory effect of SD on ILF accumulation and intestinal motility could be due to its predominant action on NO formation as only L-NAME a NOS inhibitor blocked both ILF accumulation and intestinal motility per se and in SD-treated rats while atropine (anti-cholinergic), loperamide (μ and k receptor inhibitor) and indomethacin (PGs synthesis blocker) partially blocked them. 10 g/kg oral dose (10 times of optimal effective dose) of SD did not show any acute toxic effect in mice. The result confirms the indigenous use of sun-dried fruit pulp of C. fistula in constipation.

<i>In Silico</i>, <i>In Vitro</i> and <i>In Vivo</i> Assessment of Safety and Anti-inflammatory Activity of Curcumin

Problem statement: Curcumin the active component of turmeric is known for its wide biological actions. Extensive studies on curcumin highlighted its anti-inflammatory, anti-oxidant, anti-microbial, anti-carcinogenic and anti-coagulant activity. The anti-inflammatory activities of curcumin have been demonstrated both in vitro and in vivo. Though curcumin and its anti-inflammatory properties are well documented, the exact mechanism of action and effective in vivo dosage required for potential anti-inflammatory activity of curcumin are yet to be determined. The current work reflects in identfying the the role curcumin in the inflmmatory cascade and arriving at an optimal effective dose (ED50). Approach: The objective of the current study is to understand and establish the role of curcumin in the treatment of inflammatory condition, through in-silico, in-vitro and in-vivo studies. The specificity and binding affinity of curcumin to major inflammatory mediators such as, cytokines/chemokines, signaling proteins and transcription factors were evaluated using molecular docking. Subsequently, in-vitro experiments were conducted to establish the role of curcumin in reducing the release of histamine and β-hexosaminidase form U937 human monocytes cell lines. Further, the Effective Dose (ED50) of curcumin was established for its potent in vivo anti-inflammatory activity. Results: Our study confirmed a strong affinity of curcumin to various inflammatory mediators (ERK, PKC, P38 MAP Kinase, NFkB and Lipoxygenase). Curcumin when studied for its affinity towards chemokines/cytokines and TNF-α was found to be ineffective. Proportionate reduction in histamine and β-hexosaminidase release in U937 cells in vitro and inhibition of paw edema in carrageenan induced inflammation in rats affirmed the dose dependent anti-inflammatory activity of curcumin. This in vivo study elucidated the ED50 value to be 570.6 mg kg-1 body weight for curcumin, which apparently shall be the potent dose to screen its anti-inflammatory activity. Conclusion: Overall results suggest that, curcumin mediates its anti-inflammatory activity by its direct effect on multi-target inflammatory mediators while others were mediated by the downstream effects of curcumin. Curcumin can be a potent molecule in treatment of various diseases associated with inflammation, with its multi-target potency and high safety profile.

Pharmacological evaluation of extracts of Hedychium spicatum (Ham-ex-Smith) rhizome.

Hedychium spicatum (Ham-ex-Smith), known as Shati in Ayurvedic classics, is documented for the treatment of cough, hiccough, fever and asthma. The present study includes the evaluation of aqueous and ethanolic extracts of the dried rhizome of H. spicatum for anti-histaminic and ulcer-protective activities in guinea pig (GP), anti-inflammatory and analgesic activities in rat and acute toxicity in mouse. The extracts were administered orally, daily as suspension, in 1% carboxymethyl cellulose either for 7 days in GP studies or 60 min before or just before experiment in rats and mice. An initial dose-dependent anti-histaminic action of both the extracts (100, 200 and 400 mg/kg) was performed against histamine-induced bronchospasm in GPs. The 200 mg/ kg dose of aqueous and ethanolic extracts was selected both in GP and rat for further studies. GPs treated with aqueous and ethanolic extracts showed gastric ulcer protection against histamine-induced gastric ulcer compared with the control group. Both the extracts also showed an anti-inflammatory effect against carrageenan-induced paw edema in rats from 1 h onwards, and this was maximum at 3 h. Analgesic effect was determined by using hot plate and tail flick tests in rats, and both the extracts at 200 mg/kg showed a significant increase in the latent period from 30 min onwards till 120 min of their study period. Both the extracts did not show any toxic effect like increased motor activity, salivation, clonic convulsion, coma and death in mice even at the 2000 mg/kg dose (nearly 10 times of the optimal effective dose), indicating the safety of the extracts. The result confirms the indigenous use of this plant in respiratory disorders.

Chemoprevention of Colon Cancer in a Rat Carcinogenesis Model Using a Novel Nanotechnology-Based Combined Treatment System

Colorectal cancer (CRC) is the third most common cause of cancer death in the United States, accounting for approximately 51,000 deaths each year. We have previously shown in vitro chemopreventive effects of mixtures of aspirin, folic acid, and calcium (AFAC) on colon cancer cell lines. The objective of the present study was to evaluate the in vivo effects of orally administered, colon targeted chemopreventive combination regimens on the inhibition of aberrant crypt foci (ACF) in a rat model of colon carcinogenesis using (i) unmodified (free drug) combinations of AFAC and (ii) nanoparticle-encapsulated combinations of the same agents. A 14-week animal study was conducted in three phases to determine an optimal effective dose from AFAC combinations and evaluate the efficacy of nanotechnology-based chemopreventive regimens administered in combined (mixtures) and individual (single entity) forms. ACF inhibition when compared with azoxymethane-treated rat control group was significant in both the unmodified and the modified nanoparticle-mediated chemopreventive regimens, showing a range of 31% to 38% (P < 0.05) and 50% to 75% (P < 0.001) reduction, respectively, in the number of ACFs. In addition, the nanoparticulate combination regimens of AFAC showed a 2-fold increase in suppression of ACF compared with free drug mixtures. Individual administration of nanoparticle-encapsulated drugs showed no significant effect on the reduction of ACF. Histochemical analysis provided further confirmation of chemopreventive effects, showing a significant reduction in cell nuclear proliferation. Overall, our results provide a strong proof of concept using nanoparticle-mediated combination treatment in the chemoprevention of colon cancer.

Perfusion CT Assessment of Tissue Hemodynamics Following Hepatic Arterial Infusion of Increasing Doses of Angiotensin II in a Rabbit Liver Tumor Model

To investigate the effects of increasing doses of angiotensin II on hepatic hemodynamics in the normal rabbit liver and in hepatic VX2 tumors by using dynamic contrast material-enhanced perfusion computed tomography (CT). This study was approved by the institutional animal care and use committee. Solitary hepatic VX2 tumors were implanted into 12 rabbits. In each animal, perfusion CT of the liver was performed before (at baseline) and after hepatic arterial infusion of varying doses (0.1-50.0 μg/mL) of angiotensin II. Images were acquired continuously for 80 seconds after the start of the intravenous contrast material administration. Blood flow (BF), blood volume (BV), mean transit time (MTT), and capillary permeability-surface area product were calculated for the tumor and the adjacent and distant normal liver tissue. Generalized linear mixed models were used to estimate the effects of angiotensin II dose on outcome measures. Angiotensin II infusion increased contrast enhancement of the tumor and distal liver vessels. Tumor BF increased in a dose-dependent manner after administration of 0.5-25.0 μg/mL angiotensin II, but only the 2.5 μg/mL dose induced a significant increase in tumor BF compared with BF in the adjacent (68.0 vs 26.3 mL/min/100 g, P < .0001) and distant (68.0 vs 28.3 mL/min/100 g, P = .02) normal liver tissue. Tumor BV varied with angiotensin II dose but was greater than the BV of the adjacent and distant liver tissue at only the 2.5 μg/mL (4.8 vs 3.5 mL/100 g for adjacent liver [P < .0001], 4.8 vs 3.3 mL/100 g for distant liver [P = .0006]) and 10.0 μg/mL (4.9 vs 4.4 mL/100 g for adjacent liver [P = .007], 4.9 vs 4.3 mL/100 g for distant liver [P = .04]) doses. Tumor MTT was significantly shorter than the adjacent liver tissue MTT at angiotensin II doses of 2.5 μg/mL (9.7 vs 15.8 sec, P = .001) and 10.0 μg/mL (5.1 vs 13.2 sec, P = .007) and significantly shorter than the distant liver tissue MTT at 2.5 μg/mL only (9.7 vs 15.3 sec, P = .0006). The capillary permeability-surface area product for the tumor was higher than that for the adjacent liver tissue at the 2.5 μg/mL angiotensin II dose only (11.5 vs 8.1 mL/min/100 g, P = .01). Perfusion CT enables a mechanistic understanding of angiotensin II infusion in the liver and derivation of the optimal effective dose. The 2.5 μg/mL angiotensin II dose increases perfusion in hepatic VX2 tumors versus that in adjacent and distant normal liver tissue primarily by constricting normal distal liver vessels and in turn increasing tumor BF and BV.

Proepithelin Regulates Prostate Cancer Cell Biology by Promoting Cell Growth, Migration, and Anchorage-Independent Growth

The growth factor proepithelin has recently emerged as an important regulator of transformation in several physiological and pathological systems. In this study, we determined the biological roles of proepithelin in prostate cancer cells using purified human recombinant proepithelin as well as proepithelin-depletion strategies. Proepithelin promoted the migration of androgen-dependent and -independent human prostate cancer cells; androgen-independent DU145 cells were the more responsive. In these cells, proepithelin additionally stimulated wound closure, invasion, and promotion of cell growth in vitro. These effects required the activation of both the Akt and mitogen-activated protein kinase pathways. We have analyzed proepithelin expression levels in different available prostate cancer microarray studies using the Oncomine database and found a statistically significant increase in proepithelin mRNA expression levels in prostate cancers compared with nonneoplastic controls. Notably, depletion of endogenous proepithelin by siRNA and antisense strategies impaired the ability of DU145 cells to grow and migrate after serum withdrawal and inhibited anchorage-independent growth. Our results provide the first evidence for a role of proepithelin in stimulating the migration, invasion, proliferation, and anchorage-independent growth of prostate cancer cells. This study supports the hypothesis that proepithelin may play a critical role as an autocrine growth factor in the establishment and initial progression of prostate cancer. Furthermore, proepithelin may prove to be a useful clinical marker for the diagnosis of prostate tumors.

Pain Treatment with Opioids

Appropriate and successful management of pain with opioid analgesics is based on tailoring pharmacologic treatment to the individual and identifying the minimal effective dose at which pain is controlled with minimal adverse effects. Morphine and morphine-like-agonists exhibit similar pharmacodynamic profiles, but substantially different receptor affinities and pharmacokinetic properties, which dictate the dosage, route and regimen required to achieve analgesic effect. Opioids exhibit differences in drug elimination resulting in marked variations in the plasma half-life value. Although fentanyl is more potent than morphine, with a shorter duration of action than parenteral morphine, its oral bioavailability is poor and it is administered transdermally. Morphine, with a short half-life and a time to steady-state plasma concentrations of 10-12 hours is better suited than transdermal fentanyl for initial opioid therapy and for the treatment of unstable pain, which requires a fluctuating opioid dose. International guidelines recommend normal-release morphine for initial optimization of individual dose because its pharmacokinetics allow 'real-time' dose regimen changes and rapid identification of the dose required for pain control. Once an effective normal-release morphine dosage is achieved, other administration routes, formulations and opioids can be considered as required. Despite guidelines advocating that transdermal fentanyl should only be used in patients who are shown to be tolerant to strong opioid therapy, in Italy and other European countries, controlled-release or transdermal opioids are often used when starting opioid therapy. Opioids are associated with a wide range of adverse reactions, but these can be minimized with careful drug titration and maintenance. A major challenge with pain control is polypharmacy and the risk of pharmacokinetic or pharmacodynamic drug-drug interactions. Prevention and management of interactions rely on careful and timely adjustment of drug regimens involved, according to the severity of the effect. Dose titration is the key to successful therapy initiation with strong opioids in patients with moderate-to-severe pain. It is the only way to establish the optimal and minimal effective dose and provides the best protection against adverse effects. Committed physicians should adhere to guidelines on the appropriate use of opioids in all patients, particularly those with a high risk of adverse reactions.

Intravitreal injection of tissue plasminogen activator as treatment for an occluded pars plana glaucoma tube

Implanting glaucoma tubes through the pars plana in the setting of a corneal transplant is becoming more common, and there are unique problems associated with such a procedure. A 42-year-old man with multiple previous eye surgeries presented with a nonfunctioning pars plana glaucoma tube. There was no view to the tube tip, but it was presumed to be clogged with fibrin. Intravitreal tissue plasminogen activator (tPA) was injected through the pars plana which resulted in intraocular pressure control without further surgery. This new application of intravitreal tPA has not been reported previously. Future research should investigate the optimal effective and safe dose of intravitreal tPA injection to relieve such occlusions.

Efficacy of topiramate in bulimia nervosa and binge-eating disorder: a systematic review

Objective The objective of this review was to establish the efficacy of topiramate as treatment for eating disorders associated with obesity. Methods We reviewed all five published controlled clinical trials that tested the efficacy of topiramate in treating bulimia nervosa (BN) or binge-eating disorder (BED). Two trials involving 128 patients studied topiramate efficacy in BN, and three trials (528 patients) studied patients with BED. Data on the number of participants, weeks of follow-up, dropouts, binge frequency and weight were extracted. Results Short-term treatment with topiramate is more effective than treatment with placebo in decreasing binge episodes per week (overall result: topiramate group: −5.0±0.6; placebo group: −3.3±1.2), binge days per week (topiramate group: −3.5±0.6; placebo group: −2.3±0.7) and corporal weight (topiramate group: −4.6±2.3; placebo group: −0.5±0.6) in both BN and BED. The high number of withdrawals and the small sample sizes in four of the five controlled clinical trials limit the generalizability of this result. Conclusion Topiramate is effective in the short-term treatment of eating disorders associated with obesity. Additional studies are needed to prove its efficacy in the long term and to determine the optimal effective dose.

Hépatites virales chroniques chez les patients insuffisants rénaux

Chronic viral hepatitis remains a major problem among patients with chronic renal failure. Hepatitis B and C viruses are frequent among dialysis patients and after renal transplantation and may significantly diminish the survival of both the patient and the graft. Hepatitis B and C viral infection in these patients is often characterized by normal transaminase levels despite viremia and progressive liver lesions. Liver biopsy remains essential for assessing the extent of liver disease. Cirrhosis is a contraindication to transplantation of only a kidney, because of elevated morbidity and mortality. A combined as liver-kidney transplantation may be considered. The best treatment of hepatitis infections is preventive: vaccination against the hepatitis B virus and attentive hygiene, especially to prevent nosocomial transmission. Among patients not awaiting transplant, antiviral treatment should be reserved for patients with active or even fibrotic liver disease. For hemodialysis patients awaiting kidney transplant: Alpha interferon is ineffective and poorly tolerated by dialysis patients. Lamivudine is effective and well tolerated, but its long-term efficacy and its optimal effective dose in dialysis patients remain unknown.

Preliminary studies on the effectiveness of the novel pulicide, spinosad, for the treatment and control of fleas on dogs

Spinosad is a novel mode-of-action insecticide produced from a family of natural products derived from fermentation of the actinomycete, Saccharopolyspora spinosa. Separate studies were undertaken to determine the minimum effective dose of spinosad given orally for the treatment of experimentally induced flea infestations ( Ctenocephalides felis) on dogs, and to assess any potential impacts of feeding canned or dry food at the time of dosing. Both were randomized block (blocked by gender and pre-treatment flea counts), blinded parallel-arm studies, with dogs selected on health and ability to maintain pre-treatment flea populations. For dose selection, 48 dogs were allocated among six groups (8 dogs/group; 4 males, 4 females): placebo-treated negative control, spinosad in gelatin capsules at 15, 20, 30 and 40 mg/kg administered per os; and topical imidacloprid (10 mg/kg) as a positive control. Placebo and spinosad treatments were administered on Days 0, 30 and 60, imidacloprid only on Day 0. In a second study to assess the impact of food type at the time of dosing, three groups were formed: placebo-treated control (8 dogs; 4 males, 4 females), spinosad (30 mg/kg) administered with canned food (8 male dogs, 8 females); and spinosad (30 mg/kg) with dry food (8 males, 8 females). Treatments were administered on Days 0 and 30. To assess post-treatment persistent efficacy, flea infestations were repeated at regular post-treatment intervals, beginning on Day 5 through Day 89 in the dose selection study and Day 58 in the impact of food type and dosing study. Flea counts were performed 48 h post-infestation by study personnel who were blinded to treatments. In the dose selection study, compared to geometric mean live flea counts in the control group, each spinosad dose was highly effective (99.8–100%) at 7, 14 and 21 days after treatment. Only the 30 and 40 mg/kg doses maintained high efficacy (97.2–100%) until 30 days after treatment, with no difference between the two. Imidacloprid was highly effective at Day 30, with significant difference only from the 15 mg/kg spinosad group. Because there was no significant difference between the higher spinosad rates, 30 mg/kg was selected as the optimal minimum effective dose. In the second study, spinosad was highly effective at all post-treatment flea counts (98–100%). Taken together, these studies demonstrate that repeated monthly oral treatments with spinosad at 30 mg/kg provide sustained control of C. felis on dogs. There were no treatment-related adverse events in either study, indicating that spinosad has potential to be used monthly as a safe and effective flea adulticide, providing sustained activity that matches that of currently used topical products.

Flat-Fixed Dosing Versus Body Surface Area–Based Dosing of Anticancer Drugs: There Is a Difference

In a recent review, Mathijssen et al. [1] proposed using flatfixed dosing regimens rather than body surface area (BSA)based dosing for anticancer drugs because “it does not seem worse than using BSA-based dosing” with regard to pharmacokinetic variability. We feel that this statement, together with other recent publications arguing against BSAbased dosing, requires a counterpart. Most cytotoxic drugs have a narrow therapeutic range and are often administered at a dose close to the maximumtolerated dose (MTD) because of the fact that, for many solid tumors and leukemia, increasing systemic exposure often results in higher response rates. In contrast, molecularly targeted cytostatic drugs, like tyrosine kinase inhibitors, should have a greater therapeutic range and an optimal effective dose that can be much lower than the MTD [2]. For classic cytotoxic drugs, every patient should experience the same high systemic exposure close to, but clearly below, the MTD. Systemic exposure can be quantified as the area under the curve (AUC) of the plasma concentration versus time curve. The AUC is determined by the administered dose and the individual clearance of a drug according to the formula:

A double-blind, crossover, randomized dose-comparison trial of granisetron for the prevention of acute and delayed nausea and emesis in children receiving moderately emetogenic carboplatin-based chemotherapy

Granisetron is a safe and effective prophylaxis for nausea and vomiting associated with moderate to highly emetogenic chemotherapy. Few trials have been conducted to determine the optimal effective dose of granisetron in children with cancer. The objective of this report was to compare two doses of granisetron in patients with optic pathway tumors receiving moderately emetogenic doses of carboplatin. In this double-blind, crossover, randomized study, antiemetic efficacy and tolerability of two dose levels (10 and 40 microg/kg) of granisetron in the prevention of acute and delayed nausea/emesis were compared in children and young adults. A total of 18 patients (13 boys) aged 1-23 years (median 7.7 years) treated with a moderately emetogenic dose of carboplatin were randomly assigned to receive either 10 or 40 microg/kg of slow granisetron intravenous (i.v.) infusions at alternating cycles of chemotherapy in a blinded fashion until the end of the study period or until their chemotherapy regimen ended. In this way, the patients acted as their own controls. Patients in the granisetron 10 and 40 microg/kg groups received 104 and 121 cycles of chemotherapy, respectively. There was no significant difference in antiemetic efficacy in terms of nausea and emesis between the dose groups in the first 5 days of chemotherapy. The treatment was well tolerated. We conclude that granisetron 10 and 40 microg/kg have comparable efficacy in controlling carboplatin-induced acute and delayed nausea/emesis and is well tolerated in children and young adults.

1017. Genetic Predisposition of the Sensitivity of Prostate Cancer to Radiatherapy

Top of pageAbstract Ionizing radiation (IR) is the most common modality used to control localized primary prostate cancer (PC). For such patients, recurrence after radiation therapy occurs in approximately 30% to 50% of the cases within 10 years. Failure of radiation therapy in controlling localized PC results from either resistance of certain tumor cells within the tumor to the applied dose, and/or from failure to provide the optimal effective dose of IR to the entire tumor mass. In this respect, a critical problem lies in the lack of specific clinical parameters to accurately predict the treatment outcome. To identify a gene related to radiosensitivity/resistancy of PC, we tested the effect of different doses of IR in vitro (single dose) and in vivo (both single and fractionated doses) of human PC xenografts and cell lines. Next we compared the gene expression profiles of non-irradiated and irradiated sensitive and resistant xenografts on a cDNA microarray. Cluster analysis of data using the super- paramagnetic clustering (SPC) algorithm yielded 6 stable clusters. The clustering analysis divided four out of these six clusters into 2 major subgroups: IR-resistant and IR-sensitive phenotypes. The four clusters consist of 188 probsets (including 12 ESTs) that showed more than 3 fold change in transcription. Of those, 98 (6 ESTs) displayed elevated expression, and 90 (6 ESTs) decreased expression in the radioresistant xenografts relative to the radiosensitive xenografts. Notably, similar analysis of cultured cell lines in unsupervised fashion yielded significantly identical patterns of gene expression as was obtained for the xenografts described above. Real Time PCR analysis of representative validated the gene array data. Interestingly, none of the analyzed genes demonstrates significant change in its expression level between non-irradiated and irradiated pair (derived a few months following IR). These data support a model in which the xenografts tested represent a homogeneous cell population in their response to the random effect of IR. Amongst the genes whose expression markedly differentiate between the IR resistant and sensitive phenotypes, several are related to growth and apoptosis. Further studies are being carried out to verify the involvement of some of these genes in the response to IR.

Hepatitis B virus infection in dialysis patients

Hepatitis B virus (HBV) infection remains a major issue among dialysis patients. It is associated with a high risk of hepatic complication. The liver disease runs a unique clinical course in dialysis patients, as it can progress with modest hepatic inflammation and prominent fibrosis. The conventional cut-off level of serum alanine aminotransferase (ALT) for commencing antiviral therapy may prove too high and inappropriate for dialysis patients, and liver biopsy appears to be the only definitive means to establish the activity of liver disease in dialysis patients. Liver biopsy should be considered in patients with a serum ALT level that is persistently greater than 30 IU/L, or 0.75-fold the upper limit of the normal level, and/or other clinical and laboratory findings that suggest active liver disease. For antiviral treatment, preliminary reports have shown that lamivudine is effective and well tolerated in dialysis patients. However, the long-term efficacy of lamivudine and its optimal effective dose in dialysis patients remain unknown. The prevention of nosocomial transmission among dialysis patients is also important. Universal precaution measures should be strictly observed and the segregation of hepatitis B surface antigen-positive hemodialysis patients should be considered. For HBV non-immune patients, the importance of HBV vaccination should not be overemphasized. Until a new generation of highly immunogenic vaccines that are proven to be safe and effective in patients with end-stage renal disease becomes available, early vaccination before the development of end-stage renal failure remains the best way to secure immunological protection against HBV infection in dialysis patients.

Colchicine treatment in children with familial Mediterranean fever

Prophylactic colchicine therapy has been shown to be a safe and effective method of eliminating the attacks and preventing the development of amyloidosis in patients with familial Mediterranean fever (FMF). However, information about effective dosages that control FMF attacks and prevent amyloidosis in childhood is not available. The aim of this study is to determine the 'effective colchicine dose' for children in terms of body weight and surface area. Sixty-two (34 male, 28 female) children with FMF were selected and colchicine treatment was initiated by giving 0.5-1 mg/day to each patient. The dose was gradually increased up to a maximum 2 mg/day in unresponsive patients; mean duration of therapy was 45.6 +/- 35.5 months. When the 'optimal effective dosage' (i.e. the one that reduced the frequency of attacks and ESR, CRP and fibrinogen levels during the attack-free period) was achieved, the optimal effective dose was calculated according to the body weight and body surface area for each patient. Based on these values 'mean colchicine dose' was computed for the study group and values for different age groups were evaluated. Mean colchicine doses according to the body weight and surface area of the whole group were found to be 0.03 +/- 0.02 mg/kg/day and 1.16 +/- 0.45 mg/m(2)/day, respectively. It was shown that children less than 5 years of age might need colchicine doses as high as 0.07 mg/kg/day or 1.9 mg/m(2)/day. These dosages are approximately 2.5-3 times more than the 'mean colchicine dose' for children aged 16-20 years. These results clearly show that small children need higher doses of colchicine in order to control their attacks. Thus, we conclude that colchicine, when given according to body weight or body surface area, would be more effective in childhood.

Therapeutic margin of budesonide in patients with mild to severe asthma

Background: The therapeutic margin of a drug is the difference between the optimal effective dose and the dose at which unacceptable adverse effects occur. This margin is particularly important in the case of therapies that are used long term for the control of chronic illnesses, such as inhaled corticosteroids (ICSs) in the treatment of asthma. Because data from controlled clinical studies indicate that the available ICSs have similar clinical efficacy, the safety profile is central to differentiating between them on the basis of their therapeutic margins. The main safety concern with long-term use and high doses of ICSs is systemic exposure that could result in such unwanted effects as cortisol suppression, a reduction in the final adult height of pediatric patients, and decreased bone mineral density. Objective: This article reviews data from clinical trials, including long-term prospective studies, to compare the therapeutic margin of budesonide with those of other second-generation ICSs and to determine whether there are variations in the therapeutic margin with different delivery devices, severities of disease, or patient age. Results: Based on the tolerability data for budesonide from short-term (6–12 wk) and long-term (1–9 y) studies in patients with mild to moderate persistent asthma, the dose-response and dose-tolerability curves for budesonide delivered by dry-powder inhaler can be plotted in parallel. The margin between these curves—the therapeutic margin—is favorable and consistent in pediatric and adult patients and at all degrees of asthma severity. Fewer tolerability data are available for other ICSS. Conclusion: Whereas budesonide has clinical efficacy similar to that of other currently available ICSs, it has a good safety profile—and hence a favorable therapeutic margin—that is supported by long-term clinical data. Budesonides favorable therapeutic margin is probably a result of its pharmacokinetic and physical properties.

Modifications of the hemodynamic consequences of theophylline intoxication with landiolol in halothane-anesthetized dogs.

To examine the effect of landiolol (ONO-1101), a new ultra-short acting, highly selective beta1 blocker, on hemodynamic response to acute theophylline intoxication in anesthetized dogs. Thirty-four dogs were studied during halothane anesthesia. Aminophylline (50 mg x kg(-1) over 20 min followed by infusion at 1.75 mg x kg(-1) x hr(-1)) was administered as a model of acute theophylline intoxication. Dogs were randomly enrolled into four landiolol groups (0, 1, 10, 100 microg x kg(-1) x min(-1)) to treat tachyarrhythmias. Hemodynamic variables, heart rate (HR), systemic blood pressure (SBP), pulmonary artery pressure, pulmonary artery occlusion pressure, and cardiac output (CO) were measured along with plasma concentrations of theophylline, epinephrine, and norepinephrine. After 60 min, plasma concentration of theophylline reached 46.6+/-4.0 (mean +/- SD) microg x ml(-1), HR increased from 129+/-21 to 193+/-27 bpm (P<0.0001) and CO increased from 1.6+/-0.5 l x min(-1) to 2.1+/-0.4 l x min(-1) (P<0.0001), whereas SBP decreased from 139+/-25 to 121+/-25 mm Hg (P<0.0001), with decreasing systemic vascular resistance. After intoxication, plasma epinephrine concentration increased from 125 +/-112 to 325+/-239 pg x ml(-1) (P<0.0001), and norepinephrine concentration from 103+/-61 to 133+/-61 pg x ml(-1) (P<0.0011). Landiolol 10 microg x kg(-1) x min(-1) decreased HR to pre-intoxication level, whereas HR returned to the intoxication baseline by 30 min after cessation of landiolol infusion. Landiolol controlled tachyarrhythmias associated with theophylline toxicity. The optimal effective dose of landiolol was 10 microg x kg(-1) x min(-1).