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Purpose: To appraise the incidence of liver toxicity in a population of patients receiving fosamprenavir/ritonavir (FPV/r) with a high frequency of viral hepatitis co-infection., Method: 636 patients, 341 (54%) with HCV antibodies and 38 (5.6%) bearing serum HBsAg, were recruited. All of them received FPV/r 700/100 twice every day. 93 (27%) patients who tested positive for HCV antibodies showed an AST to platelet ratio index (APRI) higher than 1.5, consistent with significant liver fibrosis., Results: After a median (range) follow-up time of 6.91 (0.46-20.66) months, 3 (0.47%) patients developed grade 3 ALT elevation. All the former patients were hepatitis virus co-infected, 2 with hepatitis C virus and 1 with hepatitis B virus. The frequency of grade 3 ALT elevation in patients with HCV antibodies was 0.58% and in those harbouring HBsAg it was 2.63%. 4 (0.62%) patients suffered from a liver decompensation and 1 died due to a hepatic cause while on follow-up. No patients with APRI equal to or higher than 1.5 showed grade 3 ALT elevation., Conclusion: The incidence of adverse hepatic events in patients receiving FPV/r including combinations seems to be low, even in subjects co-infected with hepatitis virus and in those with significant liver fibrosis.

Recent data indicate that fosamprenavir/ritonavir as part of an initial antiretroviral regimen in HIV-1-infected patients is associated with favourable efficacy and tolerability and in the KLEAN study (kaletra versus lexiva with epivir and abacavir in antiretroviral-naive patients) it was found to be non-inferior to lopinavir/ritonavir in association with abacavir/lamivudine. In our open-label, observational study conducted in 82 therapy-nasmall yi, Ukrainianve HIV-1-infected patients followed-up for 18 months, virological and immunological efficacy was comparable in subjects receiving a fosamprenavir/ritonavir-based and a lopinavir/ritonavir-based treatment (proportions of patients with HIV RNA <50 copies/mL at month 18 were 76.9% and 74.4%, respectively, when discontinuations were counted as failures). At the same time, frequency of treatment discontinuations and adverse events were similar in both groups, whereas incidence of diarrhoea and hypertriglyceridaemia was significantly higher in lopinavir-treated patients than in fosamprenavir-treated ones (53.5% vs. 25.6% and 69.8% vs. 43.6%, respectively; P < 0.01). In subjects with virological failure, no viral protease resistance mutations were detected by genotype analysis.

Purpose: Alkylphosphocholines represent a new class of cytostatic drugs with a novel mode of action. Erufosine (ErPC3), the first compound of this class that can be administered intravenously, has recently been shown to be active against human tumor and leukemic cell lines., Methods: In order to evaluate the antileukemic potential of ErPC3 in acute myeloid leukemia (AML) the lethal concentration 50% (LC 50) was determined using WST-1 assay. For analysis of cell death, staining for Annexin V and activated caspase 3 was performed. An interaction analysis was performed by calculation of combination index and construction of isobolograms., Results: The LC 50 was 7.4 microg/ml after 24 h and 3.2 microg/ml after 72 h in HL 60 cells and 30.1 and 8.6 microg/ml, respectively, in 19 fresh samples from patients with AML. ErPC3 was found to be cytotoxic in HL60 cells with distinct activation of caspase 3. ErPC3 was not cross-resistant with cytarabine, idarubicine and etoposide as shown by the linear relation of respective LC 50s. The latter agents, however, exerted an additive cytotoxicity in combination with ErPC3 as revealed by isobologram analysis and combination index, although results are uneven for idarubicine., Conclusion: Based on these data ErPC3 appears as a novel antileukemic candidate drug, which needs to be explored further in the treatment of AML.

A sensitive and specific liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of erucylphosphohomocholine (erufosine, ErPC(3)) in pharmacokinetic studies. Nine-fold deuterated ErPC(3) was used as the internal standard. Following protein precipitation, reversed phase chromatography was performed. For analyte detection, electrospray ionization in the positive mode was applied. The mass transition m/z 504.4>139.1 was recorded for ErPC(3), and the transition m/z 513.7>139.1 for the internal standard, respectively. Good linearity with a correlation coefficient >0.99 was found for the range of 0.48-15 mg/L ErPC(3) in plasma (0.93-29.8 microM), the important range for clinical pharmacokinetic analysis. Interassay coefficients (n=10) of variation between 4.2% and 5.5% were found for ErPC(3) pool samples with concentrations between 4.7 mg/L and 44.0mg/L, respectively. The method has been used for analyses during a phase I clinical trial of ErPC(3).

We investigated the magnitude and distribution of pyrethroid and organophosphate pesticide loadings within public housing dwellings in Boston, Massachusetts and compared the results using various sampling methods. We collected dust matrices from living room and kitchen in 42 apartments and analyzed for eleven pyrethoids (e.g., permethrin and cyfluthrin) and two organophosphates (chlorpyrifos and diazinon) in house dust using GC/MS. Agreement between sampling methods were evaluated using Spearman correlations and Kappa statistics. Permethrin and chlorpyrifos were detected in kitchen floor wipes in all homes, followed in frequency of detects by diazinon (98%), cypermethrin (90%) and cyfluthrin (71%). At least six pesticides were detected in kitchen floor wipes in the majority of the homes (range 3-8). Positive and statistically significant correlations among dust matrices were observed between kitchen floor wipes and living room vacuum dust, including for diazinon (r=0.62) and cyfluthrin (r=0.69). Detection of several pesticides including banned or restricted use products in some public housing units, underscore the need for alternative pest management strategies that embrace the safe and judicious use of pest control products.

Purpose: To compare activity and safety of a regimen containing lopinavir/ritonavir (LPV/r) + fosamprenavir (FPV) to regimens with LPV/r or FPV + r and to test the hypothesis that a ritonavir-enhanced dual protease inhibitor (PI) regimen has better antiviral activity., Method: This study was a multicenter, open-label, randomized study. HIV-infected adults with prior PI failure were selectively randomized based on prior PI experience to either LPV/r, FPV + r, or LPV/r + FPV. All patients received tenofovir DF and 1 to 2 nucleoside reverse transcriptase inhibitors., Results: Baseline characteristics were similar across arms. Study enrollment and follow-up were stopped early (N = 56) because pharmacokinetic analyses showed significantly lower LPV and FPV exposures in the dual-PI arm. At Week 24, proportions achieving >1 log10 decline in HIV RNA or <50 copies/mL in the dual-PI versus single-PI arms combined were 75% vs. 61% in intent-to-treat (ITT, p = .17) and 100% vs. 64% in as-treated (AT) analyses (p = .02), respectively. Median CD4+ T cell/mm3 increases were 81 vs. 41 (ITT, p = .4) and 114 vs. 43 (AT, p = .08), respectively. Clinical events and toxicity rates were not different between arms., Conclusion: The trial was unable to show a difference between dual versus single PIs in ITT analyses but favored dual PIs in AT analyses.

Objective: We searched the influence of dose and timing of atropine therapy in fenthion-induced pancreatitis model., Methods: All rats were intoxicated with fenthion except the control group. Two milligrams of atropine was administered for 24 hours in a high dose atropine group while a low dose atropine group received 100 micrograms of atropine for 24 hours. One group received 2 milligrams of atropine in the first four hours of intoxication while the other group received 2 milligrams of atropine in the last four hours before sacrifice. All rats were sacrificed 24 hours after intoxication. Pseudo-cholinesterase and lipase concentrations and histopathological markers of pancreatitis were studied., Results: None of the models in this study completely prevented pancreatitis, however high dose atropine that is administered for 24 hours or the first four hours after intoxication prevented severe pancreatitis., Conclusion: Atropine administration influence on fenthion-induced pancreatitis should be studied for other organophosphates in animals and humans.

The potency of newly developed monoxime bispyridinium compounds (K156, K203) in reactivating tabun-inhibited acetylcholinesterase and reducing tabun-induced lethal toxic effects was compared with commonly used oximes (obidoxime, trimedoxime, the oxime HI-6) using in vivo methods. Studies determining percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of newly developed oxime K203 is comparable with obidoxime and trimedoxime in blood and higher than the reactivating potency of trimedoxime and obidoxime in diaphragm and brain, where the difference in reactivating efficacy of obidoxime, trimedoxime and K203 is significant. On the other hand, the potency of newly developed K156 to reactivate tabun-inhibited acetylcholinesterase is comparable with obidoxime or trimedoxime in diaphragm and brain. It is significantly lower than the reactivating efficacy of trimedoxime and obidoxime in blood. Moreover, both newly developed oximes were found to be relatively efficacious in the reduction of lethal toxic effects in tabun-poisoned mice. Especially, the oxime K203 is able to decrease the acute toxicity of tabun nearly two times. The therapeutic efficacy of K156 and K203 corresponds to their potency to reactivate tabun-inhibited acetylcholinesterase, especially in diaphragm and brain. In contrast to obidoxime and trimedoxime, the oxime HI-6 is not effective in reactivation of tabun-inhibited acetycholinesterase and in reducing tabun lethality. While the oxime K156 does not improve the reactivating and therapeutic effectiveness of currently available obidoxime and trimedoxime, the newly developed oxime K203 is markedly more effective in reactivation of tabun-inhibited acetylcholinesterase in rats, especially in brain, and in reducing lethal toxic effects of tabun in mice and, therefore, it is suitable for the replacement of commonly used oximes for the antidotal treatment of acute tabun poisoning.

Solid organ transplantation in HIV-infected individuals requires concomitant use of immunosuppressants and antiretrovirals that may cause significant drug interactions. Here we report on a peculiar pharmacokinetic interaction between tacrolimus and protease inhibitors (PIs) which occurred in four HIV-infected liver transplant patients who had to shift PI therapy from nelfinavir to fosamprenavir as a consequence of regulatory restrictions. After the switch, tacrolimus trough blood concentrations significantly dropped in all patients (mean +/- SD 6.9 +/- 2.6 versus 3.2 +/- 2.0 ng/ml before and after the switch, respectively; P=0.01), so that a marked dosage increase was needed (0.29 +/- 0.14 versus 0.88 +/- 0.48 mg/day, 1-3 days before and 3 weeks after the switch, respectively; P=0.046) to attain the desired target (8.7 +/- 2.3 ng/ml). Consistently, marked changes of the concentration/dose ratio of tacrolimus were observed in all cases (27.2 +/- 9.7 ng/ml per mg/kg/day versus 9.7 +/- 4.0 ng/ml per mg/kg/day before and after the switch, respectively; P<0.001). Our findings suggest that fosamprenavir may be less potent than nelfinavir in inhibiting tacrolimus clearance and support the need for higher tacrolimus dosage to avoid insufficient immunosuppression in HIV-infected liver transplant patients when switching from nelfinavir to fosamprenavir or even when directly starting antiretroviral therapy with fosamprenavir.

Fingolimod (FTY720) and its phosphorylated form FTY720P are modulators of sphingosine-1-phosphate (S1P) receptors, which are G-protein coupled receptors linked to cell migration and vascular maturation. The efficacy of FTY720 in autoimmune diseases such as multiple sclerosis and its animal models has been attributed to its inhibition of lymphocyte trafficking to target organs. In this study, we examined the role of S1P receptors in cultured rat oligodendrocytes (OLGs) and OLG progenitor cells (OPCs) using the active phosphorylated form of FTY720. We found that (1) FTY720P improves the survival of neonatal rat OLGs during serum withdrawal, which is associated with the phosphorylation of extracellular signal regulated kinases (ERK1/2) and Akt; (2) FTY720P regulates OPC differentiation into OLGs in a concentration-dependent manner; and (3) S1P receptors are differentially modulated by platelet-derived growth factor (PDGF) resulting in downregulation of S1P5 and upregulation of S1P1 in OPCs. In addition, siRNA studies revealed that S1P1 participates in PDGF-induced OPC mitogenesis. We conclude that S1P1 and S1P5 serve different functions during oligodendroglial development, and possibly during remyelination., ((c) 2007 Wiley-Liss, Inc.)

Polyphenolic resveratrol has been identified as a potent antioxidant acting as both a free radical scavenger and an inhibitor of enzyme oxidative activity. However, the reactive propensity of resveratrol also limits its use in topical formulations. A transient derivative of resveratrol, resveratrol triphosphate, has been designed to provide a means for the delayed delivery of the active compound in skin tissue where endogenous enzymes capable of dephosphorylation reside. Confocal Raman microscopy studies of intact pigskin biopsies treated with modified resveratrol provided information about the spatial distribution and time-dependence of permeation and conversion to the native active form. Conversion to the active form was not observed when skin samples were exposed to steam, a procedure that likely inactivates endogenous skin enzymes. In addition, treatment with the triphosphate compared to the parent compound revealed a more homogeneous distribution of resveratrol throughout the stratum corneum and viable epidermis when the former was applied. Thus, the bioavailability of resveratrol in the epidermis appears to be enhanced upon application of the pro-molecule compared to resveratrol.

Objectives: Use of proton pump inhibitors in HIV-infected patients is common. The purpose of this study was to determine the steady-state pharmacokinetics of once-daily (qd) fosamprenavir/ritonavir (FPV/r) and atazanavir/ritonavir (ATV/r) alone and in combination with 20 mg qd omeprazole (OMP) in healthy volunteers., Design and Methods: A prospective, open-label, single-site, two-period, crossover pharmacokinetic study was carried out in healthy volunteers. Subjects received either qd FPV/r 1400 mg/200 mg or ATV/r 300 mg/100 mg in the morning for 14 days and then 20 mg OMP in the evening for an additional 7 days. The pharmacokinetics were assessed over 24 h on days 14 and 21. Following a 2-week washout, subjects repeated the process with the other regimen. Trough protease inhibitor (PI) concentrations were taken on day 16 of each period to assess the impact of a single dose of OMP on ATV and amprenavir (APV) concentrations. Plasma ATV and APV pharmacokinetic parameters were assessed by noncompartmental analysis; geometric mean ratios (GMRs; PI+OMP/PI; 90% confidence interval) were calculated between days 14 and 21., Results: Nineteen healthy, non-HIV-infected volunteers were evaluated. OMP reduced ATV exposure [area under the concentration curve at 0-24 h (AUC0-24 h)] and the minimum drug concentration (Cmin) by 27% each. In contrast, APV exposure and Cmin were decreased by 4 and 2%, respectively. Four subjects (21%) experienced greater than 50% declines in both ATV AUC0-24 h and Cmin after the addition of OMP; this was not observed in any subject following receipt of FPV/r. No alterations in APV or ATV trough concentrations were observed following a single dose of OMP., Conclusions: The addition of 20 mg OMP administered in the evening has minimal effect on APV pharmacokinetics. In contrast, ATV pharmacokinetics were altered; a number of ATV-treated subjects experienced pronounced declines in exposures upon the addition of 20 mg OMP administered in the evening, whereas others experienced little to no change.

Objectives: The purpose of this study was to evaluate the steady-state pharmacokinetics of amprenavir and ritonavir in HIV-infected patients with different degrees of hepatic impairment., Methods: HIV-positive patients receiving fosamprenavir/ritonavir (700/100 mg twice daily) were included. Patients were classified into three groups: (i) chronic hepatitis; (ii) liver cirrhosis; (iii) normal liver function. Serial blood samples for steady-state amprenavir and ritonavir pharmacokinetics (>14 days on treatment) were collected in the fasting state before the morning dose (C(trough)) and then 1, 2, 3, 4, 6, 8, 10 and 12 h after drug intake. Amprenavir and ritonavir plasma concentrations were determined by HPLC., Results: Twenty-one HIV-infected patients were included. Seven had chronic hepatitis, eight had liver cirrhosis and six patients were in the control group. Amprenavir AUC(0-12), AUC(0-infinity), C(max) and C(ss) were increased by 50% to 60% in the cirrhotic group when compared with controls, whereas CL/F was decreased by 40%. Patients with chronic hepatitis showed a significant increase in AUC(0-12), C(max) and C(ss) values when compared with controls. Ritonavir pharmacokinetics was different only in cirrhotic patients when compared with controls. Liver function parameters at weeks 4, 12 and 24 were not different from baseline in any of the groups. Overall, a significant correlation between amprenavir AUC(0-12) and total bilirubin values on the day of pharmacokinetic analysis was found (r = 0.64, P = 0.003)., Conclusions: On the basis of these data and also of data available in the literature, it seems reasonable to adapt the dose of fosamprenavir and/or ritonavir exclusively in the presence of adverse events, possibly related to protease inhibitors (i.e. liver toxicity), in subjects with high drug plasma levels. Therapeutic drug monitoring is advised in the management of these patients.

Purpose: The purpose of this study was to explore the feasibility of linking the pharmacokinetic profile of a drug with its gastrointestinal behavior by simultaneously monitoring plasma and intraluminal drug concentrations. Fosamprenavir, a phosphate ester prodrug of the poorly water-soluble HIV-inhibitor amprenavir, was selected as model compound., Methods: A single tablet of fosamprenavir (Telzir) was administered to 5 volunteers in the fasted and fed state (simulated by intake of a nutritional drink). Gastric and duodenal fluids were aspirated in function of time and characterized with respect to the concentration of (fos)amprenavir, inorganic phosphate and pH. In parallel, blood samples were collected and analyzed for amprenavir., Results: The observed plasma concentration-time profiles suggested a food-induced delay in the absorption of amprenavir: in the fed state, mean tmax increased by more than 150 min compared to the fasted state. A similar delay was seen in the duodenal appearance of fosamprenavir (concentrations in mM-range) and, after dephosphorylation, amprenavir (concentrations below 160 microM). This observation could be related to the behavior of fosamprenavir in the stomach. In the fasted state, gastric dissolution of fosamprenavir started immediately, resulting in a Cmax of 4 +/- 2 mM after 43 +/- 15 min; however, in the fed state, the fosamprenavir concentration remained below 20 microM for the first 90 min after drug intake. The postponed gastric dissolution may be attributed to a food-induced delay in tablet disintegration., Conclusion: For the first time, the pharmacokinetic profile of a drug was monitored in parallel with its gastrointestinal concentrations. The observed food effect in the plasma concentration-time profile of amprenavir after intake of its phosphate ester prodrug could be related to a food-induced delay in gastric dissolution of fosamprenavir.

The objective of this study is to investigate the functions of parotid and pancreatic glands in response to intoxication with parathion-methyl (PM) and the effects of treatment in rats. Seventy-five male Wistar rats were divided equally into five groups: Group I, control; group II, received atropine and pralidoxime (2-PAM) for 24 h, but no PM; group III, oral PM but no atropine and 2-PAM; group IV, PM and atropine for 24 h and 2-PAM; group V, PM and atropine for 96 h and 2-PAM. After the administration of the chemicals, blood samples were drawn to test for amylase, lipase, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), while pancreatic and parotid glands of each rat were removed for light microscopic examination. Amylase levels were found significantly elevated in groups II, III, IV, and V, whereas lipase levels were supranormal in groups III, IV, and V. The blood levels of AChE were decreased in groups III and IV and BChE were decreased in II, III, IV, and V. No evidence of pancreatitis and parotitis was identified in the histopathologic evaluation in any group in 96 h; however, hyperchromasia, irregularity in nuclei, and binuclear cells were observed in all parotid glands in group V. Parotitis and pancreatitis were not evident; however, hyperamylasemia and hyperlipasemia were found, whereas various histologic changes in parotid glands were documented in the groups that were administered organophosphate and treatment.

Plasma ketoconazole (KETO), amprenavir (APV), and ritonavir (RTV) pharmacokinetics were evaluated in 15 healthy subjects after being treated with KETO at 200 mg once daily (QD), fosamprenavir (FPV)/RTV at 700/100 mg twice daily (BID), and then KETO at 200 mg QD plus FPV/RTV at 700/100 mg BID in this open-label study. The KETO area under the concentration-time curve at steady state was increased 2.69-fold with FPV/RTV. APV exposure was unchanged, and RTV exposure was slightly increased.

DA-7218 (a prodrug of DA-7157), a new oxazolidinone, was hydrolysed via phosphatase to form its active metabolite, DA-7157, in rats. The pharmacokinetic parameters of DA-7218 and DA-7157 were evaluated after intravenous (5, 10 and 20 mg kg(-1)) and oral (20, 50 and 100 mg kg(-1)) administration of DA-7218 to rats. DA-7218 and DA-7157 exhibited dose-proportional pharmacokinetics after both intravenous and oral administration of DA-7218 to rats. The stability of DA-7218 and DA-7157, blood partition of DA-7157, and the plasma protein binding of DA-7157 were also evaluated. DA-7218 was unstable in rat blood, plasma, bile and liver homogenates, but DA-7157 was stable, suggesting that DA-7218 is hydrolysed via phosphatase. DA-7157 rapidly reached equilibrium between plasma and blood cells, and the mean equilibrium plasma-to-blood cells ratio was 3.18, indicating that binding of DA-7157 to blood cells was not considerable. The protein binding of DA-7157 in fresh rat plasma was 93.4%.

Oligodeoxynucleotides containing unmethylated CpG sequences (CpG DNAs) activate the vertebrate innate immune system via toll-like receptor 9 (TLR-9). Although CpG DNA is a promising immunotherapeutic agent, its short circulation time in biological fluids due to nuclease is the major drawback. This paper proposes that a natural polysaccharide called schizophyllan (SPG) can be used as an effective CpG DNA carrier because SPG can complex with CpG DNA and the resultant complex shows the nuclease resistance of the bound DNA. In order to increase cellular uptake in vitro, we chemically attached spermine, cholesterol, arginine octamer, or RGD peptide to SPG. The complexes made of the chemically modified SPG and CpG DNA having a phosphorothioate (PS) or phosphodiester (PO) backbone led to increased secretion of cytokines of about 4- to 15-fold, compared with the uncomplexed dose. Furthermore, when PO CpG DNA was complexed with unmodified SPG, the IL-12 level increased by almost 3- to 11-fold compared with the naked dose. The PO CpG DNA/unmodified SPG complex data suggested that unmodified SPG might effectively deliver PO in vivo due to the electrically neutral nature of unmodified SPG. When the complexed CpG DNAs were injected intraperitoneally, a large amount of IL-12 production was observed compared with the uncomplexed material. Both in vivo and vitro assays indicated that the SPG complex may be of use for CpG DNA therapy.

HAART has decreased the incidence of AIDS and death among HIV-infected individuals dramatically. This approach often becomes cumbersome to patients, involving multiple drugs administered on varying schedules. We investigated the pharmacokinetics, efficacy, and tolerability of a once-daily regimen of fosamprenavir, tenofovir, emtricitabine and ritonavir in HIV-infected treatment-naive subjects. No clinically significant interaction between the drugs was noted, and the regimen showed good efficacy and tolerability over the course of 48 weeks.

The effect of tenofovir disoproxil fumarate (TDF) in combination with two boosted fosamprenavir regimens on amprenavir pharmacokinetic parameters was assessed in this prospective phase I crossover study with 30 healthy volunteers. The co-administration of TDF 300 mg once a day with fosamprenavir/ritonavir 1400/200 mg or 1400/100 mg once a day has no effect on the pharmacokinetics of amprenavir and results in non-significant increases of ritonavir pharmacokinetic parameters, suggesting that no dose modification is necessary when combining fosamprenavir/ritonavir with TDF.

Fosamprenavir is a protease inhibitor (PI) approved for the treatment of HIV-1 infection. Fosamprenavir is a prodrug of amprenavir developed to reduce the pill burden yet maintain the unique resistance pattern and efficacy associated with amprenavir. In a head-to-head, noninferiority trial in antiretroviral treatment-naive HIV-infected patients, the antiviral efficacy and tolerability of ritonavir-boosted fosamprenavir was not inferior to ritonavir-boosted lopinavir, when the PIs were combined with two other nucleoside reverse transcriptase inhibitors. There are fewer studies published about fosamprenavir use in antiretroviral treatment-experienced HIV-infected patients. The high genetic barrier to the development of resistance to fosamprenavir and the low level of cross-resistance between ritonavir-boosted fosamprenavir and other PI regimens are notable. As with amprenavir, gastrointestinal disturbance and rash are the most frequent short-term treatment-limiting events with fosamprenavir. Treatment with ritonavir-boosted fosamprenavir can produce a durable response. To date, fosamprenavir is one of the recommended preferred PI components for the treatment of antiretroviral-naive HIV-infected patients.

The extrapolation from animal data to therapeutic effects in humans, a basic pharmacological issue, is especially critical in studies aimed to estimate the protective efficacy of drugs against nerve agent poisoning. Such efficacy can only be predicted by extrapolation of data from animal studies to humans. In pretreatment therapy against nerve agents, careful dose determination is even more crucial than in antidotal therapy, since excessive doses may lead to adverse effects or performance decrements. The common method of comparing dose per body weight, still used in some studies, may lead to erroneous extrapolation. A different approach is based on the comparison of plasma concentrations at steady state required to obtain a given pharmacodynamic endpoint. In the present study, this approach was applied to predict the prophylactic efficacy of the anticholinergic drug caramiphen in combination with pyridostigmine in man based on animal data. In two species of large animals, dogs and monkeys, similar plasma concentrations of caramiphen (in the range of 60-100 ng/ml) conferred adequate protection against exposure to a lethal-dose of sarin (1.6-1.8 LD(50)). Pharmacokinetic studies at steady state were required to achieve the correlation between caramiphen plasma concentrations and therapeutic effects. Evaluation of total plasma clearance values was instrumental in establishing desirable plasma concentrations and minimizing the number of animals used in the study. Previous data in the literature for plasma levels of caramiphen that do not lead to overt side effects in humans (70-100 ng/ml) enabled extrapolation to expected human protection. The method can be applied to other drugs and other clinical situations, in which human studies are impossible due to ethical considerations. When similar dose response curves are obtained in at least two animal models, the extrapolation to expected therapeutic effects in humans might be considered more reliable.

A 31-year-old female with acute myelocytic leukemia was admitted to our hospital in June 2004. She had complications of brain abscess at the WBC nadir after the second course of induction therapy. However,because the platelet count was low, neurosurgical procedures, including craniotomy/abscess resection, or abscess drainage, were not performed, and we could not detect bacteria or fungus as the cause of brain abscess. Combination therapy with meropenem trihydrate and fosfluconazole was effective. Thereafter, she underwent related peripheral blood stem cell transplantation, and has had no recurrence of brain abscess. Brain abscess during chemotherapy for patients with acute leukemia is commonly due to fungus,particularly Aspergillus, which has a very high fatality rate. Therefore, the treatment of brain abscess without the detection of bacteria and fungus requires combination therapy with antifungal agents and antibiotics. In this case, methionine-positron emission tomography was useful for the evaluation of therapeutic effectiveness for brain abscess.

In this study, named the Zephir study (Telzir-pharmacokinetics), 121 antiretroviral-experienced human immunodeficiency virus (HIV) patients failing on highly active antiretroviral therapy (HAART) were included in a prospective cohort and received a fosamprenavir-ritonavir (700 mg/100 mg twice a day)-based regimen. The impact of baseline HIV type 1 (HIV-1) mutations, pharmacokinetic (PK) parameters, and genotype inhibitory quotient (GIQ) on the virological response at week 12 (W12) was assessed. HIV reverse transcriptase and protease were sequenced at W0. The response at W12 was defined as<2.3 log10 HIV-1 RNA copies/ml or a virus load decrease of>or=1 log10 copies/ml. W4 amprenavir PK were determined by high-performance liquid chromatography. Patients had a median of nine previous treatments over 8 years. Median W0 values were as follows: 295 CD4+/microl, 4.4 log10 HIV-1 RNA copies/ml, and 6 protease- and 5 nucleotide reverse transcription inhibitor-related mutations. Respective values for minimum concentration of drug in serum (Cmin) and area under the concentration-time curve (AUC) from 0 to 24 h were 1,400 ng/ml and 35 mg.h/ml. At W12, 52% of the patients were successes, with a median decrease of -0.7 log10 HIV-1 RNA copies/ml. The Zephir mutation score included 12 IAS protease mutations associated with poorer virological response: L10I/F/R/V, L33F, M36I, M46I/L, I54L/M/T/V, I62V, L63P, A71I/L/V/T, G73A/C/F/T, V82A/F/S/T, I84V, L90M, and polymorphism mutations I13V, L19I, K55R, and L89M. Comparing<4 versus>or=4 mutations, HIV-1 RNA decreases were -2.3 log10 copies/ml versus -0.1 log10 copies/ml (P<10(-4)) with 93% versus 19% successes (P<10(-4)), respectively. This score predicted W12 failure with 94% sensitivity, versus 31% for the ANRS 2005 algorithm. Cmin (<1,600 ng/ml), AUC (<40 mg.h/ml), and GIQ (<300) values were associated with failure (all P values were <10(-4)). The need to test genotype-based algorithms using different patient databases before their implementation in clinical practice is highlighted. Specific mutations, PK and GIQ, provide relevant information for monitoring fosamprenavir-ritonavir-based HAART.

Intermittent or continuous exposure to a wide variety of chemically unrelated environmental pollutants might result in the development of multiple chemical intolerance and increased sensitivity to drugs of abuse. Interestingly, clinical evidence suggests that exposure to organophosphates might be linked to increased ethanol sensitivity and reduced voluntary consumption of ethanol-containing beverages in humans. The growing body of clinical and experimental evidence emerging in this new scientific field that bridges environmental health sciences, toxicology, and drug research calls for well-controlled studies aimed to analyze the nature of the neurobiological interactions of drugs and pollutants. Present study specifically evaluated neurobiological and behavioral responses to ethanol in Wistar rats that were previously exposed to the pesticide organophosphate chlorpyrifos (CPF). In agreement with clinical data, animals pretreated with a single injection of CPF showed long-lasting ethanol avoidance that was not secondary to altered gustatory processing or enhancement of the aversive properties of ethanol. Furthermore, CPF pretreatment increased ethanol-induced sedation without altering blood ethanol levels. An immunocytochemical assay revealed reduced c-fos expression in the Edinger-Westphal nucleus following CPF treatment, a critical brain area that has been implicated in ethanol intake and sedation. We hypothesize that CPF might modulate cellular mechanisms (decreased intracellular cAMP signaling, alpha-7-nicotinic receptors, and/or cerebral acetylcholinesterase inhibition) in neuronal pathways critically involved in neurobiological responses to ethanol.

Purpose: To determine the effect of alkylphosphocholines (APCs) on intraretinal proliferation induced by experimental retinal detachment in the rabbit., Methods: Retinal detachments were created in adult pigmented rabbits. APCs, either liposome bound (liposome, L-APC) or unbound (free, F-APC), were injected intravitreally on either day 1 or day 2 after detachment. BrdU was injected on day 3, 4 hours before death. After fixation, retinas were triple labeled with anti-BrdU, anti-vimentin, and the isolectin B4. The number of anti-BrdU-labeled cells was counted per millimeter of retina from sections imaged by laser scanning confocal microscopy. Toxicity was examined using toluidine blue-stained sections imaged by light microscopy and by electron microscopy for ultrastructural evaluation., Results: Retinal detachment initiated proliferation of all non-neuronal cells. After intravitreal injection on day 1 or 2 after experimental induction of retinal detachment, APCs significantly reduced the number of dividing cells at day 3. Liposome-bound drug given on day 2 was more effective on Müller cell proliferation than was unbound drug. Injection of F-APC on day 1 was more effective than when given on day 2. No apparent effect was seen on Müller cell hypertrophy as indicated by vimentin expression. In addition, no evidence of toxicity was observed in the retina at day 3 for any of the conditions., Conclusions: APCs significantly reduce the number of Müller cells that are stimulated to divide as a result of retinal detachment. The preliminary results indicate no evidence of significant toxicity; however, further studies are needed. APCs have the potential to be used as part of a therapeutic approach if they can be combined with other agents that can suppress the fibrosis that is also a critical event in the pathogenesis of proliferative vitreoretinal diseases such as proliferative vitreoretinopathy (PVR).

Once-daily (QD) fosamprenavir (FPV) at 1,400 mg boosted with low-dose ritonavir (RTV) at 200 mg is effective when it is used in combination regimens for the initial treatment of human immunodeficiency virus infection. Whether a lower RTV boosting dose (i.e., 100 mg QD) could ensure sufficient amprenavir (APV) concentrations with improved safety/tolerability is unknown. This randomized, two 14-day-period, crossover pharmacokinetic study compared the steady-state plasma APV concentrations, safety, and tolerability of FPV at 1,400 mg QD boosted with either 100 mg or 200 mg of RTV QD in 36 healthy volunteers. Geometric least-square (GLS) mean ratios and the associated 90% confidence intervals (CIs) were estimated for plasma APV maximum plasma concentrations (Cmax), the area under the plasma concentration-time curve over the dosing period (AUC0-tau), and trough concentrations (Ctau) during each dosing period. Equivalence between regimens (90% CIs of GLS mean ratios, 0.80 to 1.25) was observed for the plasma APV AUC0-tau (GLS mean ratio, 0.90 [90% CI, 0.84 to 0.96]) and Cmax (0.97 [90% CI, 0.91 to 1.04]). The APV Ctau was 38% lower with RTV at 100 mg QD than with RTV at 200 mg QD (GLS mean ratio, 0.62 [90% CI, 0.55 to 0.69]) but remained sixfold higher than the protein-corrected 50% inhibitory concentration for wild-type virus, with the lowest APV Ctau observed during the 100-mg QD period being nearly threefold higher. The GLS mean APV Ctau was 2.5 times higher than the historical Ctau for unboosted FPV at 1,400 mg twice daily. Fewer clinical adverse drug events and smaller increases in triglyceride levels were observed with the RTV 100-mg QD regimen. Clinical trials evaluating the efficacy and safety of FPV at 1,400 mg QD boosted by RTV at 100 mg QD are now under way with antiretroviral therapy-naïve patients.

The neuroprotective effects of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with tabun at a sublethal dose (180 micro g/kg i.m.; 80% LD(50)) were studied. The tabun-induced neurotoxicity was monitored using a functional observational battery and an automatic measurement of motor activity. The neurotoxicity of tabun was monitored at 24h and 7 days following tabun challenge. The results indicate that all oximes studied in combination with atropine allow all tabun-poisoned rats to survive within 7 days following tabun challenge while two non-treated tabun-poisoned rats died within 2h. Both newly developed oximes combined with atropine seem to be effective antidotes for a decrease in tabun-induced neurotoxicity in the case of sublethal poisoning although they are not able to eliminate tabun-induced neurotoxicity completely. The oxime K075 showed a higher neuroprotective efficacy against tabun than K074 according to the number of eliminated tabun-induced neurotoxic signs at 24h as well as 7 days after tabun challenge. The neuroprotective efficacy of obidoxime in combination with atropine is similar to the potency of newly developed oxime K075 but the ability of the oxime HI-6 to counteract tabun-induced acute neurotoxicity is significantly lower at 24h as well as 7 days after tabun poisoning. Due to their neuroprotective effects, both newly developed oximes (especially K075) appear to be more suitable oximes for the antidotal treatment of acute tabun poisonings than the oxime HI-6.

Background: Amprenavir (APV), fosamprenavir (FPV), lopinavir (LPV), ritonavir (RTV) and efavirenz (EFV) are to varying degrees substrates, inducers and inhibitors of CYP3A4. Coadministration of these drugs might result in complex pharmacokinetic drug-drug interactions., Methods: Two prospective, open-label, non-randomized studies evaluated APV and LPV steady-state pharmacokinetics in HIV-infected patients on APV 750 mg twice daily + LPV/RTV 533/133 mg twice daily with EFV (n=7) or without EFV (n=12) + background nucleosides (Study 1) and after switching FPV 1,400 mg twice daily for APV (n=10) (Study 2)., Results: In Study 1 EFV and non-EFV groups did not differ in APV minimum plasma concentration (Cmin; 1.10 versus 1.06 microg/ml, P = 0.89), area under the concentration-time curve (AUC; 17.46 versus 24.34 microg x h/ml, P = 0.22) or maximum concentration (Cmax; 2.61 versus 4.33 microg/ml, P = 0.08); for LPV there was no difference in Cmin, (median: 3.66 versus 6.18 microg/ml, P = 0.20), AUC (81.84 versus 93.75 microg x h/ml, P = 0.37) or Cmax (10.36 versus 10.93 microg/ml, P = 0.61). In Study 2, after switching from APV to FPV, APV Cmin increased by 58% (0.83 versus 1.30 microg/ml, P = 0.0001), AUC by 76% (19.41 versus 34.24 micorg x h/ml, P = 0.0001), and Cmax by 75% (3.50 versus 6.14, P = 0.001). Compared with historical controls, LPV and RTV pharmacokinetics were not changed. All treatment regimens were well tolerated. Seven of eight completers (88%) maintained HIV-1 RNA <400 copies/ml 12 weeks after the switch (1 lost to follow up)., Conclusions: EFV did not appear to significantly alter APV and LPV pharmacokinetic parameters in HIV-infected patients taking APV 750 mg twice daily + LPV 533/133 mg twice daily. Switching FPV 1400 mg twice daily for APV 750 mg twice daily resulted in an increase in APV Cmin, AUC, and Cmax without changing LPV or RTV pharmacokinetics or overall tolerability.

A cluster of Guillaine-Barre syndrome cases in the Vaalharts region, South Africa prompted an investigation of the impact of aerial organophosphate spraying on cholinesterase levels of residents in the region. A prospective study of cholinesterase levels among residents and workers in the area and a control area was performed. Standardized red blood cell cholinesterase levels amongst participants were monitored before (round 1), during (round 2), and after (round 3) the 1996/1997 aerial spraying season. Participants were assigned environmental exposure categories based on the time since (within 10 or 30 days) and distance from (on farm, on neighboring farm, <10 km from farm) aerial pesticide application. There were 342 participants in round 1, of whom 78% participated in round 2, 62% in round 3, and 56% in all three rounds. There was an increase in cholinesterase levels in round 2 (mean increase = 5.96+/-6.25 IU/g hemoglobin) and then a decrease in round 3 (6.17+/-6.51), significantly associated with environmental exposure (participants living on farm or neighboring farm and <10 km from spraying area) controlling for age, gender, alcohol dependence, and usual and recent domestic and occupational pesticide use (e.g., for round 2-round 1 cholinesterase differences, beta; (exposed group relative to unexposed)=5.72+/-1.21 IU/g hemoglobin, P = 0.000, R2 = 0.27, n = 171). The results show a shift in cholinesterase levels associated with residence in the spraying area, but in the direction opposite to that expected from the spraying of pesticides. Seasonal fluctuations in ambient temperature during the study may have influenced the results.

Background: Lopinavir-ritonavir is a preferred protease inhibitor co-formulation for initial HIV-1 treatment. Fosamprenavir-ritonavir has shown similar efficacy and safety to lopinavir-ritonavir when each is combined with two nucleoside reverse transcriptase inhibitors. We compared the two treatments directly in antiretroviral-naive patients., Methods: This open-label, non-inferiority study included 878 antiretroviral-naive, HIV-1-infected patients randomised to receive either fosamprenavir-ritonavir 700 mg/100 mg twice daily or lopinavir-ritonavir 400 mg/100 mg twice daily, each with the co-formulation of abacavir-lamivudine 600 mg/300 mg once daily. Primary endpoints were proportion of patients achieving HIV-1 RNA less than 400 copies per mL at week 48 and treatment discontinuations because of an adverse event. The intent-to-treat analysis included all patients exposed to at least one dose of randomised study medication. This study is registered with ClinicalTrials.gov, number NCT00085943., Findings: At week 48, non-inferiority of fosamprenavir-ritonavir to lopinavir-ritonavir (95% CI around the treatment difference -4.84 to 7.05) was shown, with 315 of 434 (73%) patients in the fosamprenavir-ritonavir group and 317 of 444 (71%) in the lopinavir-ritonavir group achieving HIV-1 RNA less than 400 copies per mL. Treatment discontinuations due to an adverse event were few and occurred with similar frequency in the two treatment groups (fosamprenavir-ritonavir 53, 12%; lopinavir-ritonavir 43, 10%). Diarrhoea, nausea, and abacavir hypersensitivity were the most frequent drug-related grade 2-4 adverse events. Treatment-emergent drug resistance was rare; no patient had virus that developed reduced susceptibility to fosamprenavir-ritonavir or lopinavir-ritonavir., Interpretation: Fosamprenavir-ritonavir twice daily in treatment-naive patients provides similar antiviral efficacy, safety, tolerability, and emergence of resistance as lopinavir-ritonavir, each in combination with abacavir-lamivudine.

Previous investigations have shown a significant negative two-way drug interaction between fosamprenavir (FPV) and lopinavir/ritonavir (LPV/RTV) in both human immunodeficiency virus (HIV)-infected patients and seronegative volunteers. This randomized, nonblinded, three-way crossover study of HIV-seronegative adult volunteers investigated dose separation and increased doses of RTV as a means to overcome the interaction between FPV and LPV/RTV. Eleven HIV-seronegative volunteers were given FPV plus LPV/RTV at 700 mg plus 400/100 mg every 12 hours (q12h) simultaneously for 10 days and then randomized to receive each of three 7-day treatments in one of six possible sequences, as follows: FPV plus LPV/RTV at 700 mg plus 400 mg/100 mg q12h simultaneously, FPV/RTV at 700 mg/100 mg q12h plus LPV/RTV at 400 mg/100 mg q12h, with doses separated by 4 h, and FPV/RTV at 1,400 mg/200 mg in the morning plus LPV/RTV at 800 mg/200 mg in the evening. Pharmacokinetic sampling was performed on day 8 of each treatment, and samples were analyzed for FPV, amprenavir (APV), LPV, and RTV concentrations by high-performance liquid chromatography-tandem mass spectrometry. Geometric mean ratios (GMR [with 95% confidence intervals]) for the 4- and 12-h dose separation strategies compared to simultaneous administration were calculated for the areas under the concentration-time curves from 0 to 24 h. Compared to simultaneous administration, RTV exposures increased with both 4-h and 12-h dose separation strategies (GMR, 5.30 [3.66 to 7.67] and 4.45 [3.09 to 6.41], respectively). LPV exposures also significantly increased with both 4-h and 12-h dose separation strategies (GMR, 1.76 [1.34 to 2.32] and 1.43 [1.02 to 2.01], respectively). However, both the 4- and 12-h strategies resulted in greater reductions in APV exposure (0.67 [0.54 to 0.83] and 0.77 [0.59 to 0.99], respectively) compared to simultaneous administration. Additional investigations are warranted to determine the optimal dosing of FPV with LPV/RTV.

Objectives: To evaluate the drug interaction between fosamprenavir (FPV) and esomeprazole (ESO) after repeated doses in healthy adults., Methods: Subjects received ESO 20 mg once daily (qd) for 7 days followed by either ESO 20 mg qd + FPV 1400 mg twice daily (bid) or ESO 20 mg qd + FPV 700 mg bid + ritonavir (RTV) 100 mg bid for 14 days in arms 1 and 2, respectively. After a 21- to 28-day washout, subjects received either FPV 1400 mg bid for 14 days (arm 1) or FPV 700 mg bid + RTV 100 mg bid for 14 days (arm 2). Pharmacokinetic sampling was conducted on the last day of each treatment., Results: Simultaneous coadministration of ESO 20 mg qd with either FPV 1400 mg bid or FPV 700 mg bid + RTV 100 mg bid had no effect on steady-state amprenavir pharmacokinetics. The only effect on plasma ESO exposure was a 55% increase in area under the plasma concentration-time curve during a dosing interval, tau[AUC0-tau], after coadministration of ESO 20 mg qd with FPV 1400 mg bid., Conclusions: FPV 1400 mg bid or FPV 700 mg bid + RTV 100 mg bid may be coadministered simultaneously with ESO without dose adjustment. However, the impact of staggered administration of proton pump inhibitors (PPI) on plasma amprenavir exposure is unknown at present.

Background: In the SOLO study (APV30002), once-daily antiretroviral treatment with the protease inhibitor fosamprenavir (FPV) 1,400 mg boosted by ritonavir (r) 200 mg plus abacavir/lamivudine (ABC/3TC) was found to be noninferior to nelfinavir plus ABC/3TC over 48 weeks in treatment-naive patients with HIV -1 infection., Objective: This interim report presents antiviral efficacy and tolerability data from 211 patients who received FPV/r QD for at least 48 weeks in SOLO and continued this treatment in the follow-on study (APV30005) for up to 120 weeks., Methods: APV30005 is an international, multicenter, uncontrolled, open-label, follow-on study conducted to provide continued access to FPV in patients with HIV-1 infection who had participated in previous FPV studies, including SOLO, and to obtain longer-term data on the antiviral response and tolerability of an FPV-containing regimen. Patients who had completed at least 48 weeks of FPV/r therapy in the SOLO study were eligible to enter the follow-on study and continue receiving FPV/r 1,400/200 QD, with study visits every 12 weeks. Their background regimens were chosen at the investigators' discretion and could be changed at any time. Antiviral response end points included plasma HIV-1 RNA levels <400 and <50 copies/mL, median plasma HIV-1 RNA levels, median and absolute changes from baseline in the CD4 cell count, and the frequency of HIV disease progression. Genotype and phenotype analyses were performed for patients meeting the criterion for virologic failure (defined as plasma HIV -1 RNA >1,000 copies/mL on 2 consecutive occasions on or after week 12). Tolerability was assessed in terms of adverse-event reports evaluated by the primary investigator and changes in laboratory values. Assessments were conducted at 12-week intervals during the follow-on study. Data from the baseline visit (day 1 of SOLO) were compared with data from the follow-on study through March 31, 2004, when all patients had completed at least 120 weeks of therapy with FPV/r QD. Because this was a rollover study, no significance testing was performed and all reported results are descriptive., Results: The demographic and baseline characteristics of the patients who received FPV/r QD in this follow on study (N = 211) were similar to those of the 322 patients randomized to receive FPV/r QD in the SOLO study. Their median age was 36 years, 72% were male, 49% were white, and 39% were black. The median baseline plasma HIV 1 RNA level was 4.82 log(10) copies/ mL, and the median baseline CD4+ cell count was 168 cells/mm(3). The median duration of exposure to FPV/r QD from SOLO baseline through the cutoff date was 996 days (142 weeks), ranging from 372 to 1,226 days (53-175 weeks). At week 120, plasma HIV-1 RNA levels <400 and <50 copies/mL were achieved and maintained in 75% (159) and 66% (139) of patients, respectively, when missing data and discontinuations were counted as failures. The median CD4+ cell count at week 120 was 451 cells/mm(3), a median change from baseline of 292 cells/mm(3). In 14 patients with no baseline resistance who met the criterion for virologic failure, no viral protease resistance mutations were detected. Extended treatment was generally well tolerated. The most frequently reported drug-related grade 2-4 adverse events were diarrhea (22 [10%]), nausea (17 [8%]), drug hypersensitivity (14 [7%], all cases attributed to ABC, which was a study drug in SOLO), and increased triglycerides (14 [7%]). The nature of adverse events reported after 48 weeks of therapy was comparable to that reported before week 48. Adverse events occurred at a similar or lower frequency between weeks 48 and 120 compared with before week 48. Similarly, laboratory abnormalities seen by week 120 were comparable to those seen by week 48, although they were less frequent., Conclusions: Extended treatment (120 weeks) with FPV/r QD in these antiretroviral therapy-naive, HIV-1-infected patients was associated with sustained antiviral response and immunologic improvement. Adverse events had generally developed by 48 weeks of therapy and did not occur at a higher frequency through 120 weeks of treatment.

To compare the effect of ritonavir on plasma amprenavir pharmacokinetics, healthy adults received either fosamprenavir (700 mg twice a day [BID]) or amprenavir (600 mg BID) alone and in combination with ritonavir (100 mg BID). Ritonavir increased plasma amprenavir pharmacokinetic parameters to a similar extent when coadministered with either fosamprenavir or amprenavir.

We studied the efficacy and adverse effects of rectal thiamylal in combination with oral triclofos in sedation for pediatric magnetic resonance imaging. Five hundred forty-six children underwent MRI examination from January of 1997 to December of 2001. Among them, 10mg/kg of rectal thiamylal was administrated after oral triclofos in 378 children. Successful sedation was obtained in 321 of 378 patients (85%) after a single rectal administration of thiamylal. Totally, 369 children (98%) could undergo MRI examination completely under successful sedation. Adverse effect was observed only in one patient showing respiratory depression. Rectal thiamylal is effective for sedation for MRI in children. Adverse effect was rare in our patients. Although the risk of side effect was considered to be rare, we should follow principles for the sedation of children.

Azinphos-methyl, phosalone, and phosmet were applied individually to separate rows of trees within a commercial apple orchard in Quebec, Canada, during the 2003 agricultural season. Apples were collected for residue analysis immediately prior to the harvesting of the remaining apples for market distribution and were prepared for analysis as both individual apples and as composites of eight individuals. Analysis of the three applied compounds, as well as five organophosphate insecticides that were not applied, was performed using gas chromatography-mass spectrometry. Azinphos-methyl, phosalone, and phosmet, which were applied, were detected in all samples analyzed at concentrations ranging from 0.004 ng/g to 2260 ng/g. Methidathion was not observed in any sample. Chlorpyrifos, diazinon, dimethoate, and malathion concentrations ranged from below method detection limits to 0.71 ng/g, and the detection frequency for these compounds ranged from 20% to 100%. Residues measured in this study were all below the Canadian maximum residue limit for apples. Variability factors ranged from 2 to 19 for all compounds observed in this study. Composite samples may not accurately reflect the extremes of exposure from consumption of single servings of apples.

Injectable self-curing systems based on PMMA, phosphate-free bioactive glasses and the drug fosfosal, a phosphate derivative of salicylic acid with analgesic and moderate anti-inflammatory properties, have been tested in vivo to evaluate their biocompatibility. The model consisted of the injection of dough of cement into a defect created in the femur of rabbits, and the cure of the cement in situ after implantation. The biological response was studied in the short and long terms by macroscopic, radiological and histopathological examination, and quantitatively by histomorphometric and statistical analysis considering the most representative variables at the bone-cement interface: cement, bone marrow, newly formed bone and connective tissue. All bioactive formulations presented resorption of the cement at the end of the experiment in contrast to the control of PMMA, due to the presence of resorbable components. The presence or absence of the phosphate group added by the drug fosfosal influenced mainly on the new bone formation process. The cement formulated with bioactive glasses and in absence of fosfosal produced the maximum amount of neoformed bone at 2 weeks, and then it resorbed at 4 weeks to give a higher amount of neoformed bone at the end of the experiment, compared with the formulation containing only fosfosal. The presence of fosfosal and bioactive glass together affected the ossification process strongly. The osseous tissue was produced more gradually but it continuously increased giving rise to a more stable bone at the end of the experiment.

Anticholinesterase compounds, organophosphates (OPs) and carbamates (CMs) are commonly used for a variety of purposes in agriculture and in human and veterinary medicine. They exert their toxicity in mammalian system primarily by virtue of acetylcholinesterase (AChE) inhibition at the synapses and neuromuscular junctions, leading into the signs of hypercholinergic preponderance. However, the mechanism(s) involved in brain/muscle damage appear to be linked with alteration in antioxidant and the scavenging system leading to free radical-mediated injury. OPs and CMs cause excessive formation of F2-isoprostanes and F4-neuroprostanes, in vivo biomarkers of lipid peroxidation and generation of reactive oxygen species (ROS), and of citrulline, a marker of NO/NOS and reactive nitrogen species (RNS) generation. In addition, during the course of these excitatory processes and inhibition of AChE, a high rate of ATP consumption, coupled with the inhibition of oxidative phosphorylation, compromise the cell's ability to maintain its energy levels and excessive amounts of ROS and RNS may be generated. Pretreatment with N-methyl D-aspartate (NMDA) receptor antagonist memantine, in combination with atropine sulfate, provides significant protection against inhibition of AChE, increases of ROS/RNS, and depletion of high-energy phosphates induced by DFP/carbofuran. Similar antioxidative effects are observed with a spin trapping agent, phenyl-N-tert-butylnitrone (PBN) or chain breaking antioxidant vitamin E. This review describes the mechanisms involved in anticholinesterase-induced oxidative/nitrosative injury in target organs of OPs/CMs, and protection by various agents.

Most toxicity data are based on studies using single compounds. This study assessed if there is an interaction between mixtures of the anticholinesterase insecticides chlorpyrifos (CHP) and carbaryl (CAR) using hypothermia and cholinesterase (ChE) inhibition as toxicological endpoints. Core temperature (T(c)) was continuously monitored by radiotelemetry in adult Long-Evans rats administered CHP at doses ranging from 0 to 50mg/kg and CAR doses of 0-150 mg/kg. The temperature index (TI), an integration of the change in T(c) over a 12h period, was quantified. Effects of mixtures of CHP and CAR in 2:1 and 1:1 ratios on the TI were examined and the data analyzed using a statistical model designed to assess significant departures from additivity for chemical mixtures. CHP and CAR elicited a marked hypothermia and dose-related decrease in the TI. The TI response to a 2:1 ratio of CHP:CAR was significantly less than that predicted by additivity. The TI response to a 1:1 ratio of CHP and CAR was not significantly different from the predicted additivity. Plasma and brain ChE activity were measured 4h after dosing with CHP, CAR, and mixtures in separate groups of rats. There was a dose-additive interaction for the inhibition of brain ChE for the 2:1 ratio, but an antagonistic effect for the 1:1 ratio. The 2:1 and 1:1 mixtures had an antagonistic interaction on plasma ChE. Overall, the departures from additivity for the physiological (i.e., temperature) and biochemical (i.e., ChE inhibition) endpoints for the 2:1 and 1:1 mixtures studies did not coincide as expected. An interaction between CHP and CAR appears to depend on the ratio of compounds in the mixture as well as the biological endpoint.

A 49-year-old Japanese woman treated with oral corticosteroids, methotrexate, and infliximab for malignant rheumatoid arthritis was admitted because of fever and low back pain. The white blood cell count and C-reactive protein concentration were elevated. Lumbar and pelvic computed tomography showed enlargement of the piriformis muscle including a hypodense area consistent with gas formation. The patient was treated successfully for infectious myositis with intravenous antibiotics.