Post-administration Time Research Articles

Paracetamol induced skin blood flow and blood pressure changes in febrile intensive care patients: An observational study

To determine the relationship between paracetamol administration and skin blood flow (skBF) and blood pressure (BP) in critically ill patients treated for fever. Prospective, observational study. Intensive care units of university teaching hospital. 29 adults (17 males and 12 females), aged 58±15 years treated with enteral or intravenous paracetamol for fever. APACHE II score was 17.2±8.3 and admission classifications were 41% medical (n=12), 31% surgical (n=9), and 28% neurological intervention (n=8). Thirty healthy afebrile volunteers were also studied after ingesting 1g paracetamol. Temperature, BP and skBF (laser Doppler flowmetry perfusion units) were recorded 15 min prior to administration of paracetamol, at administration (T0) and then for every 15 min for 60 min. Cutaneous vascular conductance (CVC=skBF/mean arterial pressure) was calculated. Thirty data sets were recorded from 29 patients. Temperature at T0 was 38.7±0.6°C. BP decreased over the study period whilst skBF and CVC increased (repeated measured ANOVA, p<.05). Systolic BP decreased significantly (p<.01) at all post-administration times and was 90±13% of T0 at 60 min. CVC was 128±48% of T0 at 60 min. Systolic BP fell by a clinically significant amount (≥15%) in 17 patients (59%) and hypotension was treated during 33% (n=10) of the observation periods. BP and skBF did not change significantly in afebrile volunteers. Paracetamol induced increases in skBF consistent with its antipyretic action and may be associated with significant falls in BP in the critically ill.

In vivo priming and ex vivo activation of equine neutrophils in black walnut extract-induced equine laminitis is not attenuated by systemic lidocaine administration

Laminitis is a crippling disease of horses characterized by an inflammatory response in the tissue that suspends the axial skeleton within the hoof. Pain is a common feature of laminitic pathology and its management is an important component of the treatment regime for this disease. Systemic lidocaine administration is commonly utilized to manage pain in equine laminitis; however, the potential anti-inflammatory effects of this drug during the treatment of equine laminitis have not been investigated. Here, we sought to determine if lidocaine concentrations achieved in the plasma (therapeutic concentrations) of horses systemically administered lidocaine are capable of attenuating neutrophil activation and associated inflammation. To identify markers of activation, purified neutrophils were stimulated in vitro with LPS or recombinant equine IL-8 (reqIL-8) and surface expression of CD13 and CD18 was ascertained by immunofluorescent staining. Activation with LPS or reqIL-8 in vitro induced an elevated expression of CD13 as well as a putative conformational change in CD18 detected by elevated staining with a sub-saturating concentration of anti-CD18 mAb. Lidocaine attenuated the activation-induced changes in CD13 and CD18 expression only when used at 30–70 times therapeutic concentrations. For in vivo analyses, horses were administered black walnut extract (BWE) to induce laminitis and either systemic lidocaine ( n = 6) or saline ( n = 6) as a control. Whole blood was collected and incubated with or without reqIL-8. Following which, leukocytes were stained for CD13 and CD18. Protein was extracted from laminar tissue and subjected to gelatin zymography to measure matrix metalloproteinase-9 (MMP-9) accumulation. Results obtained show that changes in neutrophil size, granularity/complexity, CD13 surface expression and CD18 staining intensity occurred over time post BWE administration irrespective of lidocaine treatment in response to incubation alone or with 100 ng/ml of reqIL-8. The mean fluorescence intensities of neutrophils stained for either CD13 or CD18 did not differ between lidocaine treated and saline controls, nor did lamellar MMP-9 content measured by gelatin zymography. Thus, using changes in surface expression of CD13 and CD18 as markers of neutrophil activation in the horse we have shown that BWE treatment activates neutrophils in vivo and this is not affected by systemic administration of lidocaine at levels used to manage pain.

Baculovirus treatment fully protects mice against a lethal challenge of FMDV

Foot-and-mouth disease virus (FMDV) causes a highly contagious and economically devastating disease that affects cattle, swine, goat and sheep among others. FMDV is able to overcome the initial host innate immune response by inhibiting the induction of antiviral molecules at both the transcriptional and the translational levels. It has been demonstrated that FMDV A/Arg/2001 causes the death of adult C57Bl/6 mice within 72h. We evaluated the capacity of Autographa californica nuclear polyhedrosis virus (AcNPV), an insect virus with potent innate immunostimulating effects, to promote early protection against FMDV A/Arg/2001 challenge in C57Bl/6 mice. Groups of 8–9 weeks old female mice were injected intravenously with AcNPV and challenged with a lethal dose of FMDV at different times post-administration. Our results showed that pretreatment of mice with a single injection of AcNPV 3h or 3 days before FMDV challenge resulted in complete abrogation of mortality and complete or partial suppression of viremia, respectively. Furthermore, no signs of disease were observed. AcNPV could be a valuable tool to improve the design of a novel vaccine that protects as an adjuvant at early times post-vaccination.

Abstract 3499: Nanoparticle formulation of SN-38 by the IVECT method results in a safer, more effective treatment for colorectal cancer

Abstract Polymeric micelles represent an emerging class of nano-scale vehicles with unmatched potential for delivering potent, targeted chemotherapy. Intezyne's advanced tri-block copolymer system, the IVECT(TM) Method, has been proven to encapsulate a wide variety of therapeutic and diagnostic agents into a proprietary micelle with unique physiochemical properties. Conventional micelles become destabilized rapidly upon dilution into the bloodstream and release a significant portion of their drug payload systemically, harming healthy tissues and limiting therapeutic effects. Intezyne's IVECT Method utilizes a unique cross-linked stabilizer block that maintains micellar structure for a longer period of time post administration and is designed such that a downshift in pH at the tumor activates drug release by destroying the zinc cross-link, allowing for focused drug exposure. The IVECT Method's unmatched plasma stability allows for longer circulation times while protecting healthy tissues, and it maximizes tumor retention and efficacy through the enhanced permeability and retention (EPR) effect and pH-responsive cross-linker. Intezyne's lead product IT-141 encapsulates the extremely potent active metabolite of irinotecan, SN-38. Recently, IT-141 has demonstrated 14-fold greater plasma exposure and 8-fold greater tumor accumulation vs. irinotecan. This superior pharmacokinetic profile confers 500% greater anti-tumor activity at half the dose (30mg/kg, 3X Q4D, vs. 60mg/kg irinotecan). In xenograft models, IT-141 has demonstrated tumor regression of up to 88%, with 60% of tumors regressing completely. The IVECT copolymer is safe and well tolerated at up to 6 times the therapeutic doses, with no sick mouse syndrome, and can be lyophilized for long-term storage (&amp;gt;1 year). Intezyne is preparing its IND for IT-141. The Company has additional programs in development that focus on delivering best-in-class chemotherapies. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3499.

Estimation of effective half life of clearance of radioactive Iodine ( 131 I) in patients treated for hyperthyroidism and carcinoma thyroid

BackgroundIn medical applications of radioisotopes, for calculations of whole body doses and radiation safety applications, there is a need to estimate radioactive body burden. Local recommendations in Oman stipulate the need for hospitalization of patients treated for radioactive-iodine (131 I) with activities above 400 MBq.Materials & Methods:A study of body burden estimation from sequentially measured exposure rates from patients treated for carcinoma thyroid and hyperthyroidism was undertaken. A digital auto-ranging beta gamma survey instrument calibrated for measurement of exposure rates is used in this study.Results:The mean measured exposure rates at 1 m in μSv/h immediately after administration and at 24 h intervals are used for estimation of effective half time of clearance of administered activity. For patients with post-operative thyroid carcinoma, the variation of body burden with time post-administration indicated tri-exponential clearance pattern, with T½eff values 14.4 h, 22 h, and 41.3 h. For patients treated for thyrotoxicosis, the body burden showed slow delayed clearance with a T½eff – 111.4 h, and exposure rates did not show appreciable fall off after 48 h.

A robotic system for ‐FMISO PET‐guided intratumoral measurements

An image‐guided robotic system was used to measure the oxygen tension in rodent tumor xenografts using interstitial probes guided by tumor hypoxia PET images. Rats with diameter tumors were anesthetized and immobilized in a custom‐fabricated whole‐body mold. Imaging was performed using a dedicated small‐animal PET scanner (R4 or Focus 120 microPET™) after the injection of the hypoxia tracer ‐fluoromisonidazole (‐FMISO). The coordinate systems of the robot and PET were registered based on fiducial markers in the rodent bed visible on the PET images. Guided by the 3D microPET image set, measurements were performed at various locations in the tumor and compared to the corresponding ‐FMISO image intensity at the respective measurement points. Experiments were performed on four tumor‐bearing rats with 4 (86), 3 (80), 7 (162), and 8 (235) measurement tracks (points) for each experiment. The ‐FMISO image intensities were inversely correlated with the measured , with a Pearson coefficient ranging from to for the 22 measurement tracks. The cumulative scatterplots of versus image intensity yielded a hyperbolic relationship, with correlation coefficients of 0.52, 0.48, 0.64, and 0.73, respectively, for the four tumors. In conclusion, PET image‐guided measurement is feasible with this robot system and, more generally, this system will permit point‐by‐point comparison of physiological probe measurements and image voxel values as a means of validating molecularly targeted radiotracers. Although the overall data fitting suggested that ‐FMISO may be an effective hypoxia marker, the use of static ‐FMISO PET postinjection scans to guide radiotherapy might be problematic due to the observed high variation in some individual data pairs from the fitted curve, indicating potential temporal fluctuation of oxygen tension in individual voxels or possible suboptimal imaging time postadministration of hypoxia‐related trapping of ‐FMISO.

Acute high dose of chlorpyrifos alters performance of rats in the elevated plus-maze and the elevated T-maze

Chlorpyrifos (CPF) is a broad spectrum organophosphate (OP) pesticide widely used in agriculture, industry and household. Several animal studies indicate emotional disturbances after CPF exposure, although the results are sometimes puzzling. Thus, both anxiolytic and anxiogenic effects of CPF have been reported in different animal models of anxiety [Sánchez-Amate MC, Flores P, Sánchez-Santed F. Effects of chlorpyrifos in the plus-maze model of anxiety. Behav Pharmacol 2001;12:285–92; Sánchez-Amate MC, Dávila E, Cañadas F, Flores P, Sánchez-Santed F. Chlorpyrifos shares stimulus properties with pentilenetetrazol as evaluated by and operant drug discrimination task. Neurotoxicology 2002;23:795–803; López-Crespo G, Carvajal F, Flores P, Sánchez-Santed F, Sánchez-Amate MC. Time-course of biochemical and behavioural effects of a single high dose of chlorpyrifos. Neurotoxicology 2007;28:541–7]. On the other hand, other behavioural effects of CPF are time-dependent [López-Crespo G, Carvajal F, Flores P, Sánchez-Santed F, Sánchez-Amate MC. Time-course of biochemical and behavioural effects of a single high dose of chlorpyrifos. Neurotoxicology 2007;28:541–7], raising the question that the effects of CPF could be task and post-administration time dependent. To test this hypothesis, three groups of rats were treated with a single high dose of CPF (250 mg/kg); one of the groups was tested on day 5 on the elevated plus-maze, to complete our previous study on day 2 [Sánchez-Amate MC, Flores P, Sánchez-Santed F. Effects of chlorpyrifos in the plus-maze model of anxiety. Behav Pharmacol 2001;12:285–92]. The remaining groups were tested on the elevated T-maze on days 2 and 5. CPF produced an increased open arm activity on the elevated plus-maze on day 5, an increased escape latency on the elevated T-maze on day 2 and an impaired inhibitory avoidance on day 5. Data are discussed taking together all studies carried out in our laboratory, confirming that CPF effects on emotional behaviour are dependent on both task contingencies and post-administration time.

Analytical method for simultaneously measuring ex vivo drug receptor occupancy and dissociation rate: Application to (R)-dimethindene occupancy of central histamine H1 receptors

We introduce a novel experimental method to determine both the extent of ex vivo receptor occupancy of administered compound and its dissociation rate constant (k4). [Here, we reference k4 as the rate of offset of unlabeled ligand in convention with Motulsky and Mahan ()]. We derived a kinetic rate equation based on the dissociation rate constant for an unlabeled compound competing for the same site as a labeled compound and describe a model to simulate fractional occupancy. To validate our model, we performed in vitro kinetics and ex vivo occupancy experiments in rat cortex with varying concentrations of (R)-dimethindene, a sedating antihistamine. Brain tissue was removed at various times post oral administration, and histamine H1 receptor ligand [3H]-doxepin binding to homogenates from drug-treated or vehicle-treated rats was measured at multiple time points at room temperature. Fractional occupancy and k4 for (R)-dimethindene binding to H1 receptors were calculated by using our proposed model. Rats dosed with 30 and 60 mg/kg (R)-dimethindene showed 42% and 67% occupancy of central H1 receptors, respectively. These results were comparable to occupancy data determined by equilibrium radioligand binding. In addition, drug k4 rate determined by using our ex vivo method was equivalent to k4determined by in vitro competition kinetics (dissociation half-life t1/2 ~ 30 min). The outlined method can be used to assess, by simulation and experiment, occupancy for compounds based on dissociation rate constants and contributes to current efforts in drug optimization to profile antagonist efficacy in terms of its kinetic drug-target binding parameters. Data described by the method may be analyzed with commercially available software. Suggested fitting procedures are given in the appendix.

Pilot Study of Targeting Magnetic Carbon Nanotubes to Lymph Nodes

The lymphatic distribution of magnetic carbon nanotubes was studied in vivo and compared with magnetic-activated carbon particles, which were selectively taken up in the lymphatic channels and delivered to the regional lymph nodes. Magnetic multiwalled carbon nanotubes functionalized with poly(acrylic acid) (mMWNTs) and magnetic-activated carbon particles were subcutaneously injected in mice. The draining lymph nodes were harvested at different times postadministration to examine the lymphatic distribution of these particles. The short-term accumulation and toxicity of mMWNTs in the major organs were studied. mMWNTs had the same properties of lymph node mapping as magnetic-activated carbon particles in mice independent of lymph node metastasis. The degree of black staining of lymph nodes and concentration of mMWNTs had a dose-response relationship. Aggregation of magnetic particles was found around the metastatic foci within the lymph nodes. Footpad injection of mMWNTs did not cause any obvious local or systemic toxicities, and no particle agglomerates were found in the major organs. The feasibility of targeting magnetic carbon nanotubes to lymph nodes was demonstrated and the results support further studies for their potential use in diagnosing and treating cancer.

Matrix-Assisted Laser Desorption Ionization Imaging Mass Spectrometry Detection of a Magnetic Resonance Imaging Contrast Agent in Mouse Liver

The present paper describes the detection of a magnetic resonance imaging (MRI) contrast agent by matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS). The contrast agent was analyzed in both frozen and paraformaldehyde-fixed mouse livers explanted after its in vivo administration, and its identity was confirmed by fragmentation experiments. Moreover, a semiquantitative analysis was performed, evaluating its content in livers from mice sacrificed at different postadministration times. To the best of our knowledge, this is the first description of a MALDI-IMS analysis of MRI contrast agents and the first time that results obtained by MALDI-IMS are validated by both an in vivo (MRI) and an ex vivo (inductively coupled plasma atomic emission spectroscopy, ICP-AES) technique. Results shown in the present paper demonstrate the possibility of using MALDI-IMS for drug biodistribution analysis. Obviously, this application is particularly interesting in the case of unlabeled compounds, which cannot be detected by any of the other imaging techniques.

Concentrations of danofloxacin 18% solution in plasma, milk and tissues after subcutaneous injection in dairy cows

Danofloxacin is a fluoroquinolone developed for use in veterinary medicine. Its concentrations and pharmacokinetic profile in plasma, milk and tissues of lactating dairy cows were determined, and its milk withdrawal time (WT) calculated. Twenty-one dairy cows received a single subcutaneous administration of 18% mesylate danofloxacin salt (6 mg kg −1). Plasma and milk samples were obtained at different times until 48 h. Groups of three animals were sacrificed at different post-administration times and tissue samples (mammary gland, uterus, duodenum, jejunum, ileum, colon and mesenteric lymph nodes) obtained. Danofloxacin concentrations were determined by liquid chromatography with fluorescence detection. The milk WT was calculated by the Time to Safe Concentration method (Software WTM 1.4, EMEA). Danofloxacin was rapidly absorbed and its distribution from plasma to all sampled tissues and milk was extensive. Milk and tissues concentrations were several times above those found in plasma. Plasma area under the curve (AUCp) was 9.69 μg h mL −1 and its elimination half life ( T β 1/2 ) was 12.53 h. AUC values for the various tissues and milk greatly exceeded AUCp. T β 1/2 from milk and tissues ranged between 4.57 and 21.91 h and the milk withdrawal time was 73.48 h. The reported results support the potential use of danofloxacin in the treatment of mastitis and other infections in milk cows with 3 days of withdrawal.

Differential motivational properties of ethanol during early ontogeny as a function of dose and postadministration time

While appetitive reinforcement effects of ethanol are easily detected in rat neonates, such phenomena rarely have been observed in older infants. Recently, Molina et al. [Molina, J. C., Ponce L. F., Truxell, E., & Spear N. E. (2006). Infantile sensitivity to ethanol's motivational effects: ethanol reinforcement during the third postnatal week. Alcohol Clin Exp Res 30, 1506–1519] reported such effects of ethanol in 14-day-olds using a second-order conditioning procedure. Infants also appear to be sensitive to biphasic reinforcement or general motivational effects of ethanol, with appetitive effects seeming to occur early in the state of intoxication and aversive effects predominant during late stages, but tests have been inconclusive. The present study examined the possibility of biphasic motivational effects of ethanol during infancy through the use of second-order conditioning procedures. Preweanling rats (14 days old) experienced intraoral water infusions (conditioned stimulus, CS) either 5–20 or 30–45min after administration of 0.5 or 2.0g/kg i.g. ethanol. Pups were then exposed to the CS while over a novel texture (second-order phase). Tests of tactile preference for that texture followed. Locomotive, thermal, hormonal (corticosterone release), and pharmacokinetic patterns likely to underlie the acquisition of ethanol-mediated conditioning were also examined in subsequent experiments. Intraoral CSs paired with either early or late effects of low-dose ethanol (0.5g/kg, blood ethanol concentration: 40mg%) became positive second-order reinforcers. Appetitive effects were also exhibited by pups exposed to the CS during commencement of the toxic episode induced by a 2.0g/kg ethanol dose, 5–20min after administration of ethanol, whereas aversions emerged when CS presentation occurred 30–45min postadministration time (blood ethanol concentrations: 157 and 200mg%, respectively). Overall, the results indicate that infants rapidly detect differential motivational properties of ethanol as a function of dose or drug postadministration time. Relatively neutral stimuli associated with these properties are later capable of acting as either positive or aversive reinforcers. Thermal and motor responses that accompany ethanol intoxication do not seem to be directly associated with differential hedonic properties of the drug at this stage of development.

IN VIVO COMPARISON OF CAT ALVEOLAR AND PULMONARY INTRAVASCULAR MACROPHAGES: PHAGOCYTOSIS, PARTICLE CLEARANCE, AND CYTOPLASMIC MOTILITY

The phagocytic and particle clearance function as well as the intracellular motility of cat pulmonary intravascular macrophages (PIMs) and pulmonary alveolar macrophages (PAMs) in situ were compared using ferrimagnetic γFe2O3 tracer particles and magnetometry. Submicrometric particles were injected intravenously (phagocytized by PIMs) or inhaled as respirable aerosols (phagocytized by PAMs). At various times post administration, the particles were magnetized with an external magnet. Then, the rate of decay of the remanent magnetic field (relaxation) reflecting the motion of particle-containing phagosomes was measured. There was a gradual increase in relaxation in PAMs, but a decrease in PIMs over the initial 7 hours, suggesting differences in rates of phagocytosis. From 7 to 42 days, relaxation parameters were constant in both cell types although faster in PAMs than in PIMs. Disappearance of retained particles in PIMs depended on the administered dose. Particles in PAMs cleared faster than particles in PIMs. Particle clearance from PIMs, but not from PAMs, was accompanied by translocation of particles to the liver and elsewhere. Our data show that PAMs have a slower rate of in vivo phagocytosis, higher cell motility, and faster particle clearance than PIMs.

Pharmacokinetics and bioavailability of doxycycline in ostriches (Struthio camelus) at two different dose rates

A bioavailability and pharmacokinetics study of doxycycline was carried out on 30 healthy ostriches after a single intravenous (IV), intramuscular (IM) and oral dose of 15 mg/kg body weight. The plasma doxycycline concentration was determined by HPLC/UV at 0 (pretreatment), 0.08, 0.25, 0.5 1, 2, 4, 6, 8, 12, 24 and 48 h after administration. The plasma concentration-time curves were examined using non-compartmental methods based on the statistical moment theory for only the higher dose. After IV administration, the elimination half-life (t1/2β), mean residence time (MRT), volume of distribution at the steady-state (Vss), volume of distribution (Vdarea) and total body clearance (ClB) were 7.67 ± 0.62 h, 6.68 ± 0.86 h, 0.86 ± 0.16 l/kg, 1.67 ± 0.52 l/kg and 2.51 ± 0.63 ml/min/kg, respectively. After IM and oral dosing, the mean peak plasma concentrations (Cmax) were 1.34 ± 0.33 and 0.30 ± 0.04 µg/ml, respectively, which were achieved at a post-administration time (tmax) of 0.75 ± 0.18, 3.03 ± 0.48 h, respectively. The t1/2β, Vdarea and ClB after IM administration were 25.02 ± 3.98 h, 23.99 ± 3.4 l/kg and 12.14 ± 1.71 ml/min/kg, respectively and 19.25 ± 2.53 h, 61.49 ± 7 l/kg and 40.19 ± 3.79 ml/min/kg after oral administration, respectively. The absolute bioavailability (F) of doxycycline was 5.03 and 17.52% after oral and IM administration, respectively. These results show that the dose data from other animals particularly mammals cannot be extrapolated to ostriches. Therefore, based on these results along with those reported in the literature, further studies on the pharmacokinetic/pharmacodynamic, in vitro minimum inhibitory concentration values and clinical applications of doxycycline in ostriches are required.

Improvement of Menopausal Signs by Isoflavones Derived from Sophorae fructus in Ovariectomized Female Rats and the Antioxidant Potentials in BV2 Cells

The aim of this study was to determine if the isoflavones from Sophorae fructus (SISO) have potential clinical benefit in hormone replacement therapy (HRT) for the treatment of menopausal signs, such as the levels of total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL) and follicle stimulating hormone (FSH). An additional aim was to present the potential antioxidant effect of SISO in a microglial cell line. For the animal model, the ovaries were removed from adult rats and the indicators of menopause were measured at the pre- and post-administration time points. Although no statistically significant correlation was found, SISO tended to decrease the TC level (p=0.15) and the FSH level (p=0.36), but to increase the HDL level (p=0.303). SISO (< 5 microg/mL) also exerted antioxidant activity on BV-2 microglial cells by inhibiting lipopolysaccharide-induced nitric oxide. This cytoprotective effect was confirmed by trypan blue staining, which was used to test for cellular damage from H2O2. In conclusion, this study highlights the anti-menopausal and antioxidant effect of SISO in an ovariectomized rat model, as well as in microglial cells, and provides new clinical targets for the screening of phytoestrogens as potential candidates for HRT in menopausal women.

Enhancement of Radiation Effect by &lt;i&gt;Aphanamixis polystachya&lt;/i&gt; in Mice Transplanted with Ehrlich Ascites Carcinoma

The effect of radiation on tumor tissue can be optimized by adding radiosensitizing agents, in order to achieve a greater degree of tumor damage than expected from the use of either treatment alone. The ethanolic extract of Aphanamixis polystachya (APE) was tested in Swiss albino mice transplanted with Ehrlich ascites carcinoma (EAC) and exposed to various doses of gamma-radiation. EAC mice received 0, 10, 25, 50, 75, 100, 150 or 200 mg/kg body wt APE before exposure to 6 Gy gamma-radiation followed by once daily administration for another 8 consecutive days post-irradiation. The optimum radiosensitizing dose was found to be 50 mg/kg APE that was further tested in EAC mice exposed to 0, 1, 2, 4, 6 or 8 Gy hemi body gamma-radiation. The best effect of APE and radiation was observed for 6 Gy gamma-radiation. The splitting of 50 mg into two equal fractions of 25 mg and administering the split dose with a gap of 8 h on 1, 3, 5, 7 or 9 d of tumor inoculation resulted in an increased survival even when the drug was administered at late stages (day 5) of tumor development. The APE treatment before irradiation elevated lipid peroxidation followed by a reduction in the glutathione contents. Treatment of tumor bearing mice with APE before irradiation further reduced the activities of various antioxidant enzymes like glutathione peroxidase, glutathione-s-transferase, superoxide dismutase and catalase at different post last drug administration (PLDA) times.

Selective gentamicin uptake by cytochemical subpopulations of guinea-pig geniculate ganglion cells

Cytochemical subpopulations of geniculate ganglion (GG) cells were identified in guinea-pigs using immunohistochemistry and selective gentamicin accumulation. Two subpopulations of GG cells were evident based upon their location and immunoreactivity for peptide 19 (PEP 19), for plasma membrane Ca 2+-ATPase (PMCA-ATPase), and for neurofilament proteins. Cells within the posterior part of GG were positive for PEP 19 and PMCA-ATPase, but not for 68 kD or 160 kD neurofilament proteins. Cells within the anterior part showed complementary staining properties. Cells within these populations showed differences in accumulation of gentamicin, depending upon the administration route. Cells within the posterior part showed avid accumulation of gentamicin when animals received the drug systemically. When the drug was administered directly into the middle ear, cells within the anterior part showed avid gentamicin accumulation. Immunostaining for gentamicin in both cell populations was much more extreme and remained so for longer post-administration times when compared with spiral ganglion and vestibular ganglion cells. The results suggest that cells in the anterior part of GG have little exposure to gentamicin in the serum and that perhaps they innervate the middle ear mucosa or they absorb the drug through their axons within the middle ear. In contrast, cells in the posterior part of GG have greater access to systemically administered gentamicin either directly or via their axon terminals.

Single uptake measurement for absorbed dose planning for radioiodine treatment of hyperthyroidism.

One or several radioiodine uptake measurements are usually made to calculate the activity necessary to give the prescribed absorbed dose to the thyroid of patients treated for hyperthyroidism. If the initial uptake, estimated at time zero, and the effective half-time are to be determined, more than one uptake measurement is needed. The first measurement is often made 24 h after administration of radioiodine. In this work we show that one uptake measurement taken at an appropriate time postadministration is sufficient to determine the product of the initial uptake and the effective half-time, and thus give an estimate of the absorbed dose. A total of 515 patients (14-92 years) who received radioiodine treatment for hyperthyroidism at Malmö University Hospital were analyzed. Individual effective half-times were determined from three uptake measurements, 24 h, 48 h, and a third measurement between 3 and 8 days after the intake of the test activity and were used for the absorbed dose calculations. We found a significant linear relationship between the uptake at 4 days or longer after administration and the product of initial uptake and effective half-time. The relationship was independent on diagnosis, age, and sex of the patient. Therefore a single uptake measurement is sufficient for an accurate absorbed dose determination, provided that the measurement is made at least 4 days after administration.

Adolescent rats discriminate a mild state of ethanol intoxication likely to act as an appetitive unconditioned stimulus

Practically no information is available in relation to the capability of the adolescent animal in terms of discriminating postabsorptive effects of ethanol. Three experiments were conducted to analyze whether young, genetically heterogeneous rats discriminate different stages of the process of intoxication exerted by a low dose (0.5 g/kg) of ethanol. An ethanol pharmacokinetic profile was first examined to select two stages within the process of ethanol intoxication that, as a function of the corresponding blood ethanol concentrations (BECs), could represent two potentially discriminable drug states. In a second experiment, sucrose was available when the BECs of rats peaked or were of a lesser magnitude (5 and 30 min postadministration time, respectively). When animals were tested under similar or different drug states relative to the training procedure, no behavioral evidence indicative of differential sucrose expectancy was obtained. In Experiment 3, rats discriminated each of the previously defined ethanol states from a non-drug state. Unexpectedly, it was also found that the pharmacological effects of the 0.5-g/kg dose of ethanol are likely to support appetitive associative learning that involves the taste of sucrose as a conditioned stimulus. The apparent positive affective components of the state of ethanol intoxication have rarely been observed in genetically heterogeneous rats with rather brief experiences with the drug's effects.

Assessing the Impact of Heat on the Systemic Delivery of Fentanyl Through the Transdermal Fentanyl Delivery System

To examine the effects of locally applied heat on the systemic delivery of fentanyl through the Transdermal Fentanyl Delivery System. Open, 2-period crossover randomized study conducted in the anesthesia department of a university teaching hospital. Six healthy adult volunteers received a fentanyl 25-microg/h patch with and without local heat for 240 minutes followed by administration without heat for an additional 20 hours. Participants then crossed over. Venous blood was drawn at baseline and hourly for 24 hours. Peak plasma concentration (CMax) of fentanyl was measured and the area under the curve (AUC) of the plasma fentanyl concentration versus time post administration graph was evaluated. Difference in CMax and AUC were not statistically significant over the entire 24-hour study period. However, for the 4-hour period of heat application statistically significant differences were seen in both mean CMax (heat, 0.4 ng/mL versus no heat, 0.1 ng/mL (P =.030)) and mean AUC (heat, 40 ng/mL x min versus no heat, 10 ng/mL x min (P =.010)). Local heat can speed the onset of steady state fentanyl concentration in the Fentanyl Transdermal Drug Delivery System thus limiting the delay in onset of analgesia and allowing earlier identification and treatment of side effects.