bluuebunny/crossref_metadata_2025 huggingface dataset:
The short‐term effects of carcinogens and sulphur dioxide on the nuclear size of rat nasal epithelial cells
Authors: Fowlie A. J. , Grasso P. , Benford D. J.
Published: October 2006

Enlarged nuclei have been observed frequently as an early carcinogen‐induced change in both cultured cells and in target tissues in vivo. The purpose of this work was to examine the occurrence of nuclear enlargement in the upper respiratory tract of rats to provide further evidence of whether nuclear enlargement is a reliable marker of carcinogenesis, and if it could be used as a short‐term test for respiratory carcinogens.

Carcinogen‐induced nuclear enlargement is best demonstrated in vivo when/the tissue involved has been undergoing rapid replication. Male Wistar albino rats were simultaneously exposed to an atmosphere containing sulphur dioxide (which caused a hyperplastic response in the nasal cavity) and received an i.p. injection of a nitrosamine. Sections were prepared from the nasal cavity, and the nuclear areas of respiratory epithelial cells were measured. There were some increases in nuclear size 24 and 72 h after the start of treatment. The reversal of this effect 120 h after the start of treatment may have been due to the loss of the normal ciliated mucosal epithelium, and subsequent loss of metabolic capability.
Hepatic studies of intraperitoneally administered tris(2‐ethyl hexyl)trimellitate (TOTM) and di(2‐ethyl hexyl)phthalate in rats
Authors: Rathinam K. , Srivastava S. P. , Seth Prahlad K.
Published: October 2006

Adult male rats reciving tris(2‐ethyl hexyl)trimellitate (TOTM) intraperitoneally for seven days exhibited no significant changes in the activities of hepatic aminopyrine‐N‐demethylase, aryl hydrocarbon hydroxylase or glutathione‐S‐transferase, or in the glutathione contents. However, except for the glutathkme level, the di(2‐ethyl hexyl)phthalate (DEHP)‐treated group showed significant increases in the activities of these enzymes. Changes in the body weight and the absolute and relative liver weights were also observed among the DHEP‐treated group.
Biological monitoring of workers exposed to lead stearate
Authors: Ong C. N. , Chua L. H. , Teramoto K.
Published: October 2006

This study was conducted to examine the usefulness of some of the commonly used biological parameters for monitoring of workers exposed to lead stearate. Forty‐two lead stearate workers from a lead stabilizer factory and 26 workers exposed to inorganic lead compounds were involved in this study. Although the workers had similar blood lead values (PbB), subjects exposed to lead stearate were found to have a significantly higher concentration of lead in plasma (PbP), (1.0 ± 0.57 μ dl−1) than workers exposed to inorganic lead compounds (0.42 ± 0.3). The ratio of PbP to PbB was ca. 2.5 times higher for lead stearate workers (0.38) than the inorganic lead workers (0.15). These data suggest that the different chemical properties of lead stearate may result in different distributional patterns of the metal in different blood components. On the other hand, the activity of δ‐aminolevulinic acid dehydratase (ALAD), an enzyme highly sensitive to lead, was not so much depressed among the lead stearate workers as that of workers handling inorganic lead. A poor correlation was also observed between PbB and ALAD activity of the stearate workers. These findings indicate that PbB and ALAD are not good biological indicators for evaluating the toxicological effect of lead stearate exposure.
1,2‐Dichloropropane hepatotoxicity in rats after inhalation exposure
Authors: di Nucci A. , Gregotti C. , Manzo L. , Imbriani M. , Ghittori S. , Bianco L. , Maestri L. , Capodaglio E.
Published: October 2006

The hepatic effects of 1,2‐dichloropropane (DCP) were investigated in male Wistar rats exposed to 15, 50, 100, 250, 450, 1000, 1300, 1800 or 4900 mg DCP m−3. At the end of a 4‐h period of exposure, average blood DCP levels were 0.025 and 5.38 μg ml−1 in animals treated with 15 and 1300 mg m−3, respectively. Blood DCP concentrations were correlated with the air DCP concentrations in the inhalation chamber. At DCP concentrations of 100 mg m−3 or higher, the liver non‐protein thiol (NPT) content was significantly reduced. Assays performed 20 h after 4‐h DCP exposure showed that exposure to 100–1000 mg DCP m−3 had no effect on hepatic NPT levels. The NPT content increased only in the liver of rats exposed to higher (1300–4900 mg m−3) DCP concentrations. Treatment with DCP did not cause hepatic lipid peroxidation and did not modify total protein content. The observed changes in liver cell thiol homeostasis are likely to reflect the action of reactive intermediates formed during DCP metabolism. These changes can occur in rats following exposure to considerably low levels of DCP vapour.
Variable effects of chemical allergens on serum ige concentration in mice. Preliminary evaluation of a novel approach to the identification of respiratory sensitizers
Authors: Dearman R. J. , Basketter D. A. , Kimber I.
Published: October 2006

A wide variety of chemicals may induce allergic contact dermatitis (contact sensitivity). Some chemical allergens may, in addition, cause respiratory sensitization.

Topical exposure of mice to contact and respiratory chemical sensitizers results in the initiation of divergent immune responses characteristic of preferential activation of different functional subpopulations of T helper (TH) cells. In the present study we have sought to make use of these differences, particularly differences in the ability of contact and respiratory allergens to provoke IgE responses, and to question whether opportunities exist for the identification of chemicals with the potential for respiratory sensitization. We have examined alterations in the serum concentration of IgE following topical exposure of mice to seven chemical allergens; trimellitic anhydride (TMA), phthalic anhydride, diphenylmethane‐4,4′‐diisocyanate (MDI), dicyclohexylmethane‐4,4′‐diisocyanate (HMDI), isophorone diisocyanate (IPDI), oxazolone and 2,4‐dinitrochlorobenzene (DNCB). Three of these—TMA, phthalic anhydride and MDI—are known human respiratory sensitizers. The other four—HMDI, IPDI, oxazolone and DNCB—appear not to cause respiratory allergy, or at least have a very limited potential to do so. At the concentrations tested, exposure to all chemicals caused a lymphocyte proliferative response in lymph nodes draining the site of application. However, exposure only to TMA, phthalic anhydride and MDI resulted in a substantial increase in the concentration of serum IgE. Treatment with HMDI and IPDI failed to induce any change in serum IgE concentration. DNCB and oxazolone caused only small and transient elevations of IgE that were considerably less marked than those observed with respiratory sensitizers.

These data suggest that it may be possible not only to identify chemical allergens as a function of immune responses induced in mice but also to determine the form that allergic reactions may take. It is proposed that analysis of induced alterations in the serum concentration of IgE may provide a method for the identification of those chemicals that have a significant potential to cause respiratory sensitization.
Diethylbenzene inhalation‐induced electrophysiological deficits in peripheral nerves and changes in brainstem auditory evoked potentials in rats
Authors: Gagnaire F. , Becker M. N. , Marignac B. , Bonnet P. , de Ceaurriz J.
Published: October 2006

Motor and sensory conduction velocities (MCV and SCV), amplitude of the sensory action potential (ASAP) of the tail nerve and parameters of brainstem auditory evoked potentials (BAEP) were studied in male Sprague‐Dawley rats after prolonged inhalation exposure to a commercial isomer mixture of diethylbenzene (DEB mixture) containing 6% 1, 2‐DEB. The MCV, SCV and ASAP were studied in one control group (10 rats) and three groups of 12 rats exposed to 500, 700 or 900 ppm DEB mixture for 6 h daily, 5 days per week, for 18 weeks. Rats used for recording BAEP (one control group and two other groups of 15 rats) were exposed to 600 and 800 ppm DEB mixture. The exposure time was the same.

Rats exposed to DEB mixture exhibited a time‐ and concentration‐dependent decrease in MCV, SCV and ASAP and a time‐ and concentration‐dependent increase of both the peak latencies of all BAEP components and the interpeak (I–V) differences.
Alteration of brainstem auditory evoked potentials in diethylbenzene and diacetylbenzene‐treated rats
Authors: Gagnaire F. , Becker M. N. , de Ceaurriz J.
Published: October 2006

Male Sprague‐Dawley rats were treated either with 1,2‐diethylbenzene (1,2‐DEB) or its putative active metabolite, 1,2‐diacetylbenzene (1,2‐DAB). Experimental rats and appropriate controls were examined electrophysiologically for brainstem auditory evoked potentials (BAEP). Oral administration of 1,2‐DEB (75 or 100 mg kg−1 once a day, 4 days a week, for 8 weeks) and intraperitoneal injection of 1,2‐DAB (10 or 15 mg kg−1 once a day, 4 days a week, for 8 weeks) produced time‐ and dose‐dependent increases in the peak latencies of all BAEP components as well as in interpeak (I–V) differences, and a decrease in the amplitudes of all the components. The absolute and interpeak latencies recovered partially during an 8‐week (1,2‐DEB) or a 10‐week (1,2‐DAB) recovery period, whereas there were long‐lasting decreases in peak amplitudes.
The effects of probenecid on the excretion kinetics of stanozolol, an anabolic steroid, in rats
Authors: Ryu Jae‐Chun , Kwon Oh‐Seung , Song Yun‐Seon , Yang Jong‐Soon , Park Jongsei
Published: October 2006

The pharmacokinetic behaviour and the mechanism of renal excretion of stanozolol (STZ), as affected by cotreatment with probenecid, were studied in male Sprague‐Dawley rats. Pharmacokinetic parameters following intravenous (i.v.) administration of STZ (20 mg kg−1 body wt.) were measured in both STZ‐treated (control) and STZ plus probenecid‐treated (treatment) groups. In order to assess the renal clearance of STZ, bolus doses of STZ and inulin (40 mg kg−1 body wt.) were injected i.v. either in the presence or absence of probenecid (40 mg kg−1 body wt.). The blood and urine concentrations of STZ were determined by capillary gas chromatography‐mass spectrometry (GC‐MS).

In the probenecid treatment group, the area under the plasma disappearance and urinary excretion curves (AUC) of STZ were significantly decreased (P < 0.01) and the volume of distribution (Vd) and total clearance (CLt) were significantly increased statistically (P < 0.05 and P < 0.01, respectively). No remarkable differences in the urine flow rate, urine pH values, glomerular filtration rate (GFR) or renal clearance were observed in the treatment group. However, the clearance ratio in the treatment group was significantly increased from 11.72 to 17.27. From these results, it is suggested that the significant decrease of AUC, i.e. increase of disappearance of STZ in plasma by co‐administration with probenecid, is due to the increase of the clearance ratio.
Magnetic resonance imaging of the rat brain following acute carbon monoxide poisoning
Authors: Jalukar Vishram , Penney David G. , Crowley Michael , Simpson Nicholas
Published: October 2006

Magnetic resonance (MR) may be used for repeatedly and non‐invasively imaging the brain. Until now, no studies have used this approach to study the effects of carbon monoxide (CO) poisoning in a defined animal model. Conscious, Levine‐prepared female rats (unilateral carotid artery and jugular vein occlusion) were exposed to 2400 ppm CO for 90 min, with or without the infusion of 50% glucose solution; CO‐stimulated increases in blood glucose and lactate occurred in both groups, while blood pressure and body temperature fell. One to four hours following termination of CO exposure, increased cortical pixel intensity, cortical surface area and brain midline shift were observed on the operated side of the brain in some rats of both groups (i.e. responders = R), providing evidence of edema. At sacrifice, 5 h following termination of CO exposure, gross water content was increased on the left side in the corresponding cortical slices in R rats, providing another measure of edema. Significant positive correlations were found between left to right pixel intensity difference and water content difference, and between the extent of midline shift and water content difference. The elevations of blood glucose and lactate concentrations, and the magnitudes of CO‐induced hypothermia and hypotension were similar to those in past studies, but appeared to exert no effect on the severity of cortical edema in terms of differences in pixel intensity, surface area, midline shift or gross tissue water content. Thus, the observed differences between the R rats and the non‐R rats is not explained by the available data. The results of this study demonstrate that MR imaging can detect changes in the cerebral cortices of rats given an acute toxic challenge with CO. Moreover, in responders the edema develops quickly, reaching nearly full development within 1 h after CO exposure.
The pattern of poisoning in urban zimbabwe
Authors: Nhachi Charles F. B. , Kasilo Ossy M. J.
Published: October 2006

A 10‐year (1980 to 1989 inclusively) retrospective analysis of poisoning admissions to the six major referral hospitals in Zimbabwe revealed 6018 cases. The majority of the patients were aged 0–5 years (35%) and 21–30 years (22.6%). The main agents associated with acute poisoning were traditional medicines (22.9% of the total), household chemicals (18.8%, 13.2% of which was due to paraffin), snake and insect envenomation (17.1%), orthodox medicines (16.7%) and insecticides (14.8%, 10% of which is accounted for by organophosphates). Mortality was 15% and the main agents associated with fatality were pesticides, traditional medicines and orthodox medicines, in descending order. The prevention and treatment of intoxication caused by traditional and orthodox medicines, the proper storage and disposal of pesticides and legislation regulating their sale and distribution are of high priority in the fight to reduce poisoning caused by these agents.
Influence of diltiazem and/or propranolol on rat blood glucose levels in normal and diabetic animals
Authors: Salem Hatem A. , Abdel‐Rahman Mohamed S. , Dahab Gamal M.
Published: October 2006

Diabetes mellitus and cardiovascular disorders are both common disorders, and it could be anticipated that they coexist in many patients. Diltiazem (DZ) is widely used alone or in combination with propranolol (PROP) for the treatment of hypertension and ischemic heart disease. These drugs could interfere with carbohydrate metabolism and impair glucose tolerance. The purpose of this study was to investigate the effect of oral administration of DZ, PROP (100 and 25 mg kg−1, respectively) and their combination on fasting serum glucose and insulin levels in normal and diabetic Wistar rats. Diabetes was induced by an intraperitoneal (i.p.) injection of streptozotocin (60 mg kg−1). In normal animals, serum glucose was significantly increased after DZ, PROP and DZ/PROP treatment compared to the initial values. In diabetic rats, serum glucose was significantly increased after PROP and DZ/PROP treatments, while it was slightly increased after diltiazem treatment compared to the initial values. In normal animals, plasma cAMP is significantly decreased in all treatment groups compared to the control value, while in the plasma of diabetic rats, cAMP was significantly decreased after PROP and DZ/PROP treatments when compared to the control value. Serum potassium of normal rats decreased after the diltiazem and DZ/PROP treatments, and they tend to increase slightly after PROP treatment. Serum potassium of diabetic rats was increased significantly after PROP and DZ/PROP treatments compared to the initial values. Body weight is decreased significantly in all treatment groups in normal rats while this significant decrease was observed only after DZ/PROP treatment in diabetic rats. This investigation suggests that diltiazem alone has no worsening effects on the glycemic control in diabetic rats. The hyperglycemia observed with the DZ/PROP treatment may be due to the role of PROP on increasing glucose output from the liver by cAMP.
Genetic toxicology studies with a tumor promoter
Authors: Oshiro Y. , Piper C. E. , Garriott M. L. , Balwierz P. S. , Soelter S. G. , Rohrbacher E.
Published: October 2006

A diuretic antihypertensive agent, SC‐33643 (8‐(2‐ethoxyethyl)‐7‐phenyl‐[1,2,4]triazolo[4,3‐c]pyrimidine‐5‐amine, also known as bemitradine), was tested in the Ames test, in the mouse lymphoma TK± mutation assay, in the Chinese hamster ovary cell hypoxanthine guanine phosphoribosyl transferase (CHO/HGPRT) mutation test and in the CHO chromosome aberration assay with and without metabolic activation. Additionally, the compound was tested in the rat primary hepatocyte unscheduled DNA synthesis (UDS) assay and in the mouse bone marrow micronucleus assay. The results were uniformly negative. Contrary to expectations based on the results of the battery of genetic toxicology tests, the compound produced liver, thyroid and mammary tumors in the rat (reported separately). Subsequently, SC‐36741 (5‐amino‐7‐phenyl‐[1,2,4]triazolo‐[1,5‐c] pyrimidine‐8‐ethanol, also known as desethylbemitradine), a major metabolite of SC‐33643, was tested in the Ames test, in the CHO/HGPRT mutation test and in the CHO chromosome aberration assay with and without metabolic activation, and was also tested in the rat primary hepatocyte/UDS assay and in the mouse bone marrow micronucleus assay. This metabolite also produced negative results in these tests. Therefore, SC‐33643 is a non‐genotoxic carcinogen producing tumors in rats without altering DNA or chromosomes.
Triethylbenzene‐induced sensorimotor neuropathy in rats
Authors: Gagnaire F. , Marignac B. , de Ceaurriz J.
Published: October 2006

1,2,4‐Triethylbenzene (1,2,4‐TEB) and 1,3,5‐triethylbenzene (1,3,5‐TEB) were administered orally to male Sprague‐Dawley rats. Experimental and appropriate control rats were examined electrophysiologically for motor and sensory conduction velocities (MCV and SCV), and the amplitudes of the sensory (ASAP) and muscular action potentials (AMAP), at bi‐weekly intervals. Oral administration of 1,2,4‐TEB (200 or 400 mg kg−1, once daily, 4 days per week for 8 weeks) produced a time‐ and dose‐dependent decrease in MCV, SCV, AMAP and ASAP. Rats treated with 1,2,4‐TEB exhibited a bluish discoloration of the skin and the urine was greyish‐greenish.

No changes in MCV, SCV, AMAP and ASAP developed in rats given 1,3,5‐TEB orally (200 or 400 mg kg−1, daily, 4 days per week for 8 weeks).

The results indicate that 1,2,4‐TEB is a neurotoxic isomer of TEB and that the presence of two ethyl radicals in the ortho‐position on an aromatic ring could be a critical molecular arrangement resulting in chromogenic and neurotoxic properties.
Induction of mast cell sensitization by chemical allergens: A comparative study
Authors: Holliday M. R. , Coleman J. W. , Dearman R. J. , Kimber I.
Published: October 2006

In previous investigations we have shown that chemical allergens of different classes induce in mice qualitatively divergent immune responses. Respiratory allergens provoke substantial increases in total serum concentration of IgE. In contrast, contact allergens which are known or suspected not to cause respiratory sensitization or which at most have only a very limited potential to do so, have little or no effect on total serum IgE. Such differences, we propose, provide a novel approach for the prospective identification of chemicals with potential to cause respiratory allergy. In the absence of a robust method for the direct measurement of respiratory hypersensitivity reactions in mice we have sought in the present study to determine whether the IgE responses induced in mice by respiratory allergens are specific and of sufficient magnitude to cause the active sensitization of mast cells in vivo, a prerequisite for immediate hypersensitivity, including acute‐onset respiratory hypersensitivity. Topical exposure of BALB/c mice to concentrations of ≥ 10% of the human respiratory allergen trimellitic anhydride (TMA) caused the specific sensitization of peritoneal mast cells in situ as measured by the conjugate‐induced release of [3H]‐5‐hydroxytryptamine in vitro. Experiments were performed also with 2,4‐dinitrochlorobenzene (DNCB), a contact allergen that fails to induce respiratory hypersensitivity. Treatment of mice with concentrations of DNCB of comparable immunogenicity failed to cause mast cell sensitization. These data demonstrate that a known human chemical respiratory allergen induces in mice specific mast‐cell‐sensitizing IgE antibody and reinforce the value of the mouse as a model for the evaluation of respiratory sensitization potential.
Delayed neurotoxic effect of sarin in mice after repeated inhalation exposure
Authors: Husain K. , Vijayaraghavan R. , Pant S. C. , Raza S. K. , Pandey K. S.
Published: October 2006

Delayed neurotoxicity of sarin in mice after repeated inhalation exposure has been studied. Female exposed to atmospheric sarin (5 mg m−3 for 20 min) daily for 10 days developed muscular weakness of the limbs and slight ataxia on the 14th day after the start of the exposure. These changes were accompanied by significant inhibition of neurotoxic esterase (NTE) activity in the brain, spinal cord and platelets. Histopathology of the spinal cord of exposed animals showed focal axonal degeneration. These changes were comparatively less than in animals treated with the neurotoxic organophosphate, mipafox. Results from this study indicate that sarin may induce delayed neurotoxic effects in mice following repeated inhalation exposure.
Effects of disulfiram on serum Dopamine‐β‐hydroxylase and blood carbon disulphide concentrations in alcoholics
Authors: Caroldi Stefano , Paris Paola De , Zotti Sergio , Zanella Ilia , Brugnone Francesco
Published: October 2006

The aim of this study was to investigate the effects of single and repeated disulfiram doses on serum dopamine‐β‐hydroxylase activity and blood carbon disulphide concentrations in a group of abstinent alcoholics. The increase in the blood concentration of carbon disulphide was dose dependent after the oral administration of 100–400 mg of disulfiram. Free carbon disulphide peaked at 12 h while the protein‐bound fraction increased at least up to 24 h. Both single (100–400 mg p.o.) and repeated (200 mg daily p.o. for ca. 1 month) administrations failed to inhibit the activity of serum dopamine‐β‐hydroxylase. The repeated daily administration of 200 mg of disulfiram also had no influence on copper‐activated serum dopamine‐β‐hydroxylase, which was the same before and after 1‐month treatment period. Contrary to the disulfiram group, the activity of the copper‐activated enzyme in the serum of abstinent alcoholics declined significantly during the same 30 days.
Modulation of ricin toxicity in mice by biologically active substances
Authors: Muldoon D. F. , Stohs S. J.
Published: October 2006

Ricin is a highly toxic protein produced by the castor bean (Ricinus communis). It is one of various protein toxins that consist of two subunits joined by a disulfide bridge. One chain facilitates entry of the toxin into the cell while the other chain exhibits RNA N‐glycosidase activity, which attacks a specific site on 28S rRNA, preventing polypeptide elongation and leading to cell death. Although ricin and other protein toxins are potential health hazards, no antidote against these toxins exists. Thus, a number of selected compounds were screened for their ability to alter ricin lethality in mice, based on percentage survival and time to death following a ricin LD100 of 25 μg kg−1 i.p. While no compound tested prevented lethality, dexamethasone and difluoromethylornithine (DFMO) significantly extended survival time. The effects of DFMO on ricin toxicity were markedly influenced by altering various pharmacokinetic parameters. The antioxidants butylated hydroxyanisole and vitamin E succinate also extended survival time in response to a lethal dose of ricin, but to a lesser extent than did dexamethasone and DFMO. The Golgi apparatus inhibitors monensin, swainsonine and tunicamycin enhanced ricin toxicity, as evidenced by shortened survival times. In addition, various nucleoside analogs, including acyclovir and trifluridine as well as adenosine, guanosine and dibutyryl cyclic AMP, also potentiated the toxity of ricin. The results demonstrate that the toxicity of ricin is modulated by a wide variety of structurally distinct chemicals and may involve different mechanisms. Furthermore, the extent and direction of the modulation of ricin toxicity is highly dependent upon pharmacokinetic variables, including dose and dosing interval.
Hemolysis and deformability of erythrocytes exposed to butoxyacetic acid, a metabolite of 2‐Butoxyethanol: I. Sensitivity in rats and resistance in normal humans
Authors: Udden Mark M. , Patton Cynthia S.
Published: October 2006

The effects of butoxyacetic acid (BAA), a metabolite of the important solvent 2‐butoxyethanol, on rat and human red blood cells (RBCs) were investigated. Rat RBCs demonstrated decreased deformability as assessed by a sensitive polycarbonate sieve filtration technique and an increased mean cellular volume after incubation with 0.2 and 2.0 mM BAA for 1–4 h. Evaluation of erythrocyte morphology showed that rat RBCs exposed to BAA became spherocytic and lysed to form erythrocyte membrane ghosts. Hemolysis of rat erythrocytes was rapid in 2.0 mM BAA. Changes in the deformability of rat erythrocytes appear to precede hemolysis. Treated rat erythrocytes also demonstrated a tendency to agglutinate and to release hemoglobin, which formed visible precipitates. None of the adverse effects seen in the RBCs of rats were observed in human blood similarly incubated with 2.0 mM BAA.
Proposed protocols for the determination of potential ocular effects of organophosphorus pesticides
Authors: Hamernik Karen L.
Published: October 2006

The US Environmental Protection Agency now requires ocular toxicity testing to support the registration of organophosphorus pesticides. As a first step toward guideline development for the conduct of these studies, preliminary protocols for ocular toxicity testing in the non‐rodent and rodent are being proposed by the Office of Pesticide Programs. Proposed protocol parameters include determination of animal health status, measurement of plasma, erythrocyte and retinal cholinesterase activities, ocular assessment by routine ophthalmological examination, slit lamp biomicroscopy, fundic observations, tonometry, electroretinography and determination of objective refractivity, pupillary response and tracking. Gross and detailed histopathological examinations of ocular system components would also be conducted. Associated questions and concerns with regard to ocular toxicity testing are presented. The Agency plans to hold a workshop in the near future to discuss issues related to protocol refinement and guideline development.
Effects of organophosphates on the visual system of rats
Authors: Boyes William K. , Padilla Stephanic , Tandon Pushpa , Barone Stan
Published: October 2006

The possibility that exposure to organophosphate insecticides can lead to ocular damage is suggested by Japanese studies from the 1960s and 1970s indicating that exposed humans developed chronic ocular degeneration, in addition to showing more commonly accepted effects of cholinesterase‐inhibiting compounds. Other papers reported ocular lesions in laboratory animals treated with organophosphates. More recently, retinal degeneration following chronic organophosphate treatment has been reported to the Environmental Protection Agency by pesticide manufacturers in studies conducted in compliance with good laboratory practice regulations. Several factors, however, have prompted scepticism regarding organophosphate‐induced ocular toxicity, including the widespread use of organophosphate compounds for both agricultural and ophthalmological practices without numerous additional reports of comparable ocular toxicity. We are developing a research program to address these issues involving electrophysiological, biochemical and histological investigations of rats treated with organophosphate insecticides. The research program is young, but early results are available. Notably, retinas from rats treated with a single subcutaneous injection of 100 mg kg−1 fenthion showed decreases in carbachol‐stimulated release of inositol phosphate, an indicator of cholinergically‐mediated intracellular second messenger systems. These effects persisted at least 56 days after fenthion administration. This could indicate several different toxicological actions, which are currently under investigation. It is concluded that the possible association between exposure to organophosphates and ocular toxicity cannot be dismissed, and that several important research issues need to be resolved.
Effects of collagen fiber orientation on the response of biologically derived soft tissue biomaterials to cyclic loading
Authors: Sellaro Tiffany L. , Hildebrand Daniel , Lu Qijin , Vyavahare Naren , Scott Michael , Sacks Michael S.
Published: October 2006

In the present study, the effects of initial collagen fiber orientation on the medium‐term (up to 50 × 106 cycles) fatigue response of heart valve soft tissue biomaterials was investigated. Glutaraldehyde treated bovine pericardium (GLBP), preselected for uniform structure and collagen fiber orientation, was used as the representative heart valve biomaterial. Using specialized instrumentation, GLBP specimens were subjected to cyclic tensile loading to maximum stress levels of 500 ± 50 kPa at a frequency of 22 Hz. Two sample groups were examined, one with the preferred collagen fiber direction parallel (PD) and perpendicular (XD) to the direction of applied strain. The primary findings indicated that GLBP fatigue response was highly sensitive to the direction of loading with respect to fiber orientation. Specifically, when loading perpendicular to the preferred collagen fiber orientation, fiber reorientation is the dominant mechanism. In contrast, when loaded parallel to the preferred fiber direction a reduction in both collagen fiber crimp and fiber reorientation occurred. Moreover, alterations in the degree and direction of mechanical anisotropy can be inducted by cyclic loading when specimens are loaded perpendicular to the preferred fiber direction. Fourier Transform Infrared Spectroscopy (FT‐IR) results indicate that molecular‐level damage to collagen occurs in both groups after only 20 × 106 cycles. Taken as a whole, the results of this study suggest that initial collagen orientation plays a critical role in bioprosthetic heart valve biomaterial fatigue response. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res, 2007
The effect of zoledronic acid incorporated in a poly(D,L‐lactide) implant coating on osteoblasts in vitro
Authors: Greiner S. , Kadow‐Romacker A. , Lübberstedt M. , Schmidmaier G. , Wildemann B.
Published: October 2006

Bisphosphonates such as zoledronic acid (ZOL) are used in diseases associated with osteoclast‐mediated bone loss. However, their antiresorptive activity is partly due to their effect on osteoblasts. Local application might increase the therapeutical fence and their local efficiency and reduce systemic side effects. Aim of the study was to investigate the effect of ZOL on human osteoblasts like cells in vitro with special focus on the synthesis of factors mediating osteoclast differentiation (RANKL, OPG). ZOL was incorporated in an implant coating based on poly(D,L‐lactide) (PDLLA) in different concentrations (10–150 μM). Control groups were treated with uncoated implants, PDLLA‐coated implants, and ZOL pure substance in corresponding concentrations. After an experimental period of 144 h, primary human osteoblasts were stained with alamar blue and cell viability was measured. Procollagen I synthesis, osteoprotegerin (OPG) secretion, and soluble receptor activator of nuclear factor‐κB ligand (sRANKL) were analyzed. Results showed that cell viability was not affected when treated with doses equivalent up to 100 μM ZOL‐coated implants (ZOL‐CI). Procollagen I synthesis was highest when treated with 50 μM ZOL‐CI. OPG increased significantly in the 10 μM ZOL‐CI group, whereas sRANKL decreased significantly with different concentrations of ZOL‐CI. Higher concentrations or exposure to the pure substance showed a decrease in cell viability, collagen I, OPG, and sRANKL synthesis. In conclusion, exposure to specific concentrations of ZOL‐CI showed a beneficial effect on osteoblast differentiation and protein synthesis without influencing their proliferation. Changes in sRANKL and OPG production may contribute to the inhibition of osteoclastic bone resorption. This local antiresorptive effect might be clinically useful in osseous implant integration and fracture healing. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res, 2006
Friction of total hip replacements with different bearings and loading conditions
Authors: Brockett Claire , Williams Sophie , Jin Zhongmin , Isaac Graham , Fisher John
Published: October 2006

Metal‐on‐ultra‐high molecular weight polyethylene (UHMWPE) total hip replacements have been the most popular and clinically successful implants to date. However, it is well documented that the wear debris from these prostheses contributes to osteolysis and ultimate failure of the prosthesis, hence alternative materials have been sought. A range of 28 mm diameter bearings were investigated using a hip friction simulator, including conventional material combinations such as metal‐on‐UHWMPE, ceramic‐on‐ceramic (CoC), and metal‐on‐metal (MoM), as well as novel ceramic‐on‐metal (CoM) pairings. Studies were performed under different swing‐phase load and lubricant conditions. The friction factors were lowest in the ceramic bearings, with the CoC bearing having the lowest friction factor in all conditions. CoM bearings also had low friction factors compared with MoM, and the trends were similar to CoC bearings for all test conditions. Increasing swing phase load was shown to cause an increase in friction factor in all tests. Increased serum concentration resulted in increased friction factor in all material combinations, except MoM, where increased serum concentration produced a significant reduction in friction factor. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2006
Synthesis of carboxy‐labelled l‐carnitine
Authors: Goodfellow Donald B. , Hoppel Charles L. , Turkaly Julia S.
Published: October 2006

A method for the production of carboxy‐labelled l‐carnitine is described. The first step is the chemical synthesis of 4‐N‐trimethylammoniobutanoate (butyrobetaine) from the precursors 4‐aminobutanoate and iodomethane. The second step involves the hydroxylation of butyrobetaine to form l‐carnitine using butyrobetaine hydroxylase partially purified from bovine calf liver. The method also can be used to synthesize Me‐labelled and uniformly‐chain‐labelled l‐carnitine.
18O labeled nucleosides. 1. A general method for the synthesis of specifically labeled pyrimidine deoxyribosides
Authors: Schram Karl H. , Ratcliff Steven , Neenan John
Published: October 2006

A facile method for the preparation of 18O labeled pyrimidine deoxyribosides is described. The method provides a means of selectively labeling the base, sugar or both the base and sugar moieties with high levels of 18O. Thymidine is used as a model to illustrate the method. The site and level of label was established using mass spectrometry.
Synthesis of 13C‐labelled medroxyprogesterone acetate with three 13C isotopes [1]
Authors: Rao P. Narasimha , Damodaran Kalyani M.
Published: October 2006

17α‐Hydroxyprogesterone (2) was converted to an enol‐lactone 8 in which the 20‐oxo group was selectively protected as an ethylene acetal. The enol‐lactone 8 was subjected to Claisen condensation with phenl acetate‐1,2‐13C2 in the presence of sodium hydride, which on subsequent treatment with a mixture of acetic acid and hydrochloric acid followed by acetylation gave 17α‐acetoxyprogesterone‐3,4‐13C2 (9). The enol‐ether 10 obtained from 9 was treated with tetrabromomethane‐13C, in pyridine‐dioxane solution, to give the 6‐dibromomethylene derivative 11, Which was then hydrogenated to yield finally 17α‐acetoxy‐6α‐methyl‐13C‐pregn‐4‐ene‐3,20‐dione‐3,4‐13C2 (12).
Synthesis of 2‐bromo‐[1‐14C]ethanamine hydrobromide
Authors: Bach Peter H. , Bridges James W.
Published: October 2006

2‐Bromo‐[1‐14C]ethanamine hydrobromide (BEA) was synthesized from [2‐14C]ethan‐1‐01‐2‐amine hydrochloride, by reaction with HBr in a specially designed chamber at an elevated temperature. The synthetic product was purified in the reaction chamber by fractional vacuum sublimation to give a yield of up to 90% of BEA having a purity greater than 95%.
Preparation of [2α‐14CH3]‐dihydrotestosterone 17‐propionate
Authors: Parnes Howard , Pease John
Published: October 2006

An efficient preparation of a very large quantity (650 mCi) of [2α‐14CH3]‐dihydrotestosterone 17‐propionate by methylation of the N,N‐dimethylhydrazone derivative of dihydrotestosterone is described. A variety of “classical” methylation methods failed to produce the desired product in satisfactory yields unless an unacceptably large excess of 14CH3I was employed.
Pentagastrin analogs containing α‐aminooxy acids VI. Synthesis of two pentagastrin analogs 14C‐labelled at the N‐terminal residue
Authors: Baláspiri L. , Kovács L. , Schőn I. , Kisfaludy L. , Kovács K. , Varga L. , Varró V.
Published: October 2006

Tert.‐Butyloxycarbonyl‐l‐14C‐glycyl‐L‐tryptophyl‐L‐methionyl‐L‐aspartyl‐L‐phenylalaninamide /I/, H‐l‐14C‐glycyl‐L‐tryptophyl‐L‐methionyl‐L‐aspartyl‐L‐phenyl‐ alaninamide /II/ and tert.‐butyloxycarbonyl‐l‐14C‐aminooxyacetyl‐L‐tryptophyl‐L‐methionyl‐L‐aspartyl‐L‐phenyl‐alaninamide /V/ of different specific radioactivities have been synthesized for biological studies.
Preparation of tritium labelled synthanecine a and its bis‐N‐ethylcarbamate
Authors: Mattocks A. Robin
Published: October 2006

A procedure is described for incorporating tritium into the 3‐CH2 side chain of synthanecine A, and preparing the carbamate, 2,3‐bis‐N‐ethylcarbamoyloxymethyl‐l‐methyl‐3‐pyrroline, a hepatotoxic pyrrolizidine alkaloid analogue. The pyrrolizidine amino alcohol, retronecine, can be tritium labelled in a similar way.
Synthese d'Analogues Deuteries des (5α) Androstanediol ‐ 3ξ, 17β
Authors: Jacolot F. , Berthou F. , Picart D. , Le Gall J. Y. , Floch H. H.
Published: October 2006

Six deuterated androstanediols were synthetised. The position of deuterium atoms on the molecule were checked by mass spectrometry and 1H or 13c nuclear magnetic resonance. The per cent of d0, d1,… dn‐molecules were calculated.

The use of such labelled molecules in the fields of isotopic dilution‐mass fragmentography as carriers and/or internal standards is discussed.
The synthesis of alanine multilabeled with stable isotopes
Authors: Dimitrijevich S. D. , Scanlon M. D. , Anbar M.
Published: October 2006

The work presented illustrates a practical sequence requiring relatively simple and inexpensive aoparatus, and using the commercially available isotopic sources, to produce L‐alanine from M+3 (13C2, 15N) to M+12 (13C3, 15N, D4, 18O2).
An improved synthesis of methyl propiolate‐1,2,3‐13c3
Authors: Lieberman Daniel F. , Yuan Sun‐Shine
Published: October 2006

An high yield synthesis of the title compound from 13CO2 is described. A key to the success is direct formation of the ester from the intermediate lithium propiolate‐13C3.
Synthese de 1‐alpha‐Methadol et 1‐alpha‐Acetylmethadol Trities
Authors: Do‐Cao‐Thang  , Nguyen‐Hoang‐Nam  , Pontikis R. , Pichat L.
Published: October 2006

dl‐Methadone was resolved by crystallization of its ammonium d‐ α ‐ bromocamphor‐ π ‐ sulfonate salt to give d‐methadone. The latter in ethyl acetate solution was reduced with tritium gas to 1‐ α ‐methadol 3H in presence of Adams platinum oxide at normal temperature and pressure. Acetylation of 1‐ α ‐carbinol hydrochloride by means of acetyl chloride afforded 1‐ α ‐acetylmethadol 3H, specific activity : 20 Ci/mMole. The positions and extent of tritium labelling were determined by 3H NMR spectroscopy.
Synthesis of 14C‐labeled 7α‐methoxycephalosporin derivative (14C‐cefotetan)
Authors: Tamazawa Kazuharu , Arima Hideki
Published: October 2006

[Caboxamido‐14C]Cefotetan, 7α‐[4‐(carbamoyl carboxymethylene)‐1,3‐dithietan‐2‐yl] [14C]carboxamido‐7α‐methoxy‐3‐(1‐methyl‐1H‐tetrazol‐5‐yl)thiomethyl‐y1)thiomethyl‐3‐cephem‐4‐carboxylic acid (IX), a new cephamycin derivative, was synthesized from bromo[1‐14C]acetic acid for metabolic studies. The results of duplicate preparation of 14C‐Cefotetan are described. In the second synthesis, a new improved method was adopted. The overall radiochemical yields were 21.5 % and 26.7 %, at specific activity of 44.5 μCi/mg and 53.3 μCi/mg respectively.
Incorporation of isotopic oxygen into the carbonyl group of esters and amides
Authors: Kuo Lawrence C. , Koch Timothy R. , Makinen Marvin W.
Published: October 2006

Syntheses and analyses are described for incorporation of 17O from 17O‐enriched water into the carbonyl oxygen position of the ester and amide bonds in O‐(trans‐pchlorocinnamoyl)‐L‐β‐phenyllactate and N‐(benzoyl)‐glycyl‐L‐phenylalanine.
Partial synthesis of tritium‐labelled gibberellin‐A3
Authors: Lischewski M. , Adam G. , Liebisch H.‐W. , Pleiß U.
Published: October 2006

The epimeric gibberellin‐A3‐7‐aldehydes 1 and 2 were silylated, enolised with KH and labelled with 3H2O to give after desilylation the tritium‐labelled epimeric gibberellin‐A3‐7‐aldehydes 4 and 5. Subsequent acetylation, oxidation and deacetylation afforded [6‐3H] gibberellin‐A3 (6) and [6‐3H]6‐epi‐gibberellin‐A3 (7). Thus, this route provides a convenient method for the preparation of [6‐3H]GA3 of high specific radioactivity.
The preparation of 11C‐labeled caffeine
Authors: Denutte H. R. , Vandewalle T. , Cattoir H. J. , Vandecasteele C. , Jonckheere J. A. , Slegers G. , Gelijkens C. F. , De Leenheer A. P.
Published: October 2006

A rapid and mild procedure for the preparation of [N‐7‐methyl‐11C] caffeine is described. Gaseous 11C‐methyl iodide wa led into dimethyl sulphoxide (DMSO), containing theophylline (1,3‐dimethylaxanthine) and sodium hydride. Purification of the reaction product was achieved by High Performance Liquid Chromatogrphy (HPLC).
Synthesis of iodine‐125 labelled aryl and vinyl iodides
Authors: Kabalka George W. , Sastry Kunda A. R. , Muralidhar Kompally
Published: October 2006

Iodine‐125 labelled vinyl and aryl iodides are formed via the reaction of sodium iodide‐125 with vinyl‐ and arylboronic acids. Good yields of isomerically pure products are obtained.
Synthesis of 17B‐hydroxy‐[14α, 15α‐ 3H] estra‐4,9‐dien‐3‐one
Authors: Römer J. , Teich A. , Droescher P. , Teichmüller G.
Published: October 2006

Starting with catalytic tritiation of 3‐methoxy‐estra‐1,3,5(10),8,14‐pentaen‐17B‐01 (1) the preparation of 17B‐hydroxy‐[14α,15α ‐3H] estra‐4,9‐dien‐3‐one (5) is described. The dienone (5) was obtained with a specific activity of 400 GBq/mmol and a radiochemical purity better than 96%. The intermediate unconjugated ketone (3) and also the dienone (5) were found to be very sensitive to self‐radiolysis.
Synthesis, purification and stability in solution of dithiobiuret‐2,4‐ 35S
Authors: Porter William R. , Williams Kevin D. , Peterson Richard E.
Published: October 2006

2,4‐Dithiobiuret (dithioimidodicarbonic diamide) can be labelled with 35S by isotopic exchange with hydrogen sulfide‐ 35S in boiling 0.01N hydrochloric acid. The product obtained by crystallization from the reaction medium contains more than 93% of the radioactivity as 2,4‐dithiobiuret and less than 3% as thiuret (3,5‐diimino‐1,2,4‐dithiazoline). Up to 40% of the initial radioactivity can be recovered as solid products. Solutions containing dithiobiuret must be stored under refrigeration to prevent decomposition to thiuret, monothiobiuret, and other products. Solutions prepared in this way are stable for 8 days. Dithiobiuret may be separated from thiuret, monothiobiuret, biuret and unidentified decomposition products by thin‐layer chromatography on silica gel.
18O‐labeled nucleosides 3. Preparation and mass spectrometric evaluation of 18O2‐labeled ara‐C and ara‐U
Authors: Schubert Ernst M. , Schram Karl H.
Published: October 2006

A facile method for the preparation of 18O labeled ara‐C and ara‐U is described. The method provides a means of incorporating 18O specifically at the 2‐position of the nucleobase. The site and level of label was established using mass spectrometry.
Synthesis of carbon‐13 labeled 5‐(diethylphosphono)‐2‐pentanone ethylene ketal, a reagent for synthesis of multi C‐13 labeled steroids
Authors: Degraw Joseph I. , Christie Pamela H. , Cairns Thomas
Published: October 2006

Alkylation of ethyl acetoacetate‐13C4 with ethylene oxide and ethylene oxide‐13C2 afforded 2‐acetylbutyrolactone‐13C4 (4a) and the hexalabeled form (4b), respectively. Treatment of the lactone with an excess of 48% hydrobromic acid effected decarboxylation with bromide displacement to yield 5‐bromo‐2‐pentanone labeled with 3 or 5 carbon‐13 atoms (5). The bromo ketone was converted to the ethylene ketal with ethylene glycol and p‐toluenesulfonic acid catalysis. Displacement of the bromide by sodio diethyl phosphite gave the required ethylene ketals of 5‐(diethylphosphono)‐2‐pentanone (7). A convenient process for preparation of ethylene‐13C2 oxide from acetic‐13C2 acid is also described.
Synthesis of encainide‐13C hydrochloride from 2‐nitrobenzaldehyde‐formyl‐13C
Authors: Johnson Porter C. , Covington Robert R.
Published: October 2006

A tacile synthesis of 2‐nitrobenzaldehyde‐formyl‐13C was developed. This compound was converted to the labelled antiarrhythmic agent, encainide‐13C hydrochloride, 4‐methoxy‐N‐[2‐[2‐(1‐methyl‐2‐piperidinyl)ethyl‐1‐13C]phenyl]benzamide hydrochloride.
Synthesis of deuterium labelled zomepirac
Authors: Sun Ting‐Hui , Abbott Frank S. , Burton Roland , Orr James
Published: October 2006

A simple synthetic procedure has been developed for the preparation of deuterated zomepirac. The deuterium was incorporated into the aromatic ring which is a metabolically stable position.
Synthesis of 2‐naphthalene‐d7‐sulfonic acid
Authors: Sniegoski Lorna T. , Edward White V. , Konash Pamela L.
Published: October 2006

2‐Naphthalene‐d7‐sulfonic acid, required as an internal standard for the analysis of organic compounds in water by gas chromatography/mass spectrometry, was synthesized in one step from commercially available naphthalene‐d8 and sulfuric acid‐d2. A high‐performance liquid chromatographic method was developed to separate 1‐ and 2‐naphthalene‐d7‐sulfonic acids. The electron impact mass spectrum and isotopic purity of the 2‐naphthalene‐d7‐sulfonic acid were determined.
Preparation of N(1‐ethyl‐2‐pyrrolidyl‐methyl)2‐methoxy‐4‐iodo‐125I‐ 5‐ethyl sulfonyl benzamide: A radioligand for the radioimmunoassay of sulpiride‐related compounds
Authors: Cardoso Maria Teresa , Pradelles Philippe
Published: October 2006

We describe the preparation of 125I labelling with a higher specific radioactivity of N(1‐ethyl ‐2‐pyrrolidyl‐methyl)2‐ methoxy ‐5‐ethyl sulfonyl benzamide, a potent biological analogue for sulpiride. The incorporation of iodine in the molecule was achieved by the substitution of aromatic amino groups via the diazo compound. Binding and immunological parameters of iodinated and tritiated tracers were compared.
A rapid synthesis of 2‐deoxy‐2‐fluoro‐d‐glucose from xenon difluoride suitable for labelling with 18F
Authors: Shiue Chyng‐Yann , K.‐C.  , Wolf Alfred P.
Published: October 2006

A rapid synthesis of 2‐deoxy‐2‐fluoro‐D‐glucose (3) from xenon difluoride is described. Reaction of 3,4,6‐tri‐O‐acetyl‐D‐glucal (1) with xenon difluoride in ethyl ether in the presence of BF3·OEt2 for 20 minutes gave 2‐deoxy‐2‐fluoro‐ 3,4,6‐tri‐O‐acetyl‐D‐glucopyranosyl fluoride (2) in 70‐80% chemical yield. Hydrolysis of 2 with 2 N HCl gave 2‐deoxy‐2‐fluoro‐D‐glucose (3) in 50% overall chemical yield in a synthesis time of 60 minutes. Preliminary results indicate that this method can be used to synthesize 2‐deoxy‐2‐ [18F] fluoro‐D‐glucose.