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PubMed1986

Arsenic excretion after treatment of arsenic poisoning with DMSA or DMPS in mice.

The effects of 2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane-1-sulfonic acid, Na salt (DMPS) on arsenic excretion in arsenic poisoning were studied using ICR mice. One group of mice was given arsenic trioxide (5 mg As/kg, s.c.) and another two groups were given DMSA or DMPS (100 mg/kg, i.p.) immediately after administration of the arsenic (5 mg/kg, s.c.). Arsenic excretion in urine and feces was determined by atomic absorption spectrophotometry. Results obtained showed a marked arsenic excretion in the urine collected at the first 12 hr in the group treated with DMSA. Further remarkable arsenic excretion in the feces was seen in the group treated with DMPS, suggesting that arsenic might have been excreted in the bile.

Animals↗
PubMed1977

Effects in the mouse and rat of prenatal exposure to arsenic.

Initial experiments involving mouse development employed single IP injections of 45 mg/kg sodium arsenate on one of days 6-12 of gestation and produced a spectrum of developmental defects. Embryotoxicity was indicated by high prenatal mortality and decreased fetal weights. A chelating agent, 2,3-dimercaptopropanol (BAL), was then employed in an attempt to alleviate the adverse effects of prenatal arsenate. BAL was administered 4 hr before, concurrently with, or 4 hr after arsenate. All BAL treatments diminished arsenate-induced gross malformations and growth retardation; the concurrent treatment alleviated skeletal malformation. Injection of rats IP with arsenate has also been reported to result in teratogenicity, including renal agenesis. Further reports indicated that 40 mg/kg arsenate administered to mice by gavage on days 9-11 increased prenatal mortality, reduced fetal weights, and was associated with minor malformations. According to our recent work, however, single oral doses of arsenate must be around 120 mg/kg to cause prenatal toxicity. Multiple doses of 60 mg/kg on 3 days had little effect. Sodium arsenite has also been found to be fetotoxic and teratogenic. Such effects were seen at IP doses of 10-12 mg/kg.

Abnormalities, Drug-Induced↗
PubMed1977

Effect of various treatments on toxicity of inhaled vinylidene chloride.

The toxicity of vinylidene chloride (VDC) was studied in mice and rats exposed to various concentrations of the vapors for 23 hr/day. In addition, the ability of various treatments to alter parameters of toxicity was evaluated. Mice were more sensitive than rats both to the acute lethal and hepatotoxic effects of VDC. Disulfiram treatment reduced the acute lethal and hepatotoxic effects of inhaled VDC and reduced the levels of covalent bound radioactivity in the liver and kidney after the intraperitoneal administration of 14C-VDC. Treatment with diethyldithiocarbamate and thiram also protected mice from the acute lethal effects of VDC.

Amino Acids, Sulfur↗
PubMed1984

Chelating agents and cadmium toxicity: problems and prospects.

Symptoms and signs in humans after excessive exposure to cadmium usually involve the gastrointestinal tract after single oral intake, the lung after acute inhalation, and the kidney after long-term exposure. These organs are usually considered to be the "critical" organs, i.e., the organs most sensitive at a certain type of exposure. The type of Cd-related damage that is most common in humans is probably the renal toxicity after long-term exposure. Most animal experiments, including the most recently published ones, have involved study of gross toxicity and tissue distribution after injection of cadmium in acute experiments. The observations in the older literature that the influence of chelating agents on Cd distribution and excretion is confined to the early period after acute Cd exposure has been confirmed and extended, and the relationship to the time course of metallothionein synthesis has been demonstrated. Although the injection experiments concerning cadmium distribution, particularly those employing repeated exposure, may furnish information that can form a basis for speculation about long-term toxicity to the kidney, there is a lack of direct studies in animals of possible beneficial effects of chelating agents on renal toxicity of cadmium after prolonged exposure. Among the few studies reported, either an increased renal toxicity or a lack of influence on renal toxicity has been observed. The problems in finding a treatment scheme that can be beneficial for the renal toxicity resulting from long-term cadmium exposure thus remain; however, the prospects of finding such schemes in the future seem favorable in view of some of the recent observations.

Animals↗
PubMed1984

Chelation of cadmium without increased renal cadmium deposition.

Cadmium (Cd) is mainly accumulated in liver and kidney bound to metallothionein (MT) and excreted very slowly from the body. In chronic exposure, Cd is gradually transported from liver to kidney; the renal toxic effects appear when renal Cd concentration exceeds the critical concentration. In order to prevent the Cd-induced renal disease, it is important to control the movement of Cd to the kidney and its renal deposition. However, the chelation of Cd from liver is difficult because of the high affinity of intracellular MT for Cd. A number of chelating agents containing both carboxyl and thiol groups were able to mobilize and excrete Cd more easily in a short time (1/2 hr) after Cd exposure than longer times (24 hr), after MT synthesis. The renal deposition of Cd increased on BAL (2,3-dimercaptopropanol) treatment a short time (1/2 hr) after Cd exposure. However, it was observed that if BAL was administered 24 hr after Cd exposure, it could mobilize Cd from hepatic MT and increase the biliary excretion of Cd without any increase in renal Cd concentration. Studies using a number of structurally related thiols (mono-, di- and trithiols) showed that the major structural requirement for in vivo chelation of Cd from intracellular MT were the vicinal thiol groups on an aliphatic chain, and lipophilicity. BAL was the most effective of all the compounds studied and it did not mobilize Cd to the kidney, when most of the intracellular Cd was bound to MT. Furthermore, a delayed treatment with BAL or DTPA (diethylenetriamine pentaacetic acid) after synthesis of MT resulted in an increase in fecal or urinary excretion of Cd in rat model experiment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Pediatric fiberoptic bronchoscopy with a laryngeal mask airway.

BACKGROUND AND OBJECTIVES: Bedside flexible fiberoptic bronchoscopy (FFB) with sedation has been recognized as a diagnostic modality in children. In certain circumstances, general anesthesia with endotracheal intubation is advocated. This study evaluates the usefulness of the laryngeal mask airway (LMA) as an alternative to endotracheal intubation during pediatric FFB. DESIGN, SETTING, AND PATIENTS: Between July 1995 and June 2000, we studied 92 children (51 girls; age range, 1 through 15 years) in the operating theater of a major tertiary children's hospital. The LMA was used in children with atelectasis, diffuse infiltrates, and those who required BAL under general anesthesia. The size of the LMA was chosen to accommodate a bronchoscope appropriate for the child's weight and age. RESULTS: Procedures were well tolerated, no complications were observed, and oxygen saturation exceeded 95% in all patients. Major findings included mucoid impaction and purulent bronchial secretions, and BAL was successfully accomplished in all individuals. CONCLUSIONS: Diagnostic BAL or extraction of mucous plugs should be accomplished with optimal control of the airway under general anesthesia. The use of the LMA during FFB is safe, provides excellent patient comfort, and should be utilized as an alternative to endotracheal intubation.

Adolescent↗
PubMed2003

Drug discovery targeted to the Alzheimer's APP mRNA 5'-untranslated region: the action of paroxetine and dimercaptopropanol.

We screened for drugs that specifically interact with the 5'-untranslated region of the mRNA encoding the Alzheimer's amyloid precursor protein (APP). Our goal was to use newly discovered APP 5' UTR directed compounds to limit amyloid-beta (Abeta)-peptide output in cell culture systems. The APP 5' UTR folds into a stable RNA secondary structure (Gibbs free energy: DeltaG = -54.9 kcal/mol) and is an important regulator of the amount of APP translated in response to IL-1 (Nilsson et al., 1998; Rogers et al., 1999) and iron (Rogers et al., 2002). Seventeen drug "hits" were identified from a library of 1,200 FDA preapproved drugs (Rogers et al., 2002). Six of the original 17 compounds were validated for their capacity to suppress reporter gene expression in stable neuroblastoma transfectants expressing the dicistronic reporter construct shown in Fig. 2. These six leads suppressed APP 5' UTR driven luciferase translation while causing no effect on the translation of dicistronic GFP gene translated from a viral IRES (negative control to ensure specificity during drug screens). In this report, we show that paroxetine (serotonin reuptake blocker) and dimercaptopropanol (Hg chelator) exerted significant effects on APP expression (steady-state levels of APP), whereas Azithromycin altered APP processing. None of these three compounds altered APLP-1 expression. In the future, we will identify further novel compounds that influence Abeta levels, either via translation inhibition or by changing the activity of proteins coupled between APP translation and APP processing.

5' Untranslated Regions↗
PubMed2004

FDA-preapproved drugs targeted to the translational regulation and processing of the amyloid precursor protein.

The 5' untranslated region (5'UTR) of the transcript encoding the Alzheimer's amyloid precursor protein (APP) is a key regulatory sequence that determines the amount of intracellular APP holoprotein present in brain derived cells. Using neuroblastoma cells (SY5Y) we developed a transfection based screen of a library of FDA drugs to identify compounds that limited APP luciferase reporter expression translated from the APP 5'UTR. Paroxetine (Paxil trade mark ), dimercaptopropanol, phenserine, desferrioxamine, tetrathiolmobdylate, and azithromycin were six leads that were subsequently found to also suppress APP holoprotein levels or to alter APP cleavage (azithromycin). Since APP holoprotein levels are proportionate to Abeta peptide output in many systems we tested the efficacy of paroxetine and dimercaptopropanol to limit Abeta secretion as measured by ELISA assays. Paroxetine and dimercaptopropanol limited Abeta peptide secretion from lens epithelial cells (B3 cells). Interestingly, paroxetine changed the steady-state levels of transferrin receptor mRNAs. These data suggested that this serotonin reuptake inhibitor (SSRI) provided extra pharmacological action to chelate interacellular iron or change the intracellular iron distribution. An altered iron distribution would be predicted to indirectly limit APP holoprotein expression and Abeta peptide secretion.

5' Untranslated Regions↗
PubMed2006

Effect of PAO (phenylarsine oxide) on the inhibitory effect of insulin and IGF-1 on insulin release from INS-1 cells.

Phenylarsine oxide (PAO) which complexes vicinal thiol groups is a valuable pharmacological tool to investigate the interaction of peptides such as insulin with their receptors and the signal transduction from the receptor to the cell interior. This tool was now used to elucidate the inhibitory effects of insulin and IGF-1 on insulin secretion via their receptors. Insulin and IGF-1 inhibited insulin release from INS-1 cells, an insulin secreting cell line. PAO was able to reverse this inhibitory effect of both hormones. Dimercaptopropanol (DMP), which is well known to antagonize PAO effects, inhibited the abolishment of PAO effect on the inhibitory effect of insulin and IGF-1 regarding insulin release. Membrane bound GLUT2 in INS-1 cells was increased by either insulin and IGF-1 which is counteracted by PAO. Thus the inhibitory effect of insulin and IGF-1 on insulin release is operative and can be disturbed by a thiol interacting compound such as PAO. This may happen at the receptor level or at the sub-receptor level.

Animals↗
PubMedDate not supplied

The biphasic Ca2+-uptake by the fragmented sarcoplasmic reticulum.

The non-equilibrium dialysis has been used for kinetic studies of ATP dependent calcium uptake by the sarcoplasmic reticulum. The uptake displays two phases, which are defined as fast and slow uptake. The former is an exponential function of time, with a half-life time of approximately 15--20 sec, the latter presents the characteristics of an autocatalytic reaction. The fast uptake is characterized by its amplitude, the slow uptake by its rate. Compared with the fast uptake, the slow uptake requires higher amounts of Mg2+ or ATP, and is more sensitive to pH variations and aging. The reasons which formerly prevented the resolution of the second phase from the first are discussed. It is concluded that the fast uptake is not a simple binding reaction, and that the slow uptake is more sensitive to changes by the vesicular membrane.

Adenosine Triphosphatases↗