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Biomedical subjects

M A Dorato

Publications and source records attributed to M A Dorato.

12 recordsLinked to original sources
PubMed1993

Toxicologic testing of inhaled pharmaceutical aerosols.

This paper reviews technical issues related to the toxicologic testing of inhaled pharmaceuticals. Although there are commonalities between approaches to general and inhalation toxicity testing, there also are specific challenges in the toxicity testing of inhaled pharmaceuticals. A major issue is that of dose; inhaled dose is more difficult to determine than intravenous or oral doses. Also, it is harder to relate dose in laboratory animals to that in man for inhalation exposure than for other routes of administration. Additionally, in the case of inhaled pharmaceuticals, people generally inhale through the mouth, whereas most laboratory animals inhale primarily through the nose. This presents significant challenges in exposure methodology and technology that often need innovative approaches involving alteration to particle size of the agent or dosing procedure. Because the respiratory tract is the site of deposition, local respiratory toxicity and possible damage to lung cells need to be assessed. Systemic toxicity also needs to be evaluated and may be an issue in some cases. Special studies on pulmonary function, mucociliary clearance, or immune response may be needed, depending on the nature of the inhaled pharmaceutical. This review explores the main issues involved in toxicity testing of inhaled pharmaceuticals, the approaches that have been used, and the current and future challenges.

Administration, Inhalation↗
PubMed1991

Inhalation exposure technology, dosimetry, and regulatory issues.

Inhalation toxicology technology has provided the scientific community with important advances in studies of inhaled toxicants. These advances include new and more efficient exposure systems (e.g., flow-past nose-only exposure systems), and improved approaches to inhalation chamber environmental control (e.g., temperature, humidity, air quality). Practical problems and approaches to testing and operating inhalation exposure systems and the advantages and disadvantages of the major inhalation exposure types (e.g., whole-body, nose-only) are discussed. Important aspects of study design, such as high level particulate exposures resulting in large lung burdens (e.g., greater than or equal to 2 mg/g of lung), slowed pulmonary clearance rates, and nonspecific toxicity are considered, along with practical issues of comparative dosimetry. Regulatory guidelines have continued to present challenges in designing and conducting acute, subchronic, and chronic inhalation studies. The important regulatory issue of performing acute inhalation toxicity studies at high aerosol concentrations and "respirable" particle size distribution is discussed.

Administration, Inhalation↗
PubMed1990

Overview of inhalation toxicology.

The development of inhalation toxicology as a distinct discipline can be traced back well over one hundred years. The technology has advanced in terms of materials and designs used to construct inhalation chambers and the equipment used to generate controlled test atmospheres of a wide variety of gases, vapors, dusts, and droplets. Consideration of metered dose inhalers, a relatively recent concern, has led to the design of new equipment for administering this unique dosage form. The parameters used to evaluate inhalation toxicity are similar to those used for any other route of administration. In addition, there are some unique procedures for early screening of pulmonary toxicity, especially within a series of related chemicals.

Animals↗
PubMed1983

Pulmonary mechanics in conscious Fischer 344 rats: multiple evaluations using nonsurgical techniques.

An adaptation of the method reported by Amdur and Mead (1958, Amer. J. Physiol. 192, 364-368) was used to evaluate pulmonary mechanics in conscious rats, utilizing a flow plethysmograph and intraesophageal catheter to determine compliance, resistance, respiratory flow, thoracic pressure, tidal volume, frequency, and minute volume. The procedure did not require surgery, and repeat evaluations were made in conscious rats. Real time calculations of pulmonary parameters were accomplished with an analog computer interfaced with a digital computer for display and data storage. Multiple evaluations (1, 3, 6, 13, 18, 24, 30, and 36 weeks) in 40 rats are reported. The utility of the system in establishing a base line against which pulmonary impairment, related to the effects of known pulmonary toxicants, e.g., ANTU and NO2, could be measured, was evaluated.

Aging↗
PubMed1979

Evaluation of the chronic inhalation toxocity of a manganese oxide aerosol. II. Clinical observations, hematology, clinical chemistry and histopathology.

Monkeys and rats were exposed to 11.6, 112.5, or 1152 microgram Mn/m3 as an Mn3O4 aerosol twenty-four hours per day for nine months. Various serum biochemical, and hematologic evaluations were conducted on both specie. Body weight gain was accelerated in rats exposed to 1152 microgram Mn/m3. Hemoglobin concentrations were slightly elevated for both sexes and both specie exposed to 1152 microgram Mn/m3; however, the effect may not be directly related to Mn. Some evidence of hypophosphatemia was observed. No exposure related effects were demonstrated by organ weight or histopathologic observations.

Aerosols↗
PubMed1977

Effect of lysine and diethanolamine-rutin on blood levels, withdrawal reaction, and acute toxicity of ethanol in mice.

The effects of L-Lysine and diethanolamine-rutin on blood ethanol levels and withdrawal convulsions following a 4-day exposure to ethanol vapors were evaluated in 30-40-g male Swiss-Webster mice. The animals were exposed in groups, along with simultaneous controls, in a 34-liter dynamic Plexiglas exposure chamber. Blood was collected by retro-orbital puncture and analyzed enzymatically for ethanol. At the end of the inhalation period, convulsions on handling were scored over 24 hr. In addition, the effects of L-Lysine and diethanolamine-rutin on blood ethanol levels and on acute ethanol toxicity following oral and intraperitoneal administration were evaluated. L-Lysine lowered blood ethanol levels following inhalation or oral administration of ethanol. Diethanolamine-rutin had no effect on blood ethanol levels. Both L-Lysine and diethanolamine-rutin decreased the withdrawal reaction in dependent mice. L-Lysine increased the oral LD50 of ethanol, while diethanolamine-rutin decreased the intraperitoneal LD50 of ethanol.

Animals↗
PubMedDate not supplied

Effects of high exposure concentrations of inhaled low-toxicity dust on pulmonary function in guinea pigs.

The acute pulmonary function response to graded levels of a low toxicity dust was studied in guinea pigs. Four groups of five male guinea pigs each were exposed to mean concentrations of 0, 0.25, 1.01 and 5.39 mg Foundry Hill Clay l-1 air with mass median aerodynamic diameters of 2.6, 4.6 and 6.7 microns, respectively. There was a 15-min pre-exposure period to clean air, a 1-h exposure to the test atmosphere and then a 1-h recovery period with exposure to clean air. Concentration-related changes, compared to the pre-exposure period, occurred with a rapid onset in a number of parameters. Generally, the severity of observed effects increased with exposure time and, therefore, with inhaled dose. Statistically significant changes (P < 0.05) were observed in tidal volume, dynamic compliance, dynamic resistance, flow, pressure and minute volume during the last 15 min of exposure. The observed changes were consistent with acute bronchoconstriction. These effects reversed rapidly and there were no significant changes 1 h post-exposure. These results suggest that adverse physiological responses of short duration can occur when animals are exposed via inhalation to low-toxicity materials in the concentration range 0.25-5 mg l-1.

Administration, Inhalation↗
PubMedDate not supplied

Use of a head dome system to compare i.v. methacholine-induced bronchoconstriction in conscious vs anesthetized rhesus monkeys.

The use of a newly developed head dome system has allowed measurement of pulmonary function in conscious monkeys. Such information is often desired, so that pharmacological or toxicological effects of administered compounds can be measured in the absence of effects from anesthetic agents. The current study was conducted to gain experience with this method and to allow the determination of the effects of sodium pentobarbital anesthesia (30 mg kg-1 i.v.) on the bronchoconstriction seen during i.v. infusion of methacholine in rhesus monkeys. Bronchoconstriction was measured as changes in respiratory resistance using a Buxco LS20 pulmonary mechanics computer. Four male rhesus monkeys (4.2-5.1 kg) were used. For the anesthetized exposures, the animals were intubated with a 4.0-mm cuffed endotracheal tube attached to a size 'O' Fleisch pneumotachograph. For the conscious exposures, the animals sat in restraining chairs with a custom-built head dome attached to the same pneumotachograph. In both cases, transthoracic pressure was monitored with an intrapleural catheter. Each monkey was infused with methacholine in stepwise doses, while anesthetized and conscious, until a 75% increase in respiratory resistance was seen. The ED50 values of 0.134 and 0.180 mg ml-1 methacholine were not significantly different in anesthetized vs conscious monkeys, respectively.

Airway Resistance↗