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PubMed1994

Airway inflammation after removal from the causal agent in occupational asthma due to high and low molecular weight agents.

In order to determine 1) the features of airway inflammation after removal from exposure to high (HMW) and low (LMW) molecular weight agents 2) if there are any differences in the pattern of inflammation induced by these two types of agents, we studied 18 subjects with a recently confirmed diagnosis of occupational asthma (OA) due to HMW (n = 11) and LMW (n = 7) agents. The duration of asthma symptoms varied from 2 to 108 months (mean 33 months), and withdrawal from exposure to the sensitizing agent from 3 to 24 weeks (mean 10 weeks). All subjects underwent measurements of expiratory flow rates, methacholine inhalation tests, and a flexible bronchoscopy with bronchoalveolar lavage (BAL) and bronchial biopsies. Endoscopic findings were compared with a group of 10 normal subjects. At the time of the bronchoscopy, asthma symptoms were minimal in most subjects. Although 15/18 subjects had normal forced expiratory volume in one second (FEV1 > 80% pred), all subjects had increased airway responsiveness to methacholine (provocation concentration producing a 20% fall in FEV1 = 0.2-10.0 mg.ml-1). BAL analysis showed similar median percentages of the total number of cells and differentials in control subjects and those exposed to HMW and LMW agents. Bronchial biopsies showed that mean inflammatory cell count, both epithelial and sub-epithelial, was similarly raised in OA subjects exposed to either HMW or LMW agents, compared to controls, except for epithelial lymphocyte count. In contrast to the controls, bronchial biopsy of both groups with OA also showed other changes such as extensive epithelial desquamation, ciliary abnormalities of the epithelial cells, smooth muscle hyperplasia and subepithelial fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1990

[Gypsum temporary filling material containing HY-agent. The effects of the HY-agent on the dentin].

The effects of the Tannin-Fluoride preparation, called the HY-agent, on dentin substrate were examined by immersion of the dentin previously treated with HY-agent into the calcifying fluid at 37 degrees C. The changes in the nature of the dentin surface and penetration of elements in the dentin were observed. CaF2 was formed on the dentin as a result of a reaction between F, an element of the HY-agent, and Ca which precipitated from the calcifying fluid. This observation was confirmed by means of the X-ray diffraction method. Penetration of F, Zn, Sr and Ca into dentin was confirmed by the use of an electron probe X-ray microanalyser (EPMA). Application of the HY-agent to the dentin for sevendays increased the hardness of the dentin about 10%. Application of the HY-agent to the dentin for sevendays increased the contact angle about 3%. These results suggested that the organic and inorganic matter in dentin can be stabilized effectively both chemically and physically by treatment with an HY-agent.

Calcium Sulfate↗

PubMed1983

[Release of water-soluble active agents from polymer embeddings. 2. The significance of the manufacturing process-dependent macrostructure of the embedded dosage from an active agent release].

When compressed tablets were produced, it was found that, owing to plastic deformation, the polymers flowed round the active agent particles, dependently on their elastic modulus and ball thrust hardness. A log-log plot of active agent liberation against porosity as a function of pressing pressure yielded a linear relationship. The embedding of active agents in liquid phase separation products by coacervation causes that the liberation of the active agents depends on their wettability by the high-colloid phase. The wetting behaviour of the high-colloid phase is controlled by the relative ratio of the dipole moments of the solvent and the non-solvent or, if these dipole moments are equal, by the hydrogen bridge parameter according to Gordy. In cases where the embedding of active agents via the state of the solution of the polymers necessitates the removal of the solvent, the temperature at which the removal is performed may be of importance to the liberation of the active agent. When the solvent is removed at a temperature above its boiling point, the liberation rate is likely to increase, especially with lowboiling solvents.

Chemistry, Pharmaceutical↗

PubMed1976

Survey of radioactive agents for in vitro labeling of phagocytic leukocytes. I. Soluble agents.

Twenty-three soluble (nonparticulate) radioactive agents were screened for their ability to label leukocytes in vitro in the presence or absence of plasma and red cells. The degree of cell binding was compared with that of other agents previously reported. Leukocyte binding of 2% or more of the added radioactivity was obtained with ten of these agents. High labeling yields were obtained only with nonpolar lipid-soluble complexes capable of penetrating lipid cell membranes. Unfortunately, this type of labeling tends to be reduced by plasma protein. Some lipophilic radioactive agents tend to elute from the cells after labeling. Compared with radioactive particles, soluble radiopharmaceuticals offer the advantage of easy centrifugal separation of the cell-bound from the residual activity in the suspension fluid. However, the labeling yield tends to be lower than for radioactive particles, and other cellular elements are labeled in addition to the phagocytic leukocytes. In this survey, the most promising soluble agents were 111In or 99mTc complexes of oxine, 111In-tetraphenylporphyrin, DNA labeled with radioactive iodine, and DNA labeled with 77Br and complexed with adriamycin. The ultimate value of any of these agents must await adequate in vivo testing in experimental animals and clinical trials.

DNA↗

PubMed2000

Iron chelating agents for treating malaria.

BACKGROUND: Mortality from Plasmodium falciparum malaria remains high; death and sequelae occur in even in patients treated with antimalarial drugs. Researchers are exploring the effects of adding treatments to the main antimalarial regimens in an attempt to reduce mortality. Iron chelation is one potential chemotherapeutic adjuvant treatment. Before advocating adjunctive therapy, the effects of iron chelators in improving patient outcomes needs to be examined. OBJECTIVES: To assess the effects of iron-chelating agents combined with antimalarial drugs, or iron chelators alone, for treating Plasmodium falciparum malaria in adults and children, in relation to mortality, coma recovery time, parasite clearance, and adverse effects. SEARCH STRATEGY: Electronic searches of the Cochrane Library, MEDLINE, and EMBASE, using the standard Cochrane search strategy. Bibliographies of retrieved studies were scrutinized in order to identify further relevant trials. Organisations, experts and other individuals in malaria research were contacted for unpublished studies. SELECTION CRITERIA: All randomised controlled trials of adults or children with P.falciparum malaria. DATA COLLECTION AND ANALYSIS: Trials were identified and extracted by a single reviewer (HS) and checked by a second (MM). Inclusion criteria were applied, and data were extracted independently by both reviewers. Authors were contacted for missing and additional data. Meta-analysis used Relative Risk (RR) and 95% Confidence Intervals. MAIN RESULTS: No evidence of benefit or harm were shown in relation to mortality, but studies were small, and one trial was tending towards more deaths with the intervention when it was stopped. The risk of experiencing persistent seizures was significantly lower with desferrioxamine compared to placebo treatment (RR 0.80, 95% CI 0.67 to 0.95). Many adverse effects were more common in participants treated with desferrioxamine. REVIEWER'S CONCLUSIONS: Trends suggestive of both harm (death) and potential benefit (fewer seizures) are demonstrated in this review. It is not possible to comment on time to event outcomes that include coma recovery or parasitaemia as we are clarifying data with the trialists. Whether to conduct further trials will depend on a judgement about potential benefit.

Adult↗

PubMed1995

Inhibition of aberrant crypt growth by non-steroidal anti-inflammatory agents and differentiation agents in the rat colon.

Aberrant crypts are aggregates of single to multiple colonic crypts evidencing hallmarks of dysplasia and may be the earliest detectable pathological lesions for colon cancer. The aberrant crypt assay has been developed in 2 protocols. In one, putative chemoprevention agents are tested for inhibitory effects when administered concomitantly with a carcinogen. In the other, the objective of this study, aberrant crypts were induced in F344 rats by parenteral injection of the colon carcinogen azoxymethane (AOM) and allowed to develop for 4 weeks, when an average of 90-100 aberrant crypt foci per colon were found in the methylene blue-stained colon. Then, during the second 4 weeks of the experiment, aberrant crypts were allowed to further develop to a frequency of > 150 foci per colon, a time when multi-crypt foci were observed. During this time we tested the inhibitory effects of 4 analgesic drugs and 2 differentiation agents for effects of aberrant crypt growth and development. We found the non-steroidal anti-inflammatory drugs piroxicam, aspirin and ibuprofen, but not acetaminophen, to be effective in suppressing aberrant crypt formation or the progression to foci of multiple aberrant crypts. Treatment with chemosuppressing agents 13-cis-retinoic acid (13-cRA) and 4-hydroxyphenretinamide (4-HPR), known differentiating agents, however, did suppress expansion of aberrant crypt foci, with 13-cRA being the much more potent agent.

Acetaminophen↗

PubMed1986

Interactions of antimicrobial agents and antineoplastic agents.

The in-vitro interactions of four antimicrobial agents (piperacillin, dibekacin, minocycline, norfloxacin) and four antineoplastic agents (mitomycin C, bleomycin, doxorubicin, 5-fluorouracil) were examined by the chequerboard dilution method using 108 clinical isolates of four species of Gram-negative bacilli. Among the antimicrobial agents, piperacillin showed the greatest degree of synergism and norfloxacin the least. The frequency of synergism was essentially similar among the antineoplastic agents, although 5-fluorouracil was more frequently synergistic than other antineoplastic agents against Pseudomonas aeruginosa. Among the four species, synergism was most frequently shown against Proteus vulgaris and least against Escherichia coli. Antagonism was rarely seen.

Anti-Bacterial Agents↗

PubMed2000

Beta-adrenergic blocking agents in heart failure: benefits of vasodilating and non-vasodilating agents according to patients' characteristics: a meta-analysis of clinical trials.

BACKGROUND: In patients with heart failure, beta-adrenergic blocking agents reduce overall and cardiovascular mortality. This meta-analysis aimed at clarifying their effect on sudden death, the magnitude of their benefit according to the cause of heart failure, and whether there is any difference between vasodilating and nonvasodilating agents. METHODS: Randomized, clinical trials were included if they evaluated a beta-adrenergic blocking agent without intrinsic sympathomimetic activity, included a control group receiving placebo or standard treatment, evaluated mortality on an intention-to-treat basis, and lasted at least 8 weeks. RESULTS: Twenty-one trials with 5,849 patients (3,130 receiving beta-blockers) were included. Median length of treatment was 6 months. Most patients had mild or moderate heart failure and were treated with angiotensin-converting enzyme inhibitors, diuretics, and digitalis. The beta-blockers significantly reduced overall mortality, cardiovascular mortality, and mortality due to pump failure and sudden death by 34% to 39%. The decrease in overall mortality in patients with ischemic heart disease (IHD) (30%) was no different from that among patients with non-IHD (26%) (P = .08). The reduction in overall mortality was greater with vasodilating than with nonvasodilating agents (45% vs 27%; P = .007), particularly in patients without IHD (62%), compared with those with IHD (22%; P =.03). CONCLUSIONS: In patients with heart failure, beta-blockers reduce total and cardiovascular mortality at the expense of a decrease in mortality due to pump failure and sudden death. The magnitude of the benefit is similar in patients with IHD and in those with non-IHD. Vasodilating beta-blockers have a greater effect on overall mortality than nonvasodilating agents, particularly in patients with non-IHD.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

Evaluation of neutralized chemical agent identification sets (CAIS) for skin injury with an overview of the vesicant potential of agent degradation products.

Vesication and skin irritation studies were conducted in hairless guinea-pigs to determine the vesicant and skin irritation potential of chemically-neutralized Chemical Agent Identification Sets (CAIS). The CAIS are training items that contain chemical warfare-related material--sulfur mustard (HD), nitrogen mustard (HN) or lewisite (L)--and were declared obsolete in 1971. Animals were dosed topically with 'test article'--neat HD, 10% agent/chloroform solutions or product solutions (waste-streams) from neutralized CAIS--and evaluated for skin-damaging effects (gross and microscopic). Product solutions from the chemical neutralization of neat sulfur mustard resulted in microvesicle formation. All agent-dosed (HD or agent/chloroform solutions) sites manifested microblisters as well as other histopathological lesions of the skin. Waste-streams from the neutralization of agent (agent/chloroform or agent/charcoal) were devoid of vesicant activity. Cutaneous effects (erythema and edema) were consistent with the skin-injurious activity associated with the neutralizing reagent 1,3-dichloro-5,5-dimethylhydantoin (DCDMH). Chemical neutralization of CAIS was effective in eliminating/reducing the vesicant property of CAIS containing agent in chloroform or agent on charcoal but was inefficient in reducing the vesicant potential of CAIS containing neat sulfur mustard.

Animals↗

PubMed1987

Mucosal coating agents and other nonantisecretory agents. Are they cytoprotective?

Gastric cytoprotection is protection against gross and histological gastric mucosal injury by a mechanism other than inhibition of neutralization of gastric acid secretion. Animal studies have shown that a variety of agents afford such a protective effect. With some of these agents, a similar protective effect has been shown in man. This protective effect must be distinguished from an action that enhances healing of an already established mucosal lesion as an ulcer. It is yet to be established that the cytoprotective effect of an agent enhances ulcer healing. Agents other than prostaglandins that have been shown to possess such a cytoprotective effect in animals are reviewed. Some, such as sucralfate, act via stimulation of endogenous prostaglandin synthesis, while others, such as DeNol, neomycin, and meciadanol, do not. Investigation of the mechanism through which these agents enhance gastric mucosal defense is a fertile field for investigation.

Animals↗

PubMed1991

The chemical reactivity of the modulating agent WR2721 (ethiofos) and its main metabolites with the antitumor agents cisplatin and carboplatin.

The antitumor agents cisplatin [cis-diamminedichloroplatinum(II), CDDP] and carboplatin [cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II), CBDCA] can react with a nucleophilic agent by a direct ligand exchange of the (labile) anionic ligands or through hydrolysis of these ligands followed by a fast reaction of the hydration product with the nucleophile. At pH 7.4 and 37 degrees, CDDP and CBDCA were incubated with several molar excesses of the modulating agent WR2721, its active thiol metabolite WR1065 or the symmetrical disulphide WR33278. The reaction rate constants for the hydrolysis and the direct inactivation by the WR-compounds were obtained from the pseudo first-order disappearance of the intact Pt-drug, with or without the WR-compounds at molar ratios of 50, 100 and 200. The hydrolysis of carboplatin (kaq,CBDCA = 2 x 10(-8) M-1 sec-1) was 100-fold less rapid than that of cisplatin (kaq,CDDP = 2 x 10(-6) M-1 sec-1). However, direct inactivation by WR2721, WR1065 and WR33278 was only 4-, 4- and 22-fold less rapid for carboplatin than for cisplatin, respectively. This direct inactivation was slow compared to the strong nucleophiles thiosulphate (TS) and diethyldithiocarbamate (DDTC) and decreased for both Pt-drugs in the following order: WR1065 (kWR1065/CDDP = 49.1 x 10(-4) M-1 sec-1, kWR1065/CBDCA = 12.4 x 10(-4) M-1 sec-1) greater than WR2721 (kWR2721/CDDP = 25.3 x 10(-4) M-1 sec-1, kWR2721/CBDCA = 6.07 x 10(-4) M-1 sec-1) greater than WR33278 (kWR33278/CDDP = 8.60 x 10(-4) M-1 sec-1, kWR33278/CBDCA = 0.39 x 10(-4) M-1 sec-1. Thus for CDDP, the hydrolysis-mediated interaction with the WR-compounds contributed more to the disappearance of intact platinum antitumor agent than it did for CBDCA. Considering the relatively low reactivity of WR2721 and its main metabolites with the platinum antitumor agents, in addition to their pharmacokinetic behavior, a significant inactivation of the platinum antitumor drugs by WR2721 and its main metabolites is, in contrast to TS, not expected in the circulation.

Amifostine↗

PubMed1993

Short-term effects of early intravenous treatment with a beta-adrenergic blocking agent or a specific bradycardiac agent in patients with acute myocardial infarction receiving thrombolytic therapy.

OBJECTIVES: This study was conducted to explore mechanisms that could explain the possible clinical benefit of early administration of a beta 1-selective adrenoreceptor blocking agent or a bradycardiac drug as adjunct to thrombolysis in acute myocardial infarction. BACKGROUND: The effects of beta-blockers given concomitantly with thrombolytic therapy in patients with acute myocardial infarction have not been fully examined. The potential role of specific bradycardiac agents lacking negative inotropism as an alternative to beta-blockers in this setting has never been studied in humans. METHODS: In a double-blind study, we examined the effects of early intravenous and continued oral administration of a beta-blocker (atenolol), a specific bradycardiac agent (alinidine) or placebo on left ventricular function, late coronary artery patency, infarct size, exercise capacity and incidence of arrhythmias. RESULTS: A total of 292 patients with acute myocardial infarction of < or = 5 h duration and without contraindications to thrombolytic or beta-blocker therapy were studied. Of these, 100 were allocated to treatment with atenolol (5 to 10 mg intravenously followed by 25 to 50 mg orally every 12 h), 98 to alinidine (20 to 40 mg intravenously followed by 20 to 40 mg orally every 8 h) and 94 to placebo. All patients received 100 mg of alteplase over 3 h and full intravenous heparinization. No significant differences in coronary artery patency, global ejection fraction or regional wall motion were observed at 10 to 14 days among the three groups. Likewise, enzymatic and scintigraphic infarct size were also very similar. Neither atenolol nor alinidine was associated with a significant reduction in the incidence of arrhythmias during the 1st 24 h. No significant differences in clinical events were observed, with the exception of a greater incidence of nonfatal pulmonary edema in the atenolol group (6% vs. 1% in the alinidine group and 0% in the placebo group, p = 0.021). CONCLUSIONS: In the absence of contraindications, the administration of a beta-blocker or a specific bradycardiac agent together with thrombolytic therapy was safe. In this limited number of patients, these agents did not appear to enhance myocardial salvage or preservation of left ventricular function or to reduce the incidence of major arrhythmias in the early phase of infarction.

Adult↗

PubMed2005

[Antimitochondrial agents: a new class of anticancer agents].

Over the last 2 decades, the role of apoptosis in anticancer agent cytotoxicity has become clear. Defects in the regulation of apoptosis (programmed cell death) make important contributions to the pathogenesis and progression of most cancers and leukemias. Apoptosis defects also have a key role in cell resistance to chemotherapy. Mitochondria play a central part in cell death in response to anticancer agents. Most of these agents target mitochondria via caspases or other regulator elements of the apoptotic machinery. Nevertheless, some anticancer agents, already in clinical use (paclitaxel, vinblastine, lonidamine, etoposide, arsenic trioxide) or in pre-clinical development (betulinic acid, MT21), directly target and permeabilize mitochondria. The acknowledgement of mitochondria as a new target for anticancer agents provides a new way to bypass cancer cell chemoresistance.

Antineoplastic Agents↗

PubMed2005

Respiratory agents: irritant gases, riot control agents, incapacitants, and caustics.

There are many chemical respiratory agents suitable for use by terrorists. They are the oldest chemical agents used and have caused the most casualties throughout the 20th century. Many are available in large quantities for industrial use and are susceptible to potential sabotage. This paper will concentrate on respiratory agents that are readily available and have the potential to cause a large number of casualties and panic. These agents have a lower rate of lethality when compared to other chemical agents but could produce many casualties that may overwhelm the emergency medical system.

Antidotes↗

PubMed2005

Calcium sensitizer agents: a new class of inotropic agents in the treatment of decompensated heart failure.

The clinician's primary objective in treating a patient with decompensated heart failure is rapid and effective stabilization. This goal often is achieved through the use of inotropic support. Classic inotropic agents (beta-adrenergic agonists and phosphodiesterase III inhibitors) can provide short-term hemodynamic benefits, but their long-term use has been correlated with poor survival rates. Calcium sensitizers comprise a new drug class that offers hemodynamic and symptomatic improvements without increasing cAMP and intracellular calcium concentrations. These agents enhance contractility without a concurrent increase in the risk of cardiac events and thus represent a significant improvement over classic positive inotropic agents. Levosimendan is the most potent calcium sensitizer to date, exhibiting a unique dual mechanism of action that combines a positive inotropic action mediated via calcium sensitization and a vasodilator property via ATP-dependent potassium channels. Available clinical data suggest that calcium sensitizer agents represent a promising class of inotropic agents in a field that has seen few advances in recent decades.

Arrhythmias, Cardiac↗

PubMed1999

A survey of the sequence-specific interaction of damaging agents with DNA: emphasis on antitumor agents.

This article reviews the literature concerning the sequence specificity of DNA-damaging agents. DNA-damaging agents are widely used in cancer chemotherapy. It is important to understand fully the determinants of DNA sequence specificity so that more effective DNA-damaging agents can be developed as antitumor drugs. There are five main methods of DNA sequence specificity analysis: cleavage of end-labeled fragments, linear amplification with Taq DNA polymerase, ligation-mediated polymerase chain reaction (PCR), single-strand ligation PCR, and footprinting. The DNA sequence specificity in purified DNA and in intact mammalian cells is reviewed for several classes of DNA-damaging agent. These include agents that form covalent adducts with DNA, free radical generators, topoisomerase inhibitors, intercalators and minor groove binders, enzymes, and electromagnetic radiation. The main sites of adduct formation are at the N-7 of guanine in the major groove of DNA and the N-3 of adenine in the minor groove, whereas free radical generators abstract hydrogen from the deoxyribose sugar and topoisomerase inhibitors cause enzyme-DNA cross-links to form. Several issues involved in the determination of the DNA sequence specificity are discussed. The future directions of the field, with respect to cancer chemotherapy, are also examined.

Antineoplastic Agents↗

PubMed1986

A comparison of the bronchodilating effects of a beta-2 adrenergic agent (albuterol) and an anticholinergic agent (ipratropium bromide), given by aerosol alone or in sequence.

We evaluated the effect of anticholinergic and beta-adrenergic inhaled bronchodilators, alone or in sequence, in 11 patients with chronic obstructive pulmonary disease. We compared the agents albuterol and ipratropium bromide when each was used as a single aerosol in the maximal dose. After giving a maximal dose of one agent, we compared the effect of adding the other with that of adding a placebo. When used alone, both bronchodilators significantly increased airflow and relieved hyperinflation, and there was no significant difference between the two. After the improvement with the initial bronchodilator, the subsequent effect of a second inhaled bronchodilator was not greater than that of placebo. These results suggest that in the treatment of chronic obstructive pulmonary disease, these two aerosols are usually equipotent in maximal doses and the addition of a second agent is of no practical value. The data support the prescription of a single inhaled agent in most cases but do not rule out the value of combinations of agents under special circumstances.

Aerosols↗

PubMed1978

Effect of two cancer chemotherapeutic agents on the antibacterial activity of three antimicrobial agents.

Cancer chemotherapeutic agents and antibacterial antibiotics are often given concomitantly. Daunorubicin, cytosine arabinoside, and three antibiotics (gentamicin, amikacin, and ticarcillin) were tested individually and in combinations to determine their antimicrobial activity against Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. These cytotoxic agents are commonly employed in the therapy of acute nonlymphocytic leukemia for remission induction therapy, and these antimicrobial agents are used in infection therapy. The maximum concentrations of the two cytotoxic drugs were chosen to be twice the known peak plasma levels of commonly employed dosage schedules. Neither of the cancer chemotherapeutic agents, alone or in combination, demonstrated bactericidal activity at the levels tested. However, in the presence of these agents, the antimicrobial activity of gentamicin and amikacin, although not that of ticarcillin, was depressed for 11 of 15 K. pneumoniae strains and 8 of 15 P. aeruginosa strains, but for none of the strains of E. coli. This level of decreased activity occasionally resulted in a minimal inhibitory concentration of the tested aminoglycoside well above the standard serum levels. Daunorubicin was more likely to antagonize gentamicin than was cytosine arabinoside.

Amikacin↗