Results Of Toxicity Studies Research Articles

TiO2 nanoparticles dose, application method and phosphorous levels influence genotoxicity in Rice (Oryza sativa L.), soil enzymatic activities and plant growth

The present study focused on investigating the effect of titanium dioxide nanoparticles (TiO2NPs) on rice (Oryza sativa L.) growth and changes in soil health in two contrasting soil textures (silt-loam and clay). Moreover, response of rice to different methods of TiO2NPs application and phosphorous fertilizer levels were also evaluated. For toxicity assessment, pot experiment was carried out. TiO2NPs (0, 500, 750 mg kg−1) were applied and plants were grown till vegetative stage. After harvesting, physiological parameters, stress assay, soil microbial and enzymatic activities were determined. Based on the results of toxicity study, impact of three methods of TiO2NPs application (foliar, irrigation, soil) and four phosphorous fertilizer levels (0, 10, 20, 40 mg kg−1) on rice growth were assessed. During the 1st phase, results showed an adverse effect of TiO2NPs on plant growth and soil microorganisms in both soil textures at 750 mg kg−1. The H2O2 production, lipid peroxidation and leaf membrane injury index were increased by 4.3–, 2.4–, and 1.9–folds in clay soil upon 750 mg kg−1 TiO2NPs application. Likewise, at the same level of TiO2NPs; microbial biomass, dehydrogenase, and respiration were decreased by 0.91–, 0.79–, and 0.78– folds respectively. In 2nd phase, maximum shoot length, biomass, phosphorous uptake and rice grain protein content were observed under application of TiO2NPs (500 mg kg−1) through irrigation method in combination with 40 mg P kg−1. However, 20 and 40 mg P kg−1 performed equally well upon TiO2NPs application and the results were not statistically significant. The results suggest that 750 mg kg−1 of TiO2NPs negatively affect plant growth and soil enzymatic activities. Moreover, combined application of TiO2NPs (500 mg kg−1) through irrigation and 20 mg P kg−1 is recommended to be the optimum for growth of rice plant.

New Small Molecule Drugs for Thrombocytopenia: Chemical, Pharmacological, and Therapeutic Use Considerations

This review provides details about three small molecules that were recently approved by the FDA for the treatment of thrombocytopenia. The new treatments include lusutrombopag, avatrombopag, and fostamatinib. The first two drugs are orally active thrombopoietin receptor (TPO-R) agonists which are FDA-approved for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. Fostamatinib is orally active prodrug that, after activation, becomes spleen tyrosine kinase (SYK) inhibitor. Fostamatinib is currently used to treat chronic and refractory immune thrombocytopenia in patients who have had insufficient response to previous treatment. Chemical structures, available dosage forms, recommended dosing, pharmacokinetics, results of toxicity studies in animals, most frequent adverse effects, significant outcomes of the corresponding clinical trials, and their use in specific patient populations are thoroughly described. Described also is a comparative summary of the different aspects of five currently available therapies targeting TPO-R or SYK for the treatment of thrombocytopenia.

Biogenic synthesis of gold nanoparticles from Terminalia arjuna bark extract: assessment of safety aspects and neuroprotective potential via antioxidant, anticholinesterase, and antiamyloidogenic effects.

The development of neuroprotective drugs through eco-friendly production routes is a major challenge for current pharmacology. The present study was carried out to synthesize gold nanoparticles (AuNPs) through biogenic route using ethanolic bark extract of Terminalia arjuna, a plant of high interest in Asian traditional medicine, and to evaluate its neuroprotective effects. The synthesized AuNPs were characterized by UV-Vis spectroscopy, FTIR spectroscopy, XRD, FESEM, EDX, HRTEM, DLS, and zeta potential analyses. UV-Vis spectroscopy showed a characteristics SPR absorption band at 536nm specific for AuNPs. XRD, TEM, and FESEM analyses revealed the formation of face-centered cubic crystalline, spherical and triangular shaped AuNPs, with size ranging between 20 and 50nm. DLS and ZP analysis illustrated that the average size of AuNPs was 30nm, which was found to be stable at 45mv. The neuroprotective potential of AuNPs was evaluated by assessing its antioxidant, cholinesterase inhibitory, and antiamyloidogenic activities. AuNPs showed dose-dependant inhibition of acetylcholinesterase and butyrylcholinesterase with IC50 value of 4.25±0.02 and 5.05±0.02μg/ml, respectively. In vitro antioxidant assays illustrated that AuNPs exhibited the highest reducing power and DPPH radical scavenging activity. In addition, AuNPs also efficiently suppressed the fibrillation of Aβ and destabilized the preformed mature fibrils. Results of toxicity studies in PBMC and adult zebra fish illustrated that AuNPs are non-toxic and biocompatible. Overall, our results highlighted the AuNPs promising potential in terms of antioxidant, anticholinesterase, antiamyloidogenic effects, and non-lethality allowing us to propose these nanomaterials as a suitable candidate for the development of drugs helpful in the treatment of neurodegenerative disorders like Alzheimer's disease. Graphical abstract ᅟ.

ChemInform Abstract: Medicinal Uses, Phytochemistry, and Pharmacology of Origanum onites (L.): A Review

AbstractReview: 103 refs.

Medicinal Uses, Phytochemistry, and Pharmacology of Origanum onites (L.): A Review.

Origanum onites L., known as Turkish oregano, has great traditional, medicinal, preservative, and commercial importance. It is used for the treatment of several kinds of ailments, such as gastrointestinal disorders, diabetes, high cholesterol, leukemia, bronchitis, etc. In this review, traditional use, phytochemistry, and pharmacology of O.onites reported between 1988 and 2014 were discussed. This review was prepared based on literature survey on scientific journals and books from libraries and electronic sources, such as Web of Science, PubMed, Scopus, Google Scholar, etc. All databases were searched up to June 2014. Several different classes of terpenoids, triterpene acids, phenolic acids, hydroquinones, flavonoids, hydrocarbons, sterols, pigments, fatty acids, tocopherols, and inorganic compounds were detected mainly in the aerial parts of this plant. Pharmacological studies revealed that extracts obtained from several solvents and individual compounds exhibited antimicrobial, antiviral, antioxidant, insecticidal, anticancer, hepatoprotective, genotoxic, antidiabetic, cholinesterase inhibitory, anti-inflammatory, analgesic activities, etc. O.onites, in general, exhibited remarkable activity potential in almost all test systems. The results of toxicity studies indicated that O.onites did not show any significant toxicity and mutagenicity on Drosophila and Salmonella. Toxicity of the extracts/essential oils and also individual compounds should be evaluated on mammalian cells to ensure their safety. The bioactivity of individual compounds aside from terpenoids should also be assessed in detail. Additionally, mode of action for the bioactive compounds should be evaluated to understand the complex pharmacological effects of these phytochemicals.

The assessment of sewage sludge gasification by-products toxicity by ecotoxicologial test.

The process of gasification of sewage sludge generates by-products, which may be contaminated with toxic and hazardous substances, both organic and inorganic. It is therefore important to assess the environmental risk associated with this type of waste. The feasibility of using an ecotoxicological tests for this purpose was determined in the presented study. The applied tests contained indicator organisms belonging to various biological groups (bacteria, crustaceans, plants). The subject of the study were solid (ash, char) and liquid (tar) by-products generated during gasification (in a fixed bed reactor) of dried sewage sludge from various wastewater treatment systems. The tested samples were classified based on their toxic effect. The sensitivity of the indicator organisms to the tested material was determined. In-house procedures for the preparation for toxicity analysis of both sewage sludge and by-products generated during the gasification were presented. The scope of work also included the determination of the effect of selected process parameters (temperature, amount of gasifying agent) on the toxicity of gasification by-products depending on the sewage sludge source. It was shown that both the type of sewage sludge and the parameters of the gasification process affects the toxicity of the by-products of gasification. However, the results of toxicity studies also depend on the type of ecotoxicological test used, which is associated with a different sensitivity of the indicator organisms. Nevertheless, it may be concluded that the by-products formed during the gasification of the low toxicity sewage sludge can be regarded as non-toxic or low toxic. However, the results analysis of the gasification of the toxic sludge were not conclusive, which leads to further research needs in this area.

Synthesis, culture medium stability, and in vitro and in vivo zebrafish embryo toxicity of metal-organic framework nanoparticles.

Metal-organic frameworks (MOFs) are among the most attractive porous materials available today. They have garnered much attention for their potential utility in many different areas such as gas storage, separation, catalysis, and biomedicine. However, very little is known about the possible health or environmental risks of these materials. Here, the results of toxicity studies on sixteen representative uncoated MOF nanoparticles (nanoMOFs), which were assessed for cytotoxicity to HepG2 and MCF7 cells in vitro, and for toxicity to zebrafish embryos in vivo, are reported. Interestingly, there is a strong correlation between their in vitro toxicity and their in vivo toxicity. NanoMOFs were ranked according to their respective in vivo toxicity (in terms of the amount and severity of phenotypic changes observed in the treated zebrafish embryos), which varied widely. Altogether these results show different levels of toxicity of these materials; however, leaching of solubilized metal ions plays a main role.

Orbifloxacin

The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of orbifloxacin (CAS No.113617–63-3), a family of synthetic antimicrobial agents of fluoroquinolones, based on a written application for the marketing approval of new veterinary medicinal products and its attached documents. All the in vivo data were negative in studies on genotoxicity of orbifloxacin, although some in vitro data were positive. Therefore, FSCJ concludes that orbifloxacin has no genotoxicity relevant to human health. Orbifloxacin showed photogenotoxicity in vitro and in vivo through the indirect action to DNA, suggesting that orbifloxacin has no photogenotoxicity relevant to human health. No carcinogenicity was observed in a 2 year carcinogenicity study in rats. From the results of toxicity studies, FSCJ judged it appropriate to use a lowest-observed-adverse-effect level (LOAEL) of 12.5 mg/kg bw/day observed in a 30-day subacute toxicity study in dogs, and to specify the toxicological ADI as 0.013 mg/kg bw/day, applying a safety factor of 1000 to this LOAEL. Microbiological ADI was estimated to be 0.012 mg/kg bw/day based on the VICH (the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products) guideline 36. FSCJ specified the ADI of orbifloxacin as 0.012 mg/kg bw/day which is smaller than the toxicological ADI.

Background Data for General Toxicology Parameters in RccHanTM:WIST Rats at 8, 10, 19 and 32 Weeks of Age

Recently, RccHanTM:WIST (Wistar Hannover) rats were introduced to toxicity studies in Japan. The present study was performed to obtain control data for general toxicological parameters as an aid for interpretation of results in toxicity studies using this strain of rats. Four test groups comprising of 25 male and 25 female RccHanTM:WIST rats were housed for 2, 4, 13 or 26 weeks from 6 weeks of age and observed and examined for clinical observation, body weight, food consumption, urinalysis, hematology, blood chemistry, organ weight, necropsy and/or histopathology. Ophthalmological examination was not conducted in this study, and the data in this report were obtained from an ongoing 104-week background study in RccHanTM:WIST rats. These data were compared with the historical control data of CD(SD) (Sprague-Dawley) and/or F344 (Fischer) rats. The body weights of RccHanTM:WIST rats were lower than those of CD(SD) rats and higher than those of F344 rats. The ophthalmological examination revealed a greater incidence of focal corneal opacity. Histopathology revealed focal mineralization of the cornea and Berlin blue-positive pigmentation in the epididymal interstitium as well as hepatocytes. Other than the above, some minor differences were found in urinalysis, hematology, blood chemistry and organ weights as compared with CD(SD) rats.

Are gadolinium-based contrast media really safer than iodinated media for digital subtraction angiography in patients with azotemia?

Gadolinium chelates, intended as intravenous contrast media for magnetic resonance imaging, have been regarded as nonnephrotoxic and recommended to replace iodinated contrast media in patients with azotemia who are undergoing digital subtraction angiography (DSA). High intraarterial doses (up to 220 mmol of gadodiamide) have been used, with a 40% incidence of nephropathy. The authors discourage the use of gadolinium for DSA for several reasons. (a) There exist no randomized studies comparing the nephrotoxic effects of gadolinium-based and iodinated media at equal-attenuating concentrations and doses. (b) Gadolinium-based media are hypertonic, a pathogenetic factor in contrast medium-induced nephropathy after renal angiography, with an osmolality two to seven times that of plasma. Iodinated media in concentrations that are equally attenuating with gadolinium-based media can be made isotonic. (c) In vitro measurements indicate that 0.5 mol/L gadolinium chelates are equally attenuating with 60-80 mg iodine per milliliter at the commonly used 70-90-kV range used for DSA. Thus, 50 mL of 0.5 mol/L gadolinium chelate ( approximately 0.3 mmol/kg in an 80-kg person) would be equally attenuating with a dose of 3-4 g of iodine in an iodinated medium (eg, 50 mL iohexol at 60-80 mg I/mL or 10-13 mL at 300 mg I/mL). (d) By combining these data on attenuation and results of toxicity studies in mice, the general toxicity of gadolinium chelates may be six to 25 times higher than that of equal-attenuating doses of iodinated media at 70-kV DSA. Thus, the authors believe that at equal-attenuating doses for DSA, modern iodinated contrast media should result in a lower toxic load on the body than with presently available gadolinium chelates.

Safety Evaluation of Synthetic β-Carotene

The safety of β-carotene was reassessed by evaluating the relevant literature on the beneficial and adverse effects of β-carotene on cancer and, in particular, by evaluating the results of toxicity studies. β-Carotene appeared neither genotoxic nor reprotoxic or teratogenic, and no signs of organ toxicity have been found in subacute, subchronic, or chronic oral toxicity studies in experimental animals receiving doses of up to 1000 mg/day β-carotene per kg body weight via the diet. Synthetic β-carotene did not exert any carcinogenic effect in Sprague-Dawley rats or in CD1 mice. An enhanced risk of lung cancer was found in two human intervention studies. Although dose and (timing of) exposure, smoking status, and imbalance of antioxidant defense have been recognized as potential factors accounting for the outcome of these studies, a conclusive explanation has not yet been found. It is concluded that exposure to β-carotene resulting in mean plasma concentrations of no more than 2.2 µmol/l (1.2 µg/ml) is safe to the general population. By contrast, in heavy smokers higher plasma concentrations may be associated with a higher lung cancer risk.

The use of microbiological end-points in the safety evaluation and elaboration of maximum residue limits for veterinary drugs intended for use in food producing animals.

The safety evaluation of veterinary drugs intended for use in food producing animals relies heavily on the results of toxicity studies in laboratory animals, supported where possible by any data resulting from human exposure. The general approach involves the calculation of an acceptable daily intake which in turn can be used to elaborate maximum residue limits. It is an approach used in the European Union, in other countries and at the international level. In recent years, concern has been expressed over the presence of microbiologically active residues of veterinary drugs in food and their possible effects on the human gastrointestinal microflora. Methodologies for conducting microbiological safety studies have been investigated and approaches to microbiological safety assessments have been debated. The whole approach has proved to be controversial, partly because there are considerable doubts over the ability of low concentrations of antibiotic substances to produce adverse effects on the human gut flora and partly because there are no validated methods for testing for these attributes. This paper reviews the problems in some detail and discusses the regulatory consequences.

水田用除草剤テニルクロールの開発

From the viewpoint of agricultural situations in Japan, safe agrochemicals for mammals and useful livings in environment have been strongly preferred. Among several hundred compounds prepared, the present authors found a novel chloroacetanilide “Thenylchlor” which shows high herbicidal activity at the dosage of 27 g/1, 000 m2 (10 are) for barnyardgrass in paddy field. Thenylchlor is extraordinarily secure herbicide, being judged from the results of toxicity studies and the studies related to environment. To launch Thenylchlor in the market, we made quite a big effort for the economical production of the key intermediate, “3-methoxythiophene” and the final product, “Thenylchlor” and established a series of epoch-making processes. Getting the registration in 1993, we commercialized Thenylchlor as mixed flowables. The sales are growing smoothly year by year, and the major sales product, “Kusamets Flowable”, became a top three best seller among many herbicides for paddy field rice in 1996.

Acute Toxicity of Insecticides to Micromus tasmaniae (Neuroptera: Hemerobiidae) and Chrysoperla carnea (Neuroptera: Chrysopidae): LC50 and LC90 Estimates for Various Test Durations

The acute toxicities of 6 insecticides deriving from 5 different insecticide classes were assessed in laboratory tests with Micromus tasmaniae (Walker) after different post treatment periods (1.5-360 h). The aim was to determine optimal test durations for the calculation of stable (i.e., no further change over time) LC 50 and LC 90 estimates. In addition, the responses of M. tasmaniae to the above insecticides were compared with those for Chrysoperla carnea (Stephens). In short-term evaluations (≤24 h), methyl-parathion caused the highest mortality in M. tasmaniae. The toxicity of methyl-parathion did not change significantly over time; however, the toxicity of azinphos-methyl, cypermethrin, fenoxycarb, and diflubenzuron did. Minimum posttreatment periods of 48, 72, 120, and 360 h were necessary before stable lethal concentrations estimates could be determined for azinphos-methyl, cypermethrin, fenoxycarb, and diflubenzuron, respectively. At the point of stable LC 50 and LC 90 , the latter compounds were more toxic to M. tasmaniae than methyl-parathion. Tebufenozide did not cause any mortality in either lacewing species. Comparisons between the 2 lacewings species showed that M. tasmaniae was more sensitive to methyl-parathion, azinphos-methyl, and cypermethrin than C. carnea, whereas the toxicity offenoxycarb and diflubenzuron was similar to both species. The results demonstrate the importance of carrying out acute toxicity studies to an adequate posttreatment period to avoid underestimating the toxicities of insecticides. In addition, the comparisons with C. carnea demonstrated that the results of toxicity studies cannot be extrapolated to closely related families.

Combustion of diesel fuel from a toxicological perspective. II. Toxicity.

Epidemiological data and results of toxicity studies in experimental animals indicate the possible health risk of diesel exhaust exposure. Acute effects of this exposure include odor, eye irritations, lung function decrements, cardiovascular symptoms, and some non-specific effects. Most of these effects are reported among persons highly exposed to diesel exhaust. Lung function decrements are reported as chronic effects. Another chronic effect that has been studied extensively among occupationally exposed persons in lung cancer. In addition to lung cancer, but at a less frequent rate, an enhanced incidence of bladder cancer is reported. The carcinogenic action of diesel exhaust exposure is ascribed to effects of the soot particles, particle-associated organics, and/or gas phase compounds. Direct effects of the particle load may include retardation of lung clearance, inflammation, and increased cell proliferation. These effects were all demonstrated in rodents. The particles may also prolong the residence time of particulate organics or induce the generation of reactive oxygen species. These compounds are known to react with macromolecules, causing lipid peroxidation, DNA damage, and/or activation of other genotoxic substances such as polycyclic aromatic hydrocarbons (PAHs). However, these results have not yet been confirmed in mammals in vivo. A direct interaction of particles with lung tissue is also suggested as a cause of cancer but a mechanism for this interaction has not yet been proposed. Organics associated with the particles are known to contain genotoxic properties attributable to PAHs and their derivatives. A number of these compounds are also identified as carcinogens in animal studies. However, it is not clear whether parent PAHs, their nitro-, oxy-, alkylated, or heterocyclic derivatives, or possibly other compounds are principally responsible for inducing tumors in the lungs of animals after diesel exhaust exposure. Furthermore, the mechanism of the bioavailability of these organics is not completely understood. The effects of gas phase constituents on the carcinogenic properties of the particles and/or particle-associated organics either have not been investigated or the findings have been inconclusive.

Preexposure temperature acclimation and diet as modifying factors for the tolerance of golden ide ( Leuciscus idus melanotus) to short-term exposure to 4-chloroaniline

The influence of different temperature and nutrition regimes on the acute toxicity of 4-chloroaniline to golden ide ( Leuciscus idus melanotus) was investigated. Acute toxicity was determined over 48 hr at 20°C without feeding after a 2-day acclimation period. In an attempt to reveal underlying mechanisms accounting for diet- and temperature-related differences in the toxicant resistance of golden ide, biochemical and quantitative morphological parameters of the liver, a central organ in the xenobiotic metabolism of fish, were recorded throughout the 12-week acclimation period. In cold-acclimated fish, acute toxicity of 4-chloroaniline was 40% higher than in fish acclimated to 20°C. If compared to 20°C, preacclimation to 14°C was characterized by a lower specific growth rate, an increase of hepatic glycogen, and a decrease of body and liver lipid deposits. The organelle composition of hepatocytes was not significantly altered by temperature acclimation. For the nutrition experiment, commercially available diets A and B of similar crude composition were used. Acute toxicity of 4-chloroaniline was 60% lower with diet B than with diet A. If compared to diet B, diet A induced a higher specific growth rate and increased hepatocellular volume of endoplasmic reticulum and Golgi fields, whereas glycogen and lipid of the liver as well as body lipid contents were reduced. The toxicity of 4-chloroaniline was correlated with the development of the endoplasmic reticulum, the major site of biotransformation enzymes. A consistent correlation with lipid contents could not be established. Results illustrate not only that assay conditions during the actual test may profoundly interact with results of toxicity studies, but also that maintenance conditions before the test can have significant consequences on results. In order to improve reproducibility of the results of acute toxicity tests, more consideration should be given to the standardization of pretest maintenance conditions of fish.

An Idiopathic Febrile Necrotizing Arteritis Syndrome in the Dog: Beagle Pain Syndrome,

The clinical, laboratory, and pathologic features of a syndrome in dogs characterized by intermittent pain, fever, neutrophilia, and necrotizing arteritis are described to alert others involved in toxicity testing to the existence of this disorder. It is considered that this idiopathic syndrome is a latent condition, the expression of which can be precipitated in predisposed dogs by experimental treatment, and thus, its occurrence could complicate interpretation of toxicity studies. We have observed the disorder in 14 beagle dogs. The syndrome is rare and most cases for study were supplied by the breeder. Typical clinical signs observed included evidence of pain when the mouth was opened, grunting when lifted, and standing with an arched back and lowered head. Appetite was usually reduced. Body temperature was elevated (e.g., 104-106 degrees F). There was progressive, bilateral atrophy of temporal and cervical musculature. Such signs have been observed to persist unremittingly or, more commonly, with periods of expression and remission. Neutrophilic leukocytosis and thrombocytosis were present. Hemoglobin and hematocrit were usually slightly decreased. Serum total protein was usually normal but albumin was reduced and alpha-2 globulins were markedly increased. Rheumatoid factor was elevated in several dogs. Arteritis was observed histologically and was characterized by necrosis, intimal proliferation, neutrophil and mononuclear cell infiltration in the media and periarterial tissues, and hemorrhage. Amyloidosis was observed in several dogs. The cause of this disorder is unknown. Knowledge of the distinct features of this syndrome should obviate complication of interpretation of results in toxicity studies and hopefully will lead to studies of this syndrome to provide an understanding of its etiopathogenesis.

Pyrolysis—high-resolution mass spectrometry of biological materials

In a diseased state in man or animals a change at eh molecular level might occur. A pyrolysis-high-resolution mass spectrometric method has been developed to measure these changes. The mass spectra are used as fingerprints. A similar approach is reported using low-resolution mass spectrometry. The difference between low resolution and high resolution is that the number of mass spectral lines is strongly increased and therefore also the information content. As a result, a change at the molecular level will be more pronounced in high-resolution mass spectra. As an application, the results of toxicity studies on Daphnia magna are given. The experiments were performed with paraoxon, parathion and malathion. The changes at the molecular level in Daphnia magna appear to be substance-dependent.

SPECIES DIFFERENCES IN EXCRETION PATTERN AND TOXICITY OF SULBENICILLIN

The results of toxicity studies on sulbenicillin (SB-PC) in rats, dogs and monkeys as well as distribution and excretion patterns in these animals and humans were reviewed and, taking into account the results of its clinical trials in 6376 patients, the following conclusion was obtained. 1. There was marked species difference in excretion and distribution of SB-PC. In dogs, unlike other animals including humans, excretion of SB-PC into bile was larger than that into urine, and its distribution in the liver at an extraordinarily high concentration was observed. When SB-PC was intravenously injected to dogs at various dosages, transient but dose-related hepatotoxic signs appeared, and a few animals died at 1500 mg/kg/day. 2. There were no abnormalities in rats treated intramuscularly with 2500 mg/kg/day of SB-PC for 6 months except for a local irritation at the injection site. The excretion pattern of SB-PC in cynomolgus monkeys was quite similar to that in humans, and they tolerated daily intravenous injections at 1500 mg/kg/day for one month well. None of the animals showed any significant changes in hematological, biochemical and histological examinations. 3. In clinical trials of SB-PC, intravenous infusion at 30 g (15 gx 2)/day/man did not affect the normal function of the liver and kidneys in the patients. The above results were compared with those reported for carbenicillin (CB-PC) and it was indicated that SB-PC is less toxic than CB-PC in humans.

Allopurinol and Cytotoxic Agents

ABSTRACT To the Editor.— The publication of Allopurinol and Cytotoxic Drugs, (227:1036, 1974) raised a number of questions concerning the use of allopurinol with cytostatic agents. The article described an increased incidence of bone marrow in patients with nonleukemic forms of malignancies who received allopurinol in combination with cytotoxic agents. The criteria were leukopenia or thrombocytopenia or both, and whether or not the physician believed there was an adverse effect.Cytotoxic drugs, by definition, cause depression of rapidly proliferating tissues, most commonly those elements cited in the article, leukocytes and thrombocytes. Some degree of leukopenia should be present to assure the clinician that optimal levels of the toxic drug are reaching the tumor. When results of toxicity studies are reported in which the base-line drugs are themselves cytotoxic, the magnitude of the leukopenia or thrombocytopenia in each group must be compared. Oncology is a clinical science that relies heavily on