2-Week Inhalation Study of N-Monomethylformamide in Rats

2-Week Inhalation Study of yV-Monomethylformamide in Rats. KENNEDY,G. L., JR., FERENZ, R. L., BURGESS, B. A., AND STULA, E. F.(1990). Fundam. Appl. Toxicol. 14, 810–816. N-Monomethylformamide(MMF) is a chemical intermediate with potential for inhalationexposure in humans. Human exposures to MMF have occurred incancer chemotherapy but have been limited due to liver damage.To assess the toxicity of MMF, groups of 15 male rats each wereexposed by nose-only inhalation, 6 hr/day, 5 days/week, for2 weeks to either 0 (control), 50, 130, or 400 ppm MMF. Fiverats per group were killed following the 10th exposure, fivewere killed after a 14-day postexposure recovery period, andfive rats were used to determine urinary MMF excretion. Parametersinvestigated were clinical observations and body weights, clinicalpathology, and gross and microscopic pathology including organweights. Liver damage occurred in rats exposed to either 130or 400 ppm. This was detected both by increases in serum enzymeactivity indicative of liver injury and by microscopic changesin the liver. The changes were more severe in the 400-ppm ratsand were partially reversible. Other organs were not adverselyaffected by inhalation of MMF. The amount of MMF excreted inthe urine was dependent on the exposure concentration and MMFwas present 14 days postexposure at the higher exposure levels.The no-observed-effect level under the conditions of this experimentwas 50 ppm.     

Chlorpyrifos: A 13-Week Nose-Only Vapor Inhalation Study in Fischer 344 Rats

Fischer 344 rats were exposed by the nose-only inhalation routeto chlorpyrifos vapors at concentrations of 0, 5.2, 10.3, or20.6 ppb, 6 hr/day, 5 days/week for 13 weeks. The exposure concentrationswere limited by the low vapor pressure of chlorpyrifos (theoreticalmaximum vapor concentration of 25 ppb at 25?C). No treatment-relatedsigns of toxicity or changes in body weights were detected duringthe course of the study. Unnalysis, hematology, clinical chemistry,organ weights, gross pathologic, and histopathologic evaluationswere performed at the end of the study with no treatment-relatedeffects observed. In addition, no differences from controlswere noted in plasma, red blood cell, or brain cholinesteraseactivities. The results of this study indicate that the no-observed-effectlevel for chlorpyrifos vapor was the highest attainable concentration,20.6 ppb, in male and female Fischer 344 rats.     

Isopropanol 13-Week Vapor Inhalation Study in Rats and Mice with Neurotoxicity Evaluation in Rats

This study was conducted to evaluate the possible subchronictoxicity as well as neurobehavioral effects of isopropanol,a widely used industrial and commercial solvent. Five groups,each containing 10 Fischer 344 rats/sex and 10 CD-I mice/sex,were exposed for 6 hr/day, 5 days/week, for 13 weeks to isopropanolvapor at concentrations of 0 (control), 100, 500, 1500, or 5000ppm. An additional 15 rats/sex were assigned to the 0, 500,1500, and 5000 ppm groups for assessment of neurobehavioralfunction. No exposure-related mortalities occurred during thestudy. The narcotic effects of isopropanol were noted only duringexposures at 1500 and 5000 ppm. These signs, noted during exposures,were typically absent following exposures. The only clinicalsigns observed following exposures included swollen perioculartissue, perinasal encrustation, and ataxia for rats of the 5000ppm group. Neurobehavioral evaluations indicated no changesin any of the parameters of the functional observational battery;however, increased motor activity for female rats in the 5000ppm group was noted at Weeks 9 and 13. Decreases in body weightand body weight gain were observed for rats of the 5000 ppmgroup at the end of the first week of exposure. During the remainingweeks, increases in body weight and/or body weight gain wereobserved for rats of the 1500 and 5000 ppm groups. No exposure-relatedeffects on body weight were noted for male mice; however, increasedbody weight and body weight gain were observed for female miceof the 5000 ppm group. Increases or decreases in food and waterconsumption generally corresponded to changes in body weightand body weight gain. Various changes in clinical pathologyparameters were observed for rats and female mice of the 5000ppm group. The only organ weight effect noted was an increasedrelative liver weight in both sexes of rats of and female miceof the 5000 ppm group. At necropsy, three were no gross lesionsdetermined to be exposure related. Furthermore, the only microscopicchange observed was hyaline droplets within the kidneys of allmale rats (including controls). The size and frequency of thehyaline droplets were increased for the isopropanol exposuregroups compared to the control group. These differences werenot clearly concentration related, although this microscopicchange was most pronouced in the high-concentration group. Neuropatholo0gicexamination revealed no exposure-related lesions in the centralor peripheral nervous system of exposed rats. Thus, repeatedexposures to isopropanol for 13 weeks produced toxic effctsonly at the highest concentration and a kidney change in malerats of unknown biological significance.     

Dimethylethanolamine: Acute, 2-Week, and 13-Week Inhalation Toxicity Studies in Rats

Dimethylethanolamine (DMEA) is a volatile, water-soluble aminethat has applications in the chemical and pharmaceutical industries.These studies evaluated the acute and subchronic inhalationtoxicity of DMEA. Acute (4-hr) exposures of Wistar rats to DMEAvapor resulted in an LC5O value (95% confidence limits) of 1641(862–3125)ppm. Clinical signs of nasal and ocular irritation, respiratorydistress, and body weight loss were observed in rats exposedto 1668 ppm DMEA and higher. In the 2-week study, F-344 ratsexposed to 98, 288, or 586 ppm DMEA for 9 days (6 hr/day) duringan 11-day period also exhibited signs of respiratory and ocularirritation (except the 98 ppm group). All animals of the 586ppm group and 4 of 15 male rats of the 288 ppm group died. Bodyweight values for the 288 ppm group were reduced to about 75%of preexposure values, while the 98 ppm group gained 35% lessweight than controls. Statistically significant differencesin clinical pathology parameters (288 ppm group) and in organweight values (288 and 98 ppm groups) probably resulted fromthe decreased food consumption and not from specific targetorgan toxicity. In the groups evaluated histologically (the98 and 288 ppm groups) the eye and nasal mucosa were the primarytarget organs. In the 13-week subchronic study, F-344 rats wereexposed to 0, 8, 24, or 76 ppm DMEA for 6 hr/day, 5 days/weekfor 13 weeks. The principal exposure-related changes were transientcorneal opacity in the 24 and 76 ppm groups; decreased bodyweight gain for the 76 ppm group; and histopathologic lesionsof the respiratory and olfactory epithelium of the anteriornasal cavity of the 76 ppm group and of the eye of several 76ppm group females. Rats maintained for a 5-week recovery periodonly exhibited histological lesions of the nasal tissue, withthe lesions being decreased in incidence and severity. DMEAacts primarily as an ocular and upper respiratory tract irritantand toxicant at vapor concentrations of 76 ppm, while 24 ppmor less produced no biologically significant toxicity in rats.Thus, 24 ppm was considered to be the no-observable-effect level.     

Dipropylene Glycol Monomethyl Ether: A 13-Week Inhalation Toxicity Study in Rats and Rabbits

Dipropylene Glycol Monomethyl Ether. A 13-Week Inhalation Studyin Rats and Rabbits. LANDRY, T. D., AND YANO, B. L. (1984).Fundam. Appl. Toxicol. 4, 612–617. Fischer 344 rats (10/sex/exposureconcentration) and New Zealand White rabbits (7/sex/exposureconcentration) were exposed to 0, 15, 50, or 200 ppm (0, 91,303, or 1212 mg/m3) of dipropylene glycol monomethyl ether (DPGME)for 6 hr/day, 5 days/week for 13 weeks. Criteria of responseincluded general observations, body weights, clinical chemistry,hematology, urinalyses (rats only), necropsy, organ weights,and histopathology. There were no effects attributed to exposureto DPGME at any exposure concentration in either male or femalerats or rabbits. The highest concentration tested (200 ppm)was approximately 40% of a saturated DPGME atmosphere. Basedon the low vapor pressure of DPGME, and results in this 13-weekstudy, DPGME appears to have a low subchronic vapor inhalationtoxicity hazard.     

Propylene Glycol Monomethyl Ether: A 13-Week Inhalation Toxicity Study in Rats and Rabbits

Propylene Glycol Monomethyl Ether: A 13-Week Inhalation ToxicityStudy in Rats and Rabbits. Landry, T.D., Gushow, T.S. and Yano,B.L. (1983). Fundam. Appl. Toxicol. 3:627–630. Fischer344 rats (10/sex/exposure concentration) and New Zealand Whiterabbits (7/sex/exposure concentration) were exposed to 0, 300,1000, or 3000 ppm (0, 1.09, 3.62, or 10.9 mg/L) of propyleneglycol monomethyl ether (PGME) for 6 hr/da, 5 da/wk, for 13weeks. Minimal effects were observed in animals exposed to 3000ppm. Indications of a transient central nervous system depressionwere observed in rats and rabbits exposed to 3000 ppm. Therewere also small increases (6 to 8%) in mean relative liver weightsof 3000 ppm exposed male and female rats relative to controls.Minimal histologic effects were observed in the livers of 3000ppm exposed female rats. These were suggestive of hepatocellularhypertrophy but were without evidence of degenerative changes.There was an increase in the urinary pH of male rats exposedto 3000 ppm PGME for 4 weeks, but this was not evident after12 weeks of exposure. There was no indication of histopathologicaleffects in the kidneys of either species, and there were nohematological effects. No treatment-related effects were foundin either rats or rabbits exposed to 300 or 1000 ppm.     

13-Week Oral Toxicity Study of Captafol in F344/DuCrj Rats

13-Week Oral Toxicity Study of Captafol in F344/DuCrj Rats TAMANO,S., KURATA, Y., SHIBATA, M.-A., TANAKA, H., OGISO, T., AND ITO,N. (1991). Fundarm Appl Toxicol. 17,390–398. Captafolfed at concentrations of 0,0.075, 0.15,0.3, and 0.6% to bothsexes of F344 rats for 13 weeks produced dose-related decreasesin body weight in males and females given 0.15% or higher concentrationsA dose-dependent decrease in urinary pH was observed in malesreceiving 0.3 or 0.6% and in females given 0.15% or higher concentrationsof captafol. The 0.3 and 0.6% doses produced slight increasesin leukocyte count and glutamic-pyruvic transaminase activityin females, along with a mild increase in alkaline phosphataseactivity in the 0.6% case. The liver and kidney-to-body weightratios were increased in both male and female rats. Histopathologicalchanges were observed in the forestomach, liver, and kidney.Squamous cell hyperplasia and edema accompanied by polynuclearleukocyte infiltration and dilation of vessels in the laminapropria were observed in the forestomach of both sexes given0.15% or higher concentrations Oval cell proliferation was apparentaround Glisson's sheath in the livers of females given 0.3 and0.6% captafol. Multifocal appearance of karycytomegaly and tubularcell atypia in the proximal tubules of the kidney was foundin the 0.3 and 0.6% groups of both sexes.     

Chronic Study of Triprolidine for Oncogenicity in Mice

Triprolidine hydrochloride was fed to groups of 60 B6C3F1 miceper sex at dietary levels of 0, 500, 2000, or 4000 ppm (as thefree base) for up to 2 years. Up to 12 mice of each sex anddose group were terminated after 65 weeks for hematology andclinical chemistry. The control and high-dose groups were examinedhistologically. A complete histopathological examination wasperformed on the remaining 48 mice from each dose group whenremoved from study due to moribund condition, early death, orterminal euthanization at 105 weeks. Triprolidine did not significantlyalter the survival of either sex. High-dose male and mid- andhigh-dose female body weights were significantly less than controlsat the end of the study. Significant trends toward lower frequencywith increasing dose were noted in females for fatty changein the liver and lymphomas (combination of lymphocytic, mixed,and histiocytic lymphomas). Similar negative trends in maleswere for lymphocytic cellular infiltration in multiple organsand lung alveolar/bronchiolar adenomas or the combination ofalveolar/bronchiolar adenomas or carcinomas. Significant trendstoward increased frequency with increasing dose were found infemale mice for lymphocytic infiltration in multiple organsand cytoplasmic alterations of the acinar cells of the parotidgland. Similar positive trends were found in males for cytoplasmicalterations of the parotid gland and various he-patocellularchanges (e.g., hypertrophy and altered foci). While there wasa positive dose-response trend for hepatocellular adenomas inmales the combination of these and hepatocellular carcinomaseliminated the significant trend, and it was concluded thatthere was no evidence of a carcinogenic response to triprolidinein B6C3F1 mice. No effects considered to be adverse were observedin either sex at 500 ppm. Body weight depression was noted infemales and liver toxicity was indicated in males at 2000 and4000 ppm.     

Chronic Feeding Study of Pyrilamine in Fischer 344 Rats

The antihistamine, pyrilamine maleate, was fed for up to 2 yearsto groups of 57 Fischer 344 (F344) rats of each sex at dietarylevels of 0, 300,1500, or 3000 ppm (free base). Eight or nineof these rats per sex and dose group were killed at 65 weeksto analyze hematology and clinical chemistry in all groups andhistopathology of control and high-dose animals. Histopathologyalso was performed on all dead or moribund rats and on all thatsurvived for 2 years. Average daily exposures were 11 to 150mg/kg pyrilamine compared to human dosages up to 3 mg/kg. Pyrilaminetreatment did not reduce survival. Final body weights were reducedrelative to controls (mid-dose males, 93%, females, 82%: high-dosemales, 82%, females, 70%). The incidences of inflammation ofthe nasolacrimal duct (chronic in females; suppurative in males),liver cytoplasmic vacuolization (males), and the combinationof animals with either liver basophilic or clear cell foci (males)tended to significantly increase with dose. Adrenal pheochromocytomas,mammary gland fibroadenomas, and neoplasms of the clitoral gland,thyroid ccell, and pituitary gland all tended to decrease withincreasing dose in females. In males only preputial gland neoplasmsexhibited a similar negative trend. While two ovarian granulosathecacell benign tumors occurred in high-dose females, these werethought to be a random occurrence. There was no evidence forthe carcinogenicity of pyrilamine in F344 rats in the currentstudy.     

Four Week Feeding Toxicity Study with Phenylphosphinic Acid in Rats

Abstract

Phenylphosphinic acid was fed in graded concentrations of either 0 (control), 100, 1,000, or 10,000 ppm to rats for 28 days. These concentrations provided average daily doses of 8, 76, and 779 mg/kg (males) and 9, 83, and 859 mg/kg (females). No signs of adverse response were detected at any concentration up to the highest levels tested, 10,000 ppm or 779 (male) or 859 (female) mg/kg. Parameters measured were clinical signs, growth, neurobehavior, ophthalmology, and clinical and anatomical pathology. Phenylphosphinic acid is very low in toxicity following 31 days of feeding to the rat.     

Triprolidine radioimmunoassay: disposition in animals and humans

A hapten derivative of triprolidine, bearing an acrylic acid side chain ortho to the pyridine ring nitrogen atom, was synthesized and coupled to bovine serum albumin. Immunization of New Zealand White rabbits with the resulting drug-protein conjugate resulted in the production of antisera capable of binding a radioiodinated tyramine conjugate of the triprolidine hapten derivative at high antiserum dilutions (1:70,000-1:150,000). These antisera were used to develop a radioimmunoassay (RIA) for triprolidine in human plasma with a sensitivity limit of 0.1 ng/mL (0.01 ng of actual mass). The known hydroxymethyl and carboxyl metabolites of triprolidine cross-reacted weakly (less than 2 and less than 0.05%, respectively) with this antiserum. The RIA could be used for the direct analysis of triprolidine in human and rabbit plasma, but not for rat or dog plasma, presumably due to the presence of other interfering substances (possibly metabolites). The validity of the RIA procedure in human plasma was demonstrated by comparative analysis of a number of samples by quantitative TLC (r = 0.985, slope = 1.076). The assay was employed to describe the pharmacokinetics of triprolidine in the rabbit (t 1/2, beta = 1.7 h). The assay had adequate sensitivity to detect low circulating drug concentrations in humans after therapeutic oral doses and also substantiated previous disposition experiments with triprolidine in humans (t 1/2, beta = 2.27 h). TLC analysis demonstrated that the absolute oral bioavailability of triprolidine (1-mg/kg dose) in the dog was low (4%). A comparison of triprolidine pharmacokinetic parameters in dogs, rabbits, rats, and humans revealed considerable similarity in elimination characteristics in these species.     

Phenyl Isocyanate-Induced Asthma in Rats Following a 2-Week Exposure Period

This study was conducted to assess the toxic effects of repeatedinhalation exposures to phenyl isocyanate vapor in male Wistarrats. Rats were exposed to design concentrations of 0, 1, 4,7, or 10 mg/m³ phenyl isocyanate air for 2 weeks (6 hr/day,5 days/week). The rats were assessed for normal toxicologicparameters, and pulmonary function tests, blood gas measurements,and analysis of bronchoalveolar lavage fluid (BALF) parameterswere utilized shortly after exposures as well as 2 months postexposure.The results indicated that rats exposed to 7 and 10 mg/m³ experienceddecreased body weights, hypoactivity, hypothermia, signs ofrespiratory tract irritation, delayed onset of mortality, andchanges in organweights. In addition, pulmonary function testsdemonstrated decreased forced expiratory flow rates and quasistaticlung compliance. Arterial blood gases showed an arterial hypoxemiaand changes consistent with a pronounced venous-admixture-likeperfusion, suggesting severe mismatch of the ventilation/perfusionrelationship. Delayed onset of mortality appeared to be associatedwith respiratory acidosis and hypoxernia. Biochemical and cellularcomponents in BALF complemented the results of the functionalalterations. Remarkable changes were indicated by increasedactivities of the BALF parameters, -GPT, protein, and sialicacid. Histopathological findings provided evidence of increasedsecretory cell activity and a concentration-dependent increasein goblet cell hyperplasia at concentrations of 4 mg/m³ andabove. In rats exposed to 7 mg/m³ further findings consistedof intraluminal inflammation of airways, hypertrophia of bronchialsmooth muscle, epithelial desquamation, and eosinophilia ofthe airways. A complete regression of morphological lesionswas not found in the animals exposed to 4 mg/m³ and above atthe 2-month postexposure time period. In conclusion, the damageto the airways comprise most of the features characteristicof chronic airway inflammation or asthma.     

2,4-Pentanedione: 9-Day and 14-Week Vapor Inhalation Studies in Fischer-344 Rats

2,4-Pentanedione: 9-Day and 14-Week Vapor Inhalation Studiesin Fischer-344 Rats. DODD, D.E., GARMAN, R.H., PRITTS, I.M.,TROUP, C.M., SNELLINGS, W.M, AND BALLANTYNE, B. (1986). Fundam.Appl. Toxicol. 7, 329–339. Fischer-344 rats, in groupsof 10 males and 10 females, were exposed for 9 days (6 hr/day)to 2,4-pentanedione (2,4-PD) vapor at mean concentrations of805, 418, 197, and 0 (control) ppm. No deaths occurred, andthe only adverse signs were of sensory irritation (partial closureof eyelids, periocular and perioral wetness) at 805 ppm. Alsoat 805 ppm were decreased body and organ weights, lymphocytosis,and moderate inflammation of the nasal mucosa. At 418 ppm therewas a decrease in body weight gain and mild inflammation ofthe nasal mucosa. Apart from minimal nasal mucosa] inflammation,there were no effects at 197 ppm. In the subchronic (14-week)study, rats were exposed (6 hr/day; 5 days/week) to 650, 307,101, and 0 (control) ppm of 2,4-PD vapor, using groups containing20 males and 20 females, with half being sacrificed at the endof the exposure period and the remainder kept for a 4-week postexposurerecovery period. An additional 10 males were added to the 650and 0 ppm groups for glutaraldehyde perfusion and subsequentelectron microscopic examination of sciatic nerves. At 650 ppm,all females and 10 of 30 males died between the second and sixthweeks of exposure. These animals had acute degenerative changesin the deep cerebellar nuclei, vestibular nuclei and corporastriata, and acute lymphoid degeneration in the thymus. Sevenof 15 male survivors of the 650 ppm group (combined 14-weekand recovery sacrifices) had gliosis and malacia in the samebrain regions, minimal squamous metaplasia in the nasal mucosa,decreased body and organ weights, lymphocytosis, and minor alterationsin serum and urine chemistries. No ultrastructural evidenceof peripheral neuropathy was observed. Except for central neuropathy,many of the adverse effects at 650 ppm were less marked in the4-week recovery animals. No deaths occurred at 307 ppm, butfemales had slightly decreased body weight gains, and in bothsexes there were minor alterations in hematology, serum chemistry,and urinalysis parameters, which were not present in the 4-weekrecovery animals. Rats exposed to 101 ppm showed no differencesfrom the control rats. Subchronic exposure to 650 ppm of 2,4-PDvapor causes serious adverse biological effects. Under thesestudy conditions, the minimum-effects concentration was 307ppm, and the no-adverse effects concentration was 101 ppm.     

高效液相色谱法测定氨酚曲麻片中盐酸曲普利啶的含量

目的改进氨酚曲麻片中盐酸曲普利啶含量的测定方法。方法采用高效液相色谱法,色谱柱为HypersilBDSC18,流动相为甲醇-0.4%醋酸铵溶液-三乙胺(70∶30∶0.1),流速为1ml/min,检测波长为233nm,进样量为10μl。结果盐酸曲普利啶检测浓度在28.8~86.3μg/ml范围内与峰面积积分值线性关系良好(r=0.9998),平均回收率为100.5%(RSD=0.5%)。结论本方法简便、准确度高、重现性好,可用于本品的含量测定与质量控制。     

Assessment of Toxicity of o-Nitrochlorobenzene in Rats following a 4-Week Inhalation Exposure

Assessment of Toxicity of o-Nitrochlorobenzene in Rats followinga 4-Week Inhalation Exposure. NAIR, R.S., JOHANNSEN, F.R., LEVINSKAS,G.J., AND TERRILL, J.B. (1986). Fundam. Appl. Toxicol. 7, 609-614.o-Nitrochlorobenzene (ONCB) is a chemical intermediate usedfor the synthesis of various industrial chemicals. To evaluatethe subchronic toxicity of this compound, three groups of 15male and 15 female Sprague-Dawley rats were exposed to ONCBvapor 6 hr/day, 5 days/week for 4 weeks at target concentrationsof 10, 30, or 60 mg/m³. A control group of 15 animals/sex wasexposed to room air in a separate inhalation chamber. Concentrationsof ONCB in the chambers were determined at least three timesa day using a uv spectrophotometer. Parameters monitored inthis study included observation for signs of toxicity, bodyweights, ophthalmoscopic exam, hematology, and clinical chemistry.At necropsy, selected organ weights were recorded and over 35tissues/animal were examined microscopically for all controland high-exposure level animals. No mortality was observed inthis study. Mean body weights of all groups were comparableto controls. Animals exposed to the mid and high concentrationsof ONCB showed a significant increase in blood methemoglobinand a significant decrease in hemoglobin, hematocrit, and redblood cell counts. Spleen and liver weights (absolute and relativeto body weight) were significantly increased for these two groups.Microscopic changes, observed only in the spleen, included increaseddegree of extramedullary hematopoiesis and hemosiderosis. Thesedata suggest that the toxicity of ONCB is comparable to thatof its structural analog, p-nitrochlorobenzene. Thus these twocompounds should have similar workplace exposure limits.     

A Short-Term Feeding Study with Deoxynivalenol (Vomitoxin) Using Rats

A Short-Term Feeding Study with Deoxynivalenol (Vomitoxin) UsingRats. ARNOLD, D. L., KARPINSKI, K. F., MCGUIRE, P. F., NERA,E. A., ZAW1DZKA, Z. Z., LOK, E., CAMPBELL, J. S., TRYPHONAS,L., AND SCOTT, P. M. (1986). Fundam. Appl. Toxicol 6,691–696.Groups of 25 male and 25 female Sprague-Dawley rats were feddiets containing 0, 0.25, 0.5, or 1.0 mg of deoxynivalenol (DON)/kgbody wt for approximately 9 weeks. Each animal's body weightand feed consumption were measured weekly. Upon terminationof the study, each animal's body, heart, liver, spleen, thymus,and kidneys were weighed. A hematological assessment and a 16-parameterserum evaluation were conducted and 8 animals from each groupwere randomly selected to receive tritiated thymidine iv toassess mitotic activity in the esophagus, jejunum, and spleen.A statistically significant, dose-related decrease in body weightgain was observed for all treated females, but only the malesdosed at 1.0 mg/kg were found to have a treatment-related weightgain suppression. The reduced body weight was attributed toa reduced feed consumption. Reductions that were observed inabsolute organ weights, were not apparent after adjusting forbody weight suppression. No dose-related hematological findingswere found. Serum chemistry changes included increased concentrationsof chloride and decreased concentrations of CO₂ and albumin,but only in the females. No histopathological lesions were attributedto DON treatment, but significant decreases in thymidine labelingoccurred in the spleens and jejunums from the males dosed at1.0 mg/kg.     

曲普利啶与马来酸氯苯那敏治疗荨麻疹的比较

目的 :观察曲普利啶对荨麻疹的疗效。方法 :117例患荨麻疹病人 ,男性 4 5例 ,女性 72例 ;年龄33.0±s 1.5a。分为治疗组 60例 ,对照组 57例。病程分别为 2 .0± 1.7a与 2 .0± 1.9a。治疗组用曲普利啶胶囊 5mg ,po ,bid ;对照组用马来酸氯苯那敏 8mg ,po ,tid。疗程为急性荨麻疹 7d ,慢性荨麻疹 30d。结果 :曲普利啶组总有效率为 83% ,与马来酸氯苯那敏组的 53%比较有显著性差异 (P<0 .0 1)。结论 :曲普利啶是治疗荨麻疹有效药物     

Population Pharmacodynamic Modeling of Exenatide After 2-Week Treatment in STZ/NA Diabetic Rats

The purpose of this study is to investigate the effect of exenatide on glycemic control following two administration routes in a streptozotocin/nicotinamide (STZ/NA)-induced diabetic rat model, and to develop a pharmacodynamic model to better understand the disease progression and the action of exenatide in this experimental system. Two groups of STZ/NA-induced diabetic rats were treated for 2 weeks with 20 (μg/kg/day) of exenatide, either by continuous subcutaneous (SC) infusion or two SC injections daily. Disease progression was associated with slower glucose utilization. Fasting blood glucose was significantly reduced by 30 mg/dL in both treatment groups at the end of 2 weeks. A subsequent intravenous glucose tolerance test (IVGTT) confirmed an improved glucose tolerance in both treatment groups; however, overall glycemic control was similar between groups, likely due to the relatively low and short-term drug exposure. A population indirect response model was successfully developed to simultaneously describe the STZ/NA-induced disease progression, responses to an IVGTT, and exenatide effects on these systemic challenges. The unified model includes a single set of parameters, and the cumulative area under the drug–receptor concentration curve was used as a unique driving force to account for systemic effects long after drug elimination.     

90-Day Feeding and One-Generation Reproduction Study in Crl:CD BR Rats with 17{beta}-Estradiol

Over the past several years, there has been increasing concernthat chemicals and pesticides found in the environment may mimicendogenous estrogens, potentially producing adverse effectsin wildlife and human populations. Because estrogenicity isone of the primary concerns, a 90-day/one-generation reproductionstudy with 17ß-estradiol was designed to set doselevels for future multigenerational reproduction and combinedchronic tox-icity/oncogenicity studies. The purpose of thesestudies is to evaluate the significance of a range of responsesas well as to provide benchmark data for a risk assessment forchemicals with estrogen-like activities. This 90-day/one-generationreproduction study was conducted in male and female Crl: CDBR rats using dietary concentrations of 0, 0.05, 2.5, 10, and50 ppm 17ß-estradiol. Endpoints were chosen in orderto evaluate both subchronic and reproductive toxicity. In addition,several mechanistic/biochemical endpoints were evaluated fortheir usefulness in follow-up studies. In the P₁ generation,dietary administration of 2.5, 10, and 50 ppm 17ß-estradiolproduced dose-dependent decreases in body weight, body weightgain, food consumption, and food efficiency. At 10 and 50 ppm17ß-estradiol, minimal to mild nonregenerative anemia,lymphopenia, decreased serum cholesterol (50 ppm only), andaltered splenic lymphocyte subtypes were also observed in theP₁ generation. Additionally, at these concentrations, therewere changes in the weights of several organs. Evidence of ovarianmalfunction, characterized by reduced numbers of corpora luteaand large antral follicles, was observed at 2.5 ppm 17ß-estradioland above. Other pathologic changes in males and females fed10 and 50 ppm 17ß-estradiol included centrilobularhepatocellular hypertrophy; diffuse hyperplasia of the pituitarygland; feminiza-tion of the male mammary glands; mammary glandhyperplasia in females; increased number of cystic folliclesin the ovary; hypertrophy of the endometrium and endometrialglands in the uterus; degeneration of seminiferous epithelium;and atrophy of the testes and the accessory sex glands. In thereproduction portion of this study, rats fed 10 or 50 ppm 17ß-estradioldid not produce litters. While there was no evidence that the50 ppm treated rats mated, 33.3% of the rats fed 10 ppm matedbut did not produce litters. No effects on mating and fertilityindices were observed in rats fed 0.05 and 2.5 ppm 17ß-estradiol.Pup weights at birth were statistically decreased relative tocontrol in the groups fed 0.05 and 2.5 ppm 17ß-estradiol.Weights of the rats in the 0.05 ppm group recovered by postnatalday 4 and remained similar to control throughout the remainderof the study. The mean gestation length of the 0.05 ppm groupwas slightly, albeit not statistically significantly, shorter(0.5 days) than that of the control group, which may have contributedto the decrease in birth weight of the 0.05 ppm group. In contrast,the weights of the F₁ generation rats fed 2.5 ppm 17ß-estradiolremained decreased relative to the control group throughoutthe study. Parental administration of 17ß-estradioldid not alter anogenital distance in male or female pups. Theonset of sexual maturation, as measured by day of preputialseparation in males and day of vaginal opening in females, wasdelayed in male rats fed 2.5 ppm (by 8.2 days) and was hastenedin female rats fed 0.05 and 2.5 ppm (by 1.6 and 8.8 days, respectively).The age at vaginal opening ranged from 26 to 37, 26 to 35, and21 to 25 days for rats fed 0, 0.05, and 2.5 ppm 17ß-estradiol,respectively. Hence, the range of age at vaginal opening wassimilar between the control and 0.05 ppm group. The organ weightand pathologic alterations observed in the adult F₁ generationrats were similar to those observed in the P₁ generation rats.However, in some instances the observed effects, such as histopathologicalfindings in the female reproductive organs, were more severein the F₁ generation than in the P₁ generation. Apparent differencesin sensitivity between the P₁ and F₁ generations may be explainedby the increased daily intake of 17ß-estradiol bythe young F₁ generation rats, in utero exposure, or a combinationof both. Dietary administration of 10 and 50 ppm 17ß-estradiolclearly exceeded a maximum tolerated dose. Future studies areneeded to define the dose-response curve at dietary concentrationsbelow 10 ppm.     

盐酸曲普利啶胶囊在中国健康志愿者体内的药物动力学

目的:研究单剂量和多剂量盐酸曲普利啶胶囊在中国健康志愿者体内的药物动力学特征。方法:健康受试者单次(2.5 mg)或多次(2.5 mg,tid,连续服药6d)口服盐酸曲普利啶胶囊,用LC-MS法测定血浆中曲普利啶浓度,用DAS 2.0处理数据。结果:本法线性良好,精密度、准确度、回收率均符合要求。所得药物动力学参数如下,单剂量:t_(1/2)=(5.88±1.62)h,t_(max)=(2.21±0.62)h,C_(max)=(27.50±6.32)ng·ml~(-1),AUC_(0-∞)=(216.74±67.18)h·ng·ml~(-1),MRT_(0-∞)=8.64±1.24 h。多剂量:t_(1/2)=(6.38±2.58)h,t_(max)=(1.71±0.58)h,AUC_(8S)=139.29±47.22 h·ng·ml~(-1),C_(max)=(27.78±6.52)ng·ml~(-1),C_(min)= (10.12±9.26)ng·ml~(-1),C_(av)=(17.41±5.90)ng·ml~(-1),DF=1.13±0.60。结论:该法灵敏度高,操作简便,盐酸曲普利啶胶囊多剂量给药与单剂量给药的药物动力学参数基本一致,无蓄积,给药后安全性良好。