Neurophysiological and anatomical variability of the greater auricular nerve

Micro-porous ethylcellulose (EC) membrane capsules were prepared by dissolving polyvinylalcohol (PVA) particles from membranes which were made of a mixture of EC (a water-insoluble polymer). The pore size was approximately 400 microns. Since the dissolution rate of theophylline from the micro-porous EC membrane capsules was fast, gel-forming polymer, poly(acyclic) acid (Carbomer), was incorporated inside the capsule at 10, 20 or 30 mg. Using test capsules containing 100 microns of theophylline, in vitro dissolution studies were performed. By including Carbomer in capsule formulations, the dissolution rate of theophylline was decreased. However, there were not significant differences in dissolution rates between preparations containing the three different amounts of Carbomer. In vivo evaluation studies using beagle dogs showed that AUC, Cmax and Tmax were inversely proportional to the formulated amount of Carbomer. The capsule containing 20 mg of Carbomer gave plasma theophylline concentrations between 5 and 15 micrograms mL-1, which reflect levels within the therapeutic window. The effect of food intake on the pharmacokinetics of theophylline was also studied with the same capsule. Food increased AUC, Cmax and Tmax, although plasma theophylline levels were maintained within the therapeutic range.     

Application of a colon delivery capsule to 5-aminosalicylic acid and evaluation of the pharmacokinetic profile after oral administration to beagle dogs

Pressure-controlled colon delivery capsule (PCC) containing 5-aminosalicylic acid (5-ASA) for the treatment of inflammatory bowel disease (IBD) was prepared and evaluated by an in vivo experiment using beagle dogs. As a reference drug, sulfasalazine (SASP), prodrug of 5-ASA, was used as a plain gelatin capsule preparation. After the oral administration of SASP at the does of 25.0 mg/kg, the mean time when the plasma 5-ASA concentration reaches to its maximum (Tmax) was 9.0 hr. In the case of 5-ASA administered in PCC, at the doses of 12.5 and 25.0 mg/kg, Tmaxs were 5.3 and 5.3 hr, respectively. Although the time for the first appearance of 5-ASA into the systemic circulation was almost the same value between SASP capsule and PCC containing 5-ASA, longer Tmax was observed from SASP capsule than from PCC. These results suggest that this 5-ASA preparation would be an useful dosage form for the therapy of IBD from the point of avoiding the side effect of sulfapyridine, one of the metabolites of SASP.     

Immunolabelling of collagen types I, III and IV, laminin and fibronectin in the human lens capsule

PURPOSE: To localize collagen types I, III, and IV, laminin and fibronectin in the anterior human lens capsule. MATERIAL AND METHODS: Twenty-one anterior capsules were sampled by capsulorhexis during extracapsular cataract extraction (mean age 71.5). All capsules were labelled by an immunostaining specific for each antibodies. Immunostaining of four capsules was revealed with immunoperoxydase and seventeen using indirect immunofluorescence. RESULTS: Labelling of collagen types I and III was observed throughout the entire thickness of the capsule for each technique, the strongest labelling was found in the base of the epithelial cells with immunofluorescence. Collagen type IV was observed at the base of the epithelial cells whichever technique was used. Laminin could be detected in the inner layer of the capsule, using immunoperoxydase or immunofluorescence. No specific labelling was found for fibronectin using the two techniques. CONCLUSIONS: Different kinds of collagens have been found in capsules, more particularly the type III. The latter does not appear on other ocular basement membrane. Because of this uneven distribution in the capsule's thickness, each collagen might have a specific function.     

In vitro performance of floating sustained-release capsule of verapamil

Capsules filled with mixtures of verapamil, hydroxypropoxyl cellulose (HPC), and effervescent are proposed to provide floating sustained release over 10 hr. The effects of weight filled in the capsule, amount of HPC, and the addition of effervescent on the dissolution kinetics are studied. The conventional capsules were filled with different amounts and weights of the mixtures of verapamil, HPC, and effervescent. The release of verapamil from the capsules followed the Higuchi release model. However, when effervescent was added, a zero-order drug release was observed after the burst phase. The conventional capsule, when filled with active ingredients, polymers, and effervescent, can achieve a zero-order release system. Entrapped air was considered as a barrier to diffusion and matrix relaxation in drug release.     

Determination of extent of formaldehyde-induced crosslinking in hard gelatin capsules by near-infrared spectrophotometry

PURPOSE: To predict the degree of crosslinking from formaldehyde-stressed hard gelatin capsules (HGCs) using near-infrared spectrophotometry (NIR). METHODS: HGCs were exposed to a 150 ppb atmosphere of formaldehyde for 2.25, 4.60, 9.42, 16.0 and 24.0 hours. The capsules were filled with fresh amoxicillin, placed in a 90 degrees conical reflector cone, and scanned in a NIR spectrophotometer. Principal component regression (PCR) was employed to analyze the spectra of the intact capsules. Dissolution profiles were then obtained for each experimental group. RESULTS: The dissolution of amoxicillin from the capsules at pH 1.2 was found to decrease with increasing time of exposure to the formaldehyde atmosphere. A set of principal components (PCs) was formed by a linear combination of the absorbance values at each wavelength scanned. A good correlation was established (r2 = 0.963) when PC values from the NIR spectra of the HGCs were regressed against percentage of amoxicillin dissolved at 45 minutes, at pH 1.2. Water content of the capsules was found to be the largest determinant in the variation between HGC spectra at each exposure time. CONCLUSIONS: NIR spectrophotometry, combined with PCR, was successful at not only predicting dissolution of HGCs exposed to formaldehyde, but also at determining which wavelengths contributed most to spectral variation of these stressed HGCs.     

Importance of dissolution process on systemic availability of drugs delivered by colon delivery system

The relationship between in vitro drug release characteristics from colon delivery systems and in vivo drug absorption was investigated using three kinds of delayed-release systems. 5-aminosalicylic acid (5-ASA), tegafur (FT) and carbamazepine (CBZ) were selected as model drugs. Pressure-controlled colon delivery capsules (PCC) for liquid preparations, time-controlled colon delivery capsules (TCC) for liquid and solid preparations and Eudragit S coated tablets for solid preparations were used in this study. At first, in vitro dissolution tests for all preparations were performed. Drug release from solid preparations was delayed compared to that from liquid preparations with all three drugs. Next, these preparations were administered to fasted beagle dogs. For 5-ASA, the mean Cmaxs (peak level) of Eudragit S coated tablets and PCC were 5.52 and 16.89 micrograms ml-1, respectively. The mean Tmaxs (time when drug reached peak level) were 3.0 and 5.3 h. AUCs were 22.57 and 48.09 micrograms.h ml-1, respectively. For FT, Cmaxs of Eudragit S coated tablet and PCC were 0.87 and 1.46 micrograms ml-1, and Tmaxs were 7.0 and 6.7 h, respectively. AUCs were 9.73 and 15.55 micrograms.h ml-1 and bioavailabilities were 43.79 and 70.84%. For CBZ, the mean Cmaxs of liquid preparations and solid preparations were 0.37 and 0.22 micrograms ml-1, respectively. The mean Tmaxs were 4.7 and 4.3 h. AUCs were 0.673 and 0.392 micrograms.h ml-1. With liquid preparations, drug was thought to contact to the colonic membrane easily because of lack of interference by stools, and to be absorbed well as compared with solid preparations. From these findings, drug release from colon delivery systems and drug dissolution in the colonic lumen are very important factors for the systemic availability of drugs from the colon delivery systems.     

Role of nitric oxide in angiotensin IV-induced increases in cerebral blood flow

Whether a rapid elevation of serum gliclazide concentration in human subjects can be achieved through an acceleration of dissolution of gliclazide from a formulation was examined. A soft gelatin capsule containing PEG 400, PEG 4000, Tween 20 and glycerin was prepared as a formulation that may accelerate dissolution of gliclazide. The in vitro dissolution of gliclazide at pH 7.2 was identical for the soft capsule and conventional tablets, Diamicron and Diberin. However, at pH 1, 2 and 4.0 the dissolution from the soft capsule was more rapid compared to the tablets. When bioavailability parameters were compared following oral administration of the soft capsule and Diamicron to 16 healthy Korean male subjects, the parameters representing the amount of adsorption (i.e. the area under the serum gliclazide concentration vs. time curve up to 24 h, AUC24, and the peak serum concentration Cmax) were not statistically different for both formulations. However, the time required to reach the peak (Tmax) was significantly shorter for the soft capsule than for the Diamicron. Our results, therefore, indicate that a rapid elevation of serum gliclazide concentration following oral administration of a formulation can be achieved by accelerating the in vitro dissolution of gliclazide from the formulation into the acidic buffers. Thus, the rate of gastrointestinal absorption of gliclazide appears to be dependent on its in vivo dissolution rate in gastric fluid. A soft capsule containing a PEG 400 suspension of gliclazide appears to be an appropriate formulation for accelerating the dissolution.     

Immunoblot analysis of proteins associated with HEMA-MMA microcapsules: human serum proteins in vitro and rat proteins following implantation

Human serum proteins and their fragments, associated with hydroxyethyl methacrylate-methyl methacrylate (HEMA-MMA) copolymer microcapsules, were characterized using sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblot analysis. Capsules were incubated with serum for 1 week in vitro and then dissolved in ethanol to also precipitate the adsorbed protein. The precipitate was dissolved in 2% (w/v) SDS (the 'capsule eluate') to be assayed by electrophoresis. The majority of proteins probed for in the immunoblots were detected in the capsule eluates. These included fibronectin, plasminogen, IgG, vitronectin, Factor B, Factor H, Factor I, C3, but not beta-lipoprotein, fibrinogen, HMWK, or IgM. Complement activation fragments were detected in both the immunoblots of the capsule eluates and the medium containing serum without capsules. Thus, the adsorption of these fragments, formed independent of capsule presence, may be partially or completely responsible for the complement fragments associated with capsules. The prevention of complement activation by the addition of 5.8 mM EDTA, at the beginning of the week-long incubation, resulted in fewer low-molecular-weight C3 fragments associated with capsules. Rat proteins were also detected in immunoblots of the eluate of 'free-floating' capsules from the rat peritoneal cavity following implantation for 1 day using anti-human antibodies. Detected proteins included HMWK, fibrinogen, antithrombin III, transferrin, alpha1-antitrypsin, fibronectin, albumin, alpha2-macroglobulin, vitronectin, beta2-microglobulin, Factor B and Factor I. Rat fibrinogen, IgG, and complement C3 fragments were also detected in these immunoblots, but with monoclonal antibodies against the rat proteins.     

Effect of method of delivery of propylene glycol on plasma metabolites of feed-restricted cattle

Methods of administering propylene glycol to reduce plasma nonesterified fatty acids (NEFA) during feed restriction of cattle were evaluated. Treatments were 1) no propylene glycol supplementation, 2) propylene glycol provided as an oral drench once per day, 3) propylene glycol mixed with concentrate and fed separately from forage, or 4) propylene glycol blended as part of the total mixed ration (TMR). Prior to or during feed restriction at 50% of ad libitum intake, propylene glycol was provided once daily at 2.5 ml/kg of body weight. Prior to feed restriction, administration of propylene glycol as an oral drench or mixed with concentrate was more effective in increasing serum insulin than was feeding propylene glycol as part of the TMR. During feed restriction, administration of propylene glycol as an oral drench or mixed with concentrate resulted in higher serum insulin and lower plasma NEFA concentrations than did feeding propylene glycol as part of the TMR. Propylene glycol decreased the molar percentage of ruminal acetate and the ratio of acetate to propionate. Propylene glycol administered as an oral drench or mixed with concentrate and fed separately from forage appeared to be more effective than feeding propylene glycol as part of the TMR for influencing plasma NEFA in cattle during feed restriction.     

A study on gelatin capsule brittleness: moisture tranfer between the capsule shell and its content

Variation in moisture content of the capsule shells either due to the change of storage conditions or the moisture transfer between the capsule shell and its contents may lead to undesired physical properties, such as capsule brittleness and stickiness. DMP 504, a developmental bile-acid sequestrant, is a strongly basic anion-exchange polymer which contains randomly distributed primary, secondary, tertiary, and quaternary amine groups in their hydrochoride salt form. The alkylammonium groups which comprise this polymer form a random network containing a high level of branching and a low level of cross-linking. DMP 504 is very hygroscopic and has a tendency to gain or lose moisture with ease. The transfer of moisture from the capsule shell to DMP 504 powder contained in a hard gelatin capsule can be expected, and if a low water content of the capsule shell is achieved, the capsules become brittle and fracture easily. The sorption isotherm for DMP 504 was generated by storing the drug substance under various relative humidity conditions. After equilibrium, the moisture contents for the samples of individual isotherm points were measured by thermogravimetric analyses. This report applies the sorption-desorption moisture transfer (SDMT) model to predict the equilibrium relative humidity in a system containing DMP 504 in hard gelatin capsules and to establish target loss on drying values for DMP 504 and the capsule shell. Application of this SDMT model resulted in finding a solution to the brittleness problem. The moisture levels of capsule shells and contents for two formulations in a 12-month stability program are also reported here. Results of this study further demonstrate that the SDMT model can be used as a tool to guide the formulator to select optimal initial moisture contents for the empty capsule shell and the formulation to avoid the incidence of brittle capsule problems.     

GCr15轴承钢表面渗硼层生长动力学与机械性能

对GCr15轴承钢表面渗硼层的生长动力学与机械性能进行了研究.采用固体渗硼的方法,在1123、1173、1223和1323 K温度条件下,分别保温处理2、4、6和8 h,进行渗硼层制备.采用光学显微镜、扫描电镜、X射线衍射仪、维氏硬度计等对制备的渗硼层进行组织观察与性能分析,并通过试验数据对渗硼层的生长动力学特性进行了研究.研究结果表明:试样表面获得了均匀致密的渗硼层,渗硼层的相成分主要是FeB和Fe₂B;渗硼层的厚度随处理温度与保温时间的增加而增厚,变化范围为33.4~318.5 μm;渗硼层的表面硬度随处理温度及保温时间的增加而增大,主要是由于随着渗硼层厚度的增加,高硬度FeB相的含量上升,低硬度Fe₂B相的含量下降,表面硬度HV_0.1变化范围为1630~1950,与基体组织相比,提高了5~6倍;渗层截面硬度测试结果表明,渗层与基体之间有较宽的硬度梯度过渡;通过Arrhenius公式,对渗硼层的生长动力学方程进行了推导,可知B元素在GCr15轴承钢中的扩散激活能为188.595 kJ·mol-1,对推导的动力学方程进行了试验验证,结果表明最大误差仅4.93%,可有效的实现对渗层厚度的预测.      

Experimental hypoxemic hypoxia: changes in R2* of brain parenchyma accurately reflect the combined effects of changes in arterial and cerebral venous oxygen saturation

PURPOSE: The objective of this study was to develop and evaluate a pulsatile drug delivery system based on an impermeable capsule body filled with drug and an erodible plug placed in the opening of the capsule body. METHODS: The erodible plugs were either prepared by direct compression followed by placing the tablets in the capsule opening or by congealing a meltable plug material directly within the capsule opening. The disintegration/erosion properties of these plugs were determined and optimized for the final delivery system. In order to assure rapid drug release of the capsule content after erosion of the plug, various excipients (fillers, effervescent agents) and drugs with different solubilities were evaluated. The lag time prior to drug release and the subsequent drug release were investigated as function of capsule content, plug composition, plug preparation technique, plug hardness, weight, and thickness. RESULTS: The erosion time of the compressed plugs increased with increasing molecular weight of the hydrophilic polymer (e.g. hydroxypropyl methylcellulose, polyethylene oxide), decreasing filler (lactose) content and decreased with congealable lipidic plugs with increasing HLB-value and inclusion on surfactants. For complete and rapid release of the drug from the capsule body, effervescent agents had to be included in the capsule content. The drug delivery system showed typical pulsatile release profiles with a lag time followed by a rapid release phase. The lag time prior to the pulsatile drug release correlated well with the erosion properties of the plugs and, besides the composition of the plug, could be controlled by the thickness (weight) of the plug. CONCLUSIONS: A single-unit, capsular-shaped pulsatile drug delivery system was developed wherein the pulsatile release was controlled by the erosion properties of a compressed or congealed plug placed within the opening of the capsule opening.     

基于人工神经网络模型的Ti-6Al-4V合金离子氮化层厚度、硬度预测

利用人工神经网络技术研究Ti-6Al-4V合金离子氮化层厚度、硬度与热处理工艺参数之间的关系。以钛合金离子氮化工艺试验为基础,构建以离子氮化温度、保温时间、压力为输入参数,离子氮化层厚度、硬度为输出变量的3层BP神经网络模型,探究模型学习训练过程的最优化算法与神经元个数,预测合金离子氮化层厚度与硬度值。预测结果表明,该模型的综合复相相关系数为0.978 45,网络预测值与样本值相似度较高。获得该合金最优化离子氮化工艺区间,温度为850~880 ℃,保温时间为16 h,压力为200~300 Pa,合金氮化层厚度大于85 μm,硬度大于1 000HV。从而可为钛合金复杂零件离子氮化工艺-组织-性能控制研究提供新的方法与思路。     

基于人工神经网络模型的Ti-6Al-4V合金离子氮化层厚度、硬度预测

利用人工神经网络技术研究Ti-6Al-4V合金离子氮化层厚度、硬度与热处理工艺参数之间的关系。以钛合金离子氮化工艺试验为基础,构建以离子氮化温度、保温时间、压力为输入参数,离子氮化层厚度、硬度为输出变量的3层BP神经网络模型,探究模型学习训练过程的最优化算法与神经元个数,预测合金离子氮化层厚度与硬度值。预测结果表明,该模型的综合复相相关系数为0.978 45,网络预测值与样本值相似度较高。获得该合金最优化离子氮化工艺区间,温度为850~880 ℃,保温时间为16 h,压力为200~300 Pa,合金氮化层厚度大于85 μm,硬度大于1 000HV。从而可为钛合金复杂零件离子氮化工艺-组织-性能控制研究提供新的方法与思路。     

Preparation and transplantation of photoreceptor sheets

PURPOSE: Photoreceptor (PR) transplantation may be a treatment for blindness secondary to PR degeneration. We studied different technical aspects of PR-sheet preparation. METHODS: Geographic variation in the thickness of the cat PR layer (from the outer segments to the outer plexiform layer) and inner retina (width of the remainder of the retina) was studied. PR sheets (cat and human) were prepared through gelatin embedding and subsequent vibratoming or excimer laser ablation. Cat PR sheets were evaluated after transplantation. RESULTS: The thickness of the cat PR layer and inner retina varied in different regions. The superior central retina, including the area centralis, was thickest (PR layer: 115-123 microm, entire retina: 225-230 microm, in fixed tissue). The peripheral retina was approximately 40% thinner than the center. Fresh retina was approximately 7.9% thicker than the fixed retina. Both vibratomy and excimer laser ablation removed the inner retina, leaving a PR-layer sheet with good morphology. To produce good quality PR sheets with vibratomy, use of different gelatin concentrations (2% to 35%) at various stages of sheet preparation was crucial. To produce PR sheets of uniform thickness with excimer laser ablation, control of fluid on the retinal surface was critical. Twenty-four hours after PR transplantation surgery, donor PR cells were well oriented and in close contact with host retinal pigment epithelial cells. Gelatin supporting the transplant dissolved as early as 100 min after surgery. CONCLUSIONS: We confirmed and expanded the work of previous investigators and showed that cat and human PR sheets can be manufactured using vibratomy or excimer laser ablation. This preparation provides a well oriented and organized PR cell layer after transplantation.     

Antiarrhythmic effect of solvents: propylene glycol, benzyl alcohol

Propylene glycol and benzyl alcohol, the main constituents of most solvent vehicles, display a pronounced antiarrhythmic-antifibrillatory effects, when injected intravenously into animals (dogs, rats) with spontaneous or drug-induced arrhythmias. The antiarrhythmic dose for propylene glycol amounts to 0.2-0.3 ml/kg of a 70 per cent solution and, for benzyl alcohol to 0.2-0.4 ml/kg of a 4 per cent solution in physiologic saline, respectively. Similar effects were also obtained by the combined injection of propylene glycol + benzyl alcohol, in proportions which correspond to the formulae of numerous commercial "solvents" (vehicles): 2 to 20 per cent solutions of benzyl alcohol in 70 per cent propylene glycol (0.05-0.2 ml/kg). The mechanisms which might be responsible for the antiarrhythmic activity of solvents are discussed: lengthening of the effective refractory period, local and general anaesthetic effects, changes of osmolarity. The intravenous injection of propylene glycol and/or benzyl alcohol, in high doses, produces intravascular haemolysis. Clinical investigations are recommended as to the potential, beneficial or toxic effects of drug solvents, especially upon the cardiocirculatory system.     

The tuberculin skin test in BCG-vaccinated individualse]

Endoscopy was undertaken to examine the gastroduodenal mucosa of 24 healthy dogs after seven days and again after 28 days of oral non-steroidal anti-inflammatory drug (NSAID) administration. The dogs were divided into four groups. One group received ketoprofen (1 mg/kg every 24 hours), one group carprofen (2 mg/kg every 12 hours for seven days followed by 2 mg/kg every 24 hours), a third group meloxicam suspension (0.2 mg/kg every 24 hours), and the last group gelatin (one capsule every 24 hours). Serum biochemical and complete blood count parameters did not change significantly after NSAID administration. Gastroduodenal lesions were observed in 17 dogs, but in all cases these were mild to moderate. The dogs receiving gelatin or carprofen showed the fewest and the least severe lesions, although there was no statistically significant difference between the three test drugs and the control group (P < or = 0.05). None of the dogs showed any clinical signs related to the gastrointestinal lesions.     

The pulmonary absorption of aerosolized and intratracheally instilled rhG-CSF and monoPEGylated rhG-CSF

PURPOSE: The objective of this study was to highlight differences in the pulmonary absorption of a monoPEGylated rhG-CSF and rhG-CSF after intratracheal instillation and aerosol delivery. METHODS: Male Sprague Dawley rats (250 g) were anesthetized and intratracheally instilled (IT) with protein solution or were endotracheally intubated and administered aerosol for 20 min via a Harvard small animal ventilator. A DeVilbiss "Aerosonic" nebulizer containing 5 ml of protein solution at approximately 3 mg/ml was used to generate aerosol. The volume of protein solution deposited in the lung lobes was estimated to be approximately 13 microliters after delivery of Tc-99m HSA solutions. The PEGylated proteins consisted of a 6 kDa (P6) or 12 kDa PEG (P12) linked to the N-terminus of rhG-CSF. rhG-CSF also was administered IT in buffers at pH 4 and pH 7 and in dosing volumes ranging from 100 to 400 microliters. Blood samples were removed at intervals after dosing and the total white blood cell counts (WBC) were determined. Plasma was assayed for proteins by an enzyme immuno assay. RESULTS: The plasma protein concentration v. time profiles were strikingly different for aerosol v. IT delivery. The Cmax values for rhG-CSF and P12 after aerosol delivery were greater than found after IT (Aerosol: 598 +/- 135 (ng/ml) rhG-CSF; 182 +/- 14 P12 v. IT: 105 +/- 12 rhG-CSF; 65.9 +/- 5 P12). Similarly, Tmax was reached much earlier after aerosol administration (Aerosol: 21.7 +/- 4.8 (min) rhG-CSF; 168 +/- 31 P12 v. IT: 100 +/- 17 rhG-CSF; 310 +/- 121 P12). Estimated bioavailabilities (F(lung)%) were significantly greater via aerosol delivery than those obtained after IT (Aerosol: 66 +/- 14 rhG-CSF; 12.3 +/- 1.9 P12 v. IT: 11.9 +/- 1.5 rhG-CSF; 1.6 +/- 0.1 P12). An increase in circulating WBC counts was induced by all proteins delivered to the lungs. The rate and extent of absorption of rhG-CSF was not influenced by the pH employed nor the instilled volume. CONCLUSIONS: Estimates of bioavailability are dependent upon the technique employed to administer drug to the lungs. Aerosol administration provides a better estimate of the systemic absorption of macromolecules.     

Biotransformation, excretion, and nephrotoxicity of the hexachlorobutadiene metabolite (E)-N-acetyl-S-(1,2,3,4, 4-pentachlorobutadienyl)-L-cysteine sulfoxide

The disposition of ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4- triazol-1-ylmethyl) quinoline-3-carboxylate (CAS 158146-85-1, TAK-603) after single oral dosing of 14C-labeled TAK-603 ([14C]TAK-603) at 10 mg/kg to rats and dogs was studied. In rats, the concentration of unchanged drug in plasma reached a peak (Cmax, 0.31 microgram/ml) 2 h (Tmax) after dosing of TAK-603 and declined biphasically with apparent half-lives (t 1/2 alpha, t 1/2 beta) of 1.5 and 3.6 h. In dogs, Tmax, Cmax, T 1/2 alpha, and t 1/2 beta were 1.7 h, 0.36 microgram/ml, 1.2, and 10.8 h, respectively. [14C]TAK-603 dosed orally was absorbed quantitatively in rats, while the extent of absorption in dogs was 54%. The bioavailability of TAK-603 was 53% and 42% in rats and dogs, respectively. In rats, 14C was distributed widely in various tissues, with relatively high concentrations in the liver, adrenal gland, and gut. The elimination of 14C from the thyroid was slower than that from other tissues. Unchanged TAK-603 and its pharmacologically active metabolite, M-I, which has the same potency as TAK-603, were distributed in articular soft tissues and synovial fluids, as target tissues, in rats and dogs, respectively. After oral administration of [14C]TAK-603, most of the 14C dosed was excreted within 48 h in rats and within 96 h in dogs. In both animals, a greater amount of the 14C dosed was excreted in feces than in urine. In biliary duct cannulated rats given [14C]TAK-603 intraduodenally, 69% of the dose was excreted in bile, and biliary 14C in part underwent enterohepatic circulation.     

Effects of oral administration of anti-inflammatory doses of prednisone on thyroid hormone response to thyrotropin-releasing hormone and thyrotropin in clinically normal dogs

Prednisone was given orally to 12 dogs daily for 35 days at an anti-inflammatory dosage (1.1 mg/kg of body weight in divided dose, q 12 h) to study its effect on thyroxine (T4) and triiodothyronine (T3) metabolism. Six of these dogs were surgically thyroidectomized (THX-Pred) and maintained in euthyroid status by daily SC injections of T4 to study peripheral metabolism while receiving prednisone; 6 dogs with intact thyroid gland (Pred) were given prednisone; and 6 additional dogs were given gelatin capsule vehicle as a control group (Ctrl). Baseline T4 concentration after 4 weeks of treatment was not significantly different in dogs of the THX-Pred or Pred group (mean +/- SEM, 2.58 +/- 0.28 or 3.38 +/- 0.58 micrograms/dl, respectively) vs dogs of the Ctrl group (2.12 +/- 0.30 micrograms/dl). A supranormal response of T4 to thyrotropin was observed in dogs of the Pred group, but the T4 response to thyrotropin-releasing hormone was normal. Baseline T3 concentration in dogs of both steroid-treated groups was significantly (P < 0.05) lower after 2 and 4 weeks of prednisone administration vs pretreatment values, but normalized 2 weeks after prednisone was stopped. Free T3 (FT3) and T4 (FT4) fractions and absolute FT3 and FT4 concentrations were not altered by prednisone administration. Reverse T3 (rT3) concentration in vehicle-treated Ctrl dogs (26.6 +/- 3.5 ng/dl) was not different from rT3 concentration in dogs of the THX-Pred (25.7 +/- 4.3 ng/dl) and Pred (28.9 +/- 3.8 ng/dl) groups after 4 weeks of medication.(ABSTRACT TRUNCATED AT 250 WORDS)