Effect on dissolution from halving methylphenidate extended-release tablets

Factor V is a single chain glycoprotein that plays an essential role in the regulation of blood coagulation. After initiation of coagulation, factor V is converted into factor Va through limited proteolysis. Factor Va acts as protein cofactor in the prothrombin-activating complex, which is comprised of the serine protease factor Xa, Ca2+ ions and a procoagulant membrane surface. Factor Va accelerates factor Xa-catalysed conversion of prothrombin into thrombin more than 10(4)-fold. The cofactor activity of factor Va in prothrombin activation is down-regulated by activated protein C (APC). The physiological importance of this regulatory pathway is demonstrated by the occurrence of hereditary thrombophilia in individuals with a genetic defect that makes factor Va less sensitive to proteolytic inactivation by APC (APC resistance).     

In vitro dissolution and urinary excretion study of metoclopramide tablets

Changes in cardiac troponin I (cTnI) in Kawasaki disease before and after treatment with intravenous gamma-globulins (i.v.GG) were investigated in 42 cases in order to confirm the usefulness of cTnI as a serological test for the early onset of acute myocarditis and the effectiveness of i.v.GG as treatment for it. The level of cTnI before i.v.GG treatment was increased in 42.9% (18/42), but 89% (16/18) were in the normal range after treatment as shown by improved clinical symptoms and signs; 9.5% (4/42) were treated twice with i.v.GG because of recurrent high fever, with a positive level of cTnI in the second test. Despite the improved clinical symptoms and signs after retreatment with i.v.GG, 4.7% (2/42) continued to have an increased level of cTnI in follow-up studies. In conclusion, the measurement of cTnI is a useful serologic test for the early diagnosis of myocarditis or myocardial cell injury and for confirming the effectiveness of i.v.GG therapy for the cure and prevention of cardiovascular abnormalities in KD patients.     

Polymorphism in anhydrous theophylline--implications on the dissolution rate of theophylline tablets

The objects of this investigation were (i) to prepare and characterize a new anhydrous theophylline phase that is metastable under ambient conditions, and (ii) to prepare model tablet formulations containing either this metastable anhydrate (I*) or stable anhydrous theophylline (I), store them under different relative humidity (RH) conditions, and compare their dissolution behavior. I* was prepared by dehydration of theophylline monohydrate (II). Variable temperature X-ray powder diffractometry of II revealed the following series of transitions: II-->I*-->I. The metastable anhydrate, I*, which has not yet been reported in the literature, appears to be related monotropically to I. It was characterized by ambient and variable temperature X-ray powder diffractometry, Karl Fischer titrimetry, and thermoanalytical techniques (differential scanning calorimetry and thermogravimetric analysis). Tablet formulations containing either I* or I were prepared and stored at 33 and 52% RH (room temperature). The solid state of the drug was monitored by X-ray powder diffractometry and the tablets were subjected to the USP dissolution test. In tablets, I* completely converted to I in < or = 10 days when stored at either 33 or 52% RH. Scanning electron microscopy provided direct visual evidence of recrystallization. This recrystallization was accompanied by a decrease in the dissolution rate of the stored formulations that was so pronounced in the formulations stored at 52% RH that they failed the USP dissolution test. The in situ solid-state transition appears to be responsible for the decrease in dissolution rate observed following storage. Stored tablets containing I showed neither a phase transition nor an alteration in their dissolution behavior.     

Methods to compare dissolution profiles and a rationale for wide dissolution specifications for metoprolol tartrate tablets

The objectives of this work were to apply several profile comparison approaches to dissolution data of four different but bioequivalent metoprolol tartrate tablet formulations to (1) identify the advantages and disadvantages of each approach, (2) quantify the metric for comparing dissolution profiles of each method, (3) determine metric limits that are consistent with the observed bioequivalence, and (4) rationalize the observed metric limits with respect to the role of dissolution in overall metoprolol absorption. Dissolution was performed by the USP monograph method on four formulations of metoprolol tartrate tablets (Lopressor plus fast, medium, and slow dissolving test formulations). Three general approaches to compare dissolution profiles were examined; they were ANOVA-based, model-independent, and model-dependent approaches. It is concluded that model-independent approaches and several model-dependent approaches yielded numerical results that can serve as objective and quantitative metrics for comparing entire dissolution profiles of the four metoprolol tartrate formulations. However, these methods presented complications. Some metrics were dependent on the length of the dissolution profile and the sampling scheme. Results from the pairwise procedures also depended on the pairing assignment of individual profiles. In spite of complications, these methods suggested wide dissolution specification limits. Wide dissolution specifications were rationalized through an analysis of in vitro-in vivo relationships, which indicated metoprolol dissolution from these formulations was not the rate-limiting step; hence, a range of dissolution profiles can be expected to yield equivalent plasma profiles.     

Effects of humidity and temperature on in vitro dissolution of carbamazepine tablets

The rate and extent of dissolution of various approved marketed carbamazepine (CBZ) tablets exposed to 33, 52, 75, and 97% relative humidities at both room temperature and 40 degrees C, and saturated water vapor at room temperature were compared to fresh unstressed tablets. The dissolution data indicate that exposure of CBZ tablets to high humidity and temperature can have a profound effect on tablet disintegration and dissolution. The dissolution rates of some batches of CBZ products exposed to 97% humidity at 40 degrees C or saturated water vapor at room temperature were drastically reduced in only 6-7 days.     

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.     

Rate of dissolution of solid nickel in liquid tin under static conditions

The dissolution kinetics of solid nickel in liquid tin have been investigated under static conditions. The cylindrical nickel specimens were immersed in liquid tin over the temperature range of 551 to 803 K in the reaction time range of 0.9 to 6.0 ks. A natural convection model for mass transfer and the dissolution rate equation derived by considering intermetallic compound layer formation were used to interpret the experimental dissolution data. A larger dissolution at the upper part of specimen causing natural convection and an intermetallic layer formation with a linear relationship at solid/liquid interface occurred. Below 628 K, the dissolution rate appears to be controlled by chemical reaction of an intermetallic compound layer. At mid-range temperatures (of 681 K), the dissolution process was governed by a mixed control mechanism involving diffusion in liquid tin and chemical reaction of the intermetallic compound layer. At temperatures above 735 K, the rate seems to be controlled by diffusion across a concentration boundary layer in liquid tin. The formation of an intermetallic compound layer did not interfere with the dissolution.     

Identification of formulation and manufacturing variables that influence in vitro dissolution and in vivo bioavailability of propranolol hydrochloride tablets

The purpose of this study was to evaluate the effect of formulation and processing changes on the dissolution and bioavailability of propranolol hydrochloride tablets. Directly compressed blends of 6 kg (20,000 units) were prepared by mixing in a 16-qt V blender and tablets were compressed on an instrumented Manesty D3B tablet press. A half-factorial (2(5-1), Resolution V) design was used to study the following variables: filler ratio (lactose/dicalcium phosphate), sodium starch glycolate level, magnesium stearate level, lubricant blend time, and compression force. The levels and ranges of the excipients and processing changes studied represented level 2 or greater changes as indicated by the Scale-up and Post Approval Changes (SUPAC-IR) Guidance. Changes in filler ratio, disintegrant level, and compression force were significant in affecting percent drug released (Q) in 5 min (Q5) and Q10. However, changes in magnesium stearate level and lubricant blend time did not influence Q5 and Q10. Hardness was found to be affected by changes in all of the variables studied. Some interaction effects between the variables studied were also found to be significant. To examine the impact of formulation and processing variables on in vivo absorption, three batches were selected for a bioavailability study based on their dissolution profiles. Thirteen subjects received four propranolol treatments (slow-, medium-, and fast-dissolving formulations and Inderal 80 mg) separated by 1 week washout according to a randomized crossover design. The formulations were found to be bioequivalent with respect to the log Cmax and log AUC0-infinity. The results of this study suggest that (i) bioavailability/bioequivalency studies may not be necessary for propranolol and perhaps other class 1 drugs after level 2 type changes, and (ii) in vitro dissolution tests may be used to show bioequivalence of propranolol formulations with processing or formulation changes within the specified level 2 ranges examined.     

Bioavailability of rifampicin, isoniazid and pyrazinamide from fixed-dose combination capsules

Due to the observation of severe neurological symptoms in single patients as well as brain imaging, neuropsychological and neurophysiological abnormalities, the long-term prognosis of treated phenylketonuria is still under discussion. We investigated the neurological outcome of 57 (24 male, 33 female) patients with phenylketonuria (diet onset < 3 months) at a mean age of 23.6 (17-33) years in comparison to control subjects. Methods used were a clinical-neurological examination, tests for fine motor abilities, IQ test (WAIS-R), a neuropsychological attention task and MRI (30 patients only). Tremor was increased in the patients (28%) compared to controls (15%). Fine motor abilities were significantly reduced in three areas: hand-wrist steadiness, finger-hand dexterity and hand-wrist speed. Tremor as well as reduced fine motor skills were not associated with treatment-related variables, e.g. diet onset, strictness of biochemical control or amount of MRI white matter change. IQ was lower in patients (mean 97.6) compared to matched control subjects (mean 105.5). IQ at 12 years was correlated with biochemical control from birth up to the age of 12 and remained stable up to adult age, independent of biochemical control after 12 years of age. In contrast to the other outcome parameters, the performance in a neuropsychological attention task was influenced by the concurrent plasma phenylalanine concentration. Specific late-onset neurological impairment was not identified in this sample of early-treated adults with phenylketonuria. CONCLUSION: Careful neurological investigation revealed subtle symptoms of brain damage even after early-initiated treatment in adult patients with phenylketonuria. At present it cannot be excluded that further neurological deterioration could emerge later in life. Thus, patients with phenylketonuria - either on or off diet - should be monitored throughout life.     

Iron sufficiency in breast-fed infants and the availability of iron from human milk

Four infants were studied who had been exclusively breast-fed for periods varying from 8 to 18 months. All had grown sufficiently to have exhausted their prenatally acquired iron endowment with respect to meeting current needs for maintaining normal hemoglobin levels. All infants had normal hemoglobin values and normal serum iron values. Studies of iron absorption from breast milk and cow's milk were performed in ten normal adults. The absorption of iron from the human milk was significantly higher. These findings suggest that the iron present in human milk is sufficient to meet the iron requirements of the exclusively breast-fed infant until he approximately triples his birthweight.     

Controlled-release tablet matrices from carrageenans: compression and dissolution studies

The corpus luteum (CL) is an organ that exhibits extremely rapid growth, development, and regression during the course of each nonpregnant cycle. The CL consists of steroidogenic (parenchymal) and nonsteroidogenic (nonparenchymal) cells. The small and large parenchymal cells differ in numerous morphological and functional characteristics, and are thought to interact with each other to maintain normal luteal function. These steroidogenic luteal cells also interact with the nonsteroidogenic cells; for example, they produce factors that stimulate proliferation and migration of endothelial cells and proliferation of fibroblasts; they also may enhance or suppress immune cell function. Conversely, endothelial cells produce factors that modulate steroidogenesis, and immune cells produce cytokines that modify the secretory function of steroidogenic cells. Cellular interactions may be mediated by several mechanisms, including humoral (endocrine and paracrine) pathways as well as contact-dependent (gap junctional) pathways. Thus, hormones, growth factors and cytokines produced locally by steroidogenic or nonsteroidogenic cells may be transferred from cell to cell indirectly or directly to regulate luteal function. Gap junctions are present in luteal tissues of several species, and gap junctional intercellular communication is affected by the stage of luteal development and systemic and local regulators of luteal function. Such cellular interactions probably are important in luteal hormone production, signal transduction, angiogenesis, and luteolysis because of their role in coordinating function among the various luteal cell types.     

Typical variability in drug dissolution testing: study with USP and FDA calibrator tablets and a marketed drug (glibenclamide) product

To evaluate variability in drug dissolution testing 28 laboratories analyzed USP calibrators, US FDA prednisone tablets and a marketed glibenclamide tablet product. The experiments were conducted using paddle and basket methods at 50 (calibrators) and 75 (glibenclamide) rpm. The media employed were deaerated by equilibrating at 37 degrees C for 24 h and by the USP recommended method. The 95% CI values for percent drug release for the USP calibrator tablets were similar to the reported tolerances for the USP Acceptance Ranges; however, individual results from 15 of 28 laboratories suggest that the apparatus would not comply with the USP Apparatus Suitability Criteria. For FDA prednisone calibrator tablets, percent drug release using equilibrated medium was different (P=0.003) than by the USP recommended method. For the glibenclamide tablet results, a CV of 14-37% was observed, depending upon the sampling time and the type of apparatus employed. The results indicate that failure to meet the USP Dissolution Apparatus Suitability Test may not truly mean that the apparatus is 'out of compliance'. Due to the high variability in dissolution testing, in many cases the impact of formulation or manufacturing changes on drug release characteristics may not be observed, in particular with multi-point profiles.     

Change in biological availability of 137Cs in grassland ecosystems after the accident at Chernobyl Atomic Energy Station

Between 1977 and 1995, nine stapedectomies using the Robinson-vein graft technique were performed in six high-performance airplane pilots diagnosed with otosclerosis. All of them returned to full active duty after stapedectomy without any vestibular symptoms. These cases illustrate that it can be safe for fighter or test pilots to return to full flight status after stapedectomy. These cases also suggest that full flight status can be reinstated as soon as 3 months after stapedectomy without endangering flight safety.     

抗生素菌渣水热催化产油及其特性

探究了菌渣的水热液化转换成生物油燃料的过程。结果表明,抗生素菌渣在260 ℃、保留时间是135 min时,获得最大的生物油产率（28.01%）。通过6种不同的催化剂进行催化,加入催化剂后,生物油产率最大的是Na₂CO₃（36.06%）和NaOH（36.31%）。碱催化的生物油的含氮化合物的质量分数在41.16%～49.74%之间,而酸催化产生的生物油含氮化合物的量在57.62%～59.32%之间。通过调节催化剂Na₂CO₃、NaOH的添加量发现,在投加量为8%时,生物油含氮量均最低,Na₂CO₃和NaOH催化产生的生物油组分的含氮化合物质量分数分别为29.12%和35.67%。在催化剂投加量为10%时,对氧的脱除效果都最好,分别为32.12%和29.02%,此时产生的生物油的热值达到最大（达到33.3220和34.7320 MJ?kg?1）。      

Selective dissolution of uranium from Olympic Dam copper concentrates

The copper flotation concentrates produced from the Olympic Dam deposit in South Australia often contain significant amounts of uranium. Previous work indicated that uranium could be removed from a chalcocite-bornite concentrate by reaction with sulphuric acid. Reactions with djurleite, roxbyite, bornite and chalcopyrite-rich concentrates that are representative of each of the major copper sulphides in the deposit have now shown that uranium can be selectively removed from all types of copper concentrate generated from the deposit.The selective dissolution of uranium from the copper concentrates was achieved in 24 h by reaction with sulphuric acid at 30–60 ° C in an inert atmosphere. Redox potentials during most reactions were 225–250 mV vs saturated calomel electrode. It is proposed that the redox potential of the suspensions was determined by the oxidation of the copper sulphides. The addition of an oxidant (ferric alum) to increase the redox potential increased the amount of copper that dissolved but did not significantly affect the uranium dissolution rate.Oxidation of uraninite in the copper concentrates was by reaction with iron(III) from the acid dissolution of hematite, the major gangue mineral in the concentrates. It is likely that fluoride ions, from the dissolution of fluorite in the concentrates, are also involved in reactions leading to the dissolution of the uranium. Copper dissolution occurred by reaction of the copper sulphides with iron(III) and by reaction of acid with products from the aerial oxidation of the concentrates during storage.     

Selective dissolution of uranium from a copper flotation concentrate

The copper flotation concentrate produced from the Olympic Dam copper— uranium gold deposit in South Australia contains uranium associated with the copper sulphide and gangue minerals. Work with a copper concentrate in which the copper mineralization was of the chalcocite-bornite type has shown that 94–97% uranium can be dissolved with sulphuric acid (> 40 g/L) at 30–60°C in 24 h. The addition of an oxidant was not necessary. Copper was leached from the concentrate along with the uranium. In the first 15 min, 5–7% copper dissolved but thereafter virtually no further copper dissolved when the reaction was carried out under nitrogen or argon (i.e., in the absence of oxygen). In air and oxygen, copper dissolution continued over the 24 h of the reaction. The initial rapid dissolution of copper was associated with oxidation of djurleite to roxbyite and dissolution of surface oxidation products. In air and oxygen, oxidation of roxbyite and bornite to blaubleibender covellite was associated with further dissolution of copper. The redox potential of the suspensions was controlled by reactions of the copper sulphide minerals. For reactions under nitrogen the redox potential of the system was 225–250 mV vs. saturated calomel electrode (SCE), while in air or oxygen the potential gradually rose (to 350 mV vs. SCE) as successive copper sulphides were oxidized. These results, and work at the Olympic Dam metallurgical pilot plant, have shown that uranium can be removed selectively from copper flotation concentrates produced from the Olympic Dam deposit.     

Characterization of genes involved in biosynthesis of a novel antibiotic from Burkholderia cepacia BC11 and their role in biological control of Rhizoctonia solani

Genetic manipulation of fluorescent pseudomonads has provided major insight into their production of antifungal molecules and their role in biological control of plant disease. Burkholderia cepacia also produces antifungal activities, but its biological control activity is much less well characterized, in part due to difficulties in applying genetic tools. Here we report genetic and biochemical characterization of a soil isolate of B. cepacia relating to its production of an unusual antibiotic that is very active against a variety of soil fungi. Purification and preliminary structural analyses suggest that this antibiotic (called AFC-BC11) is a novel lipopeptide associated largely with the cell membrane. Analysis of conditions for optimal production of AFC-BC11 indicated stringent environmental regulation of its synthesis. Furthermore, we show that production of AFC-BC11 is largely responsible for the ability of B. cepacia BC11 to effectively control the damping-off of cotton caused by the fungal pathogen Rhizoctonia solani in a gnotobiotic system. Using Tn5 mutagenesis, we identified, cloned, and characterized a region of the genome of strain BC11 that is required for production of this antifungal metabolite. DNA sequence analysis suggested that this region encodes proteins directly involved in the production of a nonribosomally synthesized lipopeptide.     

Evaluation of changes in primary health care availability and provision from the patient perspective

This study was designed to investigate changes in primary care following recent NHS reforms. The study was carried out by home interview of random samples of people aged 65 years and over in three district health authorities; 1500 in 1990 and 1500 in 1992, before and after the introduction of the reforms. The response rate was 94% (1413 in 1990 and 1405 in 1992). Few patients (6%) changed their general practitioner (GP) in 1990 or 1992. There was an increase in the provision of written practice information in 1992, but more than 60% of patients could not recall receiving leaflets. More practices included practice nurses and appointments systems and fewer used rotas of local practices or deputizing services for 'out of hours' calls. In 1992 more patients aged 75 years and over saw their GP within the previous year and significantly more were assessed for vision, hearing, continence, foot problems and blood pressure and had their urine tested, but most of these health assessments, except blood pressure (64%), were recalled by few patients. There have been small changes in the provision and use of primary health care by older people since the introduction of the new GP contract.