Pharmacokinetic aspects of Tert-Butylaminoethyl disulfide, an experimental drug against schistosomiasis in mice

A preliminary study of the pharmacokinetic parameters of t-Butylaminoethyl disulfide was performed after administration of two different single doses (35 and 300 mg/kg) of either the cold or labelled drug. Plasma or blood samples were treated with dithiothreitol, perchloric acid, and, after filtration, submitted to further purification with anionic resein. In the final step, the drug was retained on a cationic resin column, eluted with NaCl 1M and detected according to the method of Ellman (1958). Alternatively, radioactive drug was detected by liquid scintillation counting. The results corresponding to the smaller dose of total drug suggested a pharmacokinetic behavior related to a one open compartment model with the following parameters: area under the intravenous curve (AUC i.v.):671 ± 14; AUC oral: 150 ± 40 µg.min. ml [raised to the power of -1]; elimination rate constant: 0.071 min [raised to the power of -1]; biological half life: 9.8 min; distribution volume: 0.74 ml/g. For the higher dose, the results seemed to obey a more complex undertermined model. Combining the results, the occurence of a dose-dependent pharmacokinetic behavior is suggested, the drug being rapidly absorbed and rapidly eliminated; the elimination process being related mainly to metabolization. The drug seems to be more toxic when administered I.V. because by this route it escapes first pass metabolism, while being quickly distributed to tissues. The maximum tolerated blood level seems to be around 16 µg/ml.

A simple HPLC-fluorescence method for the measurement of R,S-sotalol in the plasma of patients with life-threatening cardiac arrhythmias

R,S-sotalol, a ß-blocker drug with class III antiarrhythmic properties, is prescribed to patients with ventricular, atrial and supraventricular arrhythmias. A simple and sensitive method based on HPLC-fluorescence is described for the quantification of R,S-sotalol racemate in 500 µl of plasma. R,S-sotalol and its internal standard (atenolol) were eluted after 5.9 and 8.5 min, respectively, from a 4-micron C18 reverse-phase column using a mobile phase consisting of 80 mM KH2PO4, pH 4.6, and acetonitrile (95:5, v/v) at a flow rate of 0.5 ml/min with detection at lex = 235 nm and lem = 310 nm, respectively. This method, validated on the basis of R,S-sotalol measurements in spiked blank plasma, presented 20 ng/ml sensitivity, 20-10,000 ng/ml linearity, and 2.9 and 4.8% intra- and interassay precision, respectively. Plasma sotalol concentrations were determined by applying this method to investigate five high-risk patients with atrial fibrillation admitted to the Emergency Service of the Medical School Hospital, who received sotalol, 160 mg po, as loading dose. Blood samples were collected from a peripheral vein at zero, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0 and 24.0 h after drug administration. A two-compartment open model was applied. Data obtained, expressed as mean, were: CMAX = 1230 ng/ml, TMAX = 1.8 h, AUCT = 10645 ng h-1 ml-1, Kab = 1.23 h-1, a = 0.95 h-1, ß = 0.09 h-1, t(1/2)ß = 7.8 h, ClT/F = 3.94 ml min-1 kg-1, and Vd/F = 2.53 l/kg. A good systemic availability and a fast absorption were obtained. Drug distribution was reduced to the same extent in terms of total body clearance when patients and healthy volunteers were compared, and consequently elimination half-life remained unchanged. Thus, the method described in the present study is useful for therapeutic drug monitoring purposes, pharmacokinetic investigation and pharmacokinetic-pharmacodynamic sotalol studies in patients with tachyarrhythmias.

Use of psychoactive drugs and related falls among older people living in a community in Brazil

INTRODUCTION: Population aging in Brazil has increased the prevalence of neurodegenerative diseases (Parkinson's and Alzheimer's disease) and affective disorders (anxiety, depression), all common in old age. A retrospective study was carried out with the purpose of ascertaining if there is an association between falls and psychoactive medication use among older residents of a community in Brazil. METHODS: All residents aged 65+ (n=161) of one neighborhood of Campo Belo, Brazil (population of 48,000) were evaluated regarding the use of psychoactive drugs and the occurrence of falls in the 12 months preceding the study. Vision and hearing screenings were also performed. RESULTS: From the study population, 9.3% were taking prolonged half-life benzodiazepines, 4.4% anticonvulsants (mostly barbiturates), 2.5% antidepressants (all cyclics) and 8.1% alpha-methyldopa. No subject reported use of hypnotics, neuroleptics or drugs to treat Alzheimer's or Parkinson's diseases (except biperiden). As a whole, drugs that increase the risk of falls were used by 1/5 of this population. In the 12-month period preceding the study, 27 residents (16.8%) experienced falls and, of those, 4 (14.8%) had fracture(s). There was an independent association between psychoactive drug use and falls when variables such as age, gender, vision and hearing were controlled (p=0.02). CONCLUSIONS: Although the population of this neighborhood must be considered young (only 4% are 65 years old or more), there are already problems related to the use of psychoactive drugs among people. Prescribed anxiolytics, anticonvulsants, antidepressants and antihypertensives are not appropriate for this age group and their use is associated with falls.

Pharmacokinetic profile of tert-butylaminoethanethiol

A preliminary study of the pharmacokinetic parameters of t-Butylaminoethanethiol (TBAESH) was performed after administration of a single dose (35 mg/kg) either orally or intravenously. Plasma or blood samples were treated with dithiothreitol, perchloric acid and, after filtration, submitted to further purification with anionic resin. In the final step the drug was retained on a cationic resin column, eluted with NaCl lM and detected according to the method of Ellman (1958). The results suggested a pharmacokinetic behavior related to a one open compartment model with the following values for the total drug: area under the intravenous curve (AUC i.v.): 443(+ ou -) 24.0; AUC oral: 85.5(+ ou -) 14.5 ug min.ml(elevado a -1); elimination rate constant: 0.069(+ ou -) 0.0055 min(elevado a -1), biological half-life: 10.0(+ ou -) 0.80 min; distribution volume 1.15(+ ou -) 0.15 ml/g; biodisponibility: 0.19(+ ou -) 0.02. From a pharmacokinetic standpoint, TBAESH seems to have no advantage over the analogous disulfide compound.

Pharmacokinetics and pharmacodynamics of propranolol in hypertensive patients after sublingual administration: systemic availability

The bioavailability of propranolol depends on the degree of liver metabolism. Orally but not intravenously administered propranolol is heavily metabolized. In the present study we assessed the pharmacokinetics and pharmacodynamics of sublingual propranolol. Fourteen severely hypertensive patients (diastolic blood pressure (DBP) ³115 mmHg), aged 40 to 66 years, were randomly chosen to receive a single dose of 40 mg propranolol hydrochloride by sublingual or peroral administration. Systolic (SBP) and diastolic (DBP) blood pressures, heart rate (HR) for pharmacodynamics and blood samples for noncompartmental pharmacokinetics were obtained at baseline and at 10, 20, 30, 60 and 120 min after the single dose. Significant reductions in BP and HR were obtained, but differences in these parameters were not observed when sublingual and peroral administrations were compared as follows: SBP (17 vs 18%, P = NS), DBP (14 vs 8%, P = NS) and HR (22 vs 28%, P = NS), respectively. The pharmacokinetic parameters obtained after sublingual or peroral drug administration were: peak plasma concentration (CMAX): 147 ± 72 vs 41 ± 12 ng/ml, P<0.05; time to reach CMAX (TMAX): 34 ± 18 vs 52 ± 11 min, P<0.05; biological half-life (t1/2b): 0.91 ± 0.54 vs 2.41 ± 1.16 h, P<0.05; area under the curve (AUCT): 245 ± 134 vs 79 ± 54 ng h-1 ml-1, P<0.05; total body clearance (CLT/F): 44 ± 23 vs 26 ± 12 ml min-1 kg-1, P = NS. Systemic availability measured by the AUCT ratio indicates that extension of bioavailability was increased 3 times by the sublingual route. Mouth paresthesia was the main adverse effect observed after sublingual administration. Sublingual propranolol administration showed a better pharmacokinetic profile and this route of administration may be an alternative for intravenous or oral administration.

Role of bradykinin in postprandial hypotension in humans

A transient significant decrease in mean arterial blood pressure (MAP) from 107 ± 3 to 98 ± 3 mmHg (P<0.05) was observed in elderly (59-69 years of age), healthy volunteers 25-30 min following ingestion of a test meal. In young volunteers (22-34 years of age), a postprandial decrease of MAP from 88 ± 3 to 83 ± 4 mmHg was also noted but it was not statistically significant. A 40% decrease in bradykinin (BK) content of circulatory high molecular weight kininogen had previously been observed in human subjects given the same test meal. We presently demonstrate by specific ELISA that the stable pentapeptide metabolite (1-5 BK) of BK increases from 2.5 ± 1.0 to 11.0 ± 2.5 pg/ml plasma (P<0.05) in elderly volunteers and from 2.0 ± 1.0 to 10.3 ± 3.2 pg/ml plasma (P<0.05) in young volunteers 3 h following food intake. This result suggests that ingestion of food stimulates BK release from kininogen in normal man. Postprandial splanchnic vasodilatation, demonstrated by a decrease of plasma half-life of intravenously administered indocyanine green (ICG), a marker of mesenteric blood flow to the liver, from 4.4 ± 0.4 to 3.0 ± 0.1 min (P<0.05) in young volunteers and from 5.2 ± 1.0 to 4.0 ± 0.5 min (P<0.05) in elderly volunteers, accompanied BK release. The participation of BK in this response was investigated in subjects given the BK-potentiating drug captopril prior to food intake. Postprandial decreases of ICG half-lives were not changed by this treatment in either young or elderly subjects, a result which may indicate that BK released following food intake plays no role in postprandial splanchnic vasodilatation in normal man.

Cardiopulmonary bypass alters the pharmacokinetics of propranolol in patients undergoing cardiac surgery

The pharmacokinetics of propranolol may be altered by hypothermic cardiopulmonary bypass (CPB), resulting in unpredictable postoperative hemodynamic responses to usual doses. The objective of the present study was to investigate the pharmacokinetics of propranolol in patients undergoing coronary artery bypass grafting (CABG) by CPB under moderate hypothermia. We evaluated 11 patients, 4 women and 7 men (mean age 57 ± 8 years, mean weight 75.4 ± 11.9 kg and mean body surface area 1.83 ± 0.19 m²), receiving propranolol before surgery (80-240 mg a day) and postoperatively (10 mg a day). Plasma propranolol levels were measured before and after CPB by high-performance liquid chromatography. Pharmacokinetic Solutions 2.0 software was used to estimate the pharmacokinetic parameters after administration of the drug pre- and postoperatively. There was an increase of biological half-life from 4.5 (95% CI = 3.9-6.9) to 10.6 h (95% CI = 8.2-14.7; P < 0.01) and an increase in volume of distribution from 4.9 (95% CI = 3.2-14.3) to 8.3 l/kg (95% CI = 6.5-32.1; P < 0.05), while total clearance remained unchanged 9.2 (95% CI = 7.7-24.6) vs 10.7 ml min-1 kg-1 (95% CI = 7.7-26.6; NS) after surgery. In conclusion, increases in drug distribution could be explained in part by hemodilution during CPB. On the other hand, the increase of biological half-life can be attributed to changes in hepatic metabolism induced by CPB under moderate hypothermia. These alterations in the pharmacokinetics of propranolol after CABG with hypothermic CPB might induce a greater myocardial depression in response to propranolol than would be expected with an equivalent dose during the postoperative period.

Decomposition of ground biomass of secondary forest and yield of annual crops in no tillage

ABSTRACT The objective of this work was to evaluate the dynamics of decomposition process of chopped secondary forest system, previously enriched with legumes Inga velutina Willd. and Stryphnodendron pulcherrimum (Willd.) Hochr. and the contribution of this process to the nutrient input to the cultivation of corn and bean under no-tillage. The experimental design was a randomized block, split plot with four replications. The plots were two species (I. velutina and S. pulcherrimum) and the subplots were seven times of evaluation (0, 7, 28, 63, 189, 252, 294 days after experiment installation). There was no difference (p ≥ 0.05) between the secondary forest systems enriched and no interaction with times for biomass waste, decomposition constant and half-life time. The waste of S. pulcherrimum trees had higher (p < 0.05) C/N ratio than that I. velutina. However, this one was higher (p < 0.05) in lignin content. Nevertheless, the dynamics of residue decomposition was similar. The corn yield was higher (p < 0.05) in cultivation under I.velutina waste. Meanwhile, the beans planted after corn, shows similar (p > 0.05) yield in both areas, regardless of the waste origin.

Activity of two different triazoles in a murine model of paracoccidioidomycosis

A new orally absorbable triazole (Schering 39304) with a long serum half-life in man (60 hours), was tried in a murine model of progressive paracoccidioidomycosis and compared with itraconazole, another triazole which has proven effective in this mycosis. Only 15% of the infected, untreated mice survived while 53 to 75% of the animals receiving itraconazole survived. Mice treated with Schering 39304 exhibited higher (86 - 100%) survival rates. Statistically, the 5 mg/kg Sch 39304 was superior to the 50 mg/kg itraconazole dose. Lung cultures showed that 20 mg/kg/day of Sch achieved sterilization of the infectious foci. These results indicate that the new triazole will have a place in the treatment of paracoccidioidomycosis

Grasses and legumes as cover crop in no-tillage system in northeastern Pará Brazil

Studies to select one or more species of coverage plants adapted to Amazonian soil and climate conditions of the Amazon are a promising strategy for the improvement of environmental quality, establishing no-till agricultural systems, and thereby reducing the impacts of monoculture farming. The aim of this study was to assess the persistence time, half-life time, macronutrient content and accumulation, and C:N ratio of straw coverage in a Ultisol in northeastern Pará. Experimental design was randomized blocks with five treatments and five replicates. Plants were harvested after 105 days, growth and biomass production was quantified. After 84 days, soil coverage was 97, 85, 52, 50, and 15% for signalgrass (Brachiaria brizantha) (syn. Urochloa), dense crowngrass (Panicum purpurascens), jack bean (Canavalia ensiformes), pearl millet (Pennisetum americanum) and sunn hemp (Crotalaria juncea,), respectively. Signalgrass yielded the greatest dry matter production (9,696 kg ha-1). It also had high C:N ratio (38.4), long half-life (86.5 days) and a high persistence in the field. Jack bean also showed high dry matter production (8,950 kg ha-1), but it had low C:N ratio (17.4) and lower half-life time (39 days) than the grasses. These attributes indicate that signalgrass and jack bean have a high potential for use as cover plants in no-till agricultural systems in the State of Pará.

The thermal stability of yellow fever vaccines

The assessment of yellow fever vaccine thermostability both in lyophilized form and after reconstitution were analyzed. Two commercial yellow fever vaccines were assayed for their thermal stability. Vaccines were exposed to test temperatures in the range of 8 (graus) C to 45 (graus) C. Residual infectivity was measured by a plaque assay using Vero cells. The titre values were used in an accelerated degradation test that follows the Arrhenius equation and the minimum immunizing dose was assumed to be 10 (ao cubo) particles forming unit (pfu)/dose. Some of the most relevant results include that (i) regular culture medium show the same degradation pattern of a reconstituted 17D-204 vaccine; (ii) reconstituted YF-17D-204 showed a predictable half life of more than six days if kept at 0 (graus) C; (iii) there are differences in thermostability between different products that are probably due to both presence of stabilizers in the preparation and the modernization in the vaccine production; (iv) it is important to establish a proper correlation between the mouse infectivity test and the plaque assay since the last appears to be more simple, economical, and practical for small laboratories to assess the potency of the vaccine, and (v) the accelerated degradation test appears to be the best procedure to quantify the thermostability of biological products.

Particulate soil organic carbon and stratification ratio increases in response to crop residue decomposition under no-till

In soils under no-tillage (NT), the continuous crop residue input to the surface layer leads to carbon (C) accumulation. This study evaluated a soil under NT in Ponta Grossa (State of Paraná, Brazil) for: 1) the decomposition of black oat (Avena strigosa Schreb.) residues, 2) relation of the biomass decomposition effect with the soil organic carbon (SOC) content, the particulate organic carbon (POC) content, and the soil carbon stratification ratio (SR) of an Inceptisol. The assessments were based on seven samplings (t0 to t6) in a period of 160 days of three transects with six sampling points each. The oat dry biomass was 5.02 Mg ha-1 at t0, however, after 160 days, only 17.8 % of the initial dry biomass was left on the soil surface. The SOC in the 0-5 cm layer varied from 27.56 (t0) to 30.07 g dm-3 (t6). The SR increased from 1.33 to 1.43 in 160 days. There was also an increase in the POC pool in this period, from 8.1 to 10.7 Mg ha-1. The increase in SOC in the 0-5 cm layer in the 160 days was mainly due to the increase of POC derived from oat residue decomposition. The linear relationship between SOC and POC showed that 21 % of SOC was due to the more labile fraction. The results indicated that the continuous input of residues could be intensified to increase the C pool and sequestration in soils under NT.

Influence of repeated applications of glyphosate on its persistence and soil bioactivity

Pesticide degradation studies are essential to evaluate its impact in the environment and on non-target organisms. The effect of repeated soil applications of the herbicide glyphosate on its dissipation and on soil microorganisms was studied by radiometric and microbial techniques. Results indicated fast dissipation of the [14C]-glyphosate or [14C]metabolites extractable residues (half-life of 0.92±0.29 month), but increasing half-lives of total mineralization ranging from 2.2 to 3.4 months as the number of applications increased from 1 to 4. No significant correlation was found between 14CO2 production and dehydrogenase activity.

Green manure incorporation timing for organically grown broccoli

The objective of this work was to determine the effect of incorporation timing of the velvet bean (Stizolobium cinereum) (GM) on both organic broccoli yield and N status. Mineral N content in the soil, biologically fixed N recovery by broccoli, GM biomass decomposition and N release kinetics were also determined. Plots were fertilized with 12 Mg ha-1 of organic compost and received GM either at 0, 15, 30 or 45 days after transplant. Other treatments were compost (12 or 25 Mg ha-1), GM, mineral fertilizers and control (no fertilizer). The data were collected in four completely randomized blocks. GM decomposition increased mineral N content in soil as rapidly as mineral fertilizer or the supply of 25 Mg ha-1 of compost. The N half-life in GM (24 days) is smaller than the mass half-life (35 days) and the biological fixation contributed with 23.6% of N present in the aboveground biomass of broccoli. The result suggests a higher synchrony between the crop relative growth rate and N release from the GM when incorporated at crop early growth stage. The incorporation of GM until 15 days after transplanting replaces 50% of the highest compost dose, without yield loss.

Sustainability, certification, and regulation of biochar

Biochar has a relatively long half-life in soil and can fundamentally alter soil properties, processes, and ecosystem services. The prospect of global-scale biochar application to soils highlights the importance of a sophisticated and rigorous certification procedure. The objective of this work was to discuss the concept of integrating biochar properties with environmental and socioeconomic factors, in a sustainable biochar certification procedure that optimizes complementarity and compatibility between these factors over relevant time periods. Biochar effects and behavior should also be modelled at temporal scales similar to its expected functional lifetime in soils. Finally, when existing soil data are insufficient, soil sampling and analysis procedures need to be described as part of a biochar certification procedure.