Actual Half-life Research Articles

In silico approaches for predicting the half-life of natural and modified peptides in blood.

This paper describes a web server developed for designing therapeutic peptides with desired half-life in blood. In this study, we used 163 natural and 98 modified peptides whose half-life has been determined experimentally in mammalian blood, for developing in silico models. Firstly, models have been developed on 261 peptides containing natural and modified residues, using different chemical descriptors. The best model using 43 PaDEL descriptors got a maximum correlation of 0.692 between the predicted and the actual half-life peptides. Secondly, models were developed on 163 natural peptides using amino acid composition feature of peptides and achieved a maximum correlation of 0.643. Thirdly, models were developed on 163 natural peptides using chemical descriptors and attained a maximum correlation of 0.743 using 45 selected PaDEL descriptors. In order to assist researchers in the prediction and designing of half-life of peptides, the models developed have been integrated into PlifePred web server (http://webs.iiitd.edu.in//raghava/plifepred/).

Biodegradation of nonylphenols using nitrifying sludge, 4-chlorophenol-adapted consortia and activated sludge in liquid and solid phases

The biodegradation of a technical mixture of nonylphenols (tNP) with three different biomasses (nitrifying sludge, 4-chlorophenol-adapted consortia and activated sludge) was evaluated in batch tests. The tNP degradation was determined in solid and liquid phases. The three biomasses studied were able to biodegrade the technical mixture of nonylphenols. It was found that 33% to 44% of the initial tNP was adsorbed on to the sludge after 250 h. Nitrifying sludge presented the highest biodegradation percentage (43.1%±2.3% ) and degradation rate (3.10×10−3 μmol/d). Acclimated 4-chlorophenol and activated sludge degraded 34.3%±1.2% and 18.2%±0.5% of the initial tNP, respectively. Actual half-life times of 10.9, 12.0 and 22.8 days were obtained for the biodegradation of tNP by nitrifying, acclimated 4-chlorophenol and activated sludge, respectively. It was concluded that, although nitrifiying biomass posses a high initial adsorption rate, this biomass can also biodegrade the tNP faster than the other tested biomasses.

Quantum yields of decomposition and homo-dimerization of solid L-alanine induced by 7.2 eV Vacuum ultraviolet light irradiation: an estimate of the half-life of L-alanine on the surface of space objects.

One of the leading hypotheses regarding the origin of prebiotic molecules on primitive Earth is that they formed from inorganic molecules in extraterrestrial environments and were delivered by meteorites, space dust and comets. To evaluate the availability of extraterrestrial amino acids, it is necessary to examine their decomposition and oligomerization rates as induced by extraterrestrial energy sources, such as vacuum ultraviolet (VUV) and X-ray photons and high energy particles. This paper reports the quantum yields of decomposition ((8.2 ± 0.7) × 10(-2) photon(-1)) and homo-dimerization ((1.2 ± 0.3) × 10(-3) photon(-1)) and decomposition of the dimer (0.24 ± 0.06 photon(-1)) of solid L-alanine (Ala) induced by VUV light with an energy of 7.2 eV. Using these quantum yields, the half-life of L-Ala on the surface of a space object in the present earth orbit was estimated to be about 52 days, even when only photons with an energy of 7.2 eV emitted from the present Sun were considered. The actual half-life of solid L-Ala on the surface of a space object orbit around the present day Earth would certainly be much shorter than our estimate, because of the added effect of photons and particles of other energies. Thus, we propose that L-Ala needs to be shielded from solar VUV in protected environments, such as the interior of a meteorite, within a time scale of days after synthesis to ensure its arrival on the primitive Earth.

Effect of spatial distribution of T-Cells and HIV load on HIV progression

We present a spatial-temporal (ST) human immunodeficiency virus (HIV) simulation model to investigate the spatial distribution of viral load and T-cells during HIV progression. The proposed model uses the Finite Element (FE) method to divide a considered infected region into interconnected subregions each containing viral population and T-cells. HIV T-cells and viral load are traced and counted within and between subregions to estimate their effect upon neighboring regions. The objective is to estimate overall ST changes of HIV progression and to study the ST therapeutic effect upon HIV dynamics in spatial and temporal domains. We introduce sub-regional (spatial) parameters of T-cells and viral load production and elimination to estimate the spatial propagation and interaction of HIV dynamics under the influence of a 3TC D4T Reverse Transcriptase Inhibitors (RTI) drug regimen. In terms of percentage change standard deviation, we show that the average rate per 10 weeks (throughout a 10-year clinical trial) of the ST CD4+ change is 5.35% 1.3 different than that of the CD4+ rate of change in laboratory datasets, and the average rate of change of the ST CD8+ is 4.98% 1.93 different than that of the CD8+ rate of change. The half-life of the ST CD4+ count is 1.68% 3.381 different than the actual half-life of the CD4+ count obtained from laboratory datasets. The distribution of the viral load and T-cells in a considered region tends to cluster during the HIV progression once a threshold of 86-89% viral accumulation is reached. Executable code and data libraries are available by contacting the corresponding author. C++ and Java have been used to simulate the suggested model. A Pentium III or higher platform is recommended.

In Vivo Regulation of Acetylcholinesterase Insertion at the Neuromuscular Junction

The efficiency of synaptic transmission between nerve and muscle depends on the number and density of acetylcholinesterase molecules (AChE) at the neuromuscular junction. However, little is known about the way this density is maintained and regulated in vivo. By using time lapse and quantitative fluorescence imaging assays in living mice, we demonstrated that insertion of new AChEs occurs within hours of saturating pre-existing AChEs with fasciculin2, a snake toxin that selectively labels AChE. In the absence of muscle postsynaptic activity or evoked nerve presynaptic neurotransmitter release, AChE insertion was decreased significantly, whereas direct stimulation of the muscle completely restored AChE insertion to control levels. This activity-dependent AChE insertion is mediated by intracellular calcium. In muscle stimulated in the presence of a Ca2+ channel blocker or calcium-permeable Ca2+ chelator, AChE insertion into synapses was significantly decreased, whereas ryanodine or ionophore A12387 treatment of blocked and unstimulated synapses significantly increased AChE insertion. These results demonstrated that synaptic activity is critical for AChE insertion and indicated that a rise in intracellular calcium either through voltage-gated calcium channels or from intracellular stores is critical for proper AChE insertion into the adult synapse.

D1-D2 protein degradation in the chloroplast. Complex light saturation kinetics.

The D1 and D2 proteins of the photosystem II (PSII) reaction center are stable in the dark, while rapid degradation occurs in the light. Thus far, a quantitative correlation between degradation and photon fluences has not been determined. In Spirodela oligorrhiza, D1-D2 degradation increases with photon flux. We find that kinetics for D2 degradation mirror those for D1, except that the actual half-life times of the D2 protein are about three times larger than those of the D1. The degradation ratio, D2/D1, is fluence independent, supporting the proposal [Jansen, M.A.K., Greenberg, B.M., Edelman, M., Mattoo, A.K. & Gaba, V. (1996), Photochem. Photobiol. 63, 814-817] that degradation of the two proteins is coupled. It is commonly conceived that D1 degradation is predominantly associated with photon fluences that are supersaturating for photosynthesis. We now show that a fluence as low as 5 mumol.m-2.s-1 elicited a reaction constituting > 25% of the total degradation response, while > 90% of the degradation potential was attained at intensities below saturation for photosynthesis (approximately 750 mumol.m-2.s-1). Thus, in intact plants, D1 degradation is overwhelmingly associated with fluences limiting for photosynthesis. D1 degradation increases with photon flux in a complex, multiphasic manner. Four phases were uncovered over the fluence range from 0-1600 mumol.m-2.s-1. The multiphasic saturation kinetics underscore that the D1 and D2 degradation response is complex, and emanates from more than one parameter. The physiological processes associated with each phase remain to be determined.

Prognostic Significance of Marker Half-life during Chemotherapy in Non-seminomatous Germ Cell Testicular Tumors

Decrease in serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) levels is considered as a response during chemotherapy of non-seminomatous germ cell testicular tumors, but data on the prognostic significance of marker half-life remains inconclusive. Serum marker half-life was evaluated in 34 patients with elevated markers, receiving chemotherapy (CT). Marker half-life was calculated from the natural logarithm of the sequential AFP or HCG concentrations. The correlation between event-free (EFS) and overall survival (OS) with unfavorable half-lives of AFP and HCG was evaluated. Median actual half-life (AHL) AFP was 3.9 days (range, 1.4-21.5) and median AHL HCG was 4.4 days (range, 1.4-21.0); 82% of the patients had a satisfactory initial decline in AFP, and 71% had a satisfactory initial decline in HCG. There was a significant difference in EFS and OS between the two groups of patients with an AFP half-life <7 days and >7 days. HCG half-life did not adversely affect EFS and OS. The correlation of better EFS and OS with appropriate AFP marker half-life during chemotherapy could provide a dynamic method, which could complement the standard baseline prognostic factors, for the prediction of prognosis.

Actual half-life of alpha-fetoprotein as a prognostic tool in pediatric malignant tumours: S.J. Han, S.-Y. Yoo, S.H. Choi, et al. Pediatr Surg Int 12:599–602, (November), 1997

Actual half-life of alpha-fetoprotein as a prognostic tool in pediatric malignant tumours: S.J. Han, S.-Y. Yoo, S.H. Choi, et al. Pediatr Surg Int 12:599–602, (November), 1997

Actual half-life of alpha-fetoprotein as a prognostic tool in pediatric malignant tumors

Actual half-life of alpha-fetoprotein as a prognostic tool in pediatric malignant tumors

Significance of postoperative serum level of carcinoembryonic antigen (CEA) and actual half life of CEA in colorectal cancer patients.

The postoperative levels of carcinoembryonic antigen (CEA) and the actual half life (T1/2) of CEA were evaluated to ascertain their potency in predicting the recurrence of colorectal cancer after curative surgery in patients who had an abnormally high level of preoperative carcinoembryonic antigen (CEA, > or = 5 ng/ml). Ninety-four patients who underwent curative surgery were enrolled and 24 patients (25.5%) had recurrence during the follow-up period (median: 30 months, range: 2-69 months). T1/2 of CEA for all patients ranged from 1.2 days to 88.1 days, with a median of 4.4 days. T1/2 of CEA (mean +/- standard deviation) was 11.7 +/- 17.9 days in recurrent patients, whereas it was 6.2 +/- 4.9 days in patients without recurrence (p = 0.0224). The patients' age, gender, size of the tumor, location of the tumor, pre-, and postoperative CEA level, pathologic type of the tumor and Dukes stage had no significance in recurrence. The 1-year, 2-year, and 5-year disease-free survival rates were 95.1%, 81.1%, and 73.8% in patients with postoperative CEA levels less than 5 ng/ml (n = 62), respectively, and 71.4%, 64.8%, and 64.8% in patients with postoperative CEA levels higher than or equal to 5 ng/ml (n = 32), respectively (p = 0.04). Patients were divided into Group S (T1/2 of CEA < 4.4 days, n = 43) and Group L (T1/2 of CEA > or = 4.4 days, n = 51). The 1-year, 2-year, and 5-year disease-free survival rates were 95.3%, 85.1%, and 77.7% in Group S, respectively, and 80%, 67.5%, and 64.1% in Group L, respectively (p = 0.0261). In conclusion, the disease-free survival of colorectal cancer patients was prolonged in patients who had a short T1/2 of CEA or a low level of postoperative CEA. In high-risk colorectal cancer patients with an abnormally high level of preoperative CEA, recurrence may be predicted by checking an early postoperative CEA level and/or by a simple calculation of the actual half life of CEA.

A Nomogram To Predict the Best Biological Half-Life Values for Candidates for Oral Prolonged-Release Formulations

It is sometimes possible to maintain plasma concentrations between desired maximum and minimum limits by repetitively administering a drug in an oral prolonged-release formulation when this goal cannot be achieved with a rapid-release formulation. However, this approach does not work with all drugs. The biological half-life value of the drug can be one cause for failure of this approach. Although it is recognized that a half-life may be too long or too short, neither the criteria for determining these values nor the consequences of failing to meet them have been established. The best half-life values for prolonged-release candidates were found by simulating once-a-day and twice-a-day administration of formulations and examining the capacity of these formulations to maintain steady-state plasma concentrations between various selected limits. These observations were used to establish criteria to judge the acceptability of half-lives. Half-life values were considered too long if drugs were self-sustaining and simulations of their rapid-release formulations were also successful. Half-life values were considered too short if minor variability in prolonged-release rates resulted in plasma concentrations above and/or below the selected limits. The actual half-life values that were considered too long or too short depended on the dosing interval and the selected maximum and minimum plasma concentrations. A nomogram was constructed to assess the acceptability of the biological half-life of a candidate for once-a-day or twice-a-day prolonged-release formulations. The nomogram employs the user-selected limits for the desired plasma concentrations to predict whether the half-life of a candidate is (1) too long, (2) too short, or (3) acceptable (i.e., between 1 and 2).

C-REACTIVE PROTEIN AND SERUM AMYLOID A mRNA STABILITY FOLLOWING INDUCTION BY CYTOKINES

We determined the effects of cytokine withdrawal on C-reactive protein (CRP) and serum amyloid A (SAA) mRNA abundance in Hep3B cells following 24 h of preinduction with interleukin 6 plus interleukin 1β. After cytokine withdrawal, CRP transcription rate rapidly fell to undetectable levels and mRNA levels fell with a half-disappearance time of about 2.5 h. In view of the relatively small amount of CRP transcription occurring at this time, it is likely that this value closely re?ects the actual half-life of CRP mRNA. In contrast, substantial SAA transcription continued for at least 8 h, while SAA mRNA fell with a half-disappearance time of about 8.5 h. It is not possible, under these conditions, to determine SAA mRNA half-life, but it clearly was no greater than 8.5 h. Both Actinomycin D (ActD) and cycloheximide enhanced the stability of SAA mRNA, strongly suggesting that SAA mRNA degradation requires synthesis of a short-lived protein. CRP mRNA stability was also enhanced by ActD, but cycloheximide did not have a protracted stabilizing effect, suggesting complex regulatory processes. These studies provide insight into the stability of CRP and SAA mRNA following induction with [IL-6 + IL-1β] and into the mechanisms regulating their degradation.

Predictive factors for the histologicnature of residual tumor mass after chemotherapy in patients with advanced testicular cancer

Objectives To further improve the accuracy of the prediction of histologicfindings in the residual mass after chemotherapy in patients with metastatic germ cell tumors, various predictive factors were investigated. Methods A total of 23 patients with advanced testicular cancer underwent combinationchemotherapy based on cisplatin following surgical removal of residual tumor mass in 20 patients and observation in 3. Results Complete fibrosis and/or necrosis was found in 6 (30%) operative specimens, teratoma in 3 (15%), and viable malignant tumor in 11 (55%). Three patients had no evidence of disease for a mean follow-up of 45 months. Five of the 6 patients and all of the 11 patients' results could be predicted by a combination of 4 factors, including absence of teratomatous element in the primary tumor, greater than 85% tumor reduction rate after chemotherapy, normal alpha-fetoprotein and beta-subunit of human chorionic gonadotropin levels after chemotherapy, and actual half-life of alpha-fetoprotein less than 7 days. Among these factors the tumor reduction rate and the actual half-life of alpha-fetoprotein were the most important predictions statistically on multivariate analysis. With the use of these criteria, the sensitivity rate, specificity rate, and overall predictive value of diagnosis for existence of viable malignant tumors were 83.3%, 100%, and 94.1 %, respectively. Conclusions By determining these factors it seems possible to avoid surgical removalof the postchemotherapy residual mass in approximately 30% of patients with advanced metastatic testicular cancer.

Determination, by radioimmunoassay, of the mass of lactate dehydrogenase isoenzyme 1 in human serum and of its rate of removal from serum after a myocardial infarction.

In this radioimmunoassay of lactate dehydrogenase-1 (LD-1; EC 1.1.1.27) in human serum we use a commercial LD-1-selective assay system and a goat antiserum. We have determined the fractional rate of disappearance from serum and the half-life of LD-1, in terms of both enzyme activity and enzyme mass, in 21 myocardial infarction patients. Our evidence suggests that this isoenzyme is inactivated in serum. Furthermore, our data suggest that the conventionally accepted half-life of about 110 h for serum LD-1 activity may grossly overestimate the actual LD-1 half-life in many post-myocardial infarction patients.

Platelet Half-Life, Plasma Thromboxane B2 and Circulating Endothelial-Cells in Peripheral Vascular Disease

We studied platelet half-life (T/2), plasma thromboxane B2-levels (TXB2) and circulating endothelial cells in 107 patients with a mean age of 63 +/- 6.8 years and angiographically proven peripheral vascular disease (PVD). Patients were divided into 4 groups according to Fontaine but also according to additional clinical manifestations of atherosclerosis like coronary heart disease (CHD) and cerebrovascular disease (CVD). Furthermore, the influence of sex and smoking was investigated. Compared to patients without atherosclerotic manifestations we could detect an enhanced platelet consumption measured as shortened platelet half-life time (79.2 +/- 9.1 vs 100.9 +/- 5.6 hours, p less than 0.001 and an increased platelet activity measured as increased TXB2-plasma levels (51.6 +/- 20.9 vs 23.2 +/- 11.2 ng/ml, p less than 0.001). Correspondingly, the amount of circulating endothelial cells was increased 45.2 +/- 25.7 vs 20.3 +/- 23.4, p less than 0.001). Patients with PVD who smoked had the shortest actual platelet half-life, the highest TXB2 plasma levels and the greatest amount of circulating endothelial cells compared to non-smoking patients and controls. Patients with clinical stage IV according to Fontaine had the shortest platelet half-life, the highest TXB2 plasma levels and the greatest amount of circulating endothelial cells compared to the other clinical stages. Analyzing the influence of additional clinical manifestations of atherosclerosis we could detect only in patients with PVD and CHD significant differences compared to the other groups.

The epididymis contributes minimally to serum androgen-binding protein in the rat: a whole body kinetic study.

The half-times, MCRs, and secretion rates of androgen-binding protein (rABP) were determined in male rats under a variety of conditions. After orchiectomy, the disappearance of endogenous immunoassayable rABP from serum was described by a single exponential term with half-lives of 21 +/- 0.2 and 20 +/- 0.8 h at 25 and 90 days, respectively. The MCR (milliliters per g/day) was not affected by age or hormonal status of the animals. The secretion rate of rABP into the blood was higher in the immature animals than in adults. The decrease in serum rABP concentrations after 20-25 days of age was due to a decrease in the rate of secretion into blood rather than an increase in MCR, a finding consistent with the observation that after formation of the blood-testis barrier, most of the rABP is secreted into the seminiferous tubular lumen. The disappearance curve after injection of purified epididymal rABP was best described by two exponential terms. The first component disappeared very rapidly and the second more slowly, with a half-time corresponding to that of endogenous rABP. The MCR calculated from the latter component was the same as that for endogenous rABP. Having established the kinetic parameters for rABP in serum, a series of experiments was conducted to determine whether it was possible for the epididymis to release this protein into the blood. The apparent half-time of rABP measured in rats in which the testes had been removed and the epididymides left intact was found to be 65 +/- 3 to 70 +/- 5 h in three separate experiments. This increase over the actual half-life of rABP (20 h) was due to the release of rABP from the epididymis into the blood. A similar experiment was performed in an identical group of animals (testes removed, epididymides intact) that had been treated with testosterone via Silastic implants. In these animals the apparent half-time (24 +/- 4 to 28 +/- 2 h; three experiments) closely approximated the actual half-life (20 h). These findings indicate that androgens retarded degeneration of the epididymides, thus minimizing their release of rABP into blood. Our experimental findings suggest the following conclusions. The dramatic rise and subsequent decline of serum rABP concentrations that occur before puberty are due to changes in the secretion rate rather than in the MCR, which is unaffected by age or hormonal states.(ABSTRACT TRUNCATED AT 400 WORDS)

Recent reflections on tumor markers

The necessity for monitoring serum levels of alphafetoprotein (AFP) and human chorionic gonadotropin (hCG) in patients with testicular cancer is widely known, but a few questions remain unanswered. Cross-reactivity of commercial hCG assays with luteinizing hormone remains a problem; and as patients apparently cured of testicular cancer age, they become subject to other diseases that can elevated AFP or hCG levels, creating confusion. There still are no adequate studies of the role of markers in staging, a problem that has become acute with the introduction of expectant treatment for metastases in clinical stage A disease. Calculation of the metabolic half-life of markers can be helpful in staging postoperatively, but calculations of the actual half-life of markers during induction chemotherapy is less useful than had once been hoped. Attempts to capitalize on the molecular heterogeneity of AFP have had little success, although newer analytic methods may change this; but ultrasensitive assays for urinary hCG are beginning to show promise. Studies of radioimmunodetection with anti-marker antibodies have been both encouraging and frustrating; the newly available monoclonal anti-marker antibodies may improve the results and also offer a possible means of improving chemotherapy. Placental alkaline phosphatase continues to look like a useful marker for seminoma, and lactic dehydrogenase is often helpful in all types of testicular cancer, especially in high-stage disease.

Marker Half-Life Analysis as a Prognostic Tool in Testicular Cancer

In a retrospective study we compared the actual half-life of the serum tumor markers alpha fetoprotein and human chorionic gonadotropin to the clinical course of patients who underwent an operation or chemotherapy for germ cell cancer. Of the 7 patients with residual disease postoperatively 5 had abnormal half-life values and in 3 this knowledge would have been of clinical value. Only 1 of 10 patients with a complete response to chemotherapy had an unfavorable actual half-life compared to 17 of 19 with a less than complete response. Prolonged marker decay rates during the first month of chemotherapy reflected ineffective chemotherapy and appeared to be independent of tumor bulk. Postoperatively, actual half-lives probably are useful prognostically only if the values are abnormal. Similar calculations may be of prognostic value early in the course of induction chemotherapy.

Metabolic clearance rate of inhibin in mature and immature male rats.

The half-life and metabolic clearance rate of human seminal plasma inhibin after injection into male rats was studied. Labeled inhibin was injected i.v. into 27-day-old rats (10 ng, 3.5 X i0� cpm) and 75-day-old rats (15 ng, 5.5 X i0� cpm). In both age groups, rats were killed at intervals between 1-5 and 480 mm later, and samples of blood and tissues were taken for radioimmunoassay. 112511-hSPI disappeared from blood plasma in a multi-exponential fashion. The first exponential curve, which represents the actual half-life of hSPI, was 2.34 mm in adult rats and 90 mm in 27-day-old rats. The slower component of each curve had values of 231 and 365 mm, respectively. The initial distribution volume was 13.6 ml and 4.13 ml for the adult and immature animals. The metabolic clearance rate of inhibin in adult rats was 0.12 mI/mm and 0.019 mI/mm in immature rats. In both groups, only the pituitary and the pineal gland showed specific uptake of inhibin. The pituitary and the pineal uptake (tissue/plasma) was maximal at 120 mm (3.9 and 3.4) in immature rats, while in adults pituitary uptake was maximal (1.55) at 10 mm and the pineal gland showed uptake (2.4) only at 8 mm. In vitro binding of labeled inhibin to the pituitary plasma membrane supported the above observations. We conclude that the metabolic clearance rate of inhibin was fasten in adult rats, whereas specific uptake of [22111 -hSPI was greater in the pituitary and pineal glands of immature rats.

Persistence and Residual Effectiveness of Various Formulations of Baygon (Bayer 39007) Against the House Fly1

Tests were conducted to compare the chemical persistence of Baygon® ( o -isopropoxyphenyl methylcarbamate) formulated as a 1% oil spray, 13.9% spray concentrate, and as a 75% wettable powder with its residual effectiveness against the house fly, Musca domestica L. House fly bioassay of plywood panels treated at 100 mg/square foot indicated a half-life of approximately 4 days; colorimetric analysis showed that the actual half-life of Baygon was almost 15 days. The lack of residual effectiveness appeared to be caused by a loss of the formulating materials necessary for transfer of the toxicant from the treated surface to the house fly. Maximum mortality, with minimum exposure time, was obtained with Baygon formulated as a 1% oil spray.