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PubMed2004

Dipyridamole and headache--a pilot study of initial dose titration.

Headache is reported by about one third of patients using dipyridamole (DP) after stroke or TIA. No study has systematically examined if initial dipyridamole titration may affect this headache. We therefore randomised patients to (1) standard aspirin and dipyridamole treatment b.i.d. for 2 weeks or (2) titration with aspirin only in the morning and aspirin and dipyridamole in the evening for 5 days, followed by 9 days of standard aspirin and dipyridamole treatment. Among 57 patients included for analysis, moderate to severe headache was reported by 28% in the standard treatment group and 25% in the titration group (n.s.). Headache for more than two consecutive days occurred in 24% and 11%, respectively. Rescue medication because of headache for more than 2 days was used by 14% and 0% in the respective groups. The cumulative number of days with headache was more than twice as high in the standard treatment group. The total numbers of other side effects were 25 and 11 in the two groups. The observed differences in this pilot study were not statistically significant, but nevertheless suggest that titration with an initially lower dose of dipyridamole may be considered to reduce headache and thereby increase compliance. A larger study is needed to clarify this with sufficient statistical power.

Aged↗
PubMed2006

Multicenter comparative study of a new ELISA, PLATELIA RABIES II, for the detection and titration of anti-rabies glycoprotein antibodies and comparison with the rapid fluorescent focus inhibition test (RFFIT) on human samples from vaccinated and non-vaccinated people.

The envelope glycoprotein G of rabies virus induces the production of neutralising antibodies, which are important in protection against rabies. Therefore, titration of anti-envelope glycoprotein antibodies is a good indicator of the degree of immunity in people during anti-rabies treatment or after vaccination. According to the World Health Organization (WHO) guidelines, a booster vaccine dose should be given if the rabies antibody titre falls below 0.5 IU/ml. Titration of anti-rabies antibodies is also useful for plasma centers in the preparation and standardization of human anti-rabies gamma-globulins for therapeutic use and to a lesser extent for the diagnosis of rabies in human sera and cerebrospinal fluid (CSF). This paper presents a new enzyme-linked immunosorbent assay (ELISA), PLATELIA RABIES II, developed for rabies envelope glycoprotein antibody detection or titration and its comparison to the current reference method (RFFIT). The data collected during validation of the test in a multicenter study are analysed to give a sound overall knowledge of the capabilities of the PLATELIA RABIES II, for instance specificity, linearity, accuracy, precision, detection limit and quantitation limit. To this aim, human serum samples from a total of 1348 vaccinated or non-vaccinated people were tested in parallel using the new ELISA and the RFFIT for the presence of anti-rabies antibodies. Data generated indicate a linear relationship across the range of titration between the two methods. The sensitivity reaches 98.6% and the specificity 99.4%. This study indicates that this new ELISA test is as sensitive and specific as the current standardized reference method. The method is simple, safe, rapid and can be considered as a useful alternative to the neutralisation test.

Antibodies, Viral↗
PubMed2002

Thermodynamics of cationic lipid-DNA complex formation as studied by isothermal titration calorimetry.

The detailed analysis of the cationic lipid-DNA complex formation by means of isothermal titration calorimetry is presented. Most experiments were done using 1,2-dioleyl-sn-glycero-3-ethylphosphocholine (EDOPC), but basic titrations were also done using DOTAP, DOTAP:DOPC, and DOTAP:DOPE mixtures. Complex formation was endothermic with less than 1 kcal absorbed per mole of lipid or DNA charge. This enthalpy change was attributed to DNA-DNA mutual repulsion within the lamellar complex. The exception was DOTAP:DOPE-containing lipoplex for which the enthalpy of formation was exothermic, presumably because of DOPE amine group protonation. Experimental conditions, namely, direction and titration increment as well as concentration of titrant, which dictate the structure of resulting lipoplex (whether lamellar complex or DNA-coated vesicle), were found to affect the apparent thermodynamics of complex formation. The structure, in turn, influences the biological properties of the lipoplex. If the titration of lipid into DNA was carried out in large increments, the DeltaH was larger than when the injection increments were smaller, a finding that is consistent with increased vesicle disruption under large increments and which is expected theoretically. Cationic lipid-DNA binding was weak in high ionic strength solutions, however, the effective binding constant is within micromolar range because of macromolecular nature of the interaction.

Animals↗
PubMed1982

Dependence of ion flow through channels on the density of fixed charges at the channel opening. Voltage control of inverse titration curves.

Model calculations were done to investigate the effect of titratable fixed charges at channel openings on ion flow through open channels. The current titration curves (channel current vs. bulk pH) can assume the shape expected from the change of the ionic surface concentration with pH (c-control), or be inverted, i.e., follow the change of the electrical field within the membrane (V-control). The relationships were explored pars pro toto for Goldman-Hodgkin-Katz channels, two-barrier one-site channels and six-barrier five-site channels. With net current flowing in the direction of the concentration gradient and from the titrated fixed charge layer into the channel, c-control is the sign of low channel occupancy (entrance-step limitation) and V-control the sign of high channel occupancy (exit-step limitation). At intermediate occupancy, the current titration curve can be nearly invariant to pH.

Animals↗
PubMed1995

Conformation and hydrogen ion titration of proteins: a continuum electrostatic model with conformational flexibility.

A new method for including local conformational flexibility in calculations of the hydrogen ion titration of proteins using macroscopic electrostatic models is presented. Intrinsic pKa values and electrostatic interactions between titrating sites are calculated from an ensemble of conformers in which the positions of titrating side chains are systematically varied. The method is applied to the Asp, Glu, and Tyr residues of hen lysozyme. The effects of different minimization and/or sampling protocols for both single-conformer and multi-conformer calculations are studied. For single-conformer calculations it is found that the results are sensitive to the choice of all-hydrogen versus polar-hydrogen-only atomic models and to the minimization protocol chosen. The best overall agreement of single-conformer calculations with experiment is obtained with an all-hydrogen model and either a two-step minimization process or minimization using a high dielectric constant. Multi-conformational calculations give significantly improved agreement with experiment, slightly smaller shifts between model compound pKa values and calculated intrinsic pKa values, and reduced sensitivity of the intrinsic pKa calculations to the initial details of the structure compared to single-conformer calculations. The extent of these improvements depends on the type of minimization used during the generation of conformers, with more extensive minimization giving greater improvements. The ordering of the titrations of the active-site residues, Glu-35 and Asp-52, is particularly sensitive to the minimization and sampling protocols used. The balance of strong site-site interactions in the active site suggests a need for including site-site conformational correlations.

Animals↗
PubMed1995

Electrostatic calculations of amino acid titration and electron transfer, Q-AQB-->QAQ-B, in the reaction center.

The titration of amino acids and the energetics of electron transfer from the primary electron acceptor (QA) to the secondary electron acceptor (QB) in the photosynthetic reaction center of Rhodobacter sphaeroides are calculated using a continuum electrostatic model. Strong electrostatic interactions between titrating sites give rise to complex titration curves. Glu L212 is calculated to have an anomalously broad titration curve, which explains the seemingly contradictory experimental results concerning its pKa. The electrostatic field following electron transfer shifts the average protonation of amino acids near the quinones. The pH dependence of the free energy between Q-AQB and QAQ-B calculated from these shifts is in good agreement with experiment. However, the calculated absolute free energy difference is in severe disagreement (by approximately 230 meV) with the observed experimental value, i.e., electron transfer from Q-A to QB is calculated to be unfavorable. The large stabilization energy of the Q-A state arises from the predominantly positively charged residues in the vicinity of QA in contrast to the predominantly negatively charged residues near QB. The discrepancy between calculated and experimental values for delta G(Q-AQB-->QAQ-B) points to limitations of the continuum electrostatic model. Inclusion of other contributions to the energetics (e.g., protein motion following quinone reduction) that may improve the agreement between theory and experiment are discussed.

Amino Acids↗
PubMed1996

Titration of aspartate-85 in bacteriorhodopsin: what it says about chromophore isomerization and proton release.

Titration of Asp-85, the proton acceptor and part of the counterion in bacteriorhodopsin, over a wide pH range (2-11) leads us to the following conclusions: 1) Asp-85 has a complex titration curve with two values of pKa; in addition to a main transition with pKa = 2.6 it shows a second inflection point at high pH (pKa = 9.7 in 150-mM KCl). This complex titration behavior of Asp-85 is explained by interaction of Asp-85 with an ionizable residue X'. As follows from the fit of the titration curve of Asp-85, deprotonation of X' increases the proton affinity of Asp-85 by shifting its pKa from 2.6 to 7.5. Conversely, protonation of Asp-85 decreases the pKa of X' by 4.9 units, from 9.7 to 4.8. The interaction between Asp-85 and X' has important implications for the mechanism of proton transfer. In the photocycle after the formation of M intermediate (and protonation of Asp-85) the group X' should release a proton. This deprotonated state of X' would stabilize the protonated state of Asp-85.2) Thermal isomerization of the chromophore (dark adaptation) occurs on transient protonation of Asp-85 and formation of the blue membrane. The latter conclusion is based on the observation that the rate constant of dark adaptation is directly proportional to the fraction of blue membrane (in which Asp-85 is protonated) between pH 2 and 11. The rate constant of isomerization is at least 10(4) times faster in the blue membrane than in the purple membrane. The protonated state of Asp-85 probably is important for the catalysis not only of all-trans <=> 13-cis thermal isomerization during dark adaptation but also of the reisomerization of the chromophore from 13-cis to all-trans configuration during N-->O-->bR transition in the photocycle. This would explain why Asp-85 stays protonated in the N and O intermediates.

Aspartic Acid↗
PubMed1997

Titration kinetics of Asp-85 in bacteriorhodopsin: exclusion of the retinal pocket as the color-controlling cation binding site.

The spectrum (the purple blue transition) and function of the light-driven proton pump bacteriorhodopsin are determined by the state of protonation of the Asp-85 residue located in the vicinity of the retinal chromophore. The titration of Asp-85 is controlled by the binding/unbinding of one or two divalent metal cations (Ca2+ or Mg2+). The location of such metal binding site(s) is approached by studying the kinetics of the cation-induced titration of Asp-85 using metal ions and large molecular cations, such as quaternary ammonium ions, R4N+ (R = Et, Pr, a divalent 'bolaform ion' [Et3N+-(CH2)4-N+Et3] and the 1:3 molecular complex formed between Fe2+ and 1,10-phenanthroline (OP). The basic multi-component kinetic features of the titration, extending from 10(-2) to 10(4) s, are unaffected by the charge and size of the cation. This indicates that cation binding to bR triggers the blue --> purple titration in a fast step, which is not rate-determining. In view of the size of the cations involved, these observations indicate that the cation binding site is in an exposed location on, or close to, the membrane surface. This excludes previous models, which placed the color-controlling Ca2+ ion in the retinal binding pocket.

Aspartic Acid↗
PubMed1985

The standardization of infectivity titrations of poliovaccines--a WHO collaborative study.

The reproducibility of a method for infectivity titrations of live poliovaccines using microtitre plates was investigated in a WHO collaborative study involving eight laboratories. The large variation (up to 100-fold) in estimates of infectivity observed between laboratories using their local methods of assay was reduced to no more than fourfold when a common method was used. However, expressing infectivities relative to those of the monovalent reference viruses improved the agreement between the laboratories irrespective of the titration method employed. On the basis of these results, WHO adopted the common method used in the study as its recommended method for poliovirus titrations and established the preparations studied as international reference materials for the infectivity titrations of live poliovaccines.

Animals↗
PubMedDate not supplied

The PROTECT Study: final results of a large multicenter postmarketing study in patients with type 2 diabetes. Precose Resolution of Optimal Titration to Enhance Current Therapies.

The Precose Resolution of Optimal Titration to Enhance Current Therapies (PROTECT) trial was a nationwide postmarketing study designed to assess the effectiveness, tolerability, and safety of acarbose in patients with type 2 diabetes mellitus. This prospective, multicenter, open-label, 28-week trial enrolled 6142 patients who had type 2 diabetes that was inadequately controlled with either diet alone or diet plus a sulfonylurea. The dosage of acarbose was titrated from 25 mg TID to 50 mg TID (forced titration) and then titrated from 50 mg TID to 100 mg TID based on tolerability and efficacy. Efficacy of glycemic control was assessed by recording changes in glycated hemoglobin A1c (Hb A1c) and 1-hour postprandial plasma glucose (PPG) levels. Tolerability and safety were determined on the basis of patients' reports of treatment-emergent adverse events and by review of laboratory test results. Acarbose was safe and effective in improving glycemic control in patients with type 2 diabetes, regardless of their age, weight, ethnic background, time since diagnosis, or concomitant sulfonylurea therapy. Hb A1c levels declined throughout the treatment period, for a mean change in Hb A1c of -0.66%. The mean change from baseline in 1-hour PPG levels was -41 mg/dL at the end of treatment. Although all types of patients enrolled in the study responded positively to acarbose therapy, certain subgroups responded particularly well, especially those who had been diagnosed with the disease for less than 1 year and those who were untreated at study entry. Adverse events consisted primarily of gastrointestinal disturbances.

Acarbose↗
PubMed1994

Indomethacin suppositories versus intravenously titrated morphine for the treatment of ureteral colic.

STUDY OBJECTIVES: To develop a protocol for the blinded IV titration of morphine and to compare the analgesic efficacy and side effect profile of indomethacin suppositories versus IV morphine in the treatment of acute ureteral colic. DESIGN: Randomized, double-blind, double-dummy, two-period crossover study. SETTING: Emergency department of a central-city, teaching hospital. PARTICIPANTS: Patients 18 to 75 years of age with pain suggestive of ureteral colic. Exclusions included pregnancy, adverse reactions to the study drugs, chronic nonsteroidal anti-inflammatory drug (NSAID) therapy, or any pain medicine taken within four hours of ED admission. INTERVENTIONS: Patients were randomized to one of two groups: indomethacin 100-mg rectal suppository or morphine by IV titration (5-mg loading dose and up to two additional 2.5-mg doses if needed). At the end of 30 minutes, if adequate pain relief had not been obtained, treatment was crossed over. MEASUREMENTS: Verbal analog scale (initial pain) and visual analog pain relief scale. MAIN RESULTS: Seventy-five patients were entered into the study. Only data from those patients with stone presence confirmed by IV pyelogram or stone passage were analyzed. Twenty-four could not be evaluated (23 who did not meet criteria for stone presence and one whose pain resolved spontaneously before study medications could be administered). Of the remaining 51 patients, 31 received indomethacin first and 20 received morphine first. Morphine recipients reported more pain relief at ten minutes (P = .02), but at 20 and 30 minutes, no significant difference (P = .17 and .74, respectively) existed between the two groups. CONCLUSION: IV morphine produced more rapid analgesia than rectally administered indomethacin. There were no significant differences in vital sign changes or number of side effects between the two treatment groups. This study is the first to compare an NSAID with morphine administered by IV titration, considered by many to be the "gold standard" for relief of acute, severe pain. Future studies could evaluate the simultaneous administration of an opioid combined with an NSAID or compare an IV titrated opioid with an IV NSAID.

Adult↗
PubMedDate not supplied

The pH and titratable acidity of a range of diluting drinks and their potential effect on dental erosion.

OBJECTIVES: To investigate, in vitro, the potential dental effects of diluting juices by measuring their acidity levels and to examine the effect dilution has on the potential erosive properties of the drinks. METHODS: Four commonly available diluting drinks were assessed for both pH and titratable acidity at a variety of dilutions, reflecting the range of concentrations over which such drinks may be consumed. Predetermined dilutions of citric acid and hydrochloric acid, with similar pH values to those of the drinks, were used as positive control acidic solutions. The pH measurements throughout the study were made using a pH electrode connected to an Orion EA940 IonAnalyser. RESULTS: All four drinks demonstrated a high degree of resistance to a rise in pH, indicating high intrinsic buffering capacity. The measured pH changed very little with increasing dilution ratio when compared to the citric and hydrochloric acid controls, even when considered extremely dilute. In contrast, the titratable acidity of each of the drinks reduced proportionally with increasing dilution, thereby reducing considerably its erosive potential. CONCLUSIONS: While dilution had very little effect on the measured pH values, the titratable acidity reduced as the drink became more dilute. Since there appears to be a direct relationship between dilution and titratable acidity, the erosive potential of diluting juices may be reduced substantially by the addition of water. It remains unlikely, however, that the drinks would ever be consumed at a 'safe' level of dilution due to diminished taste and colour.

Beverages↗
PubMed1999

Can a controlled-release oral dose form of oxycodone be used as readily as an immediate-release form for the purpose of titrating to stable pain control?

Two separate trials compared controlled-release (CR) oral oxycodone (administered every 12 hours) with immediate-release (IR) oxycodone (4 times a day) to determine whether patients with chronic pain could be titrated to stable pain control as readily with the CR as with the IR formulation. In one study, 48 patients with cancer pain were randomized to open-label titration with either CR or IR oxycodone (maximum dose, 400 mg/day) for a period of up to 21 days. In a study of similar design, 57 patients with low back pain were titrated with either CR or IR oxycodone (maximum dose, 80 mg/day) for a period of up to 10 days. The majority of patients in both studies were converted to oxycodone from other opioid analgesics. Results of both studies showed no difference between CR and IR oxycodone with respect to both the percentage of patients achieving stable pain control, the time to achieve stable pain control, and the degree of pain control achieved. Among cancer patients, 85% achieved stable analgesia, 92% with the CR formulation and 79% with the IR formulation. Among noncancer patients, 91% achieved stable pain control, 87% with the CR formulation and 96% with the IR formulation. The most commonly reported adverse effects in both studies were similar for the two formulations and were those anticipated with opioids: nausea, vomiting, constipation, somnolence, dizziness, and pruritus. Nausea and vomiting were the most frequently cited reasons for treatment discontinuations. These studies suggest that dose titration can be accomplished as readily with oral CR oxycodone as with IR oxycodone in patients with chronic, moderate to severe pain.

Adult↗
PubMed2003

Highly sensitive active-site titration of lipase in microscale culture media using fluorescent organophosphorus ester.

The fluorescent organophosphorus esters, diethyl 4-methylumbelliferyl phosphate (1), ethyl hexyl 4-methylumbelliferyl phosphate (2) and ethyl 4-methylumbelliferyl heptylphosphonate (3) have been synthesized and evaluated as a sensitive active-site titrant of lipase. The phosphorus esters 1, 2 and 3 inactivated the lipase from Pseudomonas aeruginosa (LPL-312) with a second-order rate constant for enzyme inactivation (k(on)) of 1.8, 32 and 5600 s(-1) M(-1), respectively. The long-chain phosphonate 3 turned out to be the most potent inactivator of the lipase to release a stoichiometric amount of highly fluorescent 4-methylumbelliferone (4MU) as a leaving group. By using the phosphate 3 as an active-site titrant, the low concentration (4.5 nM) of the active lipase was titrated successfully. The highly sensitive active-site titration with 3 enabled the direct determination of the concentration of the active lipase expressed in a microscale culture medium. Although the expression level differed significantly from one culture to another, the titrated concentration of the active lipase was proportional to the apparent activity for all the independent cultures. The molecular activity calculated for the expressed lipase was found to be the same as that of the purified lipase. The present active-site titration method is widely applicable to the biocatalytic engineering of lipases such as directed evolution, site-directed mutagenesis, chemical modification and immobilization.

Binding Sites↗
PubMed2001

Is (re)titration of nasal continuous positive airway pressure for obstructive sleep apnoea necessary?

OBJECTIVE: To assess changes in nasal continuous positive airway pressure (nCPAP) pressure requirements across time in obstructive sleep apnoea (OSA), and whether routine retitrations are indicated. BACKGROUND: Most sleep laboratories perform one nCPAP titration, although some authors have found changes in pressures with time. A cohort of patients with OSA in a randomised controlled trial of nCPAP provided us with data on changes in titration pressures with time. METHODS: One hundred and one patients with symptomatic OSA (Epworth Sleepiness Scale > or =10, and >10 episodes/h of >4% dips in SaO(2) overnight) were recruited to a 1 month trial comparing real (autotitrated) and placebo nCPAP. At 1 month all patients were titrated and received real nCPAP thereafter. Eighty five were retitrated at about 6 months. RESULTS: Average pressures did not change between the initial value and 1 month (95th centile, 8.47 (SD 3.00), 8.94 (2.85) cm H(2)O), although there were large individual changes (mean difference, +0.47, SD 2.30, range -5 to +6 cm H(2)O). There was a small fall at 6 months (mean difference -0.68, SD 2.60, range -6 to +6 cm H(2)O, P<0.03) with no suggestion that the changes from 1-6 months were clinically important. CONCLUSIONS: This study suggests that routine nCPAP retitrations are not necessary. In conjunction with other published data, the night to night variation we found implies that a nCPAP calibration using an algorithm (based on obesity and OSA severity) might be as clinically successful as conventional one night titrations. However, further studies will be needed to specifically confirm this hypothesis.

Clinical Trial↗
PubMed2004

In vitro titration of Theileria parva tick derived stabilates.

Immunization against the protozoan Theileria parva by infection and treatment has proved to be very efficient for the control of East Coast fever, an acute and often-fatal lymphoproliferative tick-borne disease of cattle in Eastern, Central and Southern Africa. The immunizing dose of live T. parva sporozoites used in this method is usually determined by in vivo titration. An alternative in vitro method of quantification of sporozoites in whole tick-derived stabilates is proposed. The method consists of incubating serially diluted T. parva stabilates with bovine peripheral blood lymphocytes, the host cell that is infected naturally. Allowing the cultures to incubate undisturbed for the full cultivation period (10 days) reduced the variability among replicate titrations. Fungal contaminations were avoided by centrifuging stabilates at 400 g prior to the incubation, which did not precipitate sporozoites significantly. Fungistatics, Nystatin and Flucytosine, did not appear to interfere with the in vitro development of T. parva but their effect on fungal growth was limited. In vitro titration data were compared to in vivo infection data for 2 stabilates. In vitro titration of T. parva sporozoites should allow more ethical and efficient research on the preparation and storage of T. parva tick-derived stabilates.

Animals↗
PubMed2006

Feasibility of closed-loop titration of propofol guided by the Bispectral Index for general anaesthesia induction: a prospective randomized study.

BACKGROUND: This study was designed to evaluate the feasibility of propofol infusion by a closed-loop system for the titration of anaesthetic induction guided by Bispectral Index. METHODS: Forty patients were prospectively and randomly allocated into two groups: the target control infusion (TCI) group, where propofol titration was performed manually guided by the Bispectral Index using a commercial pharmacokinetic model (Diprifusor device) and the closed-loop group where titration was performed using a proportional differential algorithm. For both groups, the objective was to achieve a Bispectral Index of 50. Remifentanil TCI was infused at a target of 2 ng mL-1 and was maintained constant throughout the study. Feasibility of automatic induction was evaluated with performance error and haemodynamic data. RESULTS: Bispectral Index overshoot (-9 +/- 13% vs. -16 +/- 20%, P = 0.035) and mean duration of induction (381 +/- 106 s vs. 490 +/- 131 s, P = 0.004) were lower in the closed-loop group than in the TCI group. Haemodynamic data were similar between groups with a similar use of ephedrine bolus. CONCLUSION: The system was able to allow induction clinically for all patients. Automated titration guided by Bispectral Index for propofol infusion was feasible without increase in haemodynamic adverse effects.

Algorithms↗
PubMed2001

Argentometric titration for the determination of liquid chromatographic injection reproducibility.

The reproducibility of autosamplers for high-performance liquid chromatography can be checked by the injection of a sodium chloride solution without an installed column. The dispensed chloride plug is analyzed quantitatively by argentometric titration. If the titration can be performed with high enough precision, the autosampler performance is investigated without additional effects. Experiments with a 20-microL loop were performed. We found the following repeatabilities (relative standard deviations): titration, 0.07%; 10-microL "pull loop" injection (partial filling of the loop), 0.6%; and 20-microL "full loop" injection, 0.1%. In contrast to these data, the relative standard deviations obtained from chromatographic peaks include the steps of injection, separation, detection, and integration without any knowledge of the individual contributions. Such values are higher; we found for chromatographic peak areas of parabens 2% under pull loop conditions and 0.17% by full loop. The titration approach allows the determination of the contribution of the injection to the uncertainty budget of a liquid chromatographic analysis.

Journal Article↗