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PubMed1991

Proton titration curve of yeast iso-1-ferricytochrome c. Electrostatic and conformational effects of point mutations.

The proton titration curves of yeast iso-1-ferricytochrome c and selected point mutants of this protein have been determined between pH 3 and 11 at 10 and 25 degrees C with a computer-controlled titration system. Initial titration of the wild-type protein to acidic pH followed by subsequent titrations to alkaline and then acidic pH demonstrates hysteresis, with one more group (28.7) titrating between pH 11 and 3 than originally titrated (27.7) between pH 3 and 11. Initial titration to alkaline pH, however, resulted in observation of the same number of groups in both directions of titration (28.7 vs 28.6). At 10 degrees C, 7.5 fewer groups were found to titrate over the same range of pH. Titration curves obtained for six cytochrome c mutants modified at Arg-38, Phe-82, Tyr-48, and Tyr-67 were analyzed by subtraction of the corresponding titration curve for the wild-type protein to produce difference titration curves. In most cases, the effects of these mutations as revealed in the difference titration curves could be accounted for as either the result of introduction of an additional group titrating within this pH range, the result of a change in the pK of a titrating residue, and/or the result of a change in the pK for either the first acidic or the first alkaline protein conformational transition. In addition to demonstration of the electrostatic consequences of the mutations in cytochrome c studied here, this study establishes the general usefulness of precise proton titration curve analysis in the characterization of variant proteins produced through recombinant genetic techniques.

Amino Acid Sequence↗
PubMed2006

Theoretical investigation of the behavior of titratable groups in proteins.

This paper presents a theoretical analysis of the titration behavior of strongly interacting titratable residues in proteins. Strongly interacting titratable residues exist in many proteins such as for instance bacteriorhodopsin, cytochrome c oxidase, cytochrome bc(1), or the photosynthetic reaction center. Strong interaction between titratable groups can lead to irregular titration behavior. We analyze under which circumstances titration curves can become irregular. We demonstrate that conformational flexibility alone can not lead to irregular titration behavior. Strong interaction between titratable groups is a necessary, but not sufficient condition for irregular titration curves. In addition, the two interacting groups also need to titrate in the same pH-range. These two conditions together lead to irregular titration curves. The mutation of a single residue within a cluster of interacting titratable residues can influence the titration behavior of the other titratable residues in the cluster. We demonstrate this effect on a cluster of four interacting residues. This example underlines that mutational studies directed at identifying the role of a certain titratable residue in a cluster of interacting residues should always be accompanied by an analysis of the effect of the mutation on the titration behavior of the other residues.

Hydrogen-Ion Concentration↗
PubMed1996

Treatment of obstructive sleep apnea with a self-titrating continuous positive airway pressure (CPAP) system.

Conventional manually adjusted continuous positive airway pressure (CPAP) is an effective therapy for sleep-disordered breathing. We prospectively investigated the efficacy of a self-titrating nasal CPAP system in the acute treatment of obstructive sleep apnea (OSA) syndrome. Twenty patients with moderately severe OSA [apnea hypopnea index (AHI) > 15/hour] were enrolled in a randomized, controlled, prospective clinical trial. An initial diagnostic sleep study was performed, followed by randomization to a manually adjusted CPAP titration on one night and self titrating CPAP on the other night. On the conventional CPAP night, the CPAP was manually adjusted until abolition of all apneas and electroencephalographic (EEG) arousals, whereas the self-titrating CPAP was set in automatic mode at lights out. The self-titrating CPAP system utilized an algorithm based on airway vibration patterns to detect airway stability. The AHI decreased from 50.8 +/- 28.8/hour [mean +/- standard deviation (SD)] at baseline to 3.8 +/- 3.1/hour (p < 0.005) during manually adjusted and 6.1 +/- 5.3/hour (p < 0.005) during self-titrating CPAP. The arousal index (Ar-I) decreased from 34.1 +/- 23.1/hour (baseline) to 11.2 +/- 5.0/hour on manual adjustment (p < 0.005) and 11.3 +/- 0.3/hour on self titration (p < 0.005), whereas total sleep time was unchanged. No significant differences in any measure of oxygenation or sleep architecture were observed between the manually adjusted and self-titrating CPAP nights except that the lowest arterial oxygen saturation (SaO2) was higher with manual titration (84.4 +/- 4.2% vs. 79.9 +/- 9.7%, p < 0.05). The maximum pressure required for abolition of apneas and arousals was significantly lower (p < 0.05) during the self-titrating study (10.1 +/- 3.8 cmH2O) as compared to manually adjusted CPAP (12.3 +/- 3.9 cmH2O). Failure to increase pressure and failure to maintain minimum pressure occurred in 7 of the 20 subjects during the self-titrating study. This required manual resetting of the system in five subjects, but the system self-corrected in two subjects. An unsupervised study would have resulted in undertreatment of OSA. Based on a single-night laboratory study, self-titrating CPAP was well tolerated and improved OSA and sleep architecture comparable to manually adjusted CPAP. The future modifications of this prototype will require further research to assess its efficacy and safety in the laboratory and home environments before its recommendation for general long-term use.

Adult↗
PubMed2001

Reproducibility of a standardized titration procedure for the initiation of continuous positive airway pressure therapy in patients with obstructive sleep apnoea.

BACKGROUND: Manual titration of continuous positive airway pressure (CPAP) under polysomnographic control is the method most commonly employed to establish the minimal effective pressure (P(eff)) for the treatment of the obstructive sleep apnoea syndrome (OSA). To date, however, the reproducibility of P(eff) titrated in this way has not been investigated in any detail. OBJECTIVES: The present study aims to establish the reproducibility of P(eff) determined by manual titrations of CPAP under polysomnographic control in the sleep lab. METHODS: In a group of 50 patients (5 women), with a mean (SD) apnoea-hypopnoea index of 39.3 (21.8), apnoea index of 28.1 (20.9) and oxygen desaturation index of 39.3 (22.6), with newly diagnosed OSA, manual titration of CPAP was performed on two consecutive nights using the following standard titration protocol: starting at 4 mbar, CPAP was increased by steps of 1 mbar at intervals of at least 5 min, until no signs of airway obstruction could be seen, and arousals were no longer elicited. When no airway obstruction was detected over a period of 30 min, the pressure was lowered once during the night in steps of 1 mbar at intervals of at least 10 min, until obstructive events reappeared, whereupon the pressure was again increased as described above, until, once more, no signs of airway obstruction and no arousals occurred. The second titration was carried out in a blind manner, that is the lab technician did not know the results of the first pressure titration. RESULTS: The mean (SD) P(eff) for all titrations was 8.1 mbar (2.9). A high level of correlation was found between the P(eff) titrated on the first night and that titrated on the second night (Spearman correlation coefficient = 0.89). In a few individual cases, however, differences of up to 3 mbar were found between P(eff) on the first night and P(eff) on the second night. On average, the P(eff) measured on the second night was 0.5 mbar (SD = 1.3, range: -2.0 to 3.0 mbar) higher than that of the first night. CONCLUSIONS: With standardization of the manual titration of CPAP, P(eff) is readily reproducible. In individual cases, however, a difference of as much as 3.0 mbar between the two titrations is possible.

Adult↗
PubMed2006

Titration curves: a useful instrument for assessing the buffer systems of acidic mining waters.

BACKGROUND, AIMS AND SCOPE: The acidification of mine waters is generally caused by metal sulfide oxidation, related to mining activities. These waters are characterized by low pH and high acidity due to strong buffering systems. The standard acidity parameter, the Base Neutralization Capacity (BNC), is determined by endpoint titration, and reflects a cumulative parameter of both hydrogen ions and all buffering systems, but does not give information on the individual buffer systems. We demonstrate that a detailed interpretation of titration curves can provide information about the strength of the buffering systems. The buffering systems are of importance for environmental studies and treatment of acidic mining waters. METHODS: Titrations were carried out by means of an automatic titrator using acidic mining waters from Germany and Canada. The curves were interpreted, compared with each other, to endpoint titration results and to elemental concentrations contained therein. RESULTS AND DISCUSSION: The titration curves were highly reproducible, and contained information about the strength of the buffer systems present. Interpretations are given, and the classification and comparison of acidic mining waters, by the nature and strength of their buffering systems derived from titration curves are discussed. The BNC-values calculated from the curves were more precise than the ones determined by the standard endpoint titration method. Due to the complex buffer mechanisms in acidic mining waters, the calculation of major metal concentrations from the shape of the titration curve resulted in estimates, which should not be confused with precise elemental analysis results. CONCLUSION: Titration curves provide an inexpensive, valuable and versatile tool, by which to obtain sophisticated information of the acidity in acidic water. The information about the strength of the present buffer systems can help to understand and document the complex nature of acidic mining water buffer systems. Finally, the interpretation of titration curves could help to improve treatment measurements and the ecological understanding of these acidic waters.

Acids↗
PubMed1996

Experimental infusion phlebitis: importance of titratable acidity on phlebitic potential of infusion solution.

The titratable acidity of infusion solutions has never been taken into account in infusion phlebitis. This study aims to clarify the importance of titratable acidity on the phlebitic potential of infusion solutions. Solutions with different titratable acidity (from 0.16 to 12 mEq/L) were infused into the ear veins of 6 rabbits for 6 h at 10 mL/kg/h, and the veins were later examined histopathologically. Even at pH 4.0, a commercial 10% glucose solution scarcely caused any changes because of its very low titratable acidity (0.16 mEq/L). A 10% glucose solution with its titratable acidity adjusted to 3 mEq/L (pH 4.3) with citrate and NaOH, however, caused phlebitic changes in all 6 rabbits, and adjusting the titratable acidity to 12 mEq/L (pH 4.4) increased the degree of phlebitis. On the other hand, a 10% glucose solution with a pH of 5.4 and a titratable acidity of 6 mEq/L caused slight phlebitic changes in half the rabbits. These results suggest that 1) the titratable acidity of infusion solutions is important to the phlebitic potential when the pH is low, 2) when the pHs are similar, the phlebitic potential of infusion solutions depend on the titratable acidity, and 3) the phlebitic potential of infusion solutions can not be estimated by pH or titratable acidity alone.

Journal Article↗
PubMed1999

Slowing the titration rate of tramadol HCl reduces the incidence of discontinuation due to nausea and/or vomiting: a double-blind randomized trial.

BACKGROUND: Ultram [tramadol hydrochloride (HCl)] is a centrally acting analgesic that is widely prescribed for the treatment of moderate to moderately severe chronic pain. Although tramadol is generally well tolerated, some patients discontinue use early in the course of treatment because of nausea and vomiting. OBJECTIVE: To investigate the effect of three initial titration rates of tramadol HCl on the incidence of discontinuation due to nausea and/or vomiting in patients who previously did not tolerate tramadol HCl. METHOD: A multicentre, outpatient, randomized double-blind study was conducted, comprised of two phases: a 14-day open-label run-in phase and a 28-day double-blind phase. In the run-in phase the dose of tramadol was titrated over 4 days to the target of 200 mg/day. Patients who discontinued tramadol HCl due to nausea and/or vomiting in the open-label phase were eligible to enter the 28-day double-blind phase after a 10-day wash-out. Patients were randomized to one of three groups using a 10-, 16- or a 13-day titration schedule in order to achieve a target dosage of either 200 mg/day (10- and 16-day titration groups) or 150 mg/day (13-day titration group). The number of discontinuations due to nausea and/or vomiting in each group were compared. RESULTS: Significantly fewer patients (22%) discontinued because of nausea and/or vomiting in the 13- and 16-day titration groups compared to the 10-day group (P=0.008 and P=0.006, respectively). The time to discontinuation was also significantly delayed in the 13- and 16-day groups compared to the 10-day group (P=0.006 and P=0.007, respectively). The outcome of the 13-day titration to 150 mg/day was essentially the same as that of the 16-day titration to 200 mg/day, suggesting that this is a true rate effect rather than being dose related. CONCLUSION: This study demonstrated that a slower titration rate of tramadol HCl improves tolerability in patients who previously discontinued therapy due to nausea and/or vomiting. This study also demonstrates that the rate of titration of tramadol HCl rather than the target dose is the major determinant of tolerability.

Adult↗
PubMed1983

1H nuclear magnetic resonance titration curves and microenvironments of aromatic residues in bovine pancreatic ribonuclease A.

The aromatic region of the NMR spectrum of bovine pancreatic ribonuclease A was analyzed in order to clarify the nature of the microenvironments surrounding the individual histidine, tyrosine, and phenylalanine residues and the interactions with inhibitors. The NMR titration curves of ring protons of six tyrosine and three phenylalanine residues as well as four histidine residues were determined at 37 degrees C between pH 1.5 and pH 11.5 under various conditions. The titration curves were analyzed on the basis of a scheme of a simple proton dissociation sequence and the most probable values were obtained for the macroscopic pK values and intrinsic chemical shifts. The microenvironments surrounding the residues and the effects of inhibitors are discussed on the basis of these results. Based on the titration curves of ring protons, the six tyrosine residues were classified into the following four groups: (1) titratable and different chemical shifts for C(delta) and C(epsilon) protons (two tyrosine residues), (2) titratable but similar chemical shifts for C(delta) and C(epsilon) protons (two tyrosine residues), (3) not titratable and different chemical shifts for C(delta) and C(epsilon) protons (one tyrosine residues), and (4) not titratable and similar chemical shifts for C(delta) and C(epsilon) protons (one tyrosine residue). The resonance signals of ring protons were tentatively assigned to tyrosine and phenylalanine residues. The NMR titration curves of His-48 ring protons were continuous in solution containing 0.2 M sodium acetate but were discontinuous in solution containing 0.3 M NaCl because the NMR signals disappeared at pH values between 5 and 6.5. The effects of addition of formate, acetate, propionate, and ethanol were investigated in order to elucidate the mechanism of the continuity of the titration curves of His-48 in the presence of acetate ion. The NMR signal of His-48 C(2) protons was observed at pH 6 in the presence of acetate and propionate ions but was not observed in the presence of formate ion or ethanol. This indicated that both the alkyl chain and the anionic carboxylate group are necessary for the continuity of the titration curves of His-48 ring protons. Based on the results, the mechanism of the effects of acetate ion is discussed.

Acetates↗
PubMed2006

Comparison of CPAP titration at home or the sleep laboratory in the sleep apnea hypopnea syndrome.

STUDY OBJECTIVES: Continuous positive airway pressure (CPAP) for the treatment of obstructive sleep apnea hypopnea syndrome (OSAHS) is conventionally started after in-laboratory overnight titration. This use of sleep laboratory space is both costly and limits access for diagnostic studies. This study aimed to evaluate whether automated CPAP titration in the home produced patient outcomes equal to those following laboratory-based automated CPAP titration. The main outcomes were Epworth Sleepiness Scale score, objective daytime sleepiness (Oxford SLEep Resistance test or OSLER test), and CPAP use; we also performed quality-of-life questionnaires: Functional Outcomes of Sleep Questionnaire and SF-36. DESIGN: Prospective, randomized, single-blind, parallel-group, controlled trial SETTING: Regional sleep center and patients' homes. PATIENTS: Two hundred CPAP-naïve patients with OSAHS requiring CPAP treatment. INTERVENTIONS: One hundred patients were randomly assigned to a standard 1-night in-hospital CPAP titration and 100 to 3 nights' home CPAP titration and then issued with fixed pressure CPAP. Data were analyzed on an intention-to-treat basis. MEASUREMENTS AND RESULTS: The patient groups did not differ at baseline. The CPAP pressures defined at titration (mean+/- SEM: 10.6+/-0.2, 10.4+/-0.2 cm H20, p = .19), number of mask leaks, and initial acceptance rates were similar in the sleep-laboratory and home-titrated groups. At 3-month follow-up, there was no significant difference in CPAP use (mean+/-SEM: 4.39+/-0.25, 4.38+/-0.25 h/night; p > .9), Epworth Sleepiness Scale score (9.5+/-0.5, 8.5+/-0.5, p = .14), OSLER, Functional Outcomes of Sleep Questionnaire, or SF-36 between the sleep-laboratory and home-titrated groups. CONCLUSIONS: Home-based automated CPAP titration is as effective as automatic in-laboratory titrations in initiating treatment for OSAHS.

Calibration↗
PubMedDate not supplied

Rotigotine transdermal patch enables rapid titration to effective doses in advanced-stage idiopathic Parkinson disease: subanalysis of a parallel group, open-label, dose-escalation study.

OBJECTIVE: Rotigotine (Neupro) is formulated as a transdermal delivery system designed to provide a selective, non-ergot D3/D2/D1 agonist to the systemic blood flow over a 24-hour period. In clinical trials, patches were applied once daily and uptitrated to the individual effective dose in increments of 2 mg/24 h every week. The aim of this analysis was to determine the safety of a more rapid titration of rotigotine by assessing the tolerability of escalating transdermal doses of rotigotine given in 2 different titration schemes. METHODS: We analyzed the safety of rotigotine in 2 groups of patients with advanced stage Parkinson Disease. The starting dose of 4 mg/24 h was increased every week by 2 mg/24 h in the slow-titration group and 4 mg/24 h in the fast-titration group. The primary focus of this subanalysis was the separate tolerability of rotigotine in each randomized treatment arm, during the dose-escalation period. However, the 2 titration schemes were also compared with each other. RESULTS: The dose of first reported nausea and/or vomiting was 8 mg/24 h for the fast-titration group and 4 mg/ 24 h for the slow-titration group. There were no remarkable differences concerning the side-effect profile between the 2 different titration schemes. CONCLUSIONS: The fast-titration regimen had a similar adverse event profile to slower titration, and allowed rotigotine to be introduced quickly. This subanalysis suggests that rotigotine may be uptitrated more rapidly.

Administration, Cutaneous↗
PubMed2006

Impact of active versus usual algorithmic titration of basal insulin and point-of-care versus laboratory measurement of HbA1c on glycemic control in patients with type 2 diabetes: the Glycemic Optimization with Algorithms and Labs at Point of Care (GOAL A1C) trial.

OBJECTIVE: The objective of this study was to assess the impact of active versus usual monitoring of algorithmic insulin titration and point-of-care (POC) versus laboratory HbA1c (A1C) measurement on glycemic control in primary care. RESEARCH DESIGN AND METHODS: The Glycemic Optimization with Algorithms and Labs at Point of Care (GOAL A1C) study was a 24-week, randomized, parallel-group, four-arm, open-label study of 7,893 adults with type 2 diabetes uncontrolled by oral antidiabetic agents and requiring insulin. Patients were randomly assigned by investigators from 2,164 sites in the U.S. to insulin glargine with either 1) usual (no unsolicited contact between visits) insulin titration using a simple algorithm with laboratory A1C testing, 2) usual titration with POC A1C testing, 3) active (weekly monitored) titration with laboratory A1C testing, or 4) active titration with POC A1C testing. Outcome measures included a change in A1C and fasting self-monitoring of blood glucose (SMBG) levels, percentage of patients achieving A1C <7.0%, and hypoglycemia frequency. RESULTS: Significant A1C and SMBG reductions were observed in all arms (P < 0.0001). Compared with usual insulin titration, active titration achieved greater A1C reduction (1.5 vs. 1.3%; P < 0.0001), SMBG reduction (88 vs. 79 mg/dl; P < 0.0001), and proportion of patients achieving A1C <7.0% (38 vs. 30%; P < 0.0001). Among patients receiving active titration, POC A1C testing was associated with an increase in the proportion achieving an A1C <7.0% (41% for POC vs. 36% for laboratory; P < 0.0001). Hypoglycemia rates were low (usual vs. active groups: 3.7 vs. 6.0 all confirmed episodes/patient-year [P < 0.001]; 0.09 vs. 0.14 severe episodes/patient-year [NS]). CONCLUSIONS: In a predominantly primary care setting, addition of insulin glargine using a simple algorithm achieved significant improvements in glycemic control in patients with type 2 diabetes in all four study arms. Active titration resulted in significant incremental improvements in glycemic control, and, among patients receiving active titration, POC A1C testing resulted in a greater portion achieving A1C <7.0%.

Administration, Oral↗