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PubMed2001

Impairment and deportment responses to different methylphenidate doses in children with ADHD: the MTA titration trial.

OBJECTIVE: Results of the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) were analyzed to determine whether a double-blind, placebo-controlled methylphenidate (MPH) titration trial identified the best MPH dose for each child with attention-deficit/hyperactivity disorder (ADHD). METHOD: Children with ADHD assigned to MTA medication treatment groups (n = 289) underwent a controlled 28-day titration protocol that administered different MPH doses (placebo, low, middle, and high) on successive days. RESULTS: A repeated-measures analysis of variance revealed main effects for MPH dose with greater effects on teacher ratings of impairment and deportment (F3 = 100.6, n = 223, p = .0001; effect sizes 0.8-1.3) than on parent ratings of similar endpoints (F3 = 55.61, n = 253, p = .00001; effect sizes 0.4-0.6). Dose did not interact with period, dose order, comorbid diagnosis, site, or treatment group. CONCLUSIONS: The MTA titration protocol validated the efficacy of weekend MPH dosing and established a total daily dose limit of 35 mg of MPH for children weighing less than 25 kg. It replicated previously reported MPH response rates (77%), distribution of best doses (10-50 mg/day) across subjects, effect sizes on impairment and deportment, as well as dose-related adverse events.

Analysis of Variance↗
PubMed2002

Losartan titration versus diuretic combination in type 2 diabetic patients.

METHODS: We compared the effects of Losartan dose titration to 100 mg versus the addition of 12.5 mg of hydrochlorothiazide, in 90 type 2 diabetic patients with microalbuminuria and blood pressure > 130/85 mmHg, receiving losartan 50 mg as initial treatment during 4 weeks. RESULTS: With the first dose of losartan, systolic (SBP) and diastolic blood pressure (DBP) decreased from 154.5 (152.1-157.5) to 144.4 (141.3-147.5) mmHg (P < 0.001) and from 91.1 (89.4-92.8) to 84.6 (82.8-86.4) mmHg (P < 0.001), with 20 patients attaining the expected goal blood pressure (< 130/85 mmHg); albuminuria decreased from 109.8 (90.5-133.3) to 83.5 (63.6-109.5) mg per 24 h (P = 0.006). Patients not attaining the target blood pressure were randomly allocated to titration or to the combination arm. After an additional 4 weeks, patients titrated exhibited a fall in SBP and DBP from 157.1 (152.7-161.5) to 142.1 (136.4-147.8) mmHg (P < 0.001) and from 92.4 (89.5-95.3) to 83.6 (81.1-86.1) mmHg (P < 0.001); albuminuria decreased from 136.3 (97.8-189.9) to 99.7 (69.3-143.4) mg per 24 h (P = 0.002). In the combination arm, there were similar reductions in SBP and DBP from 155.3 (151.5-159.1) to 139.1 (132.1-146.1) mmHg (P < 0.001) and from 92.1 (89.3-94.9) to 80.9 (77.4-84.4) mmHg (P < 0.001); while albuminuria fell from 107.7 (82.2-141.0) to 64.2 (45.9-89.9) mg per 24 h (P = 0.001). CONCLUSIONS: Losartan 50 mg was effective in reducing blood pressure and albuminuria in type 2 diabetic patients. When the blood pressure target was not reached, the two strategies tested seem to contribute similarly to further reductions in blood pressure and albuminuria.

Aged↗
PubMedDate not supplied

The effects of a sliding scale diuretic titration protocol in patients with heart failure.

Patients with heart failure (HF) are often instructed to temporarily adjust their diuretic dose. This approach has become routine in some HF management programs; however, no study has specifically examined the effects of a patient-directed flexible diuretic protocol. For the purposes of this study, patients were randomized into a usual care (UC) group (n = 31) or a flexible diuretic titration (DT) group (n = 35). The DT group completed a 6-item diuretic titration protocol once a day, for 3 months. The 6-minute walk distance, plasma B-type natriuretic peptide (NT-BNP), plasma norepinephrine (NE), and quality of life (QOL) were measured at baseline and at 3 months. Hospitalizations, emergency department (ED) visits, and mortality rates were measured at 3 months. Compared to baseline, at 3 months, there was a significant increase in the DT group's 6-minute walk distance (646 +/- 60 ft vs 761 +/- 61 ft, P = .01) and total QOL score (53 +/- 5 vs 38 +/- 5, P = .001), whereas these parameters remained unchanged within the UC group. There were significantly less ED visits in the DT group compared with those in the UC group (3% vs 23%, P = .015). No differences were found between the groups in HF-related hospitalizations or mortality. Within both groups, no differences were found between baseline and 3-month NE or NT-BNP plasma values. Patients with heart failure who used a sliding scale diuretic titration protocol had significant improvements in their exercise tolerance and QOL, had fewer ED visits, and had no change in plasma NE or NT-BNP levels.

Clinical Protocols↗
PubMed2003

Comparison of telmisartan versus losartan: meta-analysis of titration-to-response studies.

OBJECTIVES: To compare the ability of telmisartan and losartan to reduce mean diastolic blood pressure (DBP) during the last 6 h of the 24-h dosing interval in a prospectively planned meta-analysis of ambulatory blood pressure monitoring (ABPM) data from two independent studies. METHODS: Data were from two independent randomized, double-blind, double-dummy, titration-to-response studies conducted in patients with mild-to-moderate hypertension (seated cuff DBP 95-109 mmHg, 24-h mean ambulatory DBP >or=85 mmHg). After a 4-week placebo run-in period, patients received once-daily telmisartan 40 mg or losartan 50 mg, with up-titration after 4 weeks to telmisartan 80 mg or losartan 100 mg, respectively, if seated trough cuff DBP >or=90 mmHg. Blood pressures were recorded using ABPM immediately before randomization and after 8 weeks of active treatment. In addition, seated trough cuff blood pressures were measured at baseline and after 4 and 8 weeks of active treatment. RESULTS: Titration to the higher dose was required in 60.1% of telmisartan patients and 69.5% of losartan patients (P=0.01). Reductions from baseline in the last 6 h mean ambulatory DBP with telmisartan and losartan were 6.6+/-0.4 and 5.1+/-0.4 mmHg, respectively (P<0.01, adjusted for baseline and study); the effects were homogeneous across the two studies. During the last 6 h of the 24-h dosing interval, telmisartan produced greater reductions in each of the observed hourly mean ambulatory DBP values. Telmisartan-induced reductions were also greater for the majority of the observed hourly mean ambulatory DBP values over the entire 24-h dosing interval. Reductions from baseline in the last 6 h adjusted mean ambulatory systolic blood pressure (SBP) for telmisartan and losartan were 9.9+/-0.6 and 7.8+/-0.6 mmHg, respectively (P=0.01). The 24-h profiles of ambulatory SBP hourly mean reductions were similar to those for DBP. Both telmisartan and losartan were found to be safe and well tolerated. CONCLUSIONS: Telmisartan 40/80 mg is superior to losartan 50/100 mg in controlling DBP and SBP during the last 6 h of the 24-h dosing interval.

Adult↗
PubMed2007

Studying multisite binary and ternary protein interactions by global analysis of isothermal titration calorimetry data in SEDPHAT: application to adaptor protein complexes in cell signaling.

Multisite interactions and the formation of ternary or higher-order protein complexes are ubiquitous features of protein interactions. Cooperativity between different ligands is a hallmark for information transfer, and is frequently critical for the biological function. We describe a new computational platform for the global analysis of isothermal titration calorimetry (ITC) data for the study of binary and ternary multisite interactions, implemented as part of the public domain multimethod analysis software SEDPHAT. The global analysis of titrations performed in different orientations was explored, and the potential for unraveling cooperativity parameters in multisite interactions was assessed in theory and experiment. To demonstrate the practical potential and limitations of global analyses of ITC titrations for the study of cooperative multiprotein interactions, we have examined the interactions of three proteins that are critical for signal transduction after T-cell activation, LAT, Grb2, and Sos1. We have shown previously that multivalent interactions between these three molecules promote the assembly of large multiprotein complexes important for T-cell receptor activation. By global analysis of the heats of binding observed in sets of ITC injections in different orientations, which allowed us to follow the formation of binary and ternary complexes, we observed negative and positive cooperativity that may be important to control the pathway of assembly and disassembly of adaptor protein particles.

Adaptor Proteins, Signal Transducing↗
PubMedDate not supplied

Titration of carvedilol in elderly heart failure patients.

Physicians may withhold beta blockers from elderly heart failure patients based on perceptions of poor tolerability in this group. This study analyzed the success and tolerability of carvedilol titration in elderly (70 years and older) and younger (younger than 70) heart failure patients (n=360). The mean duration of titration was similar in both groups. The target carvedilol dosage (50 mg/d) was achieved by 55.3% and 62.0%, and a partial dose was achieved by 44.7% and 35.5% (p=0.028) of elderly and younger patients, respectively. The mean achieved dosage was lower in elderly patients than in younger patients (42.4+/-27.2 mg/d vs. 55.1+/-30.1 mg/d; p<0.0001), possibly due to significant between-group differences in baseline characteristics or rates of target dose achieved. When adjusted for body weight, the mean achieved dose was similar in elderly (0.58+/-0.32 mg/kg/d) and younger (0.64+/-0.30 mg/kg/d) patients (p=nonsignificant). Adverse events were more frequent in the elderly but did not appear to significantly impact titration duration or carvedilol dose achieved when corrected for body weight. In conclusion, carvedilol should not be withheld from elderly heart failure patients based on perceptions of poor potential tolerability.

Adrenergic beta-Antagonists↗
PubMed1991

Protamine--the need to determine the dose. Comparison of a simple protamine titration method with an empirical dose regimen for reversal of heparinisation following cardiopulmonary bypass.

A simple method of protamine titration using the Hemochron system was compared with an empirical dose protocol for reversal of heparinisation following cardiopulmonary bypass in 40 patients undergoing elective myocardial revascularisation. Protamine titration revealed a wide range for protamine requirement and resulted in a significant reduction in protamine dose compared with the empirical dose protocol (p less than 0.01). Heparin reversal was assessed as adequate in all patients. The titration technique was easy and straightforward to use in the operating theatre.

Cardiopulmonary Bypass↗
PubMed1977

Ionization behaviour of native apolipoproteins and of their complexes with lecithin. 2. Potentiometric titration of the native apo-A-II, apoC-I, apoC-III proteins and of their complexes with dimyristoyl lecithin.

A comparison of the ionization behaviour of the human apoA-II, apoC-I, apoC-III proteins and of their complexes with dimyristoyl lecithin is based on potentiometric titration of the basic and acidic residues and spectrophotometric titration of the phenolic groups. Experimental data suggest that a number of lysine, arginine, aspartic acid and glutamic acid residues are masked in the complexes. For each of these amino acids and in all three proteins the number of masked residues is consistent with the content of those regions predicted to be involved in lipid binding by the model of Segrest et al. [FEBS Lett. 38, 247-253 (1974)]. These data taken together with the results of calorimetric and titration experiments with the apoA-I protein reported in the accompanying article [Rosseneu et al. (1977) Eur. J. Biochem. 79, 251-257] strongly support the general nature of the proposed model and further suggest that ionic interactions have some role in the formation of the dimyristoyl lecithin/apolipoprotein complexes.

Amino Acid Sequence↗
PubMed1978

Active-site titration of pig-plasma benzylamine oxidase.

1. Titration of benzylamine oxidase with benzylamine under anaerobic conditions shows that full reduction of the enzymic 470-nm chromophore is obtained on the addition of one mole of substrate per mole of enzyme. Concomitantly, one mole of benzaldehyde per mole of enzyme is produced. 2. A single prosthetic group interacting with carbonyl reagents can be detected on titration of benzylamine oxidase with phenylhydrazine. Titration data reported to indicate a higher content of prosthetic groups were obtained under conditions where equilibration between enzyme and phenylhydrazine is insufficiently complete. 3. It is concluded that pig-plasma benzylamine oxidase contains a single catalytically active site. This means that the two copper atoms present in the enzyme may be structurally or functionally different.

Anaerobiosis↗
PubMed1984

Identification of the titrating group in the heme cavity of myoglobin. Evidence for the heme-protein pi-pi interaction.

The pH dependence of the proton NMR chemical shifts of met-cyano and deoxy forms of native and reconstituted myoglobins reflects a structural transition in the heme pocket modulated by a single proton with pK 5.1-5.6. Comparison of this pH dependence of sperm whale and elephant myoglobin and that of the former protein reconstituted with esterified hemin eliminates both the distal histidine as well as the heme propionates as the titrating residue. Reconstitution of sperm whale met-cyano myoglobin with hemin modified at the 2,4-positions leads to a systematic variation in the pK for the structural transition, thus indicating the presence of a coupling between the titrating group and the heme pi system. The results are consistent with histidine FG3 (His-FG3) being the titrating group, and a donor-acceptor pi-pi interaction between its imidazole and the heme is proposed.

Animals↗
PubMed1986

Active-site ionizations of papain. An evaluation of the potentiometric difference titration method.

The underlying assumption of the potentiometric difference titration method, as applied to the evaluation of the sulfhydryl-dependent ionizations in the active site of papain, is that the pKa of His-159 is independent of whether the neighboring sulfhydryl (Cys-25) is protonated or methylthiolated. That this idealized assumption may not strictly apply is indirectly indicated by the larger pKa of His-159 in S-methylpapain versus that in S-methylthiopapain, as determined from fluorometric titrations (delta pKa = 0.32 +/- 0.05, 25 degrees C). On the basis of the Wegscheider principle of the equivalence of protons and methyl groups, the potentiometric difference titration method will underestimate the concentration of thiolate-imidazolium ion pair in the active site versus that of the thiol-imidazole tautomer, provided that there is no significant H-bonding interaction in the latter species.

Binding Sites↗
PubMed1989

Augmentation of labour: does oxytocin titration to achieve preset active contraction area values produce better obstetric outcome?

The value of quantifying active contraction area to guide oxytocin titration in augmentation of labour was investigated by a randomised trial. Sixty-eight nulliparae with slow progress of labour had oxytocin titrated to achieve preset "optimal" active contraction area or "optimal" frequency of contractions in a randomised manner. There was no difference in maternal characteristics of age and height, pre-augmentation period of observed labour or cervical dilatation at the onset of augmentation between the 2 groups. The maximum dose of oxytocin, post-augmentation period and the number of operative deliveries were similar. There was no difference in the mean birth weight of neonates, or in the number of neonates who had low Apgar score or acidotic cord arterial blood pH. Our results suggest that there may be no advantage in oxytocin titration to achieve preset "optimal" active contraction area compared with "optimal" frequency of uterine contractions in nulliparae with slow progress of labour.

Female↗
PubMed2004

Pre-prandial vs. post-prandial capillary glucose measurements as targets for repaglinide dose titration in people with diet-treated or metformin-treated Type 2 diabetes: a randomized controlled clinical trial.

OBJECTIVE: Repaglinide is an oral anti-diabetic agent that has a short duration of action, and is suitable for preventing post-prandial rises in glucose levels. Targeting post-prandial glucose levels may lead to lower HbA(1c) levels and rates of hypoglycaemia than targeting pre-prandial glucose levels. RESEARCH DESIGN AND METHODS: In 42 centres, 193 drug-naive (n = 122) or metformin-treated (n = 71) individuals with Type 2 diabetes were randomly allocated to a 40-day period of repaglinide dose-titration (starting at 0.5 mg three times daily) based on either self-measured pre-prandial or post-prandial glucose levels. They were followed for a further 12 weeks and HbA(1c) and hypoglycaemia rates were recorded. RESULTS: Repaglinide reduced HbA(1c) by 1.25 and 1.07% in the post-prandial and pre-prandial groups, respectively (P for difference = 0.6), and achieved target glucose levels in 80.7 and 66.7%, respectively (P = 0.16). The effect of titration strategy differed by baseline drug therapy, and was more effective in the metformin-treated individuals who experienced a HbA(1c) fall of 0.6 vs. 1.10% with pre-prandial vs. post-prandial titration (P for metformin-allocated group interaction = 0.043). The rate of hypoglycaemia did not differ by group. CONCLUSIONS: In drug-naive individuals with Type 2 diabetes, similar HbA(1c) levels are achieved with repaglinide when dosing is adjusted according to either post-prandial or pre-prandial levels. Conversely, in metformin-treated individuals, repaglinide dosing according to post-prandial levels may lead to better glycaemic control than dosing according to pre-prandial levels.

Adult↗
PubMed1999

Dosing to efficacy with neurontin: the STEPS trial. Study of Titration to Effect Profile of Safety.

The STEPS (Study of Titration to Effect Profile of Safety) trial, a 16-week, open-label, postmarketing multicenter study, assessed the efficacy of gabapentin as adjunctive therapy in patients with inadequately controlled partial seizures. Inclusion criteria were less restrictive than for Phase III studies, to include a population more representative of the patient population treated in clinical practice. Gabapentin was titrated up to a maximal dosage of 3600 mg/day to achieve seizure control or to tolerability. The efficacy analysis included compliant patients who had completed approximately 16 weeks of therapy (n = 1055); 573 received < or = 1800 mg/day and 482 received > or = 1800 mg/day. The average decrease in seizure frequency was 61%, the percentage of seizure-free patients was 46.35%, and the percentage of patients with a > or = 50% decrease in seizure frequency was 76.05%. The cumulative percentage of responders and of patients who were seizure free increased with each dosage increase. The results confirm that titration to efficacy is appropriate for adjunctive therapy with gabapentin in patients with partial epilepsy treated in clinical practice.

Acetates↗
PubMed2006

Transcranial Doppler detection of microembolic signals during pulmonary vein antrum isolation: implications for titration of radiofrequency energy.

BACKGROUND: Cerebrovascular events are an important complication during pulmonary vein antrum isolation (PVAI). Microembolic signals (MES) have been associated with stroke and neurological impairment. However, the incidence of MES during PVAI, and their relationship to microbubble formation and radiofrequency (RF) parameters are unknown. OBJECTIVES: We sought to assess the relationship between MES, microbubble detection, and neurological outcome and the impact of RF titration strategy on these parameters. METHODS: We studied 202 patients in two groups undergoing PVAI using an intracardiac echocardiography (ICE)-guided technique. MES were detected by transcranial Doppler (TCD) using insonation of the middle cerebral arteries. The number of microbubbles on ICE were qualitatively labeled as FEW, MODERATE, and SHOWER. In group I (n = 107), RF output was titrated to avoid microbubble formation and in group II (n = 95), standard power-limited RF output was used. RESULTS: TCD detected MES in all 202 patients during PVAI with an average of 1,793 +/- 547 per patient; 90% were detected during left atrial ablation. Over 85% of MES occurred after microbubbles. Group I patients had significantly lower numbers of MES (1,015 +/- 438 per patient) compared to group II patients (2,250 +/- 864 per patient) (P < 0.05). Group II also had a 3.1% incidence of acute neurological complications versus 0.9% in group I (P = 0.10). Patients with clinical events had significantly higher numbers of MES. There were no significant correlations between RF power, temperature, or impedence and MES number. CONCLUSIONS: MES directly correlate to the amount of microbubble formation on ICE, and may result in cerebroembolic complications. Titration of RF according to microbubble formation by ICE during PVAI may be important for minimizing the occurrence of MES and possibly acute neurological complications.

Atrial Fibrillation↗
PubMed1979

The determination of aluminium in antacid formulations by Gran's Plot titration with sodium fluoride.

The aluminium content of a number of proprietary antacid formulations has been determined by titration with sodium fluoride, using the fluoride activity electrode as an end-point detector. Results compared favourably with the official method. The fluoride titration, however, involved less sample manipulation and was more rapid to carry out. End-point detection was made easier by treating titration data by the Gran's Plot method.

Aluminum↗
PubMed1980

The assay of pseudoephedrine hydrochloride in tablets and liquid formulations by two phase acid-base titration.

A novel titration method for the assay of pseudoephedrine hydrochloride in formulations is presented. Pseudoephedrine base is extracted into chloroform and titrated with acid in a two phase system. The method is specific for the drug in tablet and syrup formulations. The precision and speed of assay are comparable with existing spectrometric and titration methods for amine drugs.

Drug Stability↗
PubMed1978

Potentiometric titration of the high- and low-potential 4Fe-4S* centers of Azotobacter vinelandii ferredoxin I.

The high-potential 4Fe-4S* center ofAzotobacter vinelandii ferredoxin I has been titrated potentiometrically by a reductive procedure. The absorbance decrease at 510 nm accompanying the reduction of the high-potential center titrated with an Em of 320 mV (n = 1). The low-potential 4Fe-4S* center was titrated by using the absorbance decrease at 410 nm to monitor its reduction. This center exhibited an Em of -424 mV (n = 1).

Azotobacter↗