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Determination of promethazine hydrochloride and its preparations by highly accurate nephelometric titration.

A highly accurate nephelometric titration for the determination of promethazine hydrochloride and its preparations was presented. The titration operating conditions were studied and the solubility product constant of promethazine tetraphenylboron precipitation was determined. The result of the titration is comparable to those of control experiments. The proposed method has been found to be accurate, precise, specific and linear.

Nephelometry and Turbidimetry↗

The titration of clay minerals I. Discontinuous backtitration technique combined with CEC measurements.

Previous experimental studies on clay potentiometric titration have been unable to distinguish inorganic cation exchange in the interlayer and on basal plane surfaces from specific pH-dependent sorption of cations and anions on the edges. In this study, we refined a titration technique, combining discontinuous backtitration and cation exchange capacity (CEC) measurements, and applied it to the potentiometric titration of Na- and Ca-conditioned montmorillonites. This technique can be used to accurately measure cation exchange, edge surface proton charge, dissolution of clay, and precipitation of new phases. Thus, a precise measurement of the variations of net proton surface charge is possible. This has important implications for clay surface modeling (see part II of this article) and for processes that depend on the clay surface charge, e.g., alteration, rheological processes, and contamination retention applications. In addition, this study confirms the adsorption of ionic pairs such as CaCl+ in exchange site positions and shows that CaOH+ could behave like CaCl+. This result, together with the evidence of precipitation of a Ca?Si phase over a short time-scale (1 week) at high pH and low temperature, can be used to model clay-concrete interactions more accurately. We confirmed and quantified the H+/Na+ exchange reaction at low pH. Finally, we demonstrate that both the edge surface charge and the permanent structural charge are compensated for by the nonspecific sorption of cations from solution across the entire pH range from 4 to 11. Under these conditions, the surface potential is fully screened and does not need to be invoked in modeling sorption processes on clay particles in dilute suspensions.

Journal Article↗

The titration of clay minerals II. Structure-based model and implications for clay reactivity.

The potentiometric titration and CEC data presented in part I are modeled in this paper, part II. Two models are compared: the two pK, three complexation sites plus exchange sites nonelectrostatic model developed by Baeyens and Bradbury and a model based on the MUSIC approach developed by Hiemstra and Van Riemsdijk. Both morphological and structural information is used to develop this new model. Morphological information is taken from the literature, while structural information is taken from the literature and constrained by supporting FTIR experiments. The Baeyens and Bradbury model is found to reproduce the general tendency of the titration curve, whereas the model based on the Hiemstra and Van Riemsdijk MUSIC approach provides a better fit to the experimental data. The former uses only 3 edge reaction sites, whereas the latter uses at least 27 edge reaction sites. Five main reactive sites are sufficient to fit the MUSIC model curve, but the model allows us to derive the properties of 22 other reactive sites. Logically, the greater the number of sites, the better the fit. Nevertheless, fewer adjustable parameters are necessary for the Hiemstra and Van Riemsdijk MUSIC model than for the Baeyens and Bradbury model, thanks to structural and morphological constraints. The precision of the potentiometric titration curve is insufficient to verify that the properties of the 27 sites given by the MUSIC model are effective. Thus, we coupled some properties of clay minerals, such as dissolution, to the modeled acid-base properties of these sites to assess our model. We then questioned the ability of simplified models such as the Baeyens and Bradbury model to predict the interactions between clay minerals and solutions in natural environments. In addition, we derived the cation exchange selectivity coefficients for CaCl+ ionic pairs and H+ from our CEC data and gave an estimate for the CaOH+ selectivity coefficient.

Journal Article↗

Influence of kinetics on the determination of the surface reactivity of oxide suspensions by acid-base titration.

The effect of acid-base titration protocol and speed on pH measurement and surface charge calculation was studied on suspensions of gamma-alumina, hematite, goethite, and silica, whose size and porosity have been well characterized. The titration protocol has an important effect on surface charge calculation as well as on acid-base constants obtained by fitting of the titration curves. Variations of pH versus time after addition of acid or base to the suspension were interpreted as diffusion processes. Resulting apparent diffusion coefficients depend on the nature of the oxide and on its porosity.

Aluminum Oxide↗

Phosphorus-doped and undoped glassy carbon indicator electrodes in controlled-current potentiometric titrations of bromide- or chloride-containing active ingredients in some pharmaceutical preparations.

Phosphorus-doped glassy carbon (as a novel material) and glassy carbon (Sigri commercial sample) were applied as potentiometric indicator electrodes in the titrimetric determination of active components with bromide or chloride in their molecules in different pharmaceutical preparations (Buscopan, Prostigmine, Isoptin, Bedoxin, Akineton and Trodon). After the necessary pre-treatment of the electrode surfaces and sample dissolution, the halide was titrated with a standard solution of silver nitrate (indirect determination). Amounts of 10-20 micromol of the investigated active ingredients per titration were determined with a relative standard deviation that, depending on the nature of indicator electrode, determined molecules and filler components, was in the range of 0.3-2.7%. The results obtained were compared with those of the official methods and with those obtained by potentiometric titrations using silver electrode. The titrimetric procedures developed are relatively fast, easy, economical and can be used to analyse of a large number of pharmaceutical products.

Carbon↗

Topiramate slow dose titration: improved efficacy and tolerability.

Topiramate is an effective treatment for several types of seizures. The aim of this study is to assess the efficacy and tolerability of slow topiramate dose titration as add-on therapy in childhood epilepsy. This investigation is a prospective open-label, single-center, add-on study in 22 children with a diagnosis of refractory epilepsy. Topiramate (dose 0.5-2 mg/kg/day) was titrated at 2-week intervals up to the recommended dose of 6-12 mg/kg/day. Seizure frequency rate reduction was significant, declining from 23 +/- 5.1 seizures/week (mean +/- S.E.M.) at baseline phase to 3.5 +/- 1.2 seizures/week at the end of the 16-week stabilization phase (P < 0.001). After 16 weeks of stabilization, 19 patients (86%) had more than 50% seizure reduction. Seven patients (31%) were 100% seizure-free. Two patients (9%) manifested no improvement; only one patient (5%) did not tolerate the added drug and discontinued topiramate. One patient manifested severe side effects, whereas 21 patients experienced mild to moderate side effects mostly represented by somnolence, nervousness, and anorexia with or without weight loss. We conclude that slow dose titration improves efficacy and tolerability of topiramate as add-on therapy in the treatment in refractory epilepsy.

Adolescent↗

Chaotic dynamics of resting ventilatory flow in humans assessed through noise titration.

The mammalian ventilatory behaviour exhibits nonlinear dynamics as reflected by certain nonlinearity or complexity indicators (e.g. correlation dimension, approximate entropy, Lyapunov exponents, etc.) but this is not sufficient to determine its possible chaotic nature. To address this, we applied the noise titration technique, previously shown to discern and quantify chaos in short and noisy time series, to ventilatory flow recordings obtained in quietly breathing normal humans. Nine subjects (8 men and 1 woman, 24-42 years) were studied during 15-min epochs of ventilatory steady-state (10.1+/-3.0 breaths/min, tidal volume 0.63+/-0.2 L). Noise titration applied to the unfiltered signals subsampled at 5 Hz detected nonlinearity in all cases (noise limit 20.2+/-12.5%). Noise limit values were weakly correlated to the correlation dimension and the largest Lyapunov exponent of the signals. This study shows that the noise titration approach evidences a chaotic dimension to the behavior of ventilatory flow over time in normal humans during tidal breathing.

Adult↗

Neuropsychological and psychiatric impact of add-on titration of pregabalin versus levetiracetam: a comparative short-term study.

Cognitive and behavioral impairments are common in patients with epilepsy. Multiple factors may contribute to these difficulties; among them is antiepileptic drug (AED) treatment. We examined the short-term impact of two new add-on AEDs, pregabalin (PGB) and levetiracetam (LEV), on cognition and psychiatric states in 20 adult patients with medically refractory partial epilepsy, before and shortly after add-on titration. According to an open, prospective comparative trial, add-on PGB was titrated to 300 mg and add-on LEV to 1000 mg in 10 patients each. Patients were assessed before (T1) and 2 weeks after (T2) addition of the AED. During the trial, seizure frequency did not change significantly in either group. With PGB, patients manifested partly significant impairments in episodic memory of verbal and visual information. Psychiatric states were unchanged. With LEV treatment, we saw improvements in visual short-term memory performance and psychiatric states (i.e., interpersonal sensibility, depression, and anxiety). The comparison between PGB and LEV revealed a trend toward higher anxiety scores and higher variability in hostility scores with PGB that was significantly different from the trend with LEV. No significant differences were apparent in all other neuropsychological and psychiatric parameters investigated. This short-term study suggests that add-on LEV has a favorable neuropsychological and psychiatric impact. The negative neuropsychological effects of PGB may reflect temporary effects under titration. Still, the results did not confirm the promising effects on psychiatric comorbidity that have been emphasized by other reports.

Adult↗

Titration of vasodilator therapy in chronic heart failure according to plasma brain natriuretic peptide concentration: randomized comparison of the hemodynamic and neuroendocrine effects of tailored versus empirical therapy.

BACKGROUND: Most patients with chronic heart failure (CHF) receive the same dose of angiotensin-converting enzyme (ACE) inhibitors because there is currently no measure of treatment efficacy. We sought to determine whether titration of vasodilator therapy according to plasma brain natriuretic peptide (BNP) concentration may be of value in the individual optimization of vasodilator therapy in CHF. METHODS AND RESULTS: Twenty patients with mild to moderate CHF receiving stable conventional therapy including an ACE inhibitor were randomly assigned to titration of ACE inhibitor dosage according to serial measurement of plasma BNP concentration (BNP group) or optimal empirical ACE inhibitor therapy (clinical group) for 8 weeks. Only the BNP-driven approach was associated with significant reductions in plasma BNP concentration throughout the duration of the study and a significantly greater suppression when compared with empiric therapy after 4 weeks [-42.1% (-58.2, -19.7) vs -12.0% (-31.8, 13.8), P =.03]. Both treatment strategies were well tolerated and associated with favorable neurohormonal and hemodynamic effects; however, in comparison between groups, mean heart rate fell (P =.02) and plasma renin activity rose (P =.03) in the BNP group when compared with the clinical group. CONCLUSIONS: Plasma BNP concentration may be chronically reduced by tailored vasodilator therapy in CHF. Furthermore, titration of vasodilator therapy according to plasma BNP was associated with more profound inhibition of the renin-angiotensin-aldosterone system and significant fall in heart rate when compared with empiric therapy.

Aged↗

Effects of intravenous milrinone followed by titration of high-dose oral vasodilator therapy on clinical outcome and rehospitalization rates in patients with severe heart failure.

This study evaluated the efficacy of intravenous milrinone in improving hemodynamics and facilitating the titration of high-dose oral vasodilator therapy to improve clinical status. Fourteen patients (mean age 52 +/- 12 years) with severe heart failure and a left ventricular ejection fraction of 18 +/- 6% underwent right-side heart catheterization and an intravenous milrinone infusion followed by titration of oral vasodilator and diuretic therapy. Milrinone significantly (p <0.05) improved right atrial pressure (12 +/- 5 to 8 +/- 5 mm Hg), pulmonary capillary wedge pressure (23 +/- 7 to 15 +/- 7 mm Hg), cardiac index (1.9 +/- 0.4 to 3.4 +/- 0.5 L/min/m2), systemic vascular resistance (1,809 +/- 526 to 891 +/- 144 dynes/s/cm(-5)), and pulmonary vascular resistance (285 +/- 151 to 163 +/- 68 dynes/s/cm(-5)), which was maintained in 10 patients with titration of high-dose oral vasodilator therapy. Oral angiotensin-converting enzyme inhibitor and diuretic doses were increased 318% and 89%, respectively. Four patients also received hydralazine to optimize hemodynamics. New York Heart Association functional class improved from 3.8 +/- 0.4 to 2.6 +/- 0.6 following therapy. Ten patients who responded to therapy had fewer hospitalized days during the subsequent year compared with the year before treatment (4 +/- 17 vs 17 +/- 15), and no patient died. In contrast, the 3 patients who responded poorly to therapy tended to have more hospitalized days at 12 months compared with pretreatment (31 +/- 11 vs 20 +/- 18; NS); 1 patient died. We conclude that intravenous milrinone followed by optimization of oral medical therapy may be used as a therapeutic trial to identify patients in need of cardiac transplantation.

Adult↗

Isothermal titration calorimetric procedure to determine protein-metal ion binding parameters in the presence of excess metal ion or chelator.

Determination of binding parameters for metal ion binding to proteins usually requires preceding steps to remove protein-bound metal ions. Removal of bound metal ions from protein is often associated with decreased stability and inactivation. We present two simple isothermal titration calorimetric procedures that eliminate separate metal ion removal steps and directly monitor the exchange of metal ions between buffer, protein, and chelator. The concept is to add either excess chelator or metal ion to the protein under investigation and subsequently titrate with metal ion or chelator, respectively. It is thereby possible in the same experimental trial to obtain both chelator-metal ion and protein-metal ion binding parameters due to the different thermodynamic "fingerprints" of chelator and protein. The binding models and regression routines necessary to analyze the corresponding binding isotherms have been constructed. Verifications of the models have been done by titrations of mixtures of calcium chelators (BAPTA, HEDTA, and EGTA) and calcium ions and they were both able to account satisfactorily for the observed binding isotherms. Therefore, it was possible to determine stoichiometric and thermodynamic binding parameters. In addition, the concept has been tested on a recombinant alpha-amylase from Bacillus halmapalus where it proved to be a consistent procedure to obtain calcium binding parameters.

Bacillus↗

A dose titration study evaluating terazosin, a selective, once-a-day alpha 1-blocker for the treatment of symptomatic benign prostatic hyperplasia.

The efficacy and safety of terazosin, a selective long-acting alpha-1-adrenergic blocker, were evaluated in 45 normotensive patients with symptomatic benign prostatic hyperplasia ranging from 50 to 76 years old. All patients underwent a complete urodynamic evaluation and transrectal prostatic ultrasonography before enrollment into the study. The dose of terazosin was titrated to 5 mg. per day for a 1-month interval, provided adverse drug reactions were not observed. Of the patients 39 (87%) completed the dose titration study. The parameters used to assess the effectiveness of terazosin included peak and mean urinary flow rates, micturition symptom scores and the global assessment by the patient of symptomatic improvement. Over-all, the mean systolic and diastolic blood pressures changed by less than 1%. The peak and mean urinary flow rates increased by 42 and 48%, respectively. The obstructive and irritative symptom scores improved by 63 and 35%, respectively. Over-all, 30 of the 45 participants (67%) indicated that the voiding symptoms were markedly improved while on terazosin. Five patients did not complete the dose titration study due to development of adverse drug reactions, including erectile dysfunction (7%), tiredness (7%), light-headedness (4%), palpitations (4%), nasal congestion (2%) and asymptomatic hypotension (2%). There were 25 patients (55%) followed on terazosin for 4 to 10 months (mean 6.5 months). The improvements in urinary flow rates and symptom scores were maintained for this interval. Although this preliminary experience with terazosin is encouraging, the ultimate role of terazosin for the long-term treatment of benign prostatic hyperplasia needs further evaluation.

Adrenergic alpha-Antagonists↗

STATT: a titrate-to-goal study of simvastatin in Asian patients with coronary heart disease. Simvastatin Treats Asians to Target.

BACKGROUND: Most published studies on the use of lipid-lowering agents to treat hypercholesterolemia have focused on Western populations, with few data on Asian populations. OBJECTIVE: The Simvastatin Treats Asians to Target (STATT) study used a titrate-to-goal protocol to evaluate the efficacy and tolerability of simvastatin 20 to 80 mg/d in the treatment of Asian patients with coronary heart disease. METHODS: This was a multicenter, open-label, uncontrolled, 14-week study in patients with coronary heart disease and serum low-density lipoprotein cholesterol (LDL-C) levels of 115-180 mg/dL and triglyceride levels of < or = 400 mg/dL. The dose of simvastatin was titrated from 20 to 80 mg/d to achieve the National Cholesterol Education Program (NCEP) LDL-C target of < or = 100 mg/dL. The primary efficacy measure was the percentage of patients achieving the NCEP target. Among secondary measures were the percentage of patients achieving European Society of Cardiology/European Atherosclerosis Society/European Society of Hypertension target LDL-C levels of < or = 115 mg/dL and the percentage change from baseline in lipid parameters. Tolerability was assessed in terms of the overall incidence of adverse experiences and the incidences of the most commonly reported adverse experiences. RESULTS: The intent-to-treat analysis included 133 Asian patients (93 men, 40 women; mean age, 59.5 years), of whom 125 completed 14 weeks of therapy. Their mean blood pressure was 130.2/79.4 mm Hg. Overall, 104 (78.2%) patients treated with simvastatin achieved LDL-C levels < or = 100 mg/dL at week 14, and 125 (94.0%) achieved this target at some point during the study. Similarly, 122 (91.7%) patients achieved an LDL-C level < or = 115 mg/dL at week 14, and 130 (97.7%) achieved this target at some point during the study. Treatment with simvastatin had favorable effects on the lipid profile, producing significant percentage changes from baseline in all parameters (P < 0.001). Simvastatin was well tolerated across the dose range. Overall, 40 patients (30.1%) had > or = 1 clinical adverse experience. Only 14 (10.5%) had adverse experiences that were possibly, probably, or definitely related to study drug; none of these experiences were considered serious. The most common adverse experiences (> or = 3% incidence) were abdominal pain (6%); chest pain (5%); dizziness (4%); and asthenia/fatigue, fibromyalgia, headache, insomnia, and upper respiratory tract infection (3% each). No new or unexpected adverse experiences were seen at the higher doses. CONCLUSIONS: Simvastatin was effective and well tolerated at doses of 20, 40, and 80 mg/d in Asian patients with coronary heart disease. Titration enabled the majority to achieve target LDL-C levels of < or = 100 mg/dL.

Aged↗

PROTECT interim results: a large multicenter study of patients with type II diabetes. Precose Resolution of Optimal Titration to Enhance Current Therapies.

The Precose Resolution of Optimal Titration to Enhance Current Therapies (PROTECT) study is an ongoing Phase IV clinical trial designed to assess the effectiveness, tolerability, and safety of acarbose tablets in patients with type II diabetes when the dosage is slowly titrated upward. This multicenter, open-label, 28-week trial will enroll approximately 7,000 type II diabetic patients. The present report describes the interim results for 2,139 patients who completed the trial as of November 1, 1996. Patients with type II diabetes enrolled in the study were inadequately controlled either with diet alone or with a sulfonylurea. The dosage of acarbose was titrated from 25 mg three times a day (TID) to 100 mg TID based on tolerability and efficacy. Efficacy of glycemic control was assessed by changes in glycated hemoglobin A1c (Hb A1c) and 1-hour postprandial plasma glucose (PPG) levels. Tolerability and safety were determined by patient reports of treatment-emergent adverse events and by review of laboratory tests. The PROTECT study confirms the previously demonstrated efficacy and safety of acarbose in improving glycemic control in patients with type II diabetes regardless of a patient's age, body weight, ethnic background, time since diagnosis, or severity of disease. mean 1-hour PPG levels declined throughout the entire treatment period, with a mean decrease from baseline of -47 mg/dL at the end of treatment. Hb A1c, the most reliable indicator of long-term glycemic control, decreased over the course of treatment, resulting in a mean decrease of -0.7% (P < 0.001). Although all patient types enrolled in the study responded positively to therapy, certain subgroups responded particularly well, such as those patients diagnosed with the disease less than 1 year ago, those treated with acarbose as monotherapy, and those with higher baseline Hb A1c levels. Adverse events were experienced by 36% of all patients and consisted primarily of gastrointestinal disturbances (flatulence, diarrhea, abdominal pain). Moderate renal insufficiency (serum creatinine levels between 1.5 and 2 mg/dL) was present in 259 patients, and no patients developed serum hepatic transaminase levels more than twice the normal range.

Acarbose↗

A naturalistic comparison of adverse effects between slow titration and loading of divalproex sodium in psychiatric inpatients.

BACKGROUND: This study compares the incidence, severity and onset of treatment-emergent adverse effects between slow titration and loading of divalproex sodium in psychiatric inpatients. METHOD: Forty-seven patients were prescribed either loading or slow titration of divalproex sodium. Under single-blind conditions, adverse effects were assessed using a valproate adverse effects rating scale. Except for a statistically significant greater incidence of somnolence in the slow titration group, no statistically or clinically significant differences in incidence, severity or onset of treatment-emergent adverse effects were found between groups. RESULTS/CONCLUSION: Overall, adverse effects were well tolerated by both groups.

Adult↗

Cost analysis of employing multi-test allergy screening to guide serial endpoint titration (SET) testing versus SET alone.

OBJECTIVE: We analyzed the cost differences between 2 different modalities of allergy testing. Study design and setting Material costs, labor costs, and overhead expenditures were compared for 2 different allergy-testing algorithms. Fifty patients were placed in each group. The first group was tested for 14 allergens and 2 control substances by using multi-test II. These patients were compared with 50 patients tested for similar allergens and control substances by using serial endpoint titration. RESULTS: The initial round of tests with serial endpoint titration was nearly 3 times as costly as the multi-test for the 14 allergens and 2 control substances. Conclusion and significance Multi-testing is a cost-effective initial testing modality that can screen out negative results and enable the identification of positive reactions. These results could then be further investigated by using serial endpoint titration or RAST to quantify the patient's sensitivity and establish a starting dose for immunotherapy.

Algorithms↗

ELISA test for rabies antibody titration in orally vaccinated foxes sampled in the fields.

The assessment of the efficacy of rabies oral vaccination campaigns requires the titration of specific antibodies in the target species. Unfortunately, in Continental Europe, most fox serum samples are in fact "body fluids" taken from cadavers and the lack of a validated titration method for these poor quality sera made it impossible to survey and compare the efficacy of various oral vaccination protocols used by the different European teams. By using ready to use microplates sensitised with rabies virus glycoprotein purchased from a manufacturer and applying a simple and rapid ELISA technique on field fox sera, we obtained antibody quantitation highly correlated with seroneutralising antibody titres measured with a seroneutralisation test on cell culture. We obtained, with fox sera sampled in the same area, the same distribution of high, medium and low titres within all categories of serum quality (from high to very poor quality) and therefore conclude that this ELISA test allows a reliable titration even with highly contaminated body fluids. This test was shown to be equally capable of detecting rabies antibodies in serum samples taken from foxes vaccinated with an highly attenuated rabies virus (the SAG2 double mutant of the Street Alabama Dufferin strain) or with the VRG, the Vaccinia recombinant glycoprotein. Additionally, a strong correlation was demonstrated between titres given by this ELISA (or by the seroneutralisation test) and protection against challenge of foxes orally vaccinated with SAG2 vaccine baits. In view of this validation, this simple and reliable test is proposed for sero-surveying foxes following rabies oral vaccination campaigns.

Administration, Oral↗

Randomized, double-blind, placebo-controlled, dose-titration, phase III study assessing the efficacy and tolerability of lanthanum carbonate: a new phosphate binder for the treatment of hyperphosphatemia.

BACKGROUND: Lanthanum carbonate is a novel, non-calcium, non-aluminum phosphate binder under evaluation for the treatment of hyperphosphatemia in end-stage renal disease (ESRD) patients receiving either hemodialysis or continuous ambulatory peritoneal dialysis. METHODS: This 16-week study assessed the control of serum phosphorus with lanthanum carbonate, and its effects on serum calcium, calcium x phosphorus product, and parathyroid hormone (PTH). Hemodialysis patients > or =18 years old entered into a 1- to 3-week washout period during which serum phosphorus levels rose to >5.9 mg/dL (1.90 mmol/L). In total, 126 patients were titrated with lanthanum carbonate at doses containing 375, 750, 1,500, 2,250, or 3,000 mg/d elemental lanthanum, given in divided doses with meals over a 6-week period, to achieve serum levels < or =5.9 mg/dL. By the end of dose titration, 11/126 (9%) patients received < or =750 mg/d of lanthanum, 25 (20%) received 1,500 mg/d, 37 (29%) received 2,250 mg/d, and 53 (42%) received 3,000 mg/d. Following titration, patients were randomized to receive either lanthanum carbonate or placebo during a 4-week, double-blind maintenance phase. RESULTS: At the study endpoint, the mean difference in serum phosphorus between the lanthanum carbonate and placebo treatment arms was 1.91 mg/dL (0.62 mmol/L) (P < 0.0001). Calcium x phosphorus product (P < 0.0001) and serum PTH levels (P < 0.01) were also significantly lower with lanthanum carbonate versus placebo. The incidence of drug-related adverse events was similar between placebo- and lanthanum carbonate-treated patients. CONCLUSION: Lanthanum carbonate is an effective and well-tolerated agent for the treatment of hyperphosphatemia in patients with ESRD.

Aged↗