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PubMed2003

Titrating and evaluating multi-drug regimens within subjects.

The dosing of combination therapies is commonly undertaken empirically by practising physicians, and a coherent algorithm to approach the problem of combination dosing is currently lacking. Current methods of evaluating multiple drug combinations in clinical trials fail to provide information regarding the location of more effective doses when the combination is not found to differ from the standard, even though the absence of a difference does not necessarily mean the new combination is ineffective. Moreover, in studies where the new combination is found more effective, often a large proportion of the study participants obtain no benefit from the trial. Even with early stopping rules, the time these subjects spend on inferior treatments can have lasting detrimental effects, leading to problems with patient enrolment and adherence to study protocol. This paper describes an evolutionary operation (EVOP) direct-search procedure to titrate combination doses within individual patients. The Nelder-Mead simplex direct-search algorithm is used to titrate combinations of drugs within individual subjects. Desirability functions are utilized to define the main response of interest and additional responses or constraints. Statistical methodology for determining whether the titrated treatment combination has resulted in an improvement in subject response and for evaluating for therapeutic synergism is developed. Inferences can then be made about the efficacy of the combination or about the individual drugs that comprise the combination. The advantages of this approach include affording every patient the potential to benefit from the combination under study and permitting the consideration of multiple endpoints simultaneously.

Algorithms↗
PubMed1989

The analysis of titration studies in phase III clinical trials.

Clinical trials commonly employ the titration design for certain drugs such as antihypertensives. In a Phase III trial the design has purposes distinct from those of a Phase I or II trial, as well as from those of a trial with a parallel design. In this paper we compare the titration design with the usual parallel design in their respective purposes for Phase III trials, explore the relevant questions addressed, and examine typical data from such trials. We also discuss work which focuses primarily on the Phase I or II titration trials. We formulate the problem in the framework of one-way contingency table augmented with incomplete data and obtain the maximum likelihood estimates of the parameters and their estimated variances/covariances via the EM algorithm. An example of a Phase III study of an antihypertensive agent illustrates the proposed procedure.

Analysis of Variance↗
PubMed2001

Isothermal titration calorimetric analysis of the interaction between cationic lipids and plasmid DNA.

The effects of buffer and ionic strength upon the enthalpy of binding between plasmid DNA and a variety of cationic lipids used to enhance cellular transfection were studied using isothermal titration calorimetry at 25.0 degrees C and pH 7.4. The cationic lipids DOTAP (1,2-dioleoyl-3-trimethyl ammonium propane), DDAB (dimethyl dioctadecyl ammonium bromide), DOTAP:cholesterol (1:1), and DDAB:cholesterol (1:1) bound endothermally to plasmid DNA with a negligible proton exchange with buffer. In contrast, DOTAP: DOPE (L-alpha-dioleoyl phosphatidyl ethanolamine) (1:1) and DDAB:DOPE (1:1) liposomes displayed a negative enthalpy and a significant uptake of protons upon binding to plasmid DNA at neutral pH. These findings are most easily explained by a change in the apparent pKa of the amino group of DOPE upon binding. Complexes formed by reverse addition methods (DNA into lipid) produced different thermograms, sizes, zeta potentials, and aggregation behavior, suggesting that structurally different complexes were formed in each titration direction. Titrations performed in both directions in the presence of increasing ionic strength revealed a progressive decrease in the heat of binding and an increase in the lipid to DNA charge ratio at which aggregation occurred. The unfavorable binding enthalpy for the cationic lipids alone and with cholesterol implies an entropy-driven interaction, while the negative enthalpies observed with DOPE-containing lipid mixtures suggest an additional contribution from changes in protonation of DOPE.

Calorimetry↗
PubMed1997

Measurement of biochemical affinities with a Gill titration calorimeter.

A Gill titration calorimeter is evaluated as an instrument to determine in one experiment the equilibrium constant and the enthalpy change of a biochemical reaction. The dimensionless parameter kc (the product of the association equilibrium constant and the concentration of the reagent to be titrated; Wiseman et al., Anal. Biochem. 179, 131-137, 1989) is used to analyze the instrument performance. The analysis of simulated titration data corresponding to a simple model case shows that association equilibrium constants in the 10(2)-10(7) M-1 range may be determined when the kc parameter is between 1 and 1000. In addition we use a Monte Carlo approach to estimate the precision in the thermodynamic parameters of the reaction under study. The relative precision in the calculated constants ranges from 3 to 80% depending on the macromolecule concentration and kc value in the experiment. These results were checked with the study of the reactions of beta-trypsin with its inhibitor and ribonuclease A with cytidine 2'-monophosphate and cytidine 3'-monophosphate.

Binding Sites↗
PubMed2000

Calibrationless determination of creatinine and ammonia by coulometric flow titration.

A precise and sensitive working microflow titration procedure was developed to determine creatinine and ammonia in urine samples. This procedure is based on enzymatic conversion of creatinine, gas diffusional membrane separation of the released ammonia into an acid acceptor stream, and coulometric titration of ammonia with hypobromite. The hypobromite is formed after the electrogeneration of bromine in an electrolyte containing 1.0 M NaBr and 0.1 M sodium borate adjusted to pH 8.5. The electrolysis current follows a triangle-programmed current-time course. An amperometric flow detector records the resulting mirror symmetrical titration curves, which show two equivalence points. The analyte concentration is calculated from the time difference between the equivalence points. For quantitative conversion of creatinine and quantitative separation of present and released ammonia no calibration is necessary to get accurate results. Both ammonia/ammonium and creatinine were determined in the range between 2 microM and 2 mM with relative standard deviations between 3.0 and 1.0% (n = 5). High recoveries were obtained for the analysis of diluted urine samples for both creatinine and ammonia.

Aminohydrolases↗
PubMed2001

Method dependence of apparent stoichiometry in the binding of salicylate ion to human serum albumin: a comparison between equilibrium dialysis and fluorescence titration.

The binding of salicylate ion to human serum albumin (HSA) was studied in 100 mM potassium phosphate buffer (pH 7.4, 25 degrees C), using equilibrium dialysis and fluorescence titration methods. The protein samples tested were (a) dialyzed human plasma and (b) a commercial preparation of HSA, essentially free of globulin and fatty acids. Independent of the analytical method used, Scatchard and nonlinear regression analyses of the data pointed to a single class of high-affinity salicylate binding sites. On the other hand, the binding parameters were found to be method dependent. K(d) ranged between 25 +/- 2.4 and 62 +/- 15 microM in equilibrium dialysis and between 10 +/- 1.3 and 40 +/- 3.0 microM in fluorescence titration. (The higher limits refer to plasma samples at high [HSA]). Following the same pattern, the apparent stoichiometry of binding (though independent of sample identity and concentration) was higher in equilibrium dialysis (n(app) = 3.2 +/- 0.10) than in fluorescence titration (n(app) 1.9 +/- 0.30). The difference between the two methods could be reconciled by invoking two distinct classes of binding sites (I and II), which had identical (or marginally different) K(d) values, while differing in the magnitude of the fluorescence signal (Deltaf) generated upon ligand binding (Deltaf, PL(I) = Deltaf(I); Deltaf, PL(II) = 0). Further, it was assumed that the state of occupation of class II sites affected the fluorescence efficiency of class I sites, such that Deltaf, PL(I,II) = betaDeltaf(I) (beta = interaction factor). A random binding scheme involving P, PL(I), PL(II), and PL(I,II) was formulated. The model adequately predicted the behavior of the system when monitored through the change in protein fluorescence: Taking K(d) = 25 microM and n(T) = 3, the interaction factor beta was found to be 0.62 +/- 0.10. It was concluded that the correct parameters for the binding of salicylate ion to HSA are K(d) = 25 +/- 2.4 microM and n(T) = 3.2 +/- 0.10, as indicated by equilibrium dialysis of purified HSA. Besides updating information relating to the salicylate binding potential of HSA, this study serves to illustrate a likely complication in the study of protein-ligand interactions by fluorometric methods.

Chromatography, Gel↗
PubMed1996

Titration of recombinant aequorin with calcium chloride.

The photoprotein aequorin emits light in the presence of a trace of Ca2+. The primary structure of the protein indicates the presence of three Ca2+-binding sites, whereas the luminometric titration of heterogeneous natural aequorin with Ca2+ has shown that the light emission takes place by the binding of two Ca2+ ions. In the case of recombinant aequorin, which is more suitable for quantitative studies, the titration with Ca2+ monitored by a Ca2+-sensitive electrode revealed that the photoprotein can bind more than two, most likely three, Ca2+ ions, and the luminometric titration conclusively showed that the luminescence is triggered by the first two Ca2+ ions bound. The affinity of recombinant aequorin for the first two Ca2+ ions, which are essential for light emission, was about 20 times stronger than that for the third Ca2+ ion, which is unrelated to light emission.

Aequorin↗
PubMed1997

Constructing a Proton Titration Curve from Ion-Step Measurements, Applied to a Membrane with Adsorbed Protein

A new measuring method is described for obtaining a proton titration curve. The curve is obtained from a microporous composite membrane, consisting of polystyrene beads in an agarose matrix, with lysozyme molecules adsorbed to the bead surface. The membrane is incorporated into a sensor system by deposition on a silicon chip with a pH-sensitive ion-sensitive field effect transistor (ISFET) located in the middle of a Ag/AgCl electrode. The actual measurement is performed by creating a stepwise change in the salt concentration of the bathing electrolyte (the ion step) and measuring the ISFET potential versus the Ag/AgCl electrode. This potential shows a transient change in the ion step, which indicates a transient pH change in the membrane. This procedure is repeated at a series of pH values. Equations are presented to calculate the proton titration curve of the membrane from the amplitude and duration of the measured transients. Measurements show qualitative agreement between the curves obtained and equilibrium titration experiments on the same system.

Journal Article↗
PubMed1994

Competitive titration for probing low-abundance ion channel mRNA molecules in normal and regionally-ischaemic heart tissue.

We have measured the expression levels of a range of distinct ion channel genes in the apex/ventricle region and sino-atrial node (SAN) sub-regions of heart under conditions in which conventional Northern hybridization or ribonuclease protection methods were too insensitive or non-quantitative. The abundance of six potassium channel mRNAs was determined in relation to a single synthetic competitor RNA template which was co-reverse transcribed and PCR-amplified. By these methods we have shown that coronary artery ligation procedures which induce anoxia and ischaemic scarring in the apical region reduce amplifiable message abundance in a time-dependent, but non-specific manner. There was no evidence for any selective reduction of individual mRNA levels during this process. Despite a high reproducibility of titration endpoints, competitive RNA template amplification assays did not provide a simple marker for ischaemic damage, since it was not possible to control for tissue sample heterogeneity. We have also applied these competitive nucleic acid titration techniques to demonstrate expression of cAMP- and cGMP-gated ion channel sequences in small pieces of tissue derived from the SAN sub-region of rabbit heart. Although the ion channels encoded by these sequences are obligately coupled to intracellular signalling agonists commonly found in cardiac cells, they have not been described in functional terms within SAN or any other cardiac subregion. For rapid determination of cDNA molecular numbers, we have devised single-gene, DNA template controls to measure absolute abundance of a cAMP-gated cDNA derived from heart tissue. Competitive titration procedures therefore provide an important technique for probing gene induction and/or repression accompanying pharmacological or surgical interventions, or in progression of disease states. For rare cDNAs, they can estimate the representativeness of a given preparation prior to library construction, screening and retrieval of clones, while eliminating 'false positive' or 'false negative' signals.

Animals↗
PubMed2002

New methods to titrate EIAV-based lentiviral vectors.

Ideally, gene transfer vectors used in clinical protocols should only express the gene of interest. So far most vectors have contained marker genes to aid their titration. We have used quantitative real-time PCR to titrate equine infectious anemia virus (EIAV) vectors for gene therapy applications. Viral RNA was isolated from vector preparations and analyzed in a one-step RT-PCR reaction in which reverse transcription and amplification were combined in one tube. The PCR assay of vector stocks was quantitative and linear over four orders of magnitude. In tandem, the integration efficiency of these vectors has also been determined by real-time PCR, measuring the number of vector genomes in the target cells. We have found that these methods permit reliable and sensitive titration of lentiviral vectors independent from the expression of a transgene. They also allow us to determine the integration efficiency of different vector genomes. This technology has proved very useful, especially in the absence of marker genes and where vectors express multiple genes.

Animals↗
PubMed1987

Multiple copies of the amdS gene of Aspergillus nidulans cause titration of trans-acting regulatory proteins.

It has been established that a plasmid containing the amdS gene of Aspergillus nidulans may be used to transform amdS+ strains by selecting for increased utilization of acetamide as sole nitrogen source. Analysis of transformants has shown that multiple tandem copies of the plasmid can be integrated into the chromosome, commonly at sites other than the amdS locus. While the transformed phenotype was relatively stable through mitotic and meiotic divisions evidence was found for variation in plasmid copy number presumably due to unequal recombination events. Expression of the integrated amdS genes was related to copy number, and the amdS RNA produced was similar in size to wild-type RNA. Evidence for titration of the product of the regulatory gene amdR by multiple copies of amdS was found. No titration of the product of the areA gene was observed, and amdS expression was still dependent on areA function. Multiple copies of the amdI9 mutation resulted in poor growth on acetate. This was not observed in the case of the amdS+ gene. The cis-acting amdI9 mutation causes increased facB dependent acetate induction of amdS expression. Titration of the facB gene produce by amdI9 DNA, but not by amdS+ DNA, therefore suggested that the mutation results in increased affinity for the facB gene product.

Amidohydrolases↗
PubMed1982

Effects of a nicotine-enriched cigarette on nicotine titration, daily cigarette consumption, and levels of carbon monoxide, cotinine, and nicotine.

To test whether cigarettes with low tar, low carbon monoxide, and medium nicotine yield produce less dangerous effects than cigarettes low in tar and CO but high in nicotine, 12 subjects were recruited to smoke nicotine-enriched cigarettes. The subjects smoked three types of cigarettes in the three experimental conditions: (1) their own brand; (2) cigarettes with 4.8 mg tar, 4.0 mg CO, and 0.5 mg nicotine; (3) cigarettes with 5.8 mg tar, 4.1 mg CO, and 1.1 mg nicotine. Subjects monitored their daily consumption for 12 weeks; 4 weeks for each condition. During laboratory visits, the subjects smoked a cigarette while their heart rate and carbon monoxide in expired air were measured pre- and post-smoking. A blood sample was drawn and analyzed for nicotine and cotinine in each experimental condition. No significant differences in daily cigarette consumption were found, although a trend (P less than 0.07) in the direction of fewer nicotine-enriched cigarettes per day was found. Levels of CO varied significantly among the three conditions: The subjects' own brands yielded the highest level, while the nicotine-enriched cigarette yielded the lowest level. No differences were found for nicotine or cotinine levels. A second purpose of the experiment was to record the degree of nicotine titration displayed by individual smokers, tar and CO levels remained constant in the experimental cigarettes. No general titration effect was observed, although for daily consumption it approached significance. When the subjects' nicotine dependence, measured with a tolerance questionnaire, was taken into account, a correlation with daily consumption was found (r = 77, P less than 0.005). A cigarette with low tar and CO, but medium to high nicotine yield, would seem to produce less hazardous effects and is worthy of further investigation. The controversial question of whether smokers titrate for nicotine is a function of the individual's nicotine dependence.

Adult↗
PubMed1994

Transdermal fentanyl in uncontrolled cancer pain: titration on a day-to-day basis as a procedure for safe and effective dose finding--a pilot study in 20 patients.

All communications on the use of transdermal fentanyl as well as the recommendations of the manufacturer include the direction that patients should be titrated with a short-acting narcotic to control their cancer pain before they are converted to a fentanyl transdermal therapeutic system (TTS). We investigated the possibility of avoiding this titration phase by immediate fentanyl TTS therapy in patients with uncontrolled cancer pain. Dose finding was performed by direct titration of fentanyl TTS according to clinical necessity on a day-to-day basis. Morphine solution for rescue medication was available. Short-term follow-up was 28 days, and 20 patients (10 in- and 10 outpatients) were evaluable. On the average, sufficient pain control [visual analogue scale (VAS) < 35 mm] was reached within 48 h of the start of fentanyl TTS. The mean VAS values before and during fentanyl TTS therapy were 53 mm (before), 27 mm (week 1), 21 mm (week 2), 18 mm (week 3) and 21 mm (week 4). There were statistically significant lower VAS values at all follow-up times compared to pretreatment values (e.g. pretreatment to day 1: P = 0.019; pretreatment to day 28: P = 0.002; Wilcoxon sign-rank test). The mean fentanyl TTS doses were 70 micrograms/h (week 1), 98 micrograms/h (week 2), 107 micrograms/h (week 3) and 116 micrograms/h (week 4). The differences of mean fentanyl TTS does were significantly different between days 1 and 7 (P < 0.001) and between days 8 and 14 (P = 0.006), but not between days 15 and 21 and days 22 and 28.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1984

Glucose perfusion intragastric titration.

A comparison was made between use of isotonic 0.15 M sodium chloride and 5.8 g/100 ml glucose solutions for measurement of gastric acid secretion by intragastric titration in normal and ulcer subjects. Glucose distention did not cause significantly different acid secretion than saline distention in either group. The total amounts of glucose entering the duodenum over the 3.5-hr study period were 99 g in normal subjects and 122 g in ulcer subjects. In normal subjects, circulating gastrin-related acid secretion curves were not significantly different during endogenous peptone and exogenous G-17 stimulation using either the glucose or the saline meals. This finding provides evidence that glucose meals of this size do not alter sensitivity to gastrin. With glucose meals, inhibition of gastric emptying caused retention of a sufficient volume in the stomach to permit accurate continuous intragastric titration. Saline meals caused pronounced diarrhea which was not seen after glucose meals. Glucose distention intragastric titration allows reliable comparisons of endogenously and exogenously stimulated gastric acid secretion without serious side effects and is especially suitable for studying acid secretion in duodenal ulcer subjects.

Adult↗
PubMed1982

Analysis of creams. II. Quantitative determination of drugs in creams by titration in non-aqueous solvents.

The possibilities for the determination of active components in creams by acid-base titrations in non-aqueous solvents were investigated. Interference by cream-base components with the titration of weak organic bases and their halides with perchloric acid in acetic acid, and with the titration of weak acids with tetrabutylammonium hydroxide in N,N-dimethylformamide were studied. It appeared to be possible to determine alkaloid halides, salicylic acid, hexachlorophene and methyl salicylate without previous clean-up of the cream samples.

Ointments↗
PubMed1995

Consensus statement: octreotide dose titration in secretory diarrhea. Diarrhea Management Consensus Development Panel.

Octreotide is an effective therapeutic option in controlling secretory diarrhea of varied etiology. However, marked patient-to-patient differences in the antidiarrheal effects necessitate titration of octreotide dose in individual patients to achieve optimal symptom control. A consensus development panel established guidelines for octreotide dose titration in patients with secretory diarrhea. Overall, the panel recommended an aggressive approach in selecting the initial octreotide dose and in making subsequent dose escalations in patients with secretory diarrhea due to gastrointestinal tumors (eg, carcinoids, VIPomas), AIDS, dumping syndrome, short bowel syndrome, radiotherapy, or chemotherapy. To avoid hypoglycemia in patients with diabetes mellitus-associated secretory diarrhea, the panel recommended a low initial octreotide dose and a conservative titration regimen with close monitoring a blood glucose levels. The end point of therapy should focus on a reduction in diarrhea (frequency of bowel movements or stool volume) rather than normalization of hormonal profile. Overall, octreotide is well tolerated; principal side effects are transient injection site pain and gastrointestinal discomfort. For many patients with secretory diarrhea, octreotide therapy is expected to improve the overall health and quality of life and in the long run will lessen health care costs.

Carcinoid Tumor↗
PubMed2002

Titration of isoflurane using BIS index improves early recovery of elderly patients undergoing orthopedic surgeries.

PURPOSE: This study was designed to investigate the effect of bispectral index (BIS) monitoring on the recovery profiles, level of postoperative cognitive dysfunction, and anesthetic drug requirements of elderly patients undergoing elective orthopedic surgery with general anesthesia. METHODS: Sixty-eight patients over the age of 60 were randomized into one of two groups. In the standard practice (SP) group, the anesthesiologists were blinded to the BIS value, and isoflurane was titrated according to standard clinical practice. In the BIS group, isoflurane was titrated to maintain a BIS value between 50-60. RESULTS: The total isoflurane usage was 30% lower in the BIS group compared to the SP group (5.6 +/- 3 vs 7.7 +/- 3 mL, P <0.05). The time to orientation was faster in the BIS group compared to the SP group (9.5 +/- 3 vs 13.1 +/- 4 min, P <0.001). There were no differences in the postoperative psychometric tests between the two groups. CONCLUSIONS: There was no difference in the level of postoperative cognitive dysfunction between the two groups. However, titration of isoflurane using the BIS index decreased utilization of isoflurane and contributed to faster emergence of elderly patients undergoing elective knee or hip replacement surgery.

Aged↗
PubMed2002

Antinociceptive effects of the selective delta opioid agonist SNC80 alone and in combination with mu opioids in the squirrel monkey titration procedure.

RATIONALE: The nonpeptidic compound SNC80 [(+)-4[(alphaR)-alpha-((2S, 5R)-4-allyl-2, 5,-dimethyl-l-piperazinyl)-3-methoxybenzyl]- N, N-diethylbenzamide], has a high degree of selectivity for delta opioid receptors. Moreover, compounds with delta opioid activity have been shown to enhance the effects of mu agonists under certain conditions. OBJECTIVES: The present study examined the effects of SNC80 alone and in combination with the mu opioid agonists, morphine, butorphanol, and buprenorphine to determine whether SNC80 would enhance their antinociceptive effects. METHODS: In the squirrel monkey shock titration procedure increasing levels of shock are delivered to the monkey's tail in incremental steps and responses on a lever decrease shock intensity. The level at which monkeys maintain the shock (median shock level, MSL) and rate of responding (RR) are examined. RESULTS: SNC80 alone did not consistently alter responding under the titration procedure; however, morphine, butorphanol, and buprenorphine increased MSL without decreasing RR markedly. SNC80 (0.1-3.0 mg/kg) enhanced the effects of single doses of morphine, butorphanol, and buprenorphine that either did not increase or produced very small increases in MSL when administered alone. Interestingly, SNC80 enhanced the effects of morphine, butorphanol, and buprenorphine on MSL without decreasing RR. CONCLUSIONS: SNC80 does not produce antinociceptive effects in the squirrel monkey titration procedure but can enhance the effects of selected doses of morphine, butorphanol, and buprenorphine on MSL without decreasing RR. These data suggest that SNC80-induced enhancement of the antinociceptive effects of mu opioids is dependent on dose, time, and method of administration and is not the result of sedation or motor dysfunction.

Analgesics↗