Force titrations

In general, the SSRIs have a more tolerable side effect profile than the tricyclic antidepressants with their anticholinergic effects. Review of the rate that subjects in the controlled studies discontinued a SSRI because of adverse effects provides some perspective on how well tolerated the medications are, although the specifics may vary according to dosage and design (e.g., forced titration) and are not directly comparable. The rate of discontinuation was reported to be 12% (4/48) for fluoxetine (Emslie et ah, 1997), 9.7% for paroxetine (Keller et ah, 2001), 13% (12/92) for sertraline (March et ah, 1998), and 33% (19/57) (Riddle et ah, 2001) and 7.9% (5/63) for fluvoxamine (Walkup et ah, 2001). 

To overcome some of these limitations, a fixed dose-titration schedule can be implemented in the beginning of a flexible-dose trial in order to reach a minimum effective dose for each patient, followed by a flexible dose-titration schedule. Use of titration points, anchored to a clinical assessment (e.g. forced titration to the next level in the case of Clinical Global Impression severity scores of > 3), makes the titration schedule and the results more homogeneous and tends to unify investigators judgments (for details see Martenyi et al 2002). 

Wang, B., Chen, L., AbdulaM-Kanji, Z., Horton, J.H., Oleschuk, R.D., Aging effects on oxidized and amine-modified poly(dimethylsiloxane) surfaces studied with chemical force titrations Effects on electroosmotic flow rate in microfluidic channels. Langmuir, 2003, 19, 9792-9798. 

Carboxylic groups positioned at the open ends of SWCNTs were coupled to amines to form AFM probes with basic or hydrophobic functionalities by Wong et al. [117] (Scheme 1.8). Force titrations recorded between the ends of the SWCNT-AFM tips and hydroxy-terminated SAMs confirmed the chemical sensitivity and robustness of the AFM tips. Images recorded on patterned SAM allowed real molecular-resolution imaging [117]. 

Wang, B., Oleschuk, R. D., Petkovich, P. M. and Horton, J. H. (2007). Chemical force titrations of antigen- and antibody-modified poly(methylmethacrylate). Colloids Sutf. B Biointerfaces 55 107-114. 

Force Titrations of Flame-Treated LDPE Sample Preparation Flame-treatment [29]... 

Table 4.1 Details to prepare solutions for CFM force titrations...

The FV data acquired are analyzed as sketched in the examples above. The pull-off force values for each f-d curve are estimated and a histogram of forces for each pH and treatment condition is calculated. In Fig. 4.11 some normalized force titration curves (average pull-off force as a reference of value at pH 4 versus pH) on flame treated LDPE are shown. These titration curves display a typical sigmoidal shape, while the untreated polymer exhibited by contrast an almost constant pull-off force over the entire pH range. 

Fig. 4.11 Normalized force titration curves showing the adhesive force between hydroxyl functionalized tips and flame treated LDPE films as a function of the solution pH. The average pull-off force at pH 4 was set as a reference for each sample. The solid lines have been added as guides to the eye. (a) Untreated LDPE. (b) LDPE flame-treated 50 times, (c) LDPE treated 100 times, (d) LDPE treated 200 times. Reproduced with permission from [29]. Copyright 2007. Elsevier...

Randomized parallel group forced titration Subjects are divided into placebo and active groups. Active groups all start with the same dose, for example, 10 mg. One group continues with 10 mg, another group later increases to 20 mg and stays at this dose. A third active group then increases from 10 mg to 20 mg and finally to 40 mg progressively. 

Vezenov DV, Noy A, Rozsnyai LF, Lieber CM. Force titrations and ionization state sensitive imaging of functional groups in aqueous solutions by chemical force microscopy. J Am Chem Soc 1997 119(8) 2006-15. 

Figure 23 Adhesion force titration cmve for a PO3H2 functional tip on a PO3H2 functional substrate at constant ionic strength. (Reprinted, in part, with permission of the American Chemical Society from Ref. [182], E. W. van der Vegte and G. Hadziioannou, J. Phys. Chem. B 101 9563 (1997).)...

Geissler, A. Vallat, M.-F. Vidal, L. Voegel, J. C. Hemmerle, J. Schaaf, P. Roucoules, V., Chemical Force Titration of Plasma Polymer-Modified PDMS Substrates by Using Plasma Polymer-Modified AFM Tips. Langmuir 2008,24, 4874-4880. 

Song, J., Duval, J.F.L., Stuart, M.A.C., Hillborg, H., Gunst, U., Arlinghaus, H.F., Vancso, G.J. (2007) Surface ionization state and nanoscale chemical composition of UV-irradiated poly(dimethylsiloxane) probed by chemical force microscopy, force titration, and electrokinetic measurements. Langmuir, 23,5430-5438. 

Fig. 22. Pull-off force histograms recorded with a SiO probe on PS, isotactic PP, PVDF, and poly-(tetrafluoroethylene-co-hexafluoropropylene) (FEP), respectively, in perfluorode-caline (left) and force titration of plasma-polymerized allylamine films as measured in buffer using hydroxyl-terminated SFM tips together with representative f-d curves (right). The f-d curves display (depending on the pH of the buffered aqueous solution) (a) exclusively repulsive (pH 4.7), (b), (c) repulsive and attractive (pH 5.3 and 6.2, respectively), or (d) exclusively adhesive interactions (pH 6.8). Reprinted in part with permission from Ref. 86 (left). Copyright (1998) American Chemical Society, and Ref 216 (right). Copyright (2000) American Chemical Society.

A particnlarly powerfnl approach for the study of surface fimctional groups in polymers is the so-called method of force titration, introduced originally for monolayer systems (7,66,216,221-223). Force titration refers to the measurement of pull-off forces as a fimction of pH on polymers comprising ionizable functional groups. For instance, for plasma polymerized allylamine films, the force titration behavior (Fig. 22, right) was found to agree with the presence of primary amino groups in a locally hydrophobic environment based on the observed shift in force pi a ( 5.7) with respect to solution pi a ( 10.5) (216). 

Related observations were reported for plasma-poljnnerized allylamine films on oxidized silicon and for plasma-modified PP (216,223). On the basis of the force titration behavior (Fig. 22, right) the heterogeneous distribution of pull-off forces at pH values close to the force pR a was related to variations in local hydrophilicity and hence amino group content. 

Fig. 24 Force titration of an untreated iPP (top, left) and three oxyfluorinated iPP films using OH-terminated SFM tips. The total surface tension values are indicated. The error bars correspond to the standard deviation of the average value calculated from the corresponding histograms. (Reprinted with permission from [58]. Copyright 2000 American Chemical Society)...

Electrostatic Forces— The AFM Tip. The most frequently used commercial AFM tip consists of microfabricated silicon nitride. Under normal laboratory conditions, this is, in reality, an ill-defined, hydroxylated melange of silicon oxynitride and silicon dioxide, the precise composition of which depends on a combination of manufacturing conditions and tip history. An isoelectric point of around pH=5 has been firequently observed in force-distance measurements under electrolyte in our laboratory (15), suggesting the oxidized oxynitride composition mentioned above. In order to achieve a better reproducibility, however, we have adopted an oxygen plasma-treatment procedure, which leaves the tip coated with hydroxylated silica, as evidenced by an isoelectric point of around pH=3 (16), as measured by force titration (75). 

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