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PubMed1993

Titration of histidine 62 in R67 dihydrofolate reductase is linked to a tetramer<-->two-dimer equilibrium.

R67 dihydrofolate reductase (DHFR) is an R-plasmid encoded protein that confers clinical resistance to the antibacterial drug trimethoprim. To determine whether an acidic titration in kinetic pH profiles is related to titration of histidines 62, 162, 262, and 362, the stability of tetrameric R67 DHFR has been monitored as a function of pH. For the pH range 5-8, tetrameric R67 DHFR reversibly dissociates into dimers, as monitored by ultracentrifugation and molecular sieving techniques. From the crystal structures of dimeric and tetrameric R67 DHFR [Matthews et al. (1986) Biochemistry 25, 4194-4204] (Narayana, Matthews, and Xuong, personal communication), symmetry-related histidines 62, 162, 262, and 362 occur at the two dimer-dimer interfaces and protonation of these residues could destabilize tetrameric R67 DHFR. Ionization of these histidines was confirmed by monitoring the chemical shifts of the C2 proton in NMR experiments, and best fits of an incomplete titration curve yield a pKa of 6.77. Since tryptophans 38, 138, 238, and 338 also occur at the dimer-dimer interfaces, fluorescence additionally monitors the tetramer-two dimers equilibrium. When fluorescence was monitored over the pH range 5-8, a protein concentration dependence of fluorescence was observed and global fitting of three titration curves yielded Kd = 9.72 nM and pKa = 6.84 for the linked reactions: [formula: see text] Modification of H62, H162, H262, and H362 by diethyl pyrocarbonate stabilizes dimeric R67 DHFR and causes a 200-600-fold decrease in catalytic efficiency. Decreased catalytic activity in dimeric R67 DHFR is presumably due to loss of the putative single active site pore found in tetrameric R67 DHFR.

Chromatography, Gel↗
PubMed1986

Double-inhibitor and uncoupler-inhibitor titrations. 1. Analysis with a linear model of chemiosmotic energy coupling.

The results of double-inhibitor and uncoupler-inhibitor titrations have been simulated and analyzed with a linear model of delocalized protonic coupling using linear nonequilibrium thermodynamics. A detailed analysis of the changes of the intermediate delta muH induced by different combinations of inhibitors of the proton pumps has been performed. It is shown that with linear flow-force relationships the published experimental results of uncoupler-inhibitor titrations are not necessarily inconsistent with, and those of double-inhibitor titrations are inconsistent with, a delocalized chemiosmotic model of energy coupling in the presence of a negligible leak. Also shown and discussed are how the results are affected by a nonnegligible leak and to what extent the shape of the titration curves can be used to discriminate between localized and delocalized mechanisms of energy coupling.

Adenosine Triphosphatases↗
PubMed1981

Titration of the phase transition of phosphatidylserine bilayer membranes. Effects of pH, surface electrostatics, ion binding, and head-group hydration.

The dependence of the gel-to-fluid phase transition temperature of dimyristoyl- and dipalmitoylphosphatidylserine bilayers on pH, NaCl concentration, and degree of hydration has been studied with differential scanning calorimetry and with spin-labels. On protonation of the carboxyl group (pK2app = 5.5), the transition temperature increases from 36 to 44 degrees C in the fully hydrated state of dimyristoylphosphatidylserine (from 54 to 62 degrees C for dipalmitoylphosphatidylserine), at ionic strength J = 0.1. In addition, at least two less hydrated states, differing progressively by 1 H2O/PS, are observed at low pH with transition temperatures of 48 and 52 degrees C for dimyristoyl- and 65 and 68.5 degrees C for dipalmitoylphosphatidylserine. On deprotonation of the amino group (pK3app = 11.55) the transition temperature decreases to approximately 15 degrees C for dimyristoyl- and 32 degrees C for dipalmitoylphosphatidylserine, and a pretransition is observed at approximately 6 degrees C (dimyristoylphosphatidylserine) and 21.5 degrees C (dipalmitoylphosphatidylserine), at J = 0.1. No titration of the transition is observed for the fully hydrated phosphate group down to pH less than or equal to 0.5, but it affinity for water binding decreases steeply at pH greater than or equal to 2.6. Increasing the NaCl concentration from 0.1 to 2.0 M increases the transition temperature of dimyristoyphosphatidylserine by approximately 8 degrees C at pH 7, by approximately 5 degrees at pH 13, and by approximately 0 degrees C at pH 1. These increases are attributed to the screening of the electrostatic titration-induced shifts in transition temperature. On a further increase of the NaCl concentration to 5.5 M, the transition temperature increases by an additional 9 degree C at pH 7, 13 degree C at pH 13, approximately 7 degree C in the fully hydrated state at pH 1, and approximately 4 and approximately 0 degree C in the two less hydrated states. These shifts are attributed to displacement of water of hydration by ion binding. From the salt dependence it is deduced that the transition temperature shift at the carboxyl titration can be accounted for completely by the surface charge and change in hydration of approximately 1 H2O/lipid, whereas that of the amino group titration arises mostly from other sources, probably hydrogen bonding. The shifts in pK (delta pK2 = 2.85, delta pK3 = 1.56) are consistent with a reduced polarity in the head-group region, corresponding to an effective dielectric constant epsilon approximately or equal to 30, together with surface potentials of psi congruent to -100 and -150 mV at the carboxyl and amino group pKs, respectively. The transition temperature of dimyristoylphosphatidylserine-water mixtures decreases by approximately 4 degree C each water/lipid molecule added, reaching a limiting value at a water content of approximately 9-10 H2O/lipid molecule.

Calorimetry, Differential Scanning↗
PubMed1979

Potentiometric titrations and oxidation-reduction potentials of manganese and copper-zinc superoxide dismutases.

Bovine erythrocyte superoxide dismutase and two manganese-containing superoxide dismutases have been reduced by the indirect coulometric titration method with methylviologen as the mediator-titrant. On the basis of the titration data the manganese-containing superoxide dismutases contain 1 g-atom of metal per mol of enzyme (dimer). E0' = +0.31 V for the enzyme from Escherichia coli which exhibits a complicated pH dependence above neutral pH. The Bacillus stearothermophilus manganese-containing enzyme has an E0' = +0.26 V and delta Em/pH is 50 mV. Bovine erythrocyte superoxide dismutase exhibits anomalous behavior in the coulometric titration curves, which is indicative of two nonequivalent copper centers in the enzyme. Addition K3Fe(CN)6 or K2IrCl6 to the enzyme solution, prior to coulometric titration, indicates that these anions bind preferentially to one of the copper centers.

Animals↗
PubMed1976

Hydrogen ion titration of horse heart ferricytochrome c.

Continuous hydrogen ion titration curves of deionized solutions of horse heart ferricytochrome c have been obtained at 25 degrees C. at a constant ionic strength of 0.10 from pH 3.0 to 11.0. Titration of the oxidized protein in KCl required 28.4 equiv over that pH range, and a small hysteresis between the forward and reverse limbs was displayed. The Linderstrom-Lang approximation, which takes into account electrostatic interactions between charged groups on the protein surface, was used in a computer simulation program to analyze the forward and reverse limbs of the titration curve separately. The results indicated 1 alpha-, 12 beta- and gamma-, and 1 heme propionic carboxylic, 1 imidazole, 1 phenolic, and 18 epsilon-amino residues appear to titrate normally. Variations in the electrostatic interaction factor omega suggest conformational changes in the protein at the extremes of pH, although the relationship of the variations in omega to the magnitude of the conformational changes does not appear to be strictly quantitative for cytochrome c. These results show the acid-base behavior of cytochrome c to be complex in nature, and suggest that the Lindenstrom-Lang model may not be adequate for cytochrome c.

Animals↗
PubMed2003

Modeling complexometric titrations of natural water samples.

Complexometric titrations are the primary source of metal speciation data for aquatic systems, yet their interpretation in waters containing humic and fulvic acids remains problematic. In particular, the accuracy of inferred ambient free metal ion concentrations and parameters quantifying metal complexation by natural ligands has been challenged because of the difficulties inherent in calibrating common analytical methods and in modeling the diverse array of ligands present. This work tests and applies a new method of modeling titration data that combines calibration of analytical sensitivity (S) and estimation of concentrations and stability constants for discrete natural ligand classes ([Li]T and Ki) into a single step using nonlinear regression and a new analytical solution to the one-metal/two-ligand equilibrium problem. When applied to jointly model data from multiple titrations conducted at different analytical windows, it yields accurate estimates of S, [Li]T, Ki, and [Cu2+] plus Monte Carlo-based estimates of the uncertainty in [Cu2+]. Jointly modeling titration data at low-and high-analytical windows leads to an efficient adaptation of the recently proposed "overload" approach to calibrating ACSV/CLE measurements. Application of the method to published data sets yields model results with greater accuracy and precision than originally obtained. The discrete ligand-class model is also re-parametrized, using humic and fulvic acids, L1 class (K1 = 10(13) M(-1)), and strong ligands (L(S)) with K(S) >> K1 as "natural components". This approach suggests that Cu complexation in NW Mediterranean Sea water can be well represented as 0.8 +/- 0.3/0.2 mg humic equiv/L, 13 +/- 1 nM L1, and 2.5 +/- 0.1 nM L(S) with [CU]T = 3 nM. In coastal seawater from Narragansett Bay, RI, Cu speciation can be modeled as 0.6 +/- 0.1 mg humic equiv/L and 22 +/- 1 nM L1 or approximately 12 nM L1 and approximately 9 nM L(S), with [CU]T = 13 nM. In both waters, the large excess (approximately 10 nM) of high-affinity, Cu-binding ligands over [CU]T results in low equilibrium [Cu2+] of 10(-14.5 +/- 0.2) M and 10(-13.3 +/- 0.4) M, respectively.

Forecasting↗
PubMed2006

Chemical force titrations of functionalized Si(111) surfaces.

Chemical force titrations-plots of the adhesive force between an atomic force microscope tip and sample as a function of pH-were acquired on alkyl monolayer-derivatized Si(111) surfaces. Gold-coated AFM tips modified with thioalkanoic acid self-assembled monolayers (SAM) were employed. Alkyl monolayer-derivatized Si(111) surfaces terminated with methyl, carboxyl, and amine groups were produced via hydrosilylation reactions between 1-alkene reagents and H-terminated silicon. The functionalized surfaces were characterized using standard surface science techniques (AFM, FTIR, and XPS). Titration of the methyl-terminated surface using the modified (carboxyl-terminated) atomic force microscope tip resulted in a small pH-independent hydrophobic interaction. Titration of the amine-terminated surface using the same tip resulted in the determination of a surface pKa of 5.8 for the amine from the pH value from the maximum in the force titration curve. A pK(1/2) of 4.3 was determined for the carboxyl-terminated Si(111) in a similar way. These results will be discussed in relation to the modified Si(111) surface chemistry and organic layer structure, as well as with respect to existing results on Au surfaces modified with SAMs bearing the same functional groups.

Journal Article↗
PubMed2000

pH-metric solubility. 2: correlation between the acid-base titration and the saturation shake-flask solubility-pH methods.

PURPOSE: The objective of this study was to compare the results of a normal saturation shake-flask method to a new potentiometric acid-base titration method for determining the intrinsic solubility and the solubility-pH profiles of ionizable molecules, and to report the solubility constants determined by the latter technique. METHODS: The solubility-pH profiles of twelve generic drugs (atenolol, diclofenac.Na, famotidine, flurbiprofen, furosemide, hydrochlorothiazide, ibuprofen, ketoprofen, labetolol.HCl, naproxen, phenytoin, and propranolol.HCl), with solubilities spanning over six orders of magnitude, were determined both by the new pH-metric method and by a traditional approach (24 hr shaking of saturated solutions, followed by filtration, then HPLC assaying with UV detection). RESULTS: The 212 separate saturation shake-flask solubility measurements and those derived from 65 potentiometric titrations agreed well. The analysis produced the correlation equation: log(1/S)titration = -0.063(+/- 0.032) + 1.025(+/- 0.011) log(1/S)shake-flask, s = 0.20, r2 = 0.978. The potentiometrically-derived intrinsic solubilities of the drugs were: atenolol 13.5 mg/mL, diclofenac.Na 0.82 microg/mL, famotidine 1.1 mg/ mL, flurbiprofen 10.6 microg/mL, furosemide 5.9 microg/mL, hydrochlorothiazide 0.70 mg/mL, ibuprofen 49 microg/mL, ketoprofen 118 microg/mL, labetolol.HCl 128 microg/mL, naproxen 14 microg/mL, phenytoin 19 microg/mL, and propranolol.HCl 70 microg/mL. CONCLUSIONS: The new potentiometric method was shown to be reliable for determining the solubility-pH profiles of uncharged ionizable drug substances. Its speed compared to conventional equilibrium measurements, its sound theoretical basis, its ability to generate the full solubility-pH profile from a single titration, and its dynamic range (currently estimated to be seven orders of magnitude) make the new pH-metric method an attractive addition to traditional approaches used by preformulation and development scientists. It may be useful even to discovery scientists in critical decision situations (such as calibrating computational prediction methods).

Hydrogen-Ion Concentration↗
PubMed2002

Involvement of carboxyl and phenoxyl groups in Cajanus cajan lectin-sugar interaction: interpretation of titration curves.

Hydrogen ion titration of an affinity-purified mannose/glucose-specific lectin from Cajanus cajan seeds at 30 degrees C and ionic strength of 0.15 was reported earlier by our lab (Salahuddin and Khan, 1998). Further work has been carried out on the systematic study of H+ titration of Cajanus cajan lectin at three different temperatures, i.e., 10 degrees, 20 degrees, and 30 degrees C at ionic strength of 0.15. In all, 88 protons were dissociated reversibly in pH range 2-12. Different ionizable groups present in lectin were also determined with respect to their heat of ionization. Heat of ionization, deltaH, for 43 carboxyl groups was 1.92 Kcal/mol, and for 7 phenoxyl groups, 6.84 Kcal/mol. Spectrophotometric titration was performed in the presence and absence of 0.1 M methyl alpha-D-mannopyranoside to characterize the role of phenoxyl groups present at the active site. One phenoxyl group was found to be involved in carbohydrate binding. The presence of two carboxyl groups per subunit at the active site was confirmed by H+ titration in the presence and absence of 0.1 M methyl alpha-D-mannopyranoside. Hemagglutinating and IgM precipitating activity was checked for the chemically modified carboxyl and phenoxyl group preparation. Loss of activity further confirmed the participation of carboxyl as well as phenoxyl groups at the active site. It is interesting to note the near-UV CD changes in the aromatic environment/conformation of the lectin in the presence of specific sugar, further indicating the possible participation of phenoxyl groups in the carbohydrate-binding pocket.

Binding Sites↗
PubMed2000

Pain intensity and side effects during titration of morphine to cancer patients using a fixed schedule dose escalation.

BACKGROUND: Considerable dose variations and frequent initial side effects have been postulated during start of morphine treatment to patients with pain caused by malignant disease. However, to our knowledge, only one previous study has reported effective doses in morphine naive cancer patients and no prospective evaluation has compared symptoms before with symptoms during morphine titration. METHODS: We recruited 40 cancer patients with uncontrolled pain despite receiving codeine or dextropropoxyphen. Baseline data were obtained for two days before start of morphine titration using a fixed scheduled escalation of immediate-release (IR) morphine. When a stable morphine dose was achieved, IR morphine was replaced with slow-release (SR) morphine in equivalent doses. Intensity of pain and side effects were assessed daily. The daily consumption of morphine, rescue analgesics and rescue antiemetics were registered. RESULTS: The mean titration time to achieve adequate analgesia was 2.3 days (range: 1-6) using a mean daily morphine dose of 97 mg (range: 60-180). Nausea was unaltered after start with morphine but an increased incidence of vomiting occurred (premorphine period 5%, IR morphine period 29%). Transient sedation delayed dose increment in 9 of the 40 patients but mean sedation scores were unaltered. Constipation scores increased while other side effect scores were unaltered. Eighty-two percent of the patients were satisfied or very satisfied with the pain treatment during introduction of morphine. CONCLUSION: In cancer patients with uncontrolled pain on weak opioids, successful titration of morphine is achieved fast, with a three-fold morphine dose variation and with little increase in side effects.

Adult↗
PubMed1998

Effects of losartan titrated to losartan/hydrochlorothiazide and amlodipine on blood pressure and peripheral capillary microcirculation in patients with mild-to-moderate hypertension.

OBJECTIVE: To measure the effects of losartan and amlodipine on peripheral capillary microcirculation in hypertension. SETTING: Medical out-patient clinic, Basel, in a university teaching hospital. METHODS: After a 4-week placebo run-in period 20 patients aged 50 +/- 8 (range 36-65) years with mild-to-moderate hypertension were randomly allocated to receive active treatment with losartan 50 mg titrated to losartan 50 mg/hydrochlorothiazide (HCT) 12.5 mg, or amlodipine 5 mg titrated to 10 mg for a 12 week period. Titration was performed if diastolic blood pressure (BP) was > or=90 mm Hg after 6 weeks of treatment. BP measurements as well as video capillary microscopy of the finger nailfold at the end of the placebo period and after 12 weeks of active treatment were compared. Capillary blood cell velocity was measured at rest and immediately, 1 min and 2 min after local finger cooling. RESULTS: After 3 months of treatment with amlodipine (n = 10) and losartan titrated to losartan-HCT (n = 10) sitting BP decreased significantly from 160 +/- 7/103 +/- 4 mm Hg and 147 +/- 7/98 +/- 6 mm Hg to 131 +/- 10/86 +/- 7 mm Hg and 134 +/- 17/89 +/- 9 mm Hg, respectively (P < 0.01). After local finger cooling the area under the curve (AUC) of capillary blood cell velocities was 1.13 +/- 0.58 mm (median +/- s.d.) at baseline and increased to 1.94 +/- 1.15 (P < 0.05) in losartan/losartan-HCT treated patients. In amlodipine treated patients the increase in AUC of capillary blood cell velocity did not reach the level of statistical significance (1.59 +/- 1.36 to 2.14 +/- 1.05 mm). CONCLUSION: This small trial shows that the area under the curve of capillary blood cell velocity increases in hypertensive patients treated with both losartan/losartan-HCT and amlodipine compared with baseline values.

Adult↗
PubMed2001

Electrochemical titrations of thiosulfate, sulfite, dichromate and permanganate using dual microband electrodes.

Applications of titration using dual gold microband electrodes in generator-collector mode are presented. The main advantage is that the method dispenses with the need for accurate volume measurements and reagent preparation: rather than balancing of molar amounts, the fluxes of analyte and titrant are balanced instead. The titrant is generated electrochemically and the end-point is detected amperometrically by the appearance of a current due to the presence of the titrant at the other band. The aim is to show the versatility and capability of the method that employs disposable mass-produced electrodes and uses pulsed motion of the electrode before a measurement to renew the boundary conditions. The titration of ascorbic acid (vitamin C) with ferricyanide, which has been a model system, was extended to the determination of thiosulfate and sulfite with iodine and the determination of dichromate and permanganate with iron(II). The accuracy, limited by the present fabrication reproducibility of the disposable electrodes, is +/- 10%. The results demonstrate that the method is effective even with a very simple set-up, and the actual time needed for common titrations is significantly decreased. These examples demonstrate a comprehensive basis for further development and applications, including standard titrations in industry.

Calibration↗
PubMed2006

Selective coulometric release of ions from ion selective polymeric membranes for calibration-free titrations.

Coulometry belongs to one of the few known calibration-free techniques and is therefore highly attractive for chemical analysis. Titrations performed by the coulometric generation of reactants is a well-known approach in electrochemistry, but suffers from limited selectivity and is therefore not generally suited for samples of varying or unknown composition. Here, the selective coulometric release of ionic reagents from ion-selective polymeric membrane materials ordinarily used for the fabrication of ion-selective electrodes is described. The selectivity of such membranes can be tuned to a significant extent by the type and concentration of ionophore and lipophilic ion-exchanger and is today well understood. An anodic current of fixed magnitude and duration may be imposed across such a membrane to release a defined quantity of ions with high selectivity and precision. Since the applied current relates to a defined ion flux, a variety of non-redox active ions may be accurately released with this technique. In this work, the released titrant's activity was measured with a second ionophore-based ion-selective electrode and corresponded well with expected dosage levels on the basis of Faraday's law of electrolysis. Initial examples of coulometric titrations explored here include the release of calcium ions for complexometric titrations, including back titrations, and the release of barium ions to determine sulfate.

Calcium↗
PubMed1991

Papain labelled with fluorescent thiol-specific reagents as a probe for characterization of interactions between cysteine proteinases and their protein inhibitors by competitive titrations.

Papain was labelled by attachment of the fluorescent groups 2-(4'-acetamidoanilino)naphthalene-6-sulphonic acid (AANS) or N-(acetylaminoethyl)-8-naphthylamine-1-sulphonic acid (AEDANS) to the active-site cysteine residue, with the aim of using the labelled papains as probes in competitive titrations of unlabelled cysteine proteinases with their inhibitors. The interaction between the labelled papains and cystatins was accompanied by an increase in fluorescence emission of up to 38-fold for AANS-papain and approximately 3.5-fold for AEDANS-papain. Fluorescence titrations gave dissociation equilibrium constants of 3.1 and 0.6 microM for the binding of chicken cystatin and recombinant human cystatin C respectively to AANS-papain and of 11.9 microM for the binding of chicken cystatin to AEDANS-papain. The kinetics of interaction of chicken cystatin with AANS-papain showed an unusual biphasic dependence of the observed pseudo-first-order rate constant on inhibitor concentration, consistent with the reaction occurring via both pathways of a general two-step binding mechanism. AANS-papain was selected as the most suitable probe for competitive titrations of unlabelled active or inactivated cysteine proteinases with inhibitors. This technique, which provides stoichiometries and dissociation constants for the interaction between unlabelled enzyme and inhibitor, allows monitoring of the interactions by a large fluorescent signal in a wavelength region where the interacting proteins do not contribute to the observed fluorescence. Such competitive titrations of active papain or actinidin with chicken cystatin or recombinant human cystatin C all gave inhibitor/enzyme stoichiometries of close to 1.0. A dissociation constant of 1.8 microM for the reaction of chicken cystatin with a papain derivative, S-[N-(3-carboxypropyl)succinimidyl]-papain, was also determined by the same technique. These results show the usefulness of the fluorescent papains for the characterization of interactions between cysteine-proteinase inhibitors and their target enzymes.

Animals↗
PubMed1975

The assessment of acid-base disturbance in man by the use of carbon dioxide titration curves.

1. Carbon dioxide titration curves were determined in vivo in dog and man at various degrees of acute non-respiratory acidaemia and alkalaemia. 2. The slope of the CO2 titration curve (delta log Pco2/delta pH) was found to increase with the severity of the acute non-respiratory alkalaemia the slope (delta log Pco2/delta pH) tended towards unity. 3. A simple scheme based on the CO2 titration curves determined in vivo has been proposed for the assessment of acute acid-base disturbances in man. 4. Carbon dioxide titration curves were also determined in vivo in patients with chronic respiratory and non-respiratory acidaemia and it was found that these curves were not significantly different from those obtained in states of acute acid-base disturbances. It is therefore suggested that the scheme described in this paper is applicable to all acid-base disturbances.

Acid-Base Equilibrium↗
PubMed2000

Sustained reduction in circulating cholesterol in adult hypopituitary patients given low dose titrated growth hormone replacement therapy: a two year study.

OBJECTIVE: To study the effects of short (6 months) and longer-term (up to 24 months) growth hormone (GH) replacement therapy using a dose titration regimen, on lipid and glucose metabolism in GH-deficient, hypopituitary adults. DESIGN: On-going open study of GH treatment up to 24 months. Measurements were performed at baseline and at 6, 12, 18 months and 2 years during therapy (data shown at 6 months and 2 years only). Using a dose titration regimen the median GH dose used to achieve and maintain IGF-I levels above the median, but below the upper limit of the age-related reference range (median IGF-I 202.5 microg/l, range 76-397 microg/l), was 1.2 IU daily (range 0.4-3 IU) [0.8 IU/day, males; 1.6 IU/day, females]. PATIENTS: Ninety GH-deficient hypopituitary adults (54 female, median age 48 years, range 19-79 years) entered the study and 24 (14 female, median age 45 years, range 32-79 years) have concluded the 2 year period of assessment. MEASUREMENTS: Body mass index (BMI), waist and hip circumference ratio (WHR), fasting lipids, glucose and glycated haemoglobin (HbA1c) levels were measured at 6 month intervals during GH therapy. RESULTS: Using the dose titration regimen, compared to pretreatment values, total and low density lipoprotein (LDL)-cholesterol levels were significantly lower at 6 months (mean +/- SEM, 5.61+/-0.1 vs. 5.25+/-0.1, and 3.85+/-0.19 vs. 3.43+/-0.26, respectively, P<0.05), and were maintained throughout the study. Male patients had significantly lower pretreatment total and LDL cholesterol levels than females (mean +/- SEM, 5.33+/-0.16 mmol/l vs. 5.7+/-0.12 mmol/l and 3.8+/-0.23 mmol/l vs. 3.92+/-0.29 mmol/l, respectively, P< 0.05). A decrease in total cholesterol was confined to patients with pretreatment total cholesterol levels above 5.8 mmol/l; patients with the highest pretreatment cholesterol levels (> 6.4 mmol/l) obtained the greatest cholesterol reduction (mean +/- SEM, 7.13 +/- 0.14 mmol/l vs. 5.76+/-0.31 mmol/l, P<0.05). A cholesterol-lowering effect of GH therapy was evident in patients who had elevated pre-GH total cholesterol levels even if they were already receiving and continuing lipid lowering medication (mean +/- SEM, 5.62+/-0.22 vs. 5.03+/-0.285, P<0.05). A modest increment in high density lipoprotein (HDL)-cholesterol was evident at 18 months but there was no significant change in triglycerides at any time point. Fasting plasma glucose increased significantly at 6 months but remained within the reference range. Glycated haemoglobin increased significantly at 6 months and was maintained throughout the study; one patient developed frank diabetes mellitus while receiving treatment. There was a weak but significant correlation between the increment in glycated haemoglobin and pretreatment BMI (r = + 0.215, P<0.05). CONCLUSION: The effect of GH on lowering total and low density lipoprotein-cholesterol is more prominent in patients with higher pretreatment cholesterol levels and is evident even in patients receiving other lipid-lowering medication. A modest increment in mean fasting glucose (within the reference range) and mean glycated haemoglobin persisted throughout the study. One patient developed diabetes mellitus. A GH replacement regimen using low dose and careful titration to avoid elevated IGF-I levels and adverse effects is associated with sustained beneficial effects on circulating lipids.

Adult↗
PubMed2000

[Emergency pain treatment--ambulatory intravenous morphine titration in a patient with cancer pain].

Even when the guidelines for cancer pain management are followed, acute severe pain requiring immediate treatment will occur in some patients. Titration with intravenous morphine may provide fast and efficient pain relief and give an indication of the amount of opioid necessary for continuous treatment. In cooperation with a general practitioner we performed an intravenous morphine titration in a patient with severe cancer pain at home. Adequate analgesia was reached with 20 mg intravenous morphine. Blood pressure, cardiac frequency and oxygen saturation did not change. No side effects were reported during the titration, and the previous regimen with tramadol 150 mg per day was switched to slow release morphine 300 mg per day. This medication was prescribed by the general practitioner and provided good pain relief until the patient died two weeks later. We conclude that intravenous morphine titration may be performed even in cancer patients at home, adequate monitoring, however, should be available.

Aged↗
PubMedDate not supplied

The hemophagocytic syndrome: titrating continuous hemofiltration to the degree of lactic acidosis.

In 3 cases of severe multiple organ failure due to hemophagocytic lymphohistiocytosis (HLH) in children, the authors demonstrate the utility of continuous hemofiltration in attenuating the consequences of excess cytokine activity, with therapy titrated to the degree of lactic acidosis. HLH was diagnosed in 3 encephalopathic children with multiple organ failure, elevated ferritin (49,396-237,582 pmol/L; or 21,983-105,733 ng/mL), elevated serum triglyceride, and depressed cell lines. One had a known malignancy, one had EBV-associated lymphoproliferative disease, and one was previously healthy. Continuous hemofiltration was initiated, with the ultrafiltrate production rate and countercurrent dialysate flow titrated to metabolic acidosis as reflected by the serum lactate (maximum 3.5 mmol/L or 31.6 mg/dL). Hemofiltration was titrated upward until lactic acidosis resolved, through clearance of lactate or interruption of excess cytokine-driven activity; maximum prescription was 2000 mL/h ultrafiltrate production plus 2500 mL/h dialysate flow. Stability was achieved with hemofiltration, then substantial resolution occurred with treatment according to the HLH-94 protocol (dexamethasone, cyclosporin, VP-16, intrathecal methotrexate). One child succumbed to candidiasis. Another made a full recovery. A third succumbed to his primary malignancy. HLH should be suspected in unexplained or unresolving multiple organ failure. Titration of hemofiltration based on measurable parameters of cellular metabolism (e.g., lactate, base deficit) may stabilize the child with metabolic acidosis long enough to allow proper diagnosis and institution of definitive therapy. Hemofiltration is not a panacea but rather a stabilizing mechanism, with poorly understood effects on interstitial water and solute flux, that facilitates recovery over weeks, not days.

Acidosis, Lactic↗