Impact of produced water mineralization on the secondary treatment of hydrate development inhibitors

In the process of completion gas-condensate fields is observed an intensive increase of lifted out produced water and its mineralization influencing the process of regeneration of hydrate development inhibitors. The presence of mineral salts in the system of “hydrate development inhibitor – produced water” results in the decrease of saturated vapor pressure upon the solvent. The decrease of saturated vapors significantly influences the phase balance of the system. Moreover, the presence of salts changes the boiling temperature of water solutions of hydrate development inhibitors. This factor was not considered in the calculation and designing of existing regeneration set. The paper presents the data on the pressure of saturated vapor under the produced water with various mineralization based on which the correction coefficients were calculated and boiling temperature depending on the salt content specified as well.

Increased inhibitor incidence in severe haemophilia A since 1990 attributable to more low titre inhibitors

SummaryMany studies have reported an increased incidence of inhibitors in previously untreated patients (PUPs) with severe haemophilia A after the introduction of recombinant products. It was the objective of this study to investigate whether the inhibitor incidence has increased between 1990 and 2009 in an unselected cohort of PUPs with severe haemophilia A (FVIII < 1 %). Patients were consecutively recruited from 31 haemophilia treatment centres in 16 countries and followed until 50 exposure days or until inhibitor development. Inhibitor development was studied in five-year birth cohorts comparing cumulative incidences. Furthermore the risk for inhibitor development per five-year birth cohort was studied using multivariable Cox regression, adjusting for potential genetic and treatment-related confounders. A total of 926 PUPs were included with a total cumulative inhibitor incidence of 27.5 %. The inhibitor incidence increased from 19.5 % in 1990-1994 (lowest) to 30.9 % in 2000-2004 (highest; p-value 0.011). Low titre inhibitor incidence increased from 3.1 % in 1990-1994 to 10.5 % in 2005-2009 (p-value 0.009). High titre inhibitor incidences remained stable over time. After 2000, risk of all inhibitor development was increased with adjusted hazard ratios 1.96 (95 % CI 1.06-2.83) in 2000-2004 and 2.34 (1.42-4.92) in 2005-2009. Screening for inhibitors was intensified over this 20-year study period from a median of 1.9 to 2.9 tests/year before 2000 to 2.7 to 4.3 tests/ year after 2000. In conclusion, the cumulative inhibitor incidence has significantly increased between 1990 and 2009. The high titre inhibitor incidence has remained stable.

High Proteolytic Resistance of Spider-Derived Inhibitor Cystine Knots

Proteolytic stability in gastrointestinal tract and blood plasma is the major obstacle for oral peptide drug development. Inhibitor cystine knots (ICKs) are linear cystine knot peptides which have multifunctional properties and could become promising drug scaffolds. ProTx-I, ProTx-II, GTx1-15, and GsMTx-4 were spider-derived ICKs and incubated with pepsin, trypsin, chymotrypsin, and elastase in physiological conditions to find that all tested peptides were resistant to pepsin, and ProTx-II, GsMTx-4, and GTx1-15 showed resistance to all tested proteases. Also, no ProTx-II degradation was observed in rat blood plasma for 24 hours in vitro and ProTx-II concentration in circulation decreased to half in 40 min, indicating absolute stability in plasma and fast clearance from the system. So far, linear peptides are generally thought to be unsuitable in vivo, but all tested ICKs were not degraded by pepsin and stomach could be selected for the alternative site of drug absorption for fast onset of the drug action. Since spider ICKs are selective inhibitors of various ion channels which are related to the pathology of many diseases, engineered ICKs will make a novel class of peptide medicines which can treat variety of bothering symptoms.

Use of Factor VIII/Von Willebrand Factor Complex for Inducing Immune Tolerance in Hemophilia a Patients Who Have Failed with Recombinant Fviii: Recent Canadian Experience

Immune tolerance induction (ITI) is effective in approximately 63–83% of hemophilia patients with inhibitors. Poor prognostic factors are age &gt; 18 years, ITI started &gt; 4 years after inhibitor development, inhibitor peaks &gt; 200 BU, inhibitor titre &gt; 10 BU at ITI initiation, and previously failed ITI. It has been reported that patients who have failed ITI with a recombinant FVIII concentrate achieved and maintained immune tolerance when VWF/FVIII complex concentrates were used. We present our Canadian experience with a factor VIII/von Willebrand factor concentrate (Humate-P) for inducing immune tolerance in patients who have previously failed ITI. A questionnaire was sent to all Hemophilia Treatment Centers of Canada. Data collected included baseline FVIII level, mutation, date at initial diagnosis of inhibitor, peak titer, concentrate associated with development of inhibitor, inhibitor titer at initiation of first ITI, concentrate and regimen used, and concentrate, dosing and outcome of secondary ITI with Humate-P. All Hemophilia Centers agreed to participate. 5 Centers submitted data about 8 patients. One patient resistant to initial ITI with Kogenate FS achieved good partial response with Humate-P, with titers going down from 40 to values between 0,6 and 4 BU. One patient who responded to initial ITI with Kogenate FS with peaking of inhibitor to 380 BU was remaining above 100 BU and lowered to 28 BU on Humate-P. In three patients, Humate-P induced an anamnestic response. Two of those patients had a concomitant line infection at time of switching to Humate-P. The third of those three patients had a transient anamnestic response after introduction of Humate-P. One patient had successfull induction of immune tolerance using multiple therapies (cyclophosphamide, Immunate, IVIG, Rituximab) and maintained remission under Humate-P. One patient was on ITI for 27 months using Recombinate and switched to Humate-P when Recombinate was withdrawn from the market. After 12 months, the inhibitor had gone from 12 to 7.3 BU. One patient attained complete remission during primary ITI using recombinant FVIII concentrate (Advate) and maintained remission when switched to Humate-P. In subjects failing ITI with recombinant factor VIII concentrates, Humate-P may be considered as a second line for inducing immune tolerance.