Improving STI and HIV Passive Partner Notification using the Model for Improvement: A Quality Improvement Study in Lilongwe Malawi.

BACKGROUND: In Malawi, passive partner notification is the mainstay method of partner notification (PN). Despite its wide use, the proportion of sexual partners referred for care through this method is very low. We aimed to increase the proportion of sexual partner referral through passive PN. METHODS: We implemented a quality improvement (QI) project at Bwaila STI unit in Lilongwe, Malawi between January and June 2017 using a pre- and post- intervention quasi-experimental study design. Pre-intervention, we conducted key-informant interviews and clinic observations and used the findings to design a QI project using expert opinion. The intervention included three change ideas: early start time of the clinic, shortening of the group health talk and expedited clinic flow for sexual partners. Each change idea was tested twice through 1-week long Plan-Do-Study-Act cycles using the model for improvement (MFI) and then combined and tested twice. Process data were collected and monitored using run charts. Post-intervention, we evaluated the proportion of sexual partners who presented to the clinic, to detect a 10% increase at 95% power and α=0.05, between pre- and post-intervention periods. RESULTS: The average duration of the group health talk dropped from 56 minutes to 38 minutes and the duration of clinic stay for sexual partners reduced by 45 minutes (from 1hour 36 minutes to 51 minutes). The average clinic start time improved from 09:02 hours to 08:17 hours. The proportion of sexual partner referral increased by 37% (P=0.04) - from 15.6% to 21.4%. We observed an upward trend in the proportion of sexual partners referred in the post-intervention period. CONCLUSION: The yield of sexual partners through passive PN was improved using a simple QI intervention implemented using the MFI. However, the proportion of sexual partner referral remains suboptimal. More effort is required to increase the proportion of sexual partner referral in Malawi.

Challenging near infrared spectroscopy discriminating ability for counterfeit pharmaceuticals detection.

This study was initiated by the laboratories and control department of the French Health Products Safety Agency (AFSSAPS) as part of the fight against the public health problem of rising counterfeit and imitation medicines. To test the discriminating ability of Near InfraRed Spectroscopy (NIRS), worse cases scenarios were first considered for the discrimination of various pharmaceutical final products containing the same Active Pharmaceutical Ingredient (API) with different excipients, such as generics of proprietary medicinal products (PMP). Two generic databases were explored: low active strength hard capsules of Fluoxetine and high strength tablets of Ciprofloxacin. Then 4 other cases involving suspicious samples, counterfeits and imitations products were treated. In all these cases, spectral differences between samples were studied, giving access to API or excipient contents information, and eventually allowing manufacturing site identification. A chemometric background is developed to explain the optimisation methodology, consisting in the choices of appropriate pretreatments, algorithms for data exploratory analyses (unsupervised Principal Component Analysis), and data classification (supervised cluster analysis, and Soft Independent Modelling of Class Analogy). Results demonstrate the high performance of NIRS, highlighting slight differences in formulations, such as 2.5% (w/w) in API strength, 1.0% (w/w) in excipient and even coating variations (<1%, w/w) with identical contents, approaching the theoretical limits of NIRS sensitivity. All the different generic formulations were correctly discriminated and foreign PMP, constituted of formulations slightly different from the calibration ones, were also all discriminated. This publication addresses the ability of NIRS to detect counterfeits and imitations and presents the NIRS as an ideal tool to master the global threat of counterfeit drugs.

Comparison of universal detectors for high-temperature micro liquid chromatography.

This study compares, through micro high-temperature liquid chromatography (microHTLC), three commercial universal detectors that allow a direct detection of lipids. The detectors are: the charged aerosol detector (CAD), the evaporative light-scattering detector (ELSD) and the ion trap mass spectrometer with atmospheric pressure chemical ionization (APCI) and electrospray ionization (ESI) sources (APCI-MS and ESI-MS). This study shows the feasibility to use the high temperature with these detectors and hybrid behavior between concentration and mass flow rate detector in microHTLC. The detectors were compared in terms of response intensity, linearity and limit of detection for different high temperatures. The charged aerosol detector shows a linear response from 5 to 500 microg/mL and the correlation coefficients (r(2)) obtained for squalene, cholesterol and ceramide IIIB exceed 0.99.

HPLC microdetermination of flurbiprofen enantiomers in plasma with a glycopeptide-type chiral stationary phase column.

A rapid and stereospecific HPLC micromethod to quantify flurbiprofen enantiomers was developed. Both flurbiprofen enantiomers and indomethacin, used as internal standard, were extracted with methylene chloride from 100 microL of acidified plasma. The resolution of the R- and S-forms was performed on a bonded vancomycin chiral stationary phase (Chirobiotic V) with 20% of tetrahydrofuran in ammonium nitrate (100 mM, pH 5) as mobile phase. Calibration curves were linear in the range 0.5-10 microg/mL for both enantiomers. A good accuracy (< or = 5%) was obtained for all quality controls, with intra-day and inter-day variation coefficients equal or less than 7.7%. Recovery of both enantiomers was found in the range 77.4-86.3%. The lower limit of quantitation was 0.25 microg/mL for both enantiomers, without interference of endogenous components. This validated micromethod has been successfully applied for quantifying R- flurbiprofen and S- flurbiprofen in rat plasma.

Triazinic herbicide determination by gas chromatography-mass spectrometry in breast milk.

A solid-phase extraction procedure using a graphitized carbon black cartridge for extraction and cleaning of a series of five triazines (atrazine, deethylatrazine, deisopropylatrazine, ametryne and prometryne) from breast milk samples was developed. Using a chemometric methodology, the optimisation of both the analysis time and the triazinic herbicide separation by gas chromatography-mass spectrometry (GC-MS) was then carried out with only 18 experiments. Detection and quantification limits for 1ml breast milk sample were, respectively, 0.3 and 1 ppb for each studied compound. The variation coefficients were less than 5% over the concentration range from 1 to 100 ppb. The accuracy was between 98.63 and 104.62% for each triazinic herbicide. The recovery was between 58.64 and 63.22% for the concentration range from 1 to 100 ppb for each triazinic herbicide. The assay was successfully applied to the analysis of several breast milk samples.

Determination of pKa values of 2-amino-2-oxazolines by capillary electrophoresis.

The dissociation constants of new 2-amino-2-oxazolines were determined by capillary electrophoresis (CE) as a new technique. A method based on a linear model has been used in the CE determination. A series of eight 2-amino-2-oxazolines are investigated to determine their ionization constant. Among them, three new oxazolines synthesized are presented. The Ka values were obtained from the plots of reciprocal effective mobility against inverse concentrations of protons. The potentiometric method (PM) was performed as a comparative method. No significant differences were observed between the determined dissociation constants using both methods. Thus, the pKa values have been found to vary between 8.55 and 8.68.

Determination of mirtazapine and its demethyl metabolite in plasma by high-performance liquid chromatography with ultraviolet detection. Application to management of acute intoxication.

Mirtazapine is a new centrally acting noradrenergic and specific serotonin antidepressant, with an active demethyl metabolite. For toxicological purposes, a specific and accurate RP-HPLC assay was developed for the simultaneous plasma determination of these compounds. A linear response was observed over the concentration range 50-500 ng/ml. A good accuracy (bias <10%) was achieved for all quality controls, with intra-day and inter-day variation coefficients less than 8.3%. The lower limit of quantification was 20 ng/ml, without interferences with endogenous or exogenous components. This rapid method (run time <12 min) was used to manage three intoxications involving mirtazapine.

Influence of a polymeric formulation of ketoprofen on its diffusion into cerebrospinal fluid in rats.

Poly(D,L)lactide nanocapsules (NCs) have been proposed as an alternative carrier for many drugs. We investigated the influence of this formulation on the pharmacokinetics of ketoprofen in the plasma and cerebrospinal fluid (CSF). Male Wistar rats were given intraperitoneal dose of ketoprofen (5 mg/kg) in a suspension of NCs or in a carboxymethylcellulose (CMC) solution (reference preparation). Blood and CSF samples were collected at different times up to 24 h after dosing. The unbound fraction of ketoprofen in plasma (f(u)) was determined using ultrafiltration. The total (C(T)) and free (C(F)) concentrations of ketoprofen in plasma and the simultaneous CSF concentrations (C(CSF)) were measured by a HPLC method and the areas under the curve (AUC(T), AUC(F), AUC(CSF)) were calculated. AUC(T) of ketoprofen-loaded NCs in plasma was similar to that of the reference solution, while AUC(F) of the former (5.41 mg/l x h) was higher than that produced by the latter (4.03 mg/l x h). Accordingly, the unbound fraction (f(u)) was higher after administration of NCs than that of the solution (2.5 and 1.8%, respectively). Finally, AUC(CSF) were identical for both formulations. These findings suggest that the binding of ketoprofen to plasma proteins is not the major factor that governs its blood-to-CSF exchanges.

Rapid high-performance liquid chromatographic measurement of venlafaxine and O-desmethylvenlafaxine in human plasma. Application to management of acute intoxications.

Venlafaxine, a second-generation antidepressant, acts by inhibition of the reuptake of presynaptic noradrenaline and serotonin. The main metabolite, O-desmethylvenlafaxine was found biologically active. For toxicological purpose, a rapid specific and accurate RP-HPLC assay was developed for the simultaneous determination of venlafaxine and O-desmethylvenlafaxine in human plasma. A linear response was observed over the concentration range 0.2-4 microg/ml. A good accuracy (<8%) was achieved for all quality controls, with intra-day and inter-day variation coefficient less than 10%. Finally, no interference was observed with other psychotic drugs encountered in acute poisoning. This rapid method (run time <10 min) was used to manage four voluntary intoxications involving venlafaxine.

Single and multiple dose pharmacokinetics of acetaminophen (paracetamol) in polymedicated very old patients with rheumatic pain.

OBJECTIVE: To determine whether multiple dosing of acetaminophen would result in drug accumulation in polymedicated elderly patients with rheumatic pain. METHODS: Twelve inpatients (11 women), aged 89 +/- 4 years, weight 59 +/- 10 kg, receiving 3 to 8 concomitant medications, entered the study. Their creatinine clearance according to the Cockroft-Gault formula was 42 +/- 12 ml/min. The pharmacokinetics of 1 g acetaminophen was evaluated after the first dose (D1) and after the last dose (D7) during a 3 times daily regimen of 1 g for 5 consecutive days. RESULTS: The plasma pharmacokinetic profile of acetaminophen did not change significantly at D7 compared to D1. No significant within-patient differences were observed, especially with respect to plasma elimination half-life (2.74 +/- 0.48 and 2.77 +/- 0.32 hours, respectively), area under the concentration-time curve (82.5 +/- 21.1 and 90.1 +/- 15.2 microg x h/ml, respectively), and apparent oral clearance (3.68 +/- 0.85 and 3.28 +/- 0.52 ml/min/kg, respectively). CONCLUSION: No drug accumulation occurred during multiple dosing with acetaminophen in these very old subjects. On the basis of pharmacokinetic data alone, a dose regimen of acetaminophen 1 g tid seems to be appropriate in such patients.

Binding of ketoprofen enantiomers in various human albumin preparations.

Published data conflict with respect to the enantioselective protein binding parameters of R(-) and S(+) ketoprofen. We studied whether differences in experimental conditions used and/or presence of interfering compounds could provide a possible explanation for these discrepancies. Equilibrium dialysis, supported by ultrafiltration (67 mM Sörensen phosphate buffer pH 7.4, 580 microM HSA, 37 degrees C) allowed the characteristics of the binding sites to be determined according to Scatchard's analysis. (R) and (S)-ketoprofen concentrations were measured by HPLC. The free (R)-ketoprofen/free (S)-ketoprofen (F(R)/F(S)) concentration ratio was calculated. The effect of octanoic acid (OA) found in currently marketed intravenous HSA solutions, and hippuric acid (HA), on F(R)/F(S) concentration ratio was considered. Two classes of binding sites were characterized for both enantiomers. The free (S)-ketoprofen concentrations remained equal to those of the (R)-antipode at low concentrations of racemate (2-35 microg ml(-1)) indicating non-stereoselective albumin binding over the therapeutic range. From 35 microg ml(-1), the free (S)-ketoprofen concentrations were slighty greater than those of its antipode. Both OA and HA induced an increase of the free fraction of the enantiomers by a two-fold to a 15-fold order of magnitude. OA, but not HA, showed a more pronounced effect for the (S)-form leading to a marked decrease in F(R)/F(S) concentration ratio (0.61). Differences in HSA preparations used and/or the presence of interfering compounds may explain the variability in the reported protein binding characteristics of ketoprofen enantiomers.

Influence of molecular lipophilicity on the diffusion of arylpropionate non-steroidal anti-inflammatory drugs into the cerebrospinal fluid.

The diffusion of seven arylpropionic acid non-steroidal anti-inflammatory drugs (NSAIDs) into the cerebrospinal fluid (CSF) has been investigated in male Wistar rats by means of quantitative structure-activity relationship (QSAR) study. After intraperitoneal administration of each drug (5 mg/kg), blood and CSF samples were collected at different times (0.5, 1, 3, and 6 h). The fraction bound to plasma proteins (fb) was determined using ultracentrifugation. The total (CT) and free (CF) plasma concentrations and the concentrations in CSF (CCSF) were measured by a reversed-phase high performance liquid chromatographic (RP-HPLC) method. The areas under the curve of the free plasma (AUCF) and CSF (AUCCSF) concentrations were calculated according to the trapezoidal rule. The overall drug transit into CSF was estimated by the ratio RAUC (AUCCSF: AUCF). The lipophilicity of the compounds was expressed as their polycratic capacity factors (log k'w) measured in a RP-HPLC system. The RAUC ranged from 0.24 to 6.58 and fb from 91.4 to 99.8%. The compounds with an intermediate lipophilicity value (3 < logk'w < 3.6) easily entered the CSF (RAUC > 1). A parabolic relationship was found between log k'w and log RAUC, emphasizing the role of molecular lipophilicity in the diffusion into CSF. Considering the fb value of each drug in regard to this non-linear relationship, it can be hypothesized that the diffusion rate of NSAIDs into the CSF depends primarily on the lipophilicity.