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1.
AIDS ; 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31567162

RESUMO

OBJECTIVE: Excessive weight gain has been reported with integrase strand transfer inhibitors (INSTIs). We evaluated weight changes in virologically-suppressed adults with HIV who switched from non-INSTI regimens to raltegravir- or dolutegravir-containing antiretroviral therapy. DESIGN: Retrospective single-centre cohort. METHODS: Adults who switched to raltegravir or dolutegravir before or between January-2015 and October-2017 were identified. Virologically-suppressed, treatment-experienced (≥2 years) individuals, ≥6 months on INSTI, with weight measurements ≤2years pre- and post-switch were included. Our analysis used a random effects model with linear slope pre- and post-INSTI with adjustment for age, gender, ethnicity, pre-switch-regimen (protease inhibitor vs. non-protease inhibitor), and raltegravir vs. dolutegravir use. RESULTS: 378 individuals, 81.2% male, 70.1% white ethnicity, median age of 49 years, median of four weight measurements per participant, and median weight and body mass index (BMI) at switch, of 76.6 kg, and 25.3 kg/m respectively were included. Weight increased by an average of 0.63 kg/year (95% CI 0.17-1.09) pre-switch with no overall change in rate of weight gain post-switch [+0.05 kg/year (-0.61-0.71, p = 0.88)]. In our adjusted model, a transition from minimal weight change to weight gain post-switch was isolated to older individuals though this lacked statistical significance [e.g. +1.59 kg/year (-0.26-3.45) if aged 65 years]. Our findings did not differ by gender, ethnicity, pre-switch regimen, or raltegravir vs. dolutegravir. Similar results were seen for BMI and after adjusting for fixed nucleoside/nucleotide reverse transcriptase inhibitor backbone. CONCLUSION: We found no clear evidence of an overall increase in rate of weight gain following switch to INSTI in virologically-suppressed individuals.

2.
Clin Infect Dis ; 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31606734

RESUMO

BACKGROUND: Initiation of antiretroviral therapy (ART) often leads to weight gain. While some of this weight gain may be an appropriate return-to-health effect, excessive increases in weight may lead to obesity. We sought to explore factors associated with weight gain in several randomized comparative clinical trials of ART initiation. METHODS: We performed a pooled analysis of weight gain in 8 randomized controlled clinical trials of treatment-naïve people with HIV (PWH) initiating ART between 2003-2015, comprising over 5,000 participants and 10,000 person-years of follow-up. We used multivariate modeling to explore relationships between demographic factors, HIV disease characteristics, and ART components and weight change following ART initiation. FINDINGS: Weight gain was greater in more recent trials and with the use of newer ART regimens. Pooled analysis revealed baseline demographic factors associated with weight gain including lower CD4, higher HIV-1 RNA, no injection drug use, female sex and black race. Integrase strand transfer inhibitors (INSTIs) were associated with more weight gain than protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTI), with dolutegravir and bictegravir associated with more weight gain than elvitegravir/cobicistat. Among the NNRTIs, rilpivirine was associated with more weight gain than efavirenz. Among nucleoside/nucleotide reverse transcriptase inhibitors, tenofovir alafenamide was associated with more weight gain than tenofovir disoproxil fumarate, abacavir, or zidovudine. INTERPRETATION: Weight gain is ubiquitous in clinical trials of ART initiation, and is multifactorial in nature, with demographic factors, HIV-related factors, and the composition of ART regimens contributing. The mechanisms by which certain ART agents differentially contribute to weight gain are unknown.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31507204

RESUMO

In HIV-1-infected patients, virological failure can occur as a consequence of the mutations that accumulate in the viral genome that allow replication to continue in the presence of antiretrovirals (ARVs). The development of treatment-emergent resistance to an ARV can limit a patient's options for future therapy, prompting the need for ARV regimens that are resilient to the emergence of resistance. The genetic barrier to resistance refers to the number of mutations in an ARV's therapeutic target that are required to confer a clinically meaningful loss of susceptibility to the drug. The emergence of resistance can be affected by pharmacological aspects of the ARV, including its structure, inhibitory quotient, therapeutic index, and pharmacokinetic characteristics. Dolutegravir (DTG) has demonstrated a high barrier to resistance, including when used in a two-drug regimen (2DR) with lamivudine (3TC). In the GEMINI-1 and GEMINI-2 studies, DTG +3TC was noninferior to DTG + emtricitabine/tenofovir disoproxil fumarate in treatment-naive participants, with similar proportions achieving HIV-1 RNA <50 copies/mL through 96 weeks. Furthermore, in the TANGO study, virological suppression was maintained at 48 weeks after switching to DTG +3TC from a tenofovir alafenamide (TAF)-based regimen compared with continuing a TAF-based regimen. Most other 2DRs with successful outcomes compared with three-drug regimens have been based on protease inhibitors (PIs); however, this class is associated with adverse metabolic effects and drug-drug interactions. In this review, we discuss the barrier to resistance in the context of a 2DR in which a boosted PI is replaced with DTG +3TC.

4.
AIDS ; 33(9): 1455-1465, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30932951

RESUMO

OBJECTIVE: Compared with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) has been associated with improvement in markers of renal dysfunction in individual randomized trials; however, the comparative incidence of clinically significant renal events remains unclear. DESIGN: We used a pooled data approach to increase the person-years of drug exposure analysed, maximizing our ability to detect differences in clinically significant outcomes. METHODS: We pooled clinical renal safety data across 26 treatment-naive and antiretroviral switch studies to compare the incidence of proximal renal tubulopathy and discontinuation due to renal adverse events between participants taking TAF-containing regimens vs. those taking TDF-containing regimens. We performed secondary analyses from seven large randomized studies (two treatment-naive and five switch studies) to compare incidence of renal adverse events, treatment-emergent proteinuria, changes in serum creatinine, creatinine clearance, and urinary biomarkers (albumin, beta-2-microglobulin, and retinol binding protein-to-creatinine ratios). RESULTS: Our integrated analysis included 9322 adults and children with HIV (n = 6360 TAF, n = 2962 TDF) with exposure of 12 519 person-years to TAF and 5947 to TDF. There were no cases of proximal renal tubulopathy in participants receiving TAF vs. 10 cases in those receiving TDF (P < 0.001), and fewer individuals on TAF (3/6360) vs. TDF (14/2962) (P < 0.001) discontinued due to a renal adverse event. Participants initiating TAF-based vs. TDF-based regimens had more favourable changes in renal biomarkers through 96 weeks of therapy. CONCLUSION: These pooled data from 26 studies, with over 12 500 person-years of follow-up in children and adults, support the comparative renal safety of TAF over TDF.

5.
Nature ; 568(7751): 244-248, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30836379

RESUMO

A cure for HIV-1 remains unattainable as only one case has been reported, a decade ago1,2. The individual-who is known as the 'Berlin patient'-underwent two allogeneic haematopoietic stem-cell transplantation (HSCT) procedures using a donor with a homozygous mutation in the HIV coreceptor CCR5 (CCR5Δ32/Δ32) to treat his acute myeloid leukaemia. Total body irradiation was given with each HSCT. Notably, it is unclear which treatment or patient parameters contributed to this case of long-term HIV remission. Here we show that HIV-1 remission may be possible with a less aggressive and toxic approach. An adult infected with HIV-1 underwent allogeneic HSCT for Hodgkin's lymphoma using cells from a CCR5Δ32/Δ32 donor. He experienced mild gut graft-versus-host disease. Antiretroviral therapy was interrupted 16 months after transplantation. HIV-1 remission has been maintained over a further 18 months. Plasma HIV-1 RNA has been undetectable at less than one copy per millilitre along with undetectable HIV-1 DNA in peripheral CD4 T lymphocytes. Quantitative viral outgrowth assays from peripheral CD4 T lymphocytes show no reactivatable virus using a total of 24 million resting CD4 T cells. CCR5-tropic, but not CXCR4-tropic, viruses were identified in HIV-1 DNA from CD4 T cells of the patient before the transplant. CD4 T cells isolated from peripheral blood after transplantation did not express CCR5 and were susceptible only to CXCR4-tropic virus ex vivo. HIV-1 Gag-specific CD4 and CD8 T cell responses were lost after transplantation, whereas cytomegalovirus-specific responses were detectable. Similarly, HIV-1-specific antibodies and avidities fell to levels comparable to those in the Berlin patient following transplantation. Although at 18 months after the interruption of treatment it is premature to conclude that this patient has been cured, these data suggest that a single allogeneic HSCT with homozygous CCR5Δ32 donor cells may be sufficient to achieve HIV-1 remission with reduced intensity conditioning and no irradiation, and the findings provide further support for the development of HIV-1 remission strategies based on preventing CCR5 expression.

6.
BMJ ; 364: l1040, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30862691

Assuntos
Ética Médica
7.
Biomed Chromatogr ; 33(7): e4515, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30811616

RESUMO

The extent of human intestinal absorption (HIA) for a drug is considered to be an important pharmacokinetic parameter which must be determined for orally administered drugs. Traditional experimental methods relied upon animal testing and are renowned for being time consuming and expensive as well as being ethically unfavourable. As a result, the development of alternative methods to evaluate a drug's pharmacokinetics is crucial. Micellar liquid chromatography is considered to be one of these methods that can replace the use of animals in the prediction of HIA. In this study, the combination of an aminopropyl column with the biosurfactant sodium deoxycholate bile salt was used in the experimental determination of micelle-water partition coefficients (log Pmw ) for a group of compounds. Multiple linear regression was then used for the prediction of HIA using the experimentally determined log Pmw along with other molecular descriptors, leading to the construction of a model equation of R2 = 85% and a prediction power represented by R2 Pred. = 72%. The use of micellar liquid chromatography with an aminopropyl column in combination with sodium deoxycholate was found to be a good method for the prediction of human intestinal absorption, providing data for a far wider range of compounds compared with previous studies.


Assuntos
Cromatografia Líquida/métodos , Absorção Intestinal/fisiologia , Modelos Biológicos , Ácido Desoxicólico/análise , Ácido Desoxicólico/química , Ácido Desoxicólico/metabolismo , Humanos , Modelos Lineares , Micelas , Reprodutibilidade dos Testes
8.
Colloids Surf B Biointerfaces ; 176: 456-461, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30682618

RESUMO

The permeation of ten model drugs through silicone membrane was analysed to investigate the effect of the presence of a biosurfactant obtained from corn steep liquor. The ten selected pharmaceutical compounds were chosen to include a diverse range of physicochemical properties, such as variable hydrophobicities, pKa's, molecular masses and degrees of ionisation. When compared with compound permeation alone, the additional inclusion of biosurfactant in the donor phase altered the rate and extent of permeation. It significantly enhanced permeation for five of the compounds, whereas it decreased permeation for four of the compounds and remained approximately the same for the tenth compound. These effects were observed at both biosurfactant concentrations considered, namely 0.005 mg/mL, i.e. below the critical micellar concentration (CMC) and 0.500 mg/mL, i.e. above the CMC of the biosurfactant. Upon analysing permeation change with respect to physicochemical properties of the compounds, it was determined that compounds with a relative molecular mass below 200 resulted in an increase in permeation with biosurfactant present, and those above 200 resulted in a decrease in permeation with biosurfactant present. This effect was therefore attributed to the formation of a drug-biosurfactant interaction that enhanced permeation of smaller compounds, yet retarded permeation for those with a higher molecular mass. These in vitro findings can be considered an indication of potential novel formulation options that incorporate biosurfactant to create transdermal products that have bespoke permeation profiles.


Assuntos
Membranas Artificiais , Preparações Farmacêuticas/química , Silicones/química , Tensoativos/química , Ácido Benzoico , Permeabilidade , Procaína , Triazóis/química
9.
J Pharm Sci ; 108(5): 1772-1778, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30578801

RESUMO

Isothermal titration calorimetry was used to investigate thermodynamic and kinetic binding interactions between 4 clinically relevant drugs: doxorubicin (Dox), irinotecan (Iri), mitoxantrone (Mitox), and topotecan (Topo) and a range of commercially available embolization microspheres. Five drug-eluting beads were chosen to consider the effect of bead size (ranging from 70-150 µm to 500-700 µm) and bead type (sulfonate-modified polyvinylalcohol hydrogel, known commercially as DC BeadM1™, and a sulfonate-modified polyethylene glycol hydrogel bead, known commercially as LifePearl™). The molar ratio of drug to SO3- was found to be 0.9:1, 0.8:1, 0.4:1, and 0.9:1 for Dox, Iri, Mitox, and Topo, respectively. These findings indicate the steric effects of drug shape, charge, and size on binding ability. Four distinct bead sizes all produced drug:bead binding ratios of >0.9:1 doxorubicin:SO3-, thus indicating that bead size does not affect binding stoichiometry. Interestingly, bead size did affect the rate of binding as bead size was found to be indirectly proportional to binding rate. Finally, it was found for the sulfonate-modified polyethylene glycol hydrogel beads that doxorubicin binding was faster (at certain ratios of drug to bead) than that for the sulfonate-modified polyvinylalcohol hydrogel yet was maximal at a drug to bead ratio of only 0.7:1.

10.
Artigo em Inglês | MEDLINE | ID: mdl-30419308

RESUMO

PURPOSE: Testosterone recovery (TR) after androgen deprivation therapy (ADT) and radiation therapy (RT) is not well characterized. We studied TR in men who received RT and either short-term (ST) or long-term (LT) ADT and aimed to create a nomogram to predict TR. METHODS AND MATERIALS: We identified consecutive localized PC patients treated with ADT-RT at two academic medical centers from 1/2011-10/2016 with documented baseline testosterone (T). TR was time from last ADT injection to T normalization. The Kaplan-Meier method was used to estimate time to TR. Cox proportional hazards models identified TR predictors. A nomogram was trained with site one and externally validated with site two. RESULTS: 340 patients were included. 69.7% received STADT, median duration 6 months; 30.3% received LTADT, median duration 24.3 months. Median follow-up was 26.7 months. Median time for TR was 17.2 months for STADT and 24.0 months for LTADT patients (p = 0.004). The 2-year cumulative incidence of TR was 53.1% after LTADT vs 65.7% after STADT (p=0.004). On multivariate analysis, shorter duration ADT (HR = 0.96, p = 0.004), higher pre-treatment T (HR = 1.004, p<0.001), and lower BMI (HR = 0.95, p = 0.002) were associated with shorter time to TR. Older age (HR = 0.97, p = 0.09) and white race (HR = 0.67, p = 0.06) trended as longer TR predictors. A nomogram was generated to predict probability of TR at 1, 2, and 3 years. The c-index was 0.71 (95%CI 0.64-0.78) for the validation cohort. CONCLUSIONS: In this population of localized PC patients, TR following ADT-RT was variable. Using baseline T, ADT duration, BMI, age, and race, a predictive nomogram can estimate the likelihood of TR.

11.
J Pharm Sci ; 2018 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-30321545

RESUMO

The unique character of bile salts to self-assemble into hydrogels in the presence of halide salts was exploited in this work to facilitate the prediction of human intestinal absorption (%HIA) for a set of 25 compounds. This was achieved by firstly incorporating each compound separately within the process of gel formation to create a series of gel-drug membranes. Scanning electron microscopy analysis of the freeze-dried samples of the blank bile salt hydrogels and drug-loaded bile salt hydrogels indicated a unique microstructure made of a network of intertwined fibrils. Drug-loaded sodium deoxycholate hydrogels were then utilized as the donor phase to study permeability using flow-through and static diffusion cells. The resulting values of the release-permeability coefficient (Kp) were then analyzed, along with other molecular descriptors, for the %HIA using multiple linear regression. Overall, when comparing predicted values (using the systems presented in this study) with known literature values, it can be seen that both methods (i.e., using static and flow-through cells) had good predictability with R2PRED values of 79.8% and 79.7%, respectively. This study therefore proposes a novel, accurate, and precise way to predict HIA for compounds of pharmaceutical interest using a simple in vitro permeation system. It is important to develop alternatives to the current methods used in prediction of HIA, which are expensive and time-consuming or include the use of animals. Therefore, the proposed method in this study being economic and time-saving provides superiority over these current methods and suggests the possibility of its use as an alternate to such methods for prediction of HIA.

12.
Biomed Chromatogr ; 32(12): e4351, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30062715

RESUMO

Micellar liquid chromatography is a popular method used in the determination of a compound's lipophilicity. This study describes the use of the obtained micelle-water partition coefficient (log Pmw ) by such a method in the prediction of human intestinal absorption (HIA). As a result of the close resemblance of the novel composition of the micellar mobile phase to that of physiological intestinal fluid, prediction was deemed to be highly successful. The unique micellar mobile phase consisted of a mixed micellar mixture of lecithin and six bile salts, i.e. a composition matching that found in the human intestinal environment, prepared in ratios resembling those in the intestine. This is considered to be the first method to use a physiological mixture of biosurfactants in the prediction of HIA. As a result, a mathematical model with high predictive ability (R2 PRED = 81%) was obtained using multiple linear regression. The micelle-water partition coefficient (log Pmw ) obtained from micellar liquid chromatography was found to be a successful tool for prediction where the final optimum model included log Pmw and polar surface area as key descriptors with high statistical significance for the prediction of HIA. This can be attributed to the nature of the mobile phase used in this study which contains the lecithin-bile salt complex, thus forming a bilayer system and therefore mimicking absorption across the intestinal membrane.

13.
Clin Infect Dis ; 2018 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-29912307

RESUMO

Background: Both immediate or deferred switching from a PI/r to DTG may improve lipid profile. Methods: NEAT022 is a European, open label, randomized, trial. HIV-infected adults ≥ 50 years or with a Framingham score ≥10% were eligible if HIV RNA < 50 copies/mL. Patients were randomized to switch the PI/r to DTG immediately (DTG-I) or to deferred switch at week 48 (DTG-D) . Week 96 end-points were: proportion of patients with HIV RNA < 50 copies/ml, percentage change of lipid fractions and adverse events. Results: 415 patients were randomized: 205 to DTG-I and 210 to continue PI/r plus a deferred switch (DTG-D) at week 48 . The primary objective of non-inferiority at week 48 was met. At week 96, treatment success rate was 92.2 % in DTG-I arm and 87% in DTG-D arm (difference 5.2%, 95% CI -0.6 to 11). There were 5 virological failures in the DTG-I arm and 5 (1 while on PI/r and 4 after switching to DTG) in the DTG-D arm without selection of resistance mutations. There was no significant difference in terms of grade 3 or 4 AE´s or treatment modifying AE´s. Total cholesterol and other lipid fractions (except HDL) significantly (p<0.001) improved both after immediate and deferred switching to DTG overall and regardless of baseline PI/r strata. Conclusions: Both immediate and deferred switching from a PI/r to a DTG regimen in virologically suppressed HIV patients ≥ 50 years old or with a Framingham score ≥10% was highly efficacious, well tolerated and improved lipid profile.

14.
J Pharm Anal ; 8(3): 181-186, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29922487

RESUMO

Three mesoporous silica excipients (Syloid® silicas AL-1 FP, XDP 3050 and XDP 3150) were formulated with a model drug known for its poor aqueous solubility, namely phenylbutazone, in an attempt to enhance the extent and rate of drug dissolution. Although other forms of mesoporous silica have been investigated in previous studies, the effect of inclusion with these specific Syloid® silica based excipients and more interestingly, with phenylbutazone, is unknown. This work reports a significant enhancement for both the extent and rate of drug release for all three forms of Syloid® silica at a 1:1 drug:silica ratio over a period of 30 min. An explanation for this increase was determined to be conversion to the amorphous form and an enhanced drug loading ability within the pores. Differences between the release profiles of the three silicas were concluded to be a consequence of the physicochemical differences between the three forms. Overall, this study confirms that Syloid® silica based excipients can be used to enhance dissolution, and potentially therefore bioavailability, for compounds with poor aqueous solubility such as phenylbutazone. In addition, it has been confirmed that drug release can be carefully tailored based on the choice of Syloid® silica and desired release profile.

15.
Sci Justice ; 58(3): 219-225, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29685303

RESUMO

The illicit market for new psychoactive substances is forever expanding. Benzodiazepines and their derivatives are one of a number of groups of these substances and thus far their number has grown year upon year. For both forensic and clinical purposes it is important to be able to rapidly understand these emerging substances. However as a consequence of the illicit nature of these compounds, there is a deficiency in the pharmacological data available for these 'new' benzodiazepines. In order to further understand the pharmacology of 'new' benzodiazepines we utilised a quantitative structure-activity relationship (QSAR) approach. A set of 69 benzodiazepine-based compounds was analysed to develop a QSAR training set with respect to published binding values to GABAA receptors. The QSAR model returned an R2 value of 0.90. The most influential factors were found to be the positioning of two H-bond acceptors, two aromatic rings and a hydrophobic group. A test set of nine random compounds was then selected for internal validation to determine the predictive ability of the model and gave an R2 value of 0.86 when comparing the binding values with their experimental data. The QSAR model was then used to predict the binding for 22 benzodiazepines that are classed as new psychoactive substances. This model will allow rapid prediction of the binding activity of emerging benzodiazepines in a rapid and economic way, compared with lengthy and expensive in vitro/in vivo analysis. This will enable forensic chemists and toxicologists to better understand both recently developed compounds and prediction of substances likely to emerge in the future.


Assuntos
Benzodiazepinas/química , Relação Quantitativa Estrutura-Atividade , Receptores de GABA-A/química , Sítios de Ligação , Humanos , Modelos Químicos
16.
Drug Test Anal ; 2018 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-29582576

RESUMO

The misuse of benzodiazepines as new psychoactive substances is an increasing problem around the world. Basic physicochemical and pharmacokinetic data is required on these substances to interpret and predict their effects upon humans. Experimental log D7.4 , pKa and plasma protein binding values were determined for 11 benzodiazepines that have recently appeared as new psychoactive substances (3-hydroxyphenazepam, 4'-chlorodiazepam, desalkylflurazepam, deschloroetizolam, diclazepam, etizolam, flubromazepam, flubromazolam, meclonazepam, phenazepam, and pyrazolam) and compared with values generated by various software packages (ACD/I-lab, MarvinSketch, ADMET Predictor and PreADMET). ACD/I-LAB returned the most accurate values for log D7.4 and plasma protein binding while ADMET Predictor returned the most accurate values for pKa . Large variations in predictive errors were observed between compounds. Experimental values are currently preferable and desirable as they may aid with the future 'training' of predictive models for these new psychoactive substances.

17.
PLoS One ; 13(2): e0192081, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29389981

RESUMO

BACKGROUND & METHODS: The ICONIC project has developed an automated high-throughput pipeline to generate HIV nearly full-length genomes (NFLG, i.e. from gag to nef) from next-generation sequencing (NGS) data. The pipeline was applied to 420 HIV samples collected at University College London Hospitals NHS Trust and Barts Health NHS Trust (London) and sequenced using an Illumina MiSeq at the Wellcome Trust Sanger Institute (Cambridge). Consensus genomes were generated and subtyped using COMET, and unique recombinants were studied with jpHMM and SimPlot. Maximum-likelihood phylogenetic trees were constructed using RAxML to identify transmission networks using the Cluster Picker. RESULTS: The pipeline generated sequences of at least 1Kb of length (median = 7.46Kb, IQR = 4.01Kb) for 375 out of the 420 samples (89%), with 174 (46.4%) being NFLG. A total of 365 sequences (169 of them NFLG) corresponded to unique subjects and were included in the down-stream analyses. The most frequent HIV subtypes were B (n = 149, 40.8%) and C (n = 77, 21.1%) and the circulating recombinant form CRF02_AG (n = 32, 8.8%). We found 14 different CRFs (n = 66, 18.1%) and multiple URFs (n = 32, 8.8%) that involved recombination between 12 different subtypes/CRFs. The most frequent URFs were B/CRF01_AE (4 cases) and A1/D, B/C, and B/CRF02_AG (3 cases each). Most URFs (19/26, 73%) lacked breakpoints in the PR+RT pol region, rendering them undetectable if only that was sequenced. Twelve (37.5%) of the URFs could have emerged within the UK, whereas the rest were probably imported from sub-Saharan Africa, South East Asia and South America. For 2 URFs we found highly similar pol sequences circulating in the UK. We detected 31 phylogenetic clusters using the full dataset: 25 pairs (mostly subtypes B and C), 4 triplets and 2 quadruplets. Some of these were not consistent across different genes due to inter- and intra-subtype recombination. Clusters involved 70 sequences, 19.2% of the dataset. CONCLUSIONS: The initial analysis of genome sequences detected substantial hidden variability in the London HIV epidemic. Analysing full genome sequences, as opposed to only PR+RT, identified previously undetected recombinants. It provided a more reliable description of CRFs (that would be otherwise misclassified) and transmission clusters.


Assuntos
Genoma Viral , HIV-1/classificação , Adulto , Feminino , HIV-1/genética , Humanos , Londres , Masculino , Pessoa de Meia-Idade , Filogenia , Recombinação Genética
19.
Eur J Pharm Sci ; 112: 139-145, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-29166624

RESUMO

Poor aqueous solubility is often linked with a poor dissolution rate and ultimately, limited bioavailability of pharmaceutical compounds. This study describes the application of mesoporous materials (Syloid 244 and Syloid AL1) in improving the dissolution rate of a drug with poor aqueous solubility, namely artemether, utilising different processing methods including physical mixing, co-grinding and solid dispersions prepared by solvent evaporation and the lyophilisation technique. The prepared formulations were extensively characterised for their solid-state properties and the drug release attributes were studied. Differential scanning calorimetry and X-ray diffraction confirmed conversion of crystalline artemether into a disordered and amorphous form, whilst no intermolecular interactions were detected between artemether and silica. Both silica grades enhanced the dissolution rate of artemether in comparison with drug alone, for example from 17.43% (±0.87%) to 71.55% (±3.57%) after 120mins with lyophilisation and Syloid 244 at a 1:3 ratio. This enhancement was also dependant on the choice of processing method, for example, co-ground and lyophilised formulations prepared with Syloid 244 at 1:3 ratio produced the most extensive dissolution, thus endorsing the importance of materials as well as choice of formulation method.


Assuntos
Artemisininas/química , Dióxido de Silício/química , Antimaláricos/química , Artemeter , Liberação Controlada de Fármacos , Liofilização , Porosidade
20.
Drug Test Anal ; 10(1): 37-53, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28471096

RESUMO

The market for new psychoactive substances has increased markedly in recent years and there is now a steady stream of compounds appearing every year. Benzodiazepines consist of only a fraction of the total number of these compounds but their use and misuse has rapidly increased. Some of these benzodiazepines have only been patented, some of them have not been previously synthesised, and the majority have never undergone clinical trials or tests. Despite their structural and chemical similarity, large differences exist between the benzodiazepines in their pharmacokinetic parameters and metabolic pathways and so they are not easily comparable. As benzodiazepines have been clinically used since the 1960s, many analytical methods exist to quantify them in a variety of biological matrices and it is expected that these methods would also be suitable for the detection of benzodiazepines that are novel psychoactive substances. Illicitly obtained benzodiazepines have been found to contain a wide range of compounds such as opiates which presents a problem since the use of them in conjunction with each other can lead to respiratory depression and death. This review collates the available information on these benzodiazepines and provides a starting point for the further investigation of their pharmacokinetics which is clearly required.

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