Pharmacokinetic drug evaluation of dolutegravir plus rilpivirine for the treatment of HIV

Introduction: The search for simple, potent, metabolic-friendly and nucleoside/nucleotide sparing antiretroviral regimens has led clinical investigators to move steps towards dual therapies. Among these the association of rilpivirine and dolutegravir is emerging as a twin randomized clinical trial (SWORD1&2) and at least three observational cohort describe it as a safe and highly effective regimen for switch from other therapies

Areas covered: We review the evidence supporting the use of dolutegravir plus rilpivirine for the treatment of HIV in virologically suppressed patients taking other antiretroviral regimens. The reasons for the switch in clinical practice may range from simplification to tolerability/toxicity issues, to the prevention of future metabolic damage, to predicted drug-drug interactions when treatment of HCV co-infection is planned. Articles searchable on MEDLINE/PubMed and from the main international congresses in the field of HIV therapy were reviewed to provide context for use of dolutegravir plus rilpivirine

Expert opinion: This treatment is highly effective in maintaining HIV-1 RNA <50 copies/mL. Although the studies up to date requested patient to switch to drugs they had no experience of, a predictable ‘radical change’ effect did not impact negatively on the results. Further data from these studies may help elucidate the possible advantage in terms of safety and metabolic effect in the next few months.     

Unravelling the one-pot conversion of biomass-derived furfural and levulinic acid to 1,4-pentanediol catalysed by supported RANEY® Ni–Sn alloy catalysts

Bimetallic Ni–Sn alloys have been recognised as promising catalysts for the transformation of furanic compounds and their derivatives into valuable chemicals. Herein, we report the utilisation of a supported bimetallic RANEY® nickel–tin alloy supported on aluminium hydroxide (RNi–Sn(x)/AlOH; x is Ni/Sn molar ratio) catalysts for the one-pot conversion of biomass-derived furfural and levulinic acid to 1,4-pentanediol (1,4-PeD). The as prepared RNi–Sn(1.4)/AlOH catalyst exhibited the highest yield of 1,4-PeD (78%). The reduction of RNi–Sn(x)/AlOH with H₂ at 673–873 K for 1.5 h resulted in the formation of Ni–Sn alloy phases (e.g., Ni₃Sn and Ni₃Sn₂) and caused the transformation of aluminium hydroxide (AlOH) to amorphous alumina (AA). The RNi–Sn(1.4)/AA 673 K/H₂ catalyst contained a Ni₃Sn₂ alloy as the major phase, which exhibited the best yield of 1,4-PeD from furfural (87%) at 433 K, H₂ 3.0 MPa for 12 h and from levulinic acid (up to 90%) at 503 K, H₂ 4.0 MPa, for 12 h. Supported RANEY® Ni–Sn(1.5)/AC and three types of supported Ni–Sn(1.5) alloy (e.g., Ni–Sn(1.5)/AC, Ni–Sn(1.5)/c-AlOH, and Ni–Sn(1.5)/γ-Al₂O₃) catalysts afforded high yields of 1,4-PeD (65–87%) both from furfural and levulinic acid under the optimised reaction conditions.

The RANEY® Ni–Sn(x) alloy catalysed the one-pot conversion of biomass-derived furfural and levulinic acid to allow remarkable yield of 1,4-pentanediol (up to 90%) under the mild reaction conditions.     

Antioxidant Activity and Cytotoxicity of the Traditional Indonesian Medicine Tahongai (Kleinhovia hospita L.) Extract

We investigated the leaves of Kleinhovia hospita, a plant which has been traditionally used in Indonesia as phytotherapy to cure liver disease, to describe antioxidant materials from plant sources. K. hospita leaves were extracted with methanol and further partitioned into n-hexane, diethyl ether, and ethyl acetate. The antioxidant activity of each fraction and the residue was assessed using a 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging method and their cytotoxicity on HepG2 liver cancer cells was determined by a MTT assay. The K. hospita leaf methanol extract showed strong antioxidant activity (96%) compared with vitamin C (98%) by the DPPH method and the measured activity from the subsequent extracts of the methanol extract were 48.9% for n-hexane, 74.0% for diethyl ether, 84.3% for ethyl acetate, and 77.1% for the residue. The MTT assay showed the cytotoxicity of the methanol extract on HepG2 cells at 14%, 76%, and 80% at concentrations of 50μg/mL, 87.5μg/mL, and 125μg/mL, respectively. Leaf extracts of the medicinal plant K. hospita showed potent antioxidant activity and moderate cytotoxicity on HepG2 liver cancer cells.     

Multigene methylation analysis of Wilms' tumour and adult renal cell carcinoma

To investigate the role of epigenetic gene silencing in the pathogenesis of Wilms' tumour and renal cell carcinoma (RCC), we determined their methylation profile using a candidate gene approach. Thus, 40 Wilms' tumours and up to 49 adult RCC were analysed by methylation-specific PCR for promoter methylation at CASP8, CDH1, CDH13, DAPK, MGMT, NORE1A, p14ARF and RARB2 in primary Wilms' tumours and CASP8, CDH1, CDH13, CRBP1, DAPK, MGMT, MT1G, NORE1A, p16INK4a, SDHB and RARB2 in primary RCC. Both tumour sample sets had previously been analysed for RASSF1A promoter methylation, and p16INK4a methylation results were also available for the Wilms' tumour samples. Wilms' tumours demonstrated a high incidence of methylation at CASP8 (43%) and MGMT (30%), intermediate frequencies at NORE1A (15%), p14ARF (15%), p16INK4a (10%), DAPK (11%) and CRBP1 (9%), but promoter methylation was rare or absent at RARB2 (0%), CDH13 (0%) and CDH1 (3%). No association was detected between methylation of RASSF1A, CASP8 or MGMT in individual tumours. The frequency of MGMT methylation was higher in stage 1 and 2 tumours (50%) than in stage 3 and 4 tumours (17%) but this did not reach statistical significance (P=0.06). RCC were most frequently methylated at DAPK (24%), MT1G (20%), NORE1A (19%), CDH1 (16%) and MGMT (9%) and not or rarely at SDHB (4%), RARB2 (0%), p16INK4a (0%) and CDH13 (3%). There were no associations between methylation of RASSF1A, DAPK and CDH1 in individual tumours. Papillary RCC demonstrated a higher frequency of DAPK methylation (43%) than clear cell tumours (19%) (P=0.14). We have demonstrated that de novo promoter methylation is frequent in Wilms' tumour and RCC, and these data enable methylation profiles to be constructed for each tumour type. Thus, combining our results with data published previously, it appears that promoter methylation occurs frequently (> or =20% of primary tumours) at CASP8, SLIT2 and RASSF1A in Wilms' tumour and at RASSF1A, TIMP3, DAPK, SLIT2, MT1G and GSTP1 in RCC.     

Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility

BACKGROUND: Germline mutations in three subunits of mitochondrial complex II (SDHB, SDHC and SDHD) may be associated with susceptibility to phaeochromocytoma (PC) and/or head and neck paraganglioma (HNPGL). METHODS: To further define the role of SDH subunit mutations in these disorders, we analysed a series of 22 probands with PC and evidence of genetic susceptibility (seven with familial PC only, one with familial PC and HNPGL, 10 sporadic cases with multiple PC and four cases of isolated paediatric onset PC) for germline SDHB, SDHC and SDHD mutations. In addition, we analysed 34 cases of HNPGL (30 isolated cases with single tumours, three isolated cases with multiple tumours and one familial case with multiple tumours) for somatic and germline mutations in SDHB, SDHC and SDHD. RESULTS: We identified four germline mutations (three SDHB and one SDHD, three novel) in the 22 PC probands. Combining these results with our previous series, we have detected germline SDHB or SDHD mutations in 2/12 (17%) of familial PC only kindreds, 4/5 (80%) of familial PC and HNPGL cases, 1/10 of sporadic multiple PC cases and 2/4 (50%) of paediatric PCs. No somatic mutations were detected in the HNPGL tumours, but four cases with multiple HNPGL had the common P81L germline SDHD mutation. Intriguingly a silent SNP (c.204C > T) in SDHD was significantly more common in HNPGL cases (6/34) than in controls (1/100, P = 0.0011). Combining our results with those from two other large studies in which both SDHB and SDHD have been analysed, SDHB mutations were most commonly associated with phaeochromocytoma susceptibility and SDHD with the development of HNPGL (P = 0.025). However, germline SDHB and SDHD mutations demonstrate considerable phenotypic variability and genotype-phenotype correlations are complex. CONCLUSION: The significantly lower frequency (P = 0.028) of germline SDH subunit mutations in familial PC only cases compared to those with familial PC and HNPGL suggests that further PC susceptibility gene(s) remain to be identified.     

Association of core promoter mutations of hepatitis B virus and viral load is different in HBeAg（＋） and HBeAg（-） patients

AIM:To identify the prevalence of hepatitis B e antigen (HBeAg) and to assess the association of hepatitis B virus (HBV) core promoter mutations and viral load in Indonesian patients.METHODS:Sixty-four patients with chronic hepatitis,65 with liver cirrhosis and 50 with hepatocellular carcinoma were included in this study.HBeAg and hepatitis B e antibody (HBeAb) tests were performed using enzyme-linked immunosorbent assay and the mutations were analyzed by sequencing.Viral load was measured by real-time poly...     

Hepatitis B virus subgenotypes and basal core promoter mutations in Indonesia

AIM： To identify the distribution of hepatitis B virus （HBV） subgenotype and basal core promoter （BCP） mutations among patients with HBV-associated liver disease in Indonesia.
METHODS： Patients with chronic hepatitis （CH, n =61）, liver cirrhosis （LC, n = 62）, and hepatocellular carcinoma （HCC, n = 48） were included in this study. HBV subgenotype was identified based on S or preS gene sequence, and mutations in the HBx gene including the overlapping BCP region were examined by direct sequencing.
RESULTS： HBV genotype B （subgenotypes B2, B3, B4, 85 and B7） the major genotype in the samples, accounted for 75.4%, 71.0% and 75.0% of CH, LC and HCC patients, respectively, while the genotype C （subgenotypes C1, C2 and C3） was detected in 24.6%, 29.0%, and 25.0% of CH, LC, and HCC patients, respectively. Subgenotypes B3 （84.9%） and C1 （82.2%） were the main subgenotype in HBV genotype B and C, respectively. Serotype adw2 （84.9%） and adrq＋ （89.4%） were the most prevalent in HBV genotype B and C, respectively. Double mutation （A1762T/G1764A） in the BCP was significantly higher in LC （59.7%） and HCC （54.2%） than in CH （19.7%）, suggesting that this mutation was associated with severity of liver disease. The T1753V was also higher in LC （46.8%）, but lower in HCC （22.9%） and CH （18.0%）, suggesting that this mutation may be an indicator of cirrhosis.
CONCLUSION： HBV genotype B/B3 and C/C1 are the major genotypes in Indonesia. Mutations in BCP, such as A1762T/G1764A and T1753V, might have an association with manifestations of liver disease.     

Antidermatophyte and antimelanogenesis compound from <Emphasis Type="Italic">Eleutherine americana</Emphasis> grown in Indonesia

An active compound from the bulb of Eleutherine americana L. Merr. (Iridaceae) collected from East Kalimantan, Indonesia, was tested for its antidermatophyte and antimelanogenesis activity. Antifungal assay-directed fractionation of the n-hexane-soluble fraction of the methanolic extract of the bulb of E. americana led to the isolation of 1 as an active compound. The compound was identified as the naphthoquinone eleutherin by EI-MS and ¹H-, ¹³C-, and two-dimensional NMR analyses. Antidermatophyte assay of 1 at concentrations of 10, 20, 40, 60, and 80 μg/disk and myconazole, a commercial antidermatophyte, at 10 μg/disk displayed 7, 8, 13, 16, 17, and 14 mm of inhibition zone against Trichophyton mentagrophytes, respectively. In a melanin formation inhibition assay, compound 1 displayed potent antimelanogenesis activity at 5 ppm with low toxicity compared with arbutin, a commercial skin-whitening agent. The results showed the high potential of 1, an active compound from E. americana, to be applied as an antidermatophyte and antimelanogenesis agent.