We report the direct measurement of the 7Be solar neutrino signal rate performed with the Borexino detector at the Laboratori Nazionali del Gran Sasso. The interaction rate of the 0.862 MeV 7Be ...neutrinos is 49±3stat±4syst counts/(day·100 ton). The hypothesis of no oscillation for 7Be solar neutrinos is inconsistent with our measurement at the 4σ C.L. Our result is the first direct measurement of the survival probability for solar νe in the transition region between matter-enhanced and vacuum-driven oscillations. The measurement improves the experimental determination of the flux of 7Be, pp, and CNO solar νe, and the limit on the effective neutrino magnetic moment using solar neutrinos.
Aims
SARS-CoV-2 is a single-stranded RNA virus which is part of the ß-coronavirus family (like SARS 2002 and MERS 2012). The high prevalence of hospitalization and mortality, in addition to the lack ...of vaccines and therapeutics, forces scientists and clinicians around the world to evaluate new therapeutic options. One strategy is the repositioning of already known drugs, which were approved drugs for other indications.
Subject and method
SARS-CoV-2 entry inhibitors, RNA polymerase inhibitors, and protease inhibitors seem to be valuable targets of research. At the beginning of the pandemic, the
ClinicalTrials.gov
webpage listed
n
=479 clinical trials related to the antiviral treatment of SARS-CoV-2 (01.04.2020, “SARS-CoV-2,” “COVID-19,” “antivirals,” “therapy”), of which
n
=376 are still accessible online in January 2021 (10.01.2021). Taking into account further studies not listed in the CTG webpage, this narrative review appraises HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors as promising candidates for the treatment of COVID-19.
Results
Lopinavir/ritonavir, darunavir/cobicistat, remdesivir, tenofovir-disoproxilfumarate, favipriravir, and sofosbuvir are evaluated in clinical studies worldwide. Study designs show a high variability and results often are contradictory. Remdesivir is the drug, which is deployed in nearly 70% of the reviewed clinical trials, followed by lopinavir/ritonavir, favipiravir, ribavirine, and sofosbuvir.
Discussion
This review discusses the pharmacological/clinical background and questions the rationale and study design of clinical trials with already approved HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors which are repositioned during the SARS-CoV-2 pandemic worldwide. Proposals are made for future study design and drug repositioning of approved antiretroviral compounds.
The pharmacoenhancement of plasma concentrations of protease inhibitors by coadministration of so-called boosters has been an integral part of antiretroviral therapy for human immunodeficiency virus ...(HIV) for 1.5 decades. Nearly all HIV protease inhibitors are combined with low-dose ritonavir or cobicistat, which are able to effectively inhibit the cytochrome-mediated metabolism of HIV protease inhibitors in the liver and thus enhance the plasma concentration and prolong the dosing interval of the antiretrovirally active combination partners. Therapies created in this way are clinically effective regimens, being convenient for patients and showing a high genetic barrier to viral resistance. In addition to ritonavir, which has been in use since 1996, cobicistat, a new pharmacoenhancer, has been approved and is widely used now. The outstanding property of cobicistat is its cytochrome P450 3A-selective inhibition of hepatic metabolism of antiretroviral drugs, in contrast with ritonavir, which not only inhibits but also induces a number of cytochrome P450 enzymes, UDP-glucuronosyltransferase, P-glycoprotein, and other cellular transporters. This article reviews the current literature, and compares the pharmacokinetics, pharmacodynamics, and safety of both pharmacoenhancers and discusses the clinical utility of cobicistat in up-to-date and future HIV therapy.
Background. To determine the rate of seroconversion after 2 doses of a novel split virion, inactivated, adjuvanted pandemic H1N1 influenza vaccine (A/California/7/2009) in human immunodeficiency ...virus type 1 (HIV-1)—infected patients (ClinicalTrials.gov NCT01017172). Methods. Diagnostic study of adult HIV-1—infected patients scheduled for H1N1 influenza A vaccination. Blood samples where taken before and 21 days after the first dose and 21 days after the second dose of the vaccine. Antibody (AB) titers were determined by hemagglutination inhibition assay. Seroconversion was defined by either an AB titer ≤1:10 before and ≥1:40 after or ≥1:10 before and a ≥4-fold increase in AB titer 21 days after vaccination. Results. One hundred thirty-five patients received 2 doses of the H1N1 vaccine and were analyzed. The rate of seroconversion was 68.2% (95% confidence interval, 59.6—75.9) after the first dose and 91.9% (95% confidence interval, 85.9—95.9) after the second dose. Patients who did not seroconvert had a lower mean nadir CD4 cell count (±standard deviation; 81 ± 99 vs 190 ± 148 cells/μL; P = .006), had a longer duration of HIV infection (±standard deviation; 13.1 ± 5.9 vs 8.8 ± 6.8 years; P = .04), and were more likely to have an AB titer ≥1:40 before vaccination (4% vs 55%; P < .001) when compared with patients with seroconversion. No other differences were found between the 2 groups, including AIDS status, highly active antiretroviral therapy status, HIV RNA - polymerase chain reaction load <50 copies/mL, CD4 cell count, sex, body mass index, and chronic hepatitis. Conclusion. Among HIV-infected patients, the rate of seroconversion after the first dose of an adjuvanted H1N1 influenza A vaccine was 68% and increased to 92% after a second doses.
Addictive behavior is importantly mediated by mesolimbic dopaminergic signaling. Here, we comprehensively analyzed the DRD2 gene locus, and in addition, the ANKK1 rs1800497C>T single nucleotide ...polymorphism (SNP), formerly known as 'dopamine D2 receptor Taq1A C>T polymorphism', for associations with the risk of opiate addiction and the methadone dosage requirements.
Allelic frequencies of DRD2/ANKK1 polymorphisms were compared between 85 methadone-substituted Caucasian patients and a random sample of 99 healthy Caucasian controls. Within patients, the average and maximum daily methadone dose during the first year of treatment and the time when that maximum dose was reached were analyzed for an association with DRD2/ANKK1 genetics.
Compared with the control group, drug users carried more frequently the minor allele of DRD2 SNP rs1076560G>T SNP (P=0.022, odds ratio 2.343) or the ATCT haplotype of DRD2 rs1799978A>G, rs1076560G>T, rs6277C>T, ANKK1 rs1800497C>T (P=0.048, odds ratio 2.23), with similar tendencies for ANKK1 rs1800497C>T (P=0.056, odds ratio 2.12) and the TCCTCTT haplotype of DRD2 rs12364283T>C, rs1799732C del, rs4648317C>T, rs1076560G>T, rs6275C>T, rs6277C>T, and ANKK1 rs1800497C>T (P=0.059, odds ratio 2.31). The average and maximum daily methadone doses were significantly associated with the DRD2 rs6275C>T SNP (P=0.016 and 0.005 for average and maximum dose, respectively). Carriers of the variant rs6275T allele needed higher methadone doses than noncarriers. In addition, this variant was associated with a longer time to reach the maximum methadone dose (P=0.025).
On the basis of an analysis spanning the whole gene locus, from the DRD2 promoter to the ANKK1 rs1800497C>T polymorphism, DRD2 genetic polymorphisms modulate both the risk of opiate addiction, leading to the necessity of methadone substitution therapy, and the course of this therapy in terms of dosage requirements.
Background: In the past, protease inhibitors (PIs) and the reverse transcriptase inhibitor abacavir were identified increasing the risk for thromboembolic complications and cardiovascular events ...(CVE) of HIV infected patients taking a combination antiretroviral therapy (cART). Results of the previous HIV-PLA I-study lead to the assumption that platelet activation could play a substantial role in increasing CVE risks. Methods: The open label, monocentric HIV-PLA II-study investigated HIV-1-infected, therapy-naive adults (n=45) starting with cART, consisting either of boosted PI (atazanavir, n= 6, darunavir, n=11), NNRTI (efavirenz, n=14) or integrase inhibitor (raltegravir, n=14), each plus tenofovir/emtricitabine co-medication. Main exclusion criteria were tobacco smoking, the intake of NSAIDs or abacavir or past CVE. Platelet adhesive molecule p-selectin (CD62P) and FITC anti-human Integrin alpha-IIb/Integrin beta-3 (CD41/CD61) antibody (PAC-1) binding, monocyte CD11b/monocyte-associated CD41 expression and the endogenous thrombin potential (ETP) were assessed ex vivo-in vitro at baseline, weeks 4, 12 and 24. Therapy regimens were blinded to the investigators for laboratory and statistical analyses. Results: CD11b and ETP showed no significant changes or differences between all study groups. In contrast, the mean + SD mean fluorescence units (MFI) of CD62P and PAC-1 increased significantly in patients taking PI, indicating an enhanced potential for thrombocyte activation and aggregation. Conclusion: CD62P expression, detecting the a-platelet degranulation of pro-inflammatory and pro-thrombotic factors and adhesive proteins, and PAC-1 expression, representing a marker for conformation changes of the GIIb/IIIa receptor, increased significantly in patients taking HIV protease inhibitors. The findings of this study revealed a yet unknown pathway of platelet activation, possibly contributing to the increased risk for CVE under HIV protease inhibitor containing cART. Clinical Trial Registration No.: DRKS00000288. Keywords: HIV protease inhibitors, platelets, leucocytes, PAC-1, GIIb/IIIa-receptor
A finite number of variants in the OPRM1, COMT, MC1R, ABCB1 and CYP2D6 genes has been identified to significantly modulate the effects of opioids in controlled homogenous settings. We analyzed the ...imprint of these variants in opioid therapy in a highly variable cohort of pain patients treated in outpatient units to test whether genotyping may play a role in this clinical setting.
In a multicenter study conducted in tertiary care outpatient pain centers, 352 patients (156 men and 196 women, aged 58.5+/- 14.6 years) treated for 1-600 months (63.4 +/- 92.4 months) with various opioids for pain of various origins were included. Genotyping was performed for all the variants reportedly modulating pain in well-defined cohorts. Association analyses focused on opioid dosing, the actual 24-h pain score on a 0-10 rating scale and the occurrence of side effects.
The frequency of the genetic variants in the patients did not significantly differ from that in the average Caucasian population. Daily opioid doses ranged from 4 to 1750 mg oral morphine equivalents (133.4 +/- 203.2 mg) and significantly decreased in a gene dose-dependent manner with the P-glycoprotein variant ABCB1 3435C>T. Pain was rated on average at 3.7 +/- 2.6. There was a tendency towards increased pain in a gene dose-dependent manner with the mu-opioid receptor variant OPRM1 118A>G.
Genetics were reflected in the outpatient pain therapy only to a modest degree. The need of outpatient therapy of pain of various causes guided by the presently known functional genetic variants cannot be convincingly concluded from the present data. Using the ABCB1 3435 genotype to predefine lower individual opioid doses barely merits the laboratory effort. If any, the results suggest that a genetics guided outpatient pain therapy may be based on ABCB1 and OPRM1 variants.
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