Cerebral Venous Thrombosis in COVID-19.

Background: COVID-19 causes a hypercoagulable state leading to thrombosis. Many of these thrombotic complications occur in those with severe disease and late in the disease course. COVID-19 has recently been associated with cerebral venous thrombosis (CVT). Objective: To study the onset of CVT in relation to COVID-19 and compare their characteristics and outcomes with non-COVID CVT patients admitted during the same period. Materials and Methods: This multicentric, retrospective study conducted between April 4 and October 15, 2020, included adult patients with CVT who were positive for the SARS-CoV-2 virus and compared them with CVT patients who were negative for the SARS-CoV-2 virus hospitalized during the same period. We studied their clinical profile, risk factors for CVT, and markers of COVID coagulopathy, imaging characteristics, and factors influencing their outcomes. Results: We included 18 COVID-19-infected patients and compared them with 43 non-COVID-19 CVT patients. Fourteen patients in the COVID-19 group presented with CVT without the other typical features of COVID-19. Thirteen patients had non-severe COVID-19 disease. Twelve patients had a good outcome (mRS ≤2). Mortality and disability outcomes were not significantly different between the two groups. Conclusion: Our study suggests a possible association between COVID-19 and CVT. CVT can be the presenting manifestation of an underlying COVID-19, occurring early in the course of COVID-19 and even in those with mild disease. Patients with worse GCS on admission, abnormal HRCT chest, severe COVID-19, and need for invasive ventilation had a poor outcome.

Impact of lifestyle modification on glycemic control in patients with type 2 diabetes mellitus.

BACKGROUND: Current treatment guidelines support the role of lifestyle modification, in terms of increasing the quantity and quality of physical activity to achieve target glycemia in patients with type 2 diabetes mellitus. OBJECTIVE: To assess the effect of structured exercise training and unstructured physical activity interventions on glycemic control. MATERIALS AND METHODS: This was a randomized six-month exercise intervention study conducted with previously inactive 279 patients of type 2 diabetes mellitus. Before randomization, all enrolled T2DM participants (n: 300; 30 to 60 year old, having diabetes for more than a year with HbA1c levels of 6.5% or higher) entered a one-month run-in phase to reduce dropout and maintain adherence. RESULTS: A recommendation to increase physical activity was beneficial (0.14% HbA1c reduction; P = 0.12), but was not bringing significantly declines in HbA1c, whereas, structured exercise training is associated with a significant HbA1c decline of 0.59%. (P = 0.030). In a subgroup analysis limited to participants with a baseline HbA1c value > 7%, both the unstructured (0. 48%; P = 0.04) and structured exercise training (0.77%; P < 0.01) groups experienced significant decline in HbA1c Vs the control, whereas among participants with baseline hemoglobin A1c values less than 7%, significant reduction occurred only in the structured exercise training group. Changes in blood pressure; total cholesterol, HDL-cholesterol (high-density lipoprotein), LDL-cholesterol (low-density lipoprotein) and the atherogenic index factors did not statistically significantly differ within (baseline to follow-up) and among groups. CONCLUSION: Supervised structured training was more efficacious than unstructured activity in achieving declines in HbA1c. Although both structured and unstructured training provide benefits, only the former was associated with significant reductions in HbA1c levels. Therefore, T2DM patients should be stimulated to participate in specifically designed exercise intervention programs.

5,5'- and 6,6'-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of HCV NS5B polymerase.

The discovery of 5,5'- and 6,6'-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC50 <0.10 microM). In vitro DMPK data for selected compounds as well as crystal structures of representative inhibitors complexed with the NS5B protein are also disclosed.

Discovery of tricyclic 5,6-dihydro-1H-pyridin-2-ones as novel, potent, and orally bioavailable inhibitors of HCV NS5B polymerase.

A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C(12) (PO)/EC(50) ratios.

5,6-Dihydro-1H-pyridin-2-ones as potent inhibitors of HCV NS5B polymerase.

5,6-Dihydro-1H-pyridin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4ad displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; IC(50) (1a)<25nM, EC(50) (1b)=16nM), good in vitro DMPK properties, as well as moderate oral bioavailability in monkeys (F=24%).

Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 5: Exploration of pyridazinones containing 6-amino-substituents.

The synthesis of 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones bearing 6-amino substituents as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC(50)<0.10 microM). In vitro DMPK data (microsome t(1/2), Caco-2 P(app)) for many of the compounds are also disclosed, and a crystal structure of a representative inhibitor complexed with the NS5B protein is discussed.

Hexahydro-pyrrolo- and hexahydro-1H-pyrido[1,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase.

Hexahydro-pyrrolo- and hexahydro-1H-pyrido[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4c displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b) <10 nM; EC(50) (1b)=34 nM) as well as good stability towards human liver microsomes (HLM t(1/2) =59 min).

4-(1,1-Dioxo-1,4-dihydro-1lambda6-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-ones as potent inhibitors of HCV NS5B polymerase.

4-(1,1-Dioxo-1,4-dihydro-1lambda(6)-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-one analogs were discovered as a novel class of inhibitors of HCV NS5B polymerase. Structure-based design led to the identification of compound 3a that displayed potent inhibitory activities in biochemical and replicon assays (1b IC(50)<10 nM; 1b EC(50)=1.1 nM) as well as good stability toward human liver microsomes (HLM t(1/2)>60 min).

Structure-based design, synthesis, and biological evaluation of 1,1-dioxoisothiazole and benzo[b]thiophene-1,1-dioxide derivatives as novel inhibitors of hepatitis C virus NS5B polymerase.

A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC(50) values. The most potent compound exhibited IC(50) less than 10nM against the genotype 1b HCV polymerase and EC(50) of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.

Pyrrolo[1,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase.

Pyrrolo[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Structure-based design led to the discovery of compound 3 k, which displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; EC(50) (1b)=12 nM) as well as good stability towards human liver microsomes (HLM t(1/2)>60 min).

Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 3: Further optimization of the 2-, 6-, and 7'-substituents and initial pharmacokinetic assessments.

5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. Lead optimization led to the discovery of compound 3a, which displayed potent inhibitory activities in biochemical and replicon assays [IC(50) (1b)<10nM; IC(50) (1a)=22 nM; EC(50) (1b)=5nM], good stability toward human liver microsomes (HLM t(1/2)>60 min), and high ratios of liver to plasma concentrations 12h after a single oral administration to rats.

Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda6-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones: Part 4. Optimization of DMPK properties.

5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as potent inhibitors of genotype 1 HCV NS5B polymerase focusing on the optimization of their drug metabolism and pharmacokinetics (DMPK) profiles. This investigation led to the discovery of potent inhibitors with improved DMPK properties.

Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda6-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 1: exploration of 7'-substitution of benzothiadiazine.

5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. The synthesis, structure-activity relationships (SAR), metabolic stability, and structure-based design approach for this new class of compounds are discussed.

Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 2: Variation of the 2- and 6-pyridazinone substituents.

5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. The structure-activity relationship (SAR) associated with variation of the pyridazinone 2- and 6-substituents is discussed. The synthesis and metabolic stability of this new class of compounds are also described.

Syntheses of novel myxopyronin B analogs as potential inhibitors of bacterial RNA polymerase.

Based upon observations from our initial findings, additional myxopyronin B analogs have been prepared and tested for in vitro inhibitory activity against DNA-dependent RNA polymerase and antibacterial activity against Escherichia coli and Staphylococcus aureus.

Myxopyronin B analogs as inhibitors of RNA polymerase, synthesis and biological evaluation.

A series of myxopyronin B analogs has been prepared via a convergent synthetic route and were tested for in vitro inhibitory activity against DNA-dependent RNA polymerase and antibacterial activity against E. coli and S. aureus. The parent lead compound proved to be very sensitive to even small changes. Only the achiral desmethyl myxopyronin B (1a) provided enhanced potency.

Variants of DNA polymerase Beta extend mispaired DNA due to increased affinity for nucleotide substrate.

DNA polymerase beta offers an attractive system to study the biochemical mechanism of polymerase-dependent mutagenesis. Variants of DNA polymerase beta, Y265F and Y265W, were analyzed for misincorporation efficiency and mispair extension ability, relative to wild-type DNA polymerase beta. Our data show that the fidelity of the mutant polymerases is similar to wild-type enzyme on a one-nucleotide gapped DNA substrate. In contrast, with a six-nucleotide gapped DNA, the mutant proteins are slightly more accurate than the wild-type enzyme. The mutagenic potential of Y265F and Y265W is more pronounced when encountering a mispaired DNA substrate. Here, both variants can extend a G:G mispair quite efficiently, and Y265F can also extend a T:G mispair. The kinetic basis of the increased mispair extension efficiency is due to an improved ability to bind to the incoming nucleotide. Y265W extends the G:G mispair even with an incorrect nucleotide substrate. Overall, our results demonstrate that the Y265 hinge residue is important for stabilizing the architecture of the nucleotide binding pocket of DNA polymerase beta, and that alterations of this residue can have significant impacts upon the fidelity of DNA synthesis.