Tadalafil Improves L-NG-Nitroarginine Methyl Ester-Induced Preeclampsia With Fetal Growth Restriction

By academic.oup.com

We investigated the efficacy and mechanisms of tadalafil, a selective phosphodiesterase 5 inhibitor, in treating preeclampsia (PE) with fetal growth restriction (FGR) using L-NG-nitroarginine methyl ester (L-NAME)-induced PE with FGR in pregnant mice as our experimental model.

METHODS

C57BL/6 mice were divided into 2 groups 11 days postcoitum (d.p.c.). A control group of dams (C dam) received 0.5% carboxymethylcellulose (CMC). A L-NAME-treated group received 1 mg/ml L-NAME dissolved in CMC. The L-NAME-treated dams were divided into 2 subgroups 13 d.p.c. One subgroup continued to receive L-NAME (L dams). The other subgroup received L-NAME with 0.08 mg/ml tadalafil suspended in CMC (TL dams). Maternal systolic blood pressure (SBP) and proteinuria were assessed 16 d.p.c. Fetal weight was recorded, and placentas and maternal kidneys were collected 17 d.p.c.

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RESULTS

Maternal SBP, proteinuria, and fetal weight were improved for TL dams compared to L dams. The placental concentration of placental growth factor (PlGF) was higher for TL dams than for the C and L dams. The placental maternal blood sinuses of L dams were narrower than those of C dams, but those of TL dams improved to a similar width as C dams. Glomerular oxidative stress was ameliorated in TL dams compared to L dams.

CONCLUSIONS

Tadalafil dilates the placental maternal blood sinuses, which leads to increase PlGF production, and contributes to facilitate fetal growth and improve maternal SBP. Moreover, tadalafil ameliorates glomerular damage by reducing oxidative stress. These results suggest that tadalafil is a candidate for treatment of PE with FGR.

Source: https://academic.oup.com/ajh/article-abstract/doi/10.1093/ajh/hpx130/4061455/Tadalafil-Improves-L-NG-Nitroarginine-Methyl-Ester

Improving antibiotics to treat staph infections

By sciencedaily.com

New information about how antibiotics like azithromycin stop staph infections has been uncovered, including why staph sometimes becomes resistant to drugs. Staphylococcus aureus (familiar to many as the common and sometimes difficult to treat staph infection) is a strain of bacteria that frequently has become resistant to antibiotics, a development that has been challenging for doctors and dangerous for patients with severe infections.

In research published in Proceedings of the National Academy of Sciences, assistant professor of biochemistry and molecular biology at Saint Louis University Mee-Ngan F. Yap, Ph.D., discovered new information about how antibiotics like azithromycin stop staph infections, and why staph sometimes becomes resistant to drugs.

Her evidence suggests a universal, evolutionary mechanism by which the bacteria eludes this kind of drug, offering scientists a way to improve the effectiveness of antibiotics to which bacteria have become resistant.

Staphylococcus aureus (familiar to many as the common and sometimes difficult to treat staph infection) is a strain of bacteria that frequently has become resistant to antibiotics, a development that has been challenging for doctors and dangerous for patients with severe infections.

Yap and her research team studied staph that had been treated with the antibiotic azithromycin and learned two things: One, it turns out that the antibiotic isn’t as effective as was previously thought. And two, the process that the bacteria use to evade the antibiotic appears to be an evolutionary mechanism that the bacteria developed in order to delay genetic replication when beneficial.

The team studied the way antibiotics work within the ribosome, the site where bacteria translates the genetic codes into protein. When the bacteria encounter a potential problem in copying its genetic material, as posed by an antibiotic, it has a mechanism to thwart antibiotic inhibition by means of “ribosome stalling” that is mediated by special upstream peptide elements.

As the bacteria’s ribosome copies the strings of genetic code, “ribosome stalling” at upstream elements often promotes the rearrangement of messenger RNA and activates downstream translation of the resistance gene.

Many resistant pathogens exploit this mechanism to up-regulate antibiotic resistance genes, and so survive even in the presence of antibiotics. In effect, the delay allows the bacteria to prepare a defense against the antibiotic further down the line of genetic code.

Yap found that the azithromycin-bound ribosomes do not simply stall at random residues, but only at specific sites. Intriguingly these residues seem to be the preferred stalling site in the “ribosome stalling” peptide elements that stop genetic activity.

“Here we describe, to our knowledge, the first genome-wide snapshot of ribosome distribution along messenger RNAs in Staphylococcus aureus,” Yap said. “By globally mapping the position of stalled ribosomes in azithromycin-treated staph, we identified the proteins affected by this antibiotic.

“Our results reveal a striking similarity of stalling motifs that strongly suggests a universal stalling mechanism,” Yap said. “We have identified what appears to be an evolutionary mechanism developed by bacteria to counteract the type of antibiotics that includes azithromycin, called macrolides.”

Yap hopes this new understanding of how antibiotic resistance occurs will offer opportunities to improve existing drugs’ effectiveness and give doctors more tools to help patients with severe infections.

Source: https://www.sciencedaily.com/releases/2015/01/150123135108.htm

 

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Treatments with Viagra (Sildenafil citrate) for erectile dysfunction in male patients aged more than 18 years old with multiple sclerosis

By ncbi.nlm.nih.gov

Erectile dysfunction (ED) is a common sexual disease in male patients with multiple sclerosis (MS). Viagra (Sildenafil citrate) is considered as an effective drug forĀ  the treatment of ED in the general population, but it has not been systematically reviewed in patients with MS.

This review tried to assess its efficacy and safety in patients with MS. Among the pertinent literature, two studies, involving a total of 420 ED patients with MS, were identified. Both trials compared orally administered Viagra versus placebo up to 4-12 weeks.

The authors find limited evidence to support Viagra as an effective treatment to improve erectile function and quality of life at a short-term follow up. Adverse events were also reported: the most common were headache, flushing, rhinitis, visual disturbances and dyspepsia, but two patients suffered serious adverse events during Viagra treatment including one with coronary artery disease requiring triple bypass surgery and one with a cerebrovascular accident.

Objectives: To assess the efficacy and safety of sildenafil citrate for ED in patients with MS.

Search methods: We searched the Cochrane (November 2011), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4 of 4, 2011), MEDLINE (PubMed) (January 1966 to November 2011), EMBASE (January 1974 to November 2011) and the China Biological Medicine Database (CBM) (1979 to November 2011). We searched trials registers and conference proceedings and contacted pharmaceutical company and authors of included studies for additional data. There were no language restrictions.

Selection criteria: Randomised controlled trials comparing sildenafil citrate with placebo or no treatment for ED in patients with MS.

Data collection and analysis: Two review authors independently selected articles for inclusion, extracted data and assessed trial quality. Disagreements were resolved by discussion between review authors. Authors of included studies were contacted for additional information. Results were presented as relative risks (RR) or mean differences (MD) with 95% confidence intervals (CI).

Main results: Two randomised controlled trials involving a total of 420 patients were identified. Both trials investigated the short-term efficacy and safety of sildenafil citrate for ED in patients with MS. Patients taking sildenafil citrate were more likely to improve their ability to achieve and maintain an erection measured by International Index of Erectile Function and achieve vaginal penetration ( (RR 1.28, 95%CI 0.92 to 1.78) and complete intercourse measured by Sexual Encounter Profile diary (RR RR 1.38, 95%CI 1.00 to 1.90). and receive A global well respond measured by Global Assessment Question (RR 2.72, 95%CI 1.40 to 5.28) was reported. One trial showed sildenafil citrate is effective in quality of life improvement, while the other trial did not find any significant difference between both groups. Both included trials were judged as high risk of attrition bias. Adverse events were also reported: the most common were headache, flushing, rhinitis, visual disturbances and dyspepsia. Two patients suffered serious adverse events: one with coronary artery disease requiring triple bypass surgery and one with a cerebrovascular accident.

Authors’ conclusions: There is limited evidence to support sildenafil citrate as an effective treatment for ED in patients with MS. Future well designed randomised, double blinded, placebo-controlled trials with long-term duration are needed.

Source: https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0041574/