Current Clinical Pharmacology - Volume 12, Issue 2, 2017

Background: Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection which may result in death or developmental disability. The pathologic processes leading to CM are not fully elucidated; however, widely accepted mechanisms include parasite sequestration, release of infected red blood cell contents, activation of endothelial cells, increased inflammatory responses, and ultimately dysfunction of the neurovascular unit (NVU). The endothelium plays a central role in these processes as the site of parasitized erythrocyte sequestration and as the regulator of fluid extravasation into the central nervous system. Modulating endothelial barrier function at the NVU may provide new therapeutic approaches to improve outcomes in CM. Methods: Here we provide a narrative review of the literature of peer-reviewed research relating to adjunctive therapies for CM. We discuss regulatory pathways of the NVU, with a focus on the potential for pharmacologic modulation of the NVU to improve CM outcomes. Results: Recently licensed pharmaceuticals, developed as therapies for cancer or neurologic disease, could be re-purposed for use as host-directed therapies in CM to target pathways involved in endothelial stability and activation. Conclusion: The findings of this review highlight recently licensed pharmaceuticals that may be developed as future adjunctive therapies for CM.

Background: Nanomedicine, an emerging nanotechnology, imparts special biological features due to its quantum size and is a promising candidate for targeted drug delivery. At present, in spite of its novel applications in medical sciences, certain existing gaps still need to be addressed such as fate of nanoparticles and its toxicity assessment on human health. Behaviour of the entities post human body exposure and its deposition up to certain extent are some of the crucial factors to be considered for a successful treatment approach. Also, safety evaluation applicable for nanomedicine would be drastically different from bulk of drugs due to variation in size and they may respond differently depending upon their property. Due to inadequacy of data, multidisciplinary studies are being encouraged to understand toxicity of nanomedicines and adopt specific testing procedures or modifications in nanomaterials for safe design of nanomedicines. The current review offers a comprehensive understanding on the pressing need of toxicological assessment of nanomedicines, underlying challenges, future prospects followed by regulatory aspects. In a nutshell, the present review aims to provide a thorough compilation and regressive analysis onto safety and toxicity considerations of nanomedicines. Method: Extensive review of literature was conducted from electronic databases such as Medline and EMBASE and other bibliographies. The database was searched for articles from 1974-2017 using search terms "nanomedicines, toxicological assessment, and physicochemical parameters." Various regulatory websites (USFDA, EMA, MHRA, NANoREG, NNI) were also referred regarding the current updates on regulatory framework for nanomedicine. Results: Over 200 articles were identified and referred from which relevant data was selected to be included in the current review. The outcome of the review suggests the presence of existing gaps in the knowledge of toxicity assessment of nanomedicines and it also defines specific areas which should be addressed in the near future. Conclusion: While nanotechnology has gained immense popularity in the research industry due to its improved efficacy compared to traditional counterparts, toxicological considerations and their regulations need to be elucidated. A strategic approach towards toxicological assessment of nanomedicine within the standard set of framework will not only motivate more research on the technology but it will also stir up the conventional drug delivery system.

Background: N-acetylcysteine (NAC) is an amino acid that contains a cysteine group and is currently used widely in various fields of medical research especially in cardiology. In this review, potential benefits of NAC in the aggregation of platelet and reperfusion injury are evaluated. Methods: The available evidence was collected by searching Scopus, Pub-Med, Medline, Cochrane central register of controlled trials, and Cochrane database systematic reviews. Our searching was performed without time limitation and only English language articles were included in this review. Key words used as search terms included “N-acetylcysteine”, “platelet aggregation”, “reperfusion injury”. Results: Over the past decade, several investigations were carried out to ascertain reperfusion injury and antiplatelet properties of NAC, and in this article the results of investigations in both models (human and animal) were addressed in detail. The results revealed that NAC has an important antiplatelet property in animal models while this effect is not very significant in human models and needs more investigations. However, its reperfusion injury in both models is worth noticing. Conclusion: Due to the limited data about effectiveness of NAC in both human and animal as antiplatelet agent, more investigation is needed to evaluate NAC efficacy in platelet aggregation and reperfusion injury especially in human studies in the future.

Background: Ultrasound-guided supraclavicular brachial plexus block (USSB) provides excellent postoperative analgesia after upper extremity surgery. Dexamethasone and clonidine have been added to local anesthetics to enhance and prolong the duration of analgesia. Objective: The objective of this randomized prospective study is to evaluate the efficacy of dexamethasone, clonidine, or combination of both as adjuvants to ropivacaine on the duration of USSB for postoperative analgesia. Methods: Patients receiving USSB for postoperative pain control for upper extremity surgery were randomized to one of four groups; ropivacaine 0.5%, ropivacaine 0.5% with 4 mg dexamethasone, ropivacaine 0.5% with 100 mcg clonidine , or ropivacaine 0.5% with 4 mg dexamethasone and 100 mcg clonidine. Pain scores, sensory and motor function were evaluated at post anesthesia care unit (PACU), discharge and at 24 h postoperatively. Results: The duration of sensory and motor blocks was significantly longer in clonidine groups when compared to ropivacaine alone [Sensorial analgesia: ropivacaine alone 13.4±6, Ropivacaine- Clonidine 17.4±6; Ropivacaine-Dexamethasone-Clonidine 18.8±6.2; Motor blocks: Ropivacaine 12±5, Ropivacaine-Clonidine 16.8±5.2, Ropivacaine-Dexamethasone-Clonidine 18.2±5.7]. In clonidine groups, there was significant prolongation of motor and sensory block when compared to ropivacaine group alone. Conclusion: The results demonstrated that clonidine significantly prolongs the duration of ropivacaine effects for the postoperative analgesia in patient underwent upper arm surgeries.

Background: Aging and oxidative stress seem to play a key role in the onset and progression of ocular surface diseases. Dry Eye Syndrome (DES) is a multifactorial disease of the tears and ocular surface in which symptoms may interfere with the ability to work and carry out daily functions. Methods: This clinical trial was a pilot study to evaluate the effects of supplementation with mixture (Saccharomyces boulardii MUCL 53837 and Enterococcus faecium LMG S-28935) on the tear film. Following the run-in period subjects were randomized in two groups: group A (n.30 subjects) and group B (n.30 subjects). Group A (control) treated only with substitute tear and group B treated with substitute tear + mixture (probiotic). Results: The data obtained in the two study groups A and B were, respectively the following: Schirmer I: 9.2±0.2 vs. 12.8±0.4 (p< 0.001); Schirmer II: 3.6±0.1 vs. 4.6±0.2 (p<0.001); BUT 3.8±0.3 vs. 6.2±0.2 (p<0.001). Culture test showed initial bacterial growth in group “A” (placebo) 27 out of 60 samples tested, corresponding to 45.0% and “B” after treatment (probiotic) was found positive culture whit growth of bacteria in 18 tests equal to 30.0%. The total numbers of isolations of aerobic and anaerobic bacteria found group A and B after treatment. A reduction of 23 to 16 strains of aerobic and anaerobic isolates from 13 to 7 has been found. Conclusion: The administration of probiotics strains was effective in reducing DES. In light of these results, we have identified our probiotic (Saccharomyces boulardii MUCL 53837 and Enterococcus faecium LMG S-28935) activity integration with the action of tear substitutes, along with standardization of clinical parameters of the tear film and microbiological activity in restoring of the microbiota ocular surface subject with DES.

Background: Effect of Heteropterys aphrodisiaca (dog-node) on anxiety and function of adult female wistar mice. The project is an experiment with the use of H. aphrodisiac root extract, in order to observe the frequency of sexual exposure of females exposed to the extract, quantify the effect of the extract on the concentration of total testosterone and observe the anxiety levels of the animals exposed. Results will be measured with the laboratory testosterone test and LCE and CA tests. Methods: In preparation of the extract, the root was oven dried at 40°C and diluted in alcohol extract (100g of root for 1 liter of alcohol) and lyophilized. 40 adult female mice were enrolled, separated in control group (placebo) and treatment group (50 mg/kg/day) for 15, 30, 45 and 60 days. At each period, hormonal testosterone and anxiety levels by the Elevated-Cross Labyrinth (ECL) tests and Open Camp (CA) were measured in 10 animals that were later euthanized (SBNeC). Results: The results showed an improvement in the decrease of anxiety, as shown in the variables of number of open arm entries, time on the same side of the field, less avoidance and leakage. However, it appears that the time of exposure to the extract does not result in increased benefit, with possible decline of effect after 45 days of use. Conclusion: With this performed experiment with the “no-de-cachorro” extract, it was possible to understand a little more how this root can act in relation to anxiety, as predicted by the pharmacology that validates the animal models; anxiolytic components decrease anxiety-related behaviors, as shown in the variables of entry numbers in the open arm, time on the same side of the field, less avoidance and escape. However, it seems that the time of exposure to the extract does not modify the performance in the tests, observing until an apparent exhaustion of the anxiolytic action, which evidences the need for more specific studies on the possible effects of the extract.

Background: Recent studies have shown that antibody titers to heat shock protein 27 (anti-Hsp27) and serum hs-CRP concentrations are elevated in patients with MetS, and may be associated with an increased risk of cardiovascular disease. Crocin is a natural carotenoid with cardio protective effects. Objective: Because of the previous evidence for the beneficial effects of saffron in patients with MetS, this study investigated the effect of supplementation with crocin, the active ingredient of saffron, on serum anti-Hsp27 and hs-CRP in patients with MetS. Design: Sixty subjects with metabolic syndrome were randomized to receive crocin (n=30, 15 mg twice a day) or placebo (n=30, twice a day) for a duration of eight weeks. At the end of study, serum anti-Hsp27 and hs-CRP concentrations were measured and compared between the groups. Results: Serum anti-Hsp27 titers fell by 13% (p>0.05) in the crocin group but it rose in the placebo group by 22% (p>0.05). The magnitude of change in serum anti-Hsp27 titers was not significantly different between the study groups (p = 0.28). In the crocin group, serum anti-Hsp27 changes had a borderline negative correlation with glucose (r= -0.35, p=0.06) and a positive correlation with waist circumference (r=0.39, p=0.035). Serum hs-CRP levels were significantly reduced in both groups but these reductions were not significantly different between the study groups (p = 0.31). Conclusion: There was no significant effect of crocin on serum anti-Hsp27 titers in subjects with MetS, but this needs further confirmation in larger-scale trials.

Background/Aims: A growing body of evidence supports an important role of inflammatory cytokines in the development and progression of the Metabolic Syndrome (MetS), which explains, at least in part, its relationship with an increased cardiovascular-risk. Several studies have reported the therapeutic-impact of crocus-sativus in a preclinical/clinical setting. Here we have explored the effects of crocus-sativus, on the serum concentrations of twelve serum cytokines in subjects with MetS in a randomized control trial. Methods: Forty four adult volunteers, who met the diagnostic-criteria of MetS, were enrolled and randomly divided into 2 groups, to receive 100 mg/day crocus-sativus for 12 weeks. 12 cytokines, including IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, MCP-1, IFN-γ, EGF, and VEGF were measured using sandwich chemi-luminescence assays before/after therapy. Results: Individuals with MetS who received crocus-sativus had significantly (P<0.05) lower levels of total-cholesterol, low density-lipoprotein-cholesterol and triglyceride (TG), fasting-blood-sugar and hsCRP, however the serum concentration of high density-lipoprotein-cholesterol markedly enhanced after therapy (e.g., TG level reduced from 148.86±71.49 to 101.90±38.19 after therapy, P= 0.003). Moreover, we observed that treatment with Crocus-sativus affected the serumconcentrations of some pro-/anti-inflamatory cytokines. In particular, the level of VEGF was increased from 12.64 pg/mL (95% CI: 9.60-17.67) to 16.59 (95% CI: 11.33-35.98, P= 0.033. Similar results were detected for IL-6 and EGF. Conclusion: Our findings provide a novel insight into the therapeutic effects of this therapy in MetS patients via perturbation of serum cytokines and reducing the levels of triglyceride and LDL/TC, but further studies are required in larger populations.

Background: Rheumatoid arthritis (RA) and migraine are both common disorders which are caused by a faulty immune system and autonomic nervous system dysfunction, respectively. Although current treatment outlook has shown a great improvement in these two diseases, however many side effects have been reported. Case Report: We reported a case of 43-years-female that has suffered from rheumatoid arthritis for 3 years with a 6 years history of migraine. She had used different types of medication for both rheumatoid arthritis and migraine but during these 6 years no improvement had been observed and even migraine progression in this patient became worse. She was admitted to the hospital for 12 weeks follow-up to evaluate the effect of β-D-mannuronic acid (M2000) on her RA disease. Materials and Methods: During 12 weeks of M2000 therapy, the signs and symptoms of migraine along with RA indices including Disease Activity Score (DAS28), simple disease activity index (SDAI) and C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), anti-cyclic citrullinated peptide antibodies (anti-CCP) and blood determinants were measured. Results and Discussion: The patient achieved a strong clinical improvement after 12 weeks of M2000 therapy in DAS28, SDAI and laboratory parameters. Moreover, M2000 showed a significant effect on the severity and the duration of migraine pain as well as times of migraine attack. In the present case, both rheumatoid arthritis and migraine as two different inflammatory diseases were diagnosed. Therefore, reducing the inflammation could be a valuable target to decrease the signs and symptoms of migraine and rheumatoid arthritis and help to the treatment process. Conclusion: M2000 as a novel designed non-steroidal anti-inflammatory drug (NSAID) with immunosuppressive property is able to treat migraine in addition to its potent efficacy on treatment of rheumatoid arthritis.