Dual inhibition: a novel promising pharmacological approach for different disease conditions

To overcome the problems associated with polypharmacy, which include medication non compliance, adverse drug reactions, drug-drug interactions and increased pill-burden, various strategies, such as sustained-release drugs and fixed-dose combination regimens (polypills), have been developed. Out of these, a novel and very much promising approach is the use of dual-action drugs. Amongst the dual-action drugs, there is a class of compounds known as dual inhibitors, which possess the dual inhibitory activity. The most common examples of dual inhibitors are rivastigmine, ladostigil, asenapine, phenserine, amitriptyline, clomipramine, doxepin and desipramine. This review article focuses on the conventional drugs used in different diseases which possess dual inhibition activity as well as those which are still in the preclinical/clinical phase.     

Toll-like receptor 2 is required for control of pulmonary infection with Francisella tularensis

Toll-like receptor 2 (TLR2) deficiency enhances murine susceptibility to infection by Francisella tularensis as indicated by accelerated mortality, higher bacterial burden, and greater histopathology. Analysis of pulmonary cytokine levels revealed that TLR2 deficiency results in significantly lower levels of tumor necrosis factor alpha and interleukin-6 but increased amounts of gamma interferon and monocyte chemoattractant protein 1. This pattern of cytokine production may contribute to the exaggerated pathogenesis seen in TLR2-/- mice. Collectively, these findings suggest that TLR2 plays an important role in tempering the host response to pneumonic tularemia.     

Mucous membrane graft for cicatricial ectropion in lamellar ichthyosis: an approach revisited

A 26-year-old woman with congenital lamellar ichthyosis presented with bilateral cicatricial ectropion of the upper and lower eyelids. There was severe exposure keratopathy with corneal perforation in the left eye. The generalized skin involvement necessitated the use of an alternative to correct the cicatricial ectropion. Mucous membrane graft harvested from the oral cavity was used to correct the cicatricial ectropion of upper and lower eyelid of both eyes. Six months after treatment, the mucous membrane graft was keratinized and a significant reduction in lagophthalmos was seen. Mucous membrane graft offers a promising alternative to correct cicatricial ectropion in lamellar ichthyosis.     

Tocilizumab therapy for persistent high-grade fever in systemic lupus erythematosus: two cases and a literature review

Tocilizumab (TCZ) is a humanized immunoglobulin (Ig) G1 monoclonal antibody directed against the interleukin (IL)-6 receptor. We report on two patients with persistent high-grade fever and systemic lupus erythematosus (SLE) who were treated with TCZ. Two female Chinese patients presented with SLE and high-grade fever, with raised inflammatory markers including C-reactive protein, erythrocyte sedimentation rate, and IL-6, but no signs of opportunistic infections. Their fever and other symptoms responded poorly to broad-spectrum antibiotics, antifungals, antivirals, and glucocorticoids. They were both treated with TCZ. Their body temperatures returned to normal after treatment with TCZ, and other symptoms, including arthralgia, gradually improved. Both patients were followed-up and their conditions remained steady to date. TCZ may thus be an alternative treatment for patients with SLE and persistent high-grade fever who fail to respond to initial antibiotics and high-dose glucocorticoids.     

The Cardioprotective Potential of von Willebrand Disease in Ischemic Heart Disease

von Willebrand factor (vWF) aids coagulation at sites of vessel injury. Elevated vWF levels have been associated with an increased risk of ischemic heart disease (IHD); however, it is unclear whether vWF deficiency, seen in patients with von Willebrand disease (vWD), protects people against IHD. We determined and compared the prevalence and risk of IHD in patients with versus without vWD by using data from the National Inpatient Sample (2009–2014), excluding patients younger than 18 and older than 75 years. The primary outcome was the odds ratio (OR) of IHD in patients with versus without vWD. Secondary outcomes were major medical comorbidities and demographic characteristics in patients with vWD.Of 224,475,443 weighted hospital-discharge samples, we identified 82,809 patients with a vWD diagnosis. The odds of IHD were lower in patients with vWD than in those without (OR=0.54; 95% CI, 0.52–0.56). After multivariable logistic regression analysis and adjustment for age, sex, and typical IHD risk factors (hypertension, smoking, diabetes, hyperlipidemia, chronic kidney disease, obesity, and family history of IHD), the likelihood of IHD remained lower in patients with vWD than in patients without (OR=0.65; 95% CI, 0.63–0.67). Our study shows that vWF deficiency, as seen in patients with vWD, is associated with a decreased prevalence of IHD. Further investigation may confirm these findings.     

Regulatory Potential of Ethanol and Retinoic Acid on Human Monocyte Functions

Retinoic acid (RA), a metabolic product of vitamin A, has been shown to affect a variety of immune functions, including monocytes. Monocyte functions and mediator production are also modulated by ethanol exposure. This study demonstrates that therapeutic doses of RA (0.1–10 μM) significantly increase transforming growth factor- β (TGFβ) production both in THP-1, human myelomonocytic cells, and in human peripheral blood monocytes. We have previously reported TGFB induction by ethanol in human M ø. Combination of RA stimulation with acute in vitro ethanol treatment, however, resulted in significantly lower Mø TGFβ production than TGFB levels induced by RA alone ( p < 0.003). Down-regulation of M ø TGFβ production by ethanol was tested at the concentration range of 25–150 mM and occurred both at high and low RA concentrations (10–0.1μM). In contrast to its inhibitory effect on RA-induced M ø TGFβ production, ethanol augmented TGFB production induced by mura-my1 dipeptide (20 μg/ml), suggesting that ethanol can either up- or down-regulate Mø TGFB production, depending on the costimulatory factors. RA also induced a moderate increase in Mø tumor necrosis factor-α (TNFα) production, which was down-regulated by ethanol both at the level of secreted and cell-associated TNFα. In addition to regulation of cytokine production, both RA and ethanol decreased expression of CD4 on THP-1 cells. The degree of inhibition of CD4 expression by RA was more significant than by ethanol, but RA-induced decrease in CD4 expression was not significantly affected by the combined stimulation with ethanol. These results provide further evidence for the immunoregulatory potential of nutritional and dietary factors, such as RA and ethanol, on the immune functions of human monocytes.     

Delayed infection after instrumented spine surgery: case reports and review of the literature.

BACKGROUND CONTEXT: A delayed infection after instrumented spine surgery can be difficult to diagnose because of its low incidence and variety of clinical symptoms. PURPOSE: To describe four cases of delayed infection after instrumented spine surgery and to review the literature of such cases with regard to the clinical symptoms and risk factors, possible causes of infection and treatment. STUDY DESIGN/SETTING: Personal review of cases and literature review. PATIENT SAMPLE: Four cases in this report and 93 other cases reported in the literature. OUTCOME MEASURES: Not measured. METHODS: Summary of the clinical symptoms, risk factors, causes of infection and treatment regimens. RESULTS: Three possible causes of a delayed infection have been cited: intraoperative seeding, metal fretting causing a sterile inflammatory response or stimulating low-virulent organisms to fester and hematogenous seeding. A variety of clinical symptoms were found, but spontaneous drainage appears to be most common. Many patients had either a fluctuant mass, localized drainage or an abscess. Abscesses or drainage material is typically contiguous with the instrumentation and the fusion mass. Fever was present in only six patients. Effective treatment usually includes removal of the implants, irrigation and debridement, followed by the administration of antibiotics. CONCLUSIONS: A high level of suspicion is needed to diagnose a delayed infection after instrumented spine surgery.