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VOL.  16     ISSUE:  3  March    2018 Medical Services Department

SQUARE Pharmaceuticals Ltd.





P G Dip. Business Management







Dear Doctor:

Welcome to healthcare bulletin "e-SQUARE" !

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This issue features a variety of articles including "Antibiotics & Cornea !", "3-D Printing !", "Immunotherapy & Tumor !", "Mumps Resurgence !", "Hypertension & Gene !", "Malaria !".

In our regular feature, we have some products information of SQUARE Pharmaceuticals Ltd. as well.

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The views expressed in this publication do not necessarily reflect those of its editor or SQUARE PHARMACEUTICALS LTD.

 Antibiotics & Cornea !

                                                      Administering antibiotics through the cornea

The anatomic and physiologic structure of the eyes constitutes by itself an important barrier when administering medicine. The amount of medicine that passes through the cornea by applying creams or drops is very limited and it is necessary to develop alternative, more effective ways of administering them ocularly. Researchers at the Pharmacy Department of the CEU Cardenal Herrera University have published the design of a new bio adhesive ocular insert which is placed inside the eyelid and releases a larger amount of medicine through the cornea in a controlled way in the international journal Drug Delivery and Translational Research. Specifically, lead researcher has developed this new insert for the ocular administration of the antibiotic moxifloxacin, which is applied in cases of bacterial infections of the eyes such as corneal queratitis or bacterial endophthalmitis. Less than 5% of the medicine administered in this way manages to penetrate the eye in an effective way due to eye defense mechanism (Tear). Therefore, pharmaceutical research aims to develop ocular inserts, very thin cylinders or discs made of bio adhesive polymeric materials, which adapt to the shape of the eye and release the medicine through the cornea in a controlled manner. The lead researcher has developed and analyzed the efficiency of different types of inserts, using bio adhesive polymers with different physicochemical characteristics to compare them to discover which one could obtain the optimal degree of permeability to administer moxifloxacin. The research has made it possible to develop a very thin, practically transparent insert which is easily adhered to the ocular mucosa, providing larger concentrations of moxifloxacin through the cornea than other administration formats currently commercialized, such as orally.

SOURCE: HealthDay News, March 2018 

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 3-D Printing !

                                                       Live 3-D printing of osteogenic scaffolds into bone defects

Severe traumatic injuries to the cranium have been challenging to heal due to the large missing bone volume. Typically, metal or plastic implants are used. But, these implants can take a long time to be customized for fit and often take a longer than desired time to support bone fixation. This can often lead to multiple revision surgeries if the defect is not properly healed. Moreover, the tissue that adjoins the implant can improperly heal. For the effective treatment of these defects and injuries, it is necessary to reduce the time and improve the accuracy of implantable bone scaffold substitutes. Further, the microarchitecture and materials chemistry of the scaffold must enhance tissue regeneration and growth to hasten the healing process. The efficacy of bone scaffold substitutes is limited by the rate of bone formation, scaffold-defect mismatch and scaffold displacement during implantation. However, additive in-situ 3D printing can overcome these limitations by printing scaffolds that conform to the dimensions of the defect site. The biosilica-biopolymer scaffold was prepared by mixing Laponite (Lp) with methacrylated gelatin (MAG). Sucrose was used to increase viscosity and reduce gelation of the printing ink. IRGACURE 2529 was used as a crosslinking agent. During printing, crosslinking was initiated by UV light at the tip of the printer nozzle and scaffolds were in-situ 3D printed directly into calvaria bone defects using varied Laponite concentration to determine optimal bone density and chemical structure. Scaffolds were fabricated into a mesh design with dimensions matching that of formed defects and after four weeks, cranial bone samples were extracted. Evaluation by micro-CT showed that nearly 55% of the bone defect was healed after four weeks for higher Lp- rich-MAG scaffolds versus lower Lp-containing MAG scaffolds. Empty control defects only had 11% of the defect filled with bone after four weeks. Histological staining showed that the scaffolds recruited cells into their structure to regenerate the intra-bony layers needed to initiate the healing process. The results showed that 3D in-situ printing of bone regenerating scaffolds did improve the delivery of regenerative and reconstructive biomedical devices for the proper and rapid healing of bone fractures. The method allows for the absorption of blood and growth factors into the scaffold as it is being constructed within the defect. This provides an advantage in that cells from within the initial hematoma become incorporated into the scaffold structure, thus, giving the operator flexibility to use the printed scaffold as a structural support that stimulates healing.

SOURCE: HealthDay News, March 2018

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 Immunotherapy & Tumor !

         Immunotherapy at site of tumor surgery prevents tumors from returning

A new study by Dana-Farber Cancer Institute scientists suggests it may be possible to prevent tumors from recurring and to eradicate metastatic growths by implanting a gel containing immunotherapy during surgical removal of a tumor. In the study, published online today by Science Translational Medicine, researchers removed breast tumors from mice and placed biodegradable gels containing an immune-stimulating drug in the resulting empty space. The gels released the drug, which switches on a key type of immune cell, over an extended period of time. When researchers examined the animals over the next several months, they found that this approach cured a much higher proportion of mice than delivery of the drug by other techniques. Not only did the original tumors not recur in the breast, but metastatic tumors in the lungs far away from the site of drug delivery were eliminated as well. The lead researchers say the findings, which were duplicated in mice with lung cancer and melanoma, hold immense promise for overcoming two of the greatest obstacles to curing cancer: the tendency of the disease to recur in patients who have undergone surgery to remove solid tumors and the difficulty in eradicating distant metastases. The goal of the new approach is to convert that immunosuppressive environment into an "immune stimulatory" one, the lead researcher says, a condition in which the immune system is primed for an offensive against cancer cells. In the study, the researchers loaded a hydrogel, a half-inch disc made of a biodegradable sugar naturally found in the human body with drugs that activate dendritic cells. Dendritic cells are part of the innate immune system the body's first responders to foreign intruders or diseased cells. The hydrogel, placed in the spot where the tumor was removed, releases the drug over an extended period of time, lengthening the window of effectiveness. When the dendritic cells are activated, they train T cells their allies in the adaptive arm of the immune system to attack cancer cells anywhere in the body, whether at the site of the original tumor or distant metastases. The benefits of this approach to treatment appear to be enduring. Three months after the mice underwent the treatment, they didn't have a recurrence. When the lead researcher injected fresh breast cancer cells in the side opposite the original tumor site, the disease didn't recur in any of the mice, as the cancer was rejected by the immune system's memory.

SOURCE: HealthDay News, March 2018 

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 Mumps Resurgence !

                                     Mumps resurgence likely due to waning vaccine-derived immunity

A resurgence of mumps in the U.S. among vaccinated young adults appears to be due to waning of vaccine-induced immunity, according to a new analysis from Harvard T.H. Chan School of Public Health. The lead researcher found that vaccine-derived immune protection against mumps persists an average of about 27 years after the last dose. The findings suggest that, in addition to the currently recommended two doses of mumps vaccine in childhood, a third dose at age 18 or booster shots may help sustain protection among adults. This analysis helps address a persistent question surrounding the recent mumps outbreaks, pointing to the key role played by waning vaccine induced immunity, and helps frame the research and policy questions on how best to control mumps, the lead researcher added. After the mumps vaccine was introduced in the mid-1960s, mumps incidence in the U.S. and other developed countries declined for decades. After recommendations for children to receive a second vaccine dose were issued in 1989, sustained reductions in mumps incidence led to optimism that vaccination could eliminate the disease from the U.S. in the long term. But recent mumps outbreaks, including on college campuses, began occurring among vaccinated young adults around 2006 and have continued to the present. The resurgence is troubling, the authors wrote, because mumps infections may cause complications such as testicular inflammation meningitis, and deafness. Since cases have predominantly occurred in vaccinated populations, the mumps resurgence has prompted questions about what's to blame either waning immune protection from the mumps vaccine or new strains of the mumps that evade vaccine-driven protection. In contrast, the lead researcher found no evidence that new strains of mumps virus are contributing to changes in vaccine effectiveness. Moreover, their model suggested that new strains would not be expected to cause cases in age groups affected by recent outbreaks.

SOURCE: HealthDay News, March 2018

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 Hypertension & Gene !

                                                        Specific gene region in hypertension revealed

Genes encode proteins and proteins dictate cell function. Therefore, the thousands of genes expressed in a cell determine what that cell can do. Among the multiple elements that are involved in the precise regulation of gene expression are enhancers, which are short region of DNA that can be bound by proteins to increase the likelihood of transcription of a particular gene. One notable regulatory cascade that involves enhancers is the renin-angiotensin system (RAS) that plays a major role in blood pressure regulation and electrolyte homeostasis. Because increased expression of the protein renin leads to a rise in blood pressure, its transcription must be finely regulated. While upregulation of the gene renin in the promoter and enhancer elements is relatively well established, the mechanisms controlling its feedback transcriptional suppression are poorly understood. Gene deleted either in 5 or 3 regions of the endogenous mouse renin (mRen) in mice, and placed the animals in a hypertensive environment. While the mRen gene bearing the 3 region deletion was appropriately downregulated, the one bearing the 5 region deletion (-5E) lost hypertension responsiveness, explains by lead researcher. This means the -5E region is essential for the basal expression of the mRen gene. Based on their findings, they proposed the -5E element functions as an enhancer under normal conditions and is involved in full activation of mRen gene transcription. Conversely, in the hypertensive state, the enhancer activity somehow becomes attenuated by the hormone angiotensin signaling, which leads to suppression of mRen gene transcription. Understanding of this enhancer-mediated transcriptional modulatory mechanism for mRen gene has a broad impact on not only the RAS field but also enhancer biology in general. Also, as the mRen enhancer core sequence is fairly conserved in humans, these findings shed light on the unexplored distal regulatory region of renin genes and provide a novel mechanistic insight into renin gene regulation.

SOURCE: HealthDay News, March 2018

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 Malaria !

                Identifying the deadliest strains to design a childhood vaccine

Researchers have identified a genetic fingerprint associated with the most deadly strains of malaria parasites, making these unique DNA regions potential targets for vaccine development. An international research team led by the University of Melbourne found a small group of proteins was associated with the most severe strains of malarial infections, which are often fatal in young children who have not yet had a chance to develop a strong immune response to the parasite. To better understand this difference, we compared the parasites causing the most severe malaria to parasites that cause uncomplicated or mild disease, which can be resolved by the immune system. Each parasite has 60 of these genes that are different to other parasites and each gene is a mosaic of parts that can be shuffled to create new genes. The parasite also shuffles through the genes it uses like a pack of cards, thus appearing like different strains able to hide from our immune system. The lead researcher used RNA sequencing to sample parasites isolated from the blood of 44 adults in a location in which malaria is endemic in the state of Papua, Indonesia. Twenty three of these people had severe malaria. The lead researchers then compared 4662 pieces of var genes that were being expressed in severe cases, against those expressed in mild cases. The lead researcher showed that only 20 to 30 of the thousands of var genes were being expressed at a higher rate in patients with severe malaria than uncomplicated malaria. These 20-30 var gene pieces included many not previously investigated but also all of the proteins associated with severe malaria in India and Africa were also more highly expressed in the severe cases in Papua, suggesting that this small group of deadly proteins is highly conserved around the world, providing the promise of new targets for vaccine design. The lead researchers are now looking to test children in malaria-endemic regions of Africa, the group by far the most at risk from malaria death, to see if the novel deadly proteins they found in Papua are also present there.

SOURCE: HealthDay News, March 2018

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New Products of SQUARE Pharmaceuticals Ltd.

  Product Cefotil TM Plus PFS
  Generic Name Cefuroxime Axetil + Clavulanic Acid
  Strength (125 mg+31.25 mg) /5ml
  Dosage form PFS
  Therapeutic Category Cephalosporin Antibiotic
  Product Olistat TM
Generic Name



60 mg

Dosage form Tablet
Therapeutic Category Antiobesity
Product Efaxim TM
Generic Name Rifaximin
Strength 200 mg
  Dosage form Tablet
Therapeutic Category Antidiarrheal

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