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VOL.  18     ISSUE:  11    November  2020 Medical Services Department

SQUARE Pharmaceuticals Ltd.



Drug for HCM !





P G Dip. Business Management



Rubyeat Adnan




Dear Doctor,

Welcome to this edition of 'e-SQUARE' !

Hope that you are enjoying this online healthcare bulletin !

In this issue, we focused on some interesting features like -

"Melatonin & COVID-19 !", "Internal Clocks !", "Western diet !", "Drug Discovery !",  "COVID-19 Complications !", "Drug for HCM !".

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

We appreciate your feedback !

Click on to reply mode.

Yours sincerely,


Editorial Team

Reply Mode      : e-square@squaregroup.com

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

Melatonin & COVID-19 !

                                                Melatonin- blessing for COVID-19 treatment

Study suggest that melatonin, a hormone that regulates the sleep-wake cycle and is commonly used as an over-the-counter sleep aid, may be a viable treatment option for COVID-19. As COVID-19 continues to spread throughout the world, particularly with cases rising during what some have termed the "fall surge," repurposing drugs. Researchers identify possible drugs for COVID-19 repurposing has revealed melatonin as a promising candidate. Analysis of patient data from Cleveland Clinic's COVID-19 registry also revealed that melatonin usage was associated with a nearly 30 percent reduced likelihood of testing positive for SARS-CoV-2 after adjusting for age, race, smoking history and various disease comorbidities. Researcher said that it is very important to note these findings do not suggest people should start to take melatonin without consulting their physician. Large-scale observational studies and randomized controlled trials are critical to validate the clinical benefit of melatonin for patients with COVID-19. Researcher found that proteins associated with respiratory distress syndrome and sepsis, two main causes of death in patients with severe COVID-19, were highly connected with multiple SARS-CoV-2 proteins. Overall, they determined that autoimmune diseases showed significant network proximity to SARS-CoV-2 genes/proteins and identified 34 drugs as repurposing candidates, melatonin chief among them. Researcher said that recent studies suggest that COVID-19 is a systematic disease impacting multiple cell types, tissues and organs, so knowledge of the complex interplays between the virus and other diseases is key to understanding COVID-19-related complications and identifying repurposable drugs.

SOURCE: Science Daily News, November 2020

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Internal Clocks !

                                      Internal clocks drive beta cell regeneration

Certain parts of our body, such as the skin or liver, can repair themselves after a damage. Known as cell regeneration, this phenomenon describes how cells that are still functional start to proliferate to compensate for the loss. For the past 30 years, scientists have been investigating the regenerative potential of beta cells, pancreatic cells in charge of the production of insulin. Beta-cell population is indeed partially destroyed when diabetes occurs, and regenerating these cells represents an outstanding clinical challenge. By studying diabetic mice, scientists from the University of Geneva (UNIGE) and the University Hospitals of Geneva (HUG), observed that this regeneration mechanism was under the influence of circadian rhythms the molecular clocks regulating metabolic functions according to a 24-hour cycle of alternating day-night. In addition, the scientists identified the essential role of the core clock component BMAL1 in this process. Compensatory proliferation, in which cells begin to actively divide to replace those that have been damaged, is a biological mechanism that is both well-known and poorly understood. To explore the connection between internal biological clocks and beta cell regeneration, researcher team first observed two groups of mice with only 20% beta cells remaining after targeted massive ablation. Mice in a first group were arrhythmic, whereas the control group had perfectly functional clocks. "The result was very clear: the mice bearing dysfunctional clocks were unable to regenerate their beta cells, and suffered from severe diabetes, while the control group animals had their beta cells regenerated; in just a few weeks, their diabetes was under control. By measuring the number of dividing beta cells across 24 hours, the scientists also noted that regeneration is significantly greater at night, when the mice are active.

SOURCE: Science Daily News, November 2020

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Western diet !

                               Western diet impairs odor-related learning and olfactory memory in mice

Problems with the sense of smell appear to be an early indicator of cognitive decline in people with type 2 diabetes. However, it's unknown whether factors such as diet and obesity play a role in who develops these symptoms. Now, researchers found that mice fed a moderate-fat, high-sugar chow (simulating a Western diet) showed a faster decline in their ability to learn and remember new odors. Some people with type 2 diabetes (T2D) show signs of olfactory dysfunction, including problems with detecting, discriminating or recalling odors, or even a complete loss of smell. These symptoms are strongly associated with cognitive impairment, and evidence suggests they could be an early indicator of the condition in people with T2D. Obesity, which is the main risk factor for T2D, has also been associated with olfactory dysfunction, but the impact of obesity on the sense of smell specifically in these patients is unclear, as studies have produced conflicting results. Also, it's unknown whether certain nutrients in the diet, such as fat and sugar, affect the sense of smell. To find out, researcher wanted to compare the effects of two diets on different olfactory functions in mice: a high-fat, moderate-sugar diet (HFD); and a moderate-fat, high-sugar diet (similar to a Western diet, WD). In mice, both diets cause obesity and T2D-like features. At one, three and eight months, the team performed tests to assess different olfactory functions in the mice. By eight months, both the HFD- and WD-fed mice had impaired odor detection, odor-related learning and olfactory memory compared with the control mice. However, the WD-fed mice had a faster decline in the latter two abilities, showing olfactory dysfunction as early as 3 months after beginning the diet. These findings indicate that a high dietary sugar content, rather than hyperglycemia or weight gain, is linked with early deterioration of olfactory functions related to learning and memory, the researchers say. How sugar causes these effects, and whether they are also seen in humans, the researchers acknowledge, remains to be determined.

SOURCE: Science Daily News, November 2020

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Drug Discovery !

                                              Ion channel inhibition to open doors in drug discovery

Scientists have discovered how drug-like small molecules can regulate the activity of therapeutically relevant ion channels and their findings could transform ongoing drug development efforts. A major mechanism by which cells communicate with their environment is the movement of metal ions through channels located within their cell membranes. Researcher provides detailed insight into the regulation of TRPC5 ion channels, which allow positively charged ions such as calcium, sodium and potassium to flow in and out of cells. TRPC5 channels are considered potential therapeutic targets for the treatment of a range of conditions, including anxiety, kidney disease and cardiovascular disease. Researcher said that using cryo-electron microscopy performed to determined high-resolution structures of the TRPC5 channel in the presence and absence of Pico145. These structures show, for the first time, how Pico145 can displace a lipid bound to each of the four TRPC5 proteins. Further studies revealed the importance of individual amino acid residues in the Pico145 binding site of TRPC5. Many diseases are linked to defects in ion channel function, so controlling the opening and closing of specific ion channels is a highly successful therapeutic strategy. But drug discovery efforts are often hindered by gaps in understanding of how drug-like small molecules can be designed to control ion channel activity. The opening and closing of TRPC channels is regulated by many factors, including dietary components such as lipids, minerals and antioxidants, as well as environmental toxins. Over activity of TRPC channels is linked to a range of diseases. Therefore, small molecules that can stop TRPC channels from opening are increasingly considered as potential therapeutic agents. Researcher have done a lot of work to understand how xanthines regulate TRPC channel activity & represent a break-through that may provide new, rational approaches to the development of drug candidates that target TRPC channels. In addition to its relevance to drug discovery, their study also provides new insights into how physiological and dietary factors such as lipids and zinc ions may regulate TRPC channels.

SOURCE: Science Daily News, November 2020

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COVID-19 Complications !

                                              COVID-19 linked to silent hypoxia

Scientists are still solving the many puzzling aspects of how the novel coronavirus attacks the lungs and other parts of the body. One of the biggest and most life-threatening mysteries is how the virus causes "silent hypoxia,”. To help get to the bottom of what causes silent hypoxia, BU biomedical engineers used computer modeling to test out three different scenarios that help explain how and why the lungs stop providing oxygen to the bloodstream. The researchers first looked at how COVID-19 impacts the lungs' ability to regulate where blood is directed. Using a computational lung model, researcher tested that theory, revealing that for blood oxygen levels to drop to the levels observed in COVID-19 patients, blood flow would indeed have to be much higher than normal in areas of the lungs that can no longer gather oxygen contributing to low levels of oxygen throughout the entire body. Next, they looked at how blood clotting may impact blood flow in different regions of the lung. When the lining of blood vessels get inflamed from COVID-19 infection, tiny blood clots too small to be seen on medical scans can form inside the lungs. They found, using computer modeling of the lungs, that this could incite silent hypoxia, but alone it is likely not enough to cause oxygen levels to drop as low as the levels seen in patient data. Last, the researchers used their computer model to find out if COVID-19 interferes with the normal ratio of air-to-blood flow that the lungs need to function normally. This type of mismatched air-to-blood flow ratio is something that happens in many respiratory illnesses, such as with asthma patients, Suki says, and it can be a possible contributor to the severe, silent hypoxia that has been observed in COVID-19 patients. Their models suggest that for this to be a cause of silent hypoxia, the mismatch must be happening in parts of the lung that don't appear injured or abnormal on lung scans. Altogether, their findings suggest that a combination of all three factors are likely to be responsible for the severe cases of low oxygen in some COVID-19 patients. By having a better understanding of these underlying mechanisms, and how the combinations could vary from patient to patient, clinicians can make more informed choices about treating patients using measures like ventilation and supplemental oxygen.

SOURCE: Science Daily News, November 2020

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Drug for HCM !

                                        New drug for HCM (Hypertrophic Cardiomyopathy) reduces heart mass

For the first time, a medication has impacted heart muscle thickness and function for patients with the most common inherited heart condition, rather than simply addressing their symptoms. Researcher said that, this is the first study to show a favorable impact of a medication on cardiac structure and function in any form of hypertrophic cardiomyopathy. They also don't affect any of the heart structural abnormalities that define the disease: thickness of the heart muscle, resultant stiffness and abnormalities in other cardiac structures. A medication designed specifically for HCM, mavacamten, is currently being studied in a variety of clinical trials. It’s part of a new class of drugs called cardiac myosin inhibitors. The medication works by blocking a protein called myosin from interacting too much with other motor proteins, which then allows the heart muscle to squeeze and relax more normally. It is effective at reducing obstruction to blood flow within the heart that can occur with the disease. The primary measure for this study, the mass of the heart, was significantly reduced in those patients taking the drug as opposed to those taking placebo. Patients showed improvements in markers like exercise capacity. Researcher team observed these encouraging results after just 30 weeks of treatment, which would be a plus for patients. Patients originally had a very high ejection fraction, but after treatment it moved into the normal range. Although HCM is considered a rare disease, it affects about one in 500 people. So there's a large need for more effective therapeutics. The EXPLORER-HCM trial was a phase three trial that studied the use of mavacamten in obstructive HCM, and has moved into a five-year open-label extension. A concurrent phase two trial, MAVERICK-HCM, investigated safety and tolerability in non-obstructive HCM. Those participants are also in the five-year open-label extension study now.

SOURCE: Science Daily News, November 2020

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New Products of SQUARE Pharmaceuticals Ltd.

  Product Valmor TM    
Generic Name Sacubitril & Valsartan

50 & 100 gm

  Dosage form Tablet
Therapeutic Category Angiotensin Antagonist Combination with other drugs
  Product Ultivent™ Cozycap 
Generic Name

Glycopyrronium + Indacaterol

Strength Glycopyrronium 50 mcg and Indacaterol 110 mcg
Dosage form Dry Powder Inhaler (DPI) Capsule
Therapeutic Category Anticholinergic + β2 Stimulan
  Product D-BalanceTM 
  Generic Name Cholecalciferol EP
  Strength 200000 IU
  Dosage form Injectable Solution (Oral/IM)
Therapeutic Category Vitamin & Minerals

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