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Before going in details of the ionic mechanisms, few things:Paresthesias can be due to a) Focal Nerve Compression - involves both physical compression of the nerve and some focal ischaemia, and b) Generalized ischaemia -more pronounced form of ischaemia.Paresthesias are known to occur at two incidents in the same sensory neuron: A) During ischaemia, and B) After ischaemia. This sequence is more prominent in general ischaemia (tourniquet effect types).Numbness or conduction blocking is also simultaneously occurring in some afferents. Unlike paresthesias which peak twice, numbness increases steadily. I'm not a 100% sure about this whole simultaneous numbness part but data suggests it happens.The bar indicates the ischaemic period.Now coming back to the mechanisms behind paresthesias.Whether it's due to FNC pr general ischaemia, the underlying mechanism behind paresthesia is 'Ectopic Discharges'.Ectopic discharges, as the name suggests, are spikes of electrical conduction/changes in membrane voltage levels, at a time and place otherwise unwanted.In a clean action potential, the membrane:Depolarizes (voltage rise from -55 mV to +30mV) Na+ channels opening, K+ channels still shut.Repolarizes (voltage drops from +30 mV to -70 mV) Na+ channels are closing, K+ channels are open.Hyperpolarizes (voltage drops further from -70 mV to -90 mV) Na+ channels are closed, K+ channels are still open.Return to resting membrane potential i.e. -70 mV by closing of K+ channels.Image source: mikeclaffey.comIf this is how things proceed, the Na+/K+ pump is said to be working fine.Now what happens during ischaemia is that besides the lack of energy required for the pump to work, there is also increasing accumulation of metabolic byproducts of ischaemia, most importantly of H+ ions. Which in turn affects the pH. These factors lead to an inhibition of the Na+/K+ pump, causing depolarization, called ischaemic depolarization. This triggers the voltage dependent persistent Na+ conductances leading to spontaneous activity perceived as paresthesias. This is the first set of paresthesias in a series of two.The indirect effect of an ineffective pump is accumulation of extracellular K+ which is known to cause persistent K+ currents. After ischaemia is released, there's a rebound, compensatory over-activity of the pump. This causes the second set of paresthesias, which are more sharp/severe than the first set.Electrophysiologically, during the ischaemic phase, following changes are seen:Decrease in Stimulus Threshold.Decrease in sensory action potential amplitude.Increase in refractoriness.Increase in SDTC (Strength-Duration Time Constant, which is a measure of persistent Na+ conductances).After ischaemia is released, all of these values move towards their normal, pre-ischaemic values, in full gusto.This is why the paresthesias during ischemic phase are perceived as low-frequency buzzes whereas those perceived during the post-ischemic phase are high-frequency bursts, sharp and pricking in nature.REFERENCES:Pathophyiology of Paresthesia: Page on intechopen.comChanges in human sensory axonal excitability induced by focal nerve compressionIonic mechanisms for paresthesias arising ... [Clin Neurophysiol. 2008]Elsevier

Stock market fluctuations are too unreliable of an approach to assess an entire industrial sector. Wild speculations apart, something tangible needs to underpin any boom. While Indian Pharma doesn't have upcoming blockbusters, several trends augur its healthy growth.Indian Pharma: Essentially High Volume-Low Value Global Supplier Of GenericsThe world's 3rd largest pharmaceutical industry by volume (10% of global production) but only 14th by value (1.5% of global value) suggests Indian Pharma is a high-volume, low-value proposition (1).A highly fragmented industry with ~10000 manufacturers, though only ~250 are large-scale, generics dominate Indian Pharma (2), contributing no less than 40% of the US generic drug import for example.US FDA drug approvals reveal Indian Pharma doesn't have a strong presence in the US new drug market. Of the 96 new drugs it approved in 2013, only 2 were from Indian companies, Lupin's Suprax (active ingredient Cefuroxime) and Alembic's extended release form of anti-depressant desvenlafaxine (3). Thus, a boom can't be justified on hopes of extremely big paydays down the road from expensive new blockbusters selling on drug markets like the USA or the EU. That's simply not Indian Pharma's track record nor is such a US-like process even likely in India, where the government deliberately intervenes with powerful instruments like price controls and compulsory licenses. Through the latter mechanism, if the Indian government deems an originating firm’s listing price unaffordable, it can force them to license their technology to a generic competitor, an extremely strong countervailing force that, though seldom used, hangs like a Damocles sword over the pricing decisions originator firms make when trying to sell their products in India (2, 4), a situation utterly unlike the rampant drug price gouging that's today the norm in the US. This is why drugs in India are among the cheapest in the world (2). Also why Indian Pharma depends on drug volume not price for its profits.Indian Pharma: Nearing An Inevitable Fork In The Road, Will It Be Super Generics or Biosimilars NextOn the plus side, Indian pharma has built up an enviable infrastructure, with the largest number of US FDA compliant API (Active Pharmaceutical Ingredient) manufacturing plants outside the US (>262), ~1400 WHO GMP-approved plants and 252 European Directorate of Quality Medicines (EDQM) approved plants (1). This capacity has made Indian Pharma a global leader in generics, supplying anti-HIV drugs widely across Africa, Asia, Latin America for example.Long specializing in generics, Indian pharma faces a major fork in the road in terms of how to expand and diversify in an extremely rapidly changing global pharma landscape. In the ongoing Patent cliff, i.e., patent expiration of blockbuster drugs coming off of patent since 2011 continuing through to 2019, bulk of the patent loss on traditional pharmaceutical drugs has already occurred. Far fewer are expected after 2017. Thus the generics market can only remain a high volume-low value proposition for Indian Pharma.To gain value, Indian Pharma has to climb the value chain. Developing new drugs all by itself is an extremely costly proposition with very high regulatory burden. New drug development never having been its expertise, options that best leverage Indian Pharma's existing expertise and capability are super generics and biosimilars.Super Generics represent an incremental innovation to Indian pharma's already well-established generics capability. Though they entail greater regulatory burden, Indian Pharma's making steady inroads into this space (see below from 3, 5).As generics are to patented drugs so Biosimilar are to biologics (6). Indian Pharma is a relative newcomer in the biologics and biosimilars arena. Making biosimilars, while much more arduous and expensive compared to generics (see below from 7), may yield greater long-term payoff in terms of expanding technological capability which could serve as a launching pad for in-house new drug development down the road.The ongoing Patent cliff on biologicals (3, see below from 7) is thus a net opportunity for Indian Pharma to enter the biosimilars sector.Biocon was one of the early entrants, getting approval for its biosimilar CANMab, a remake of Roche's Trastuzumab (Herceptin), a breast cancer drug (8).Indian Pharma: Steadily Increasing Global Reach Through Mergers, Acquisitions & Joint VenturesJoint ventures offer a ready-made platform for global pharma to leverage R&D capabilities of well-established Indian entities as Contract research organization (CRO), which helps to considerably reduce cost of new drug development.In the long-term, expansion of Indian CROs can also help Indian Pharma gain the technological, managerial and regulatory know-how necessary for new drug development, something they currently lack.Indian Pharma's also been steadily increasing its presence in other countries through acquisitions. A 2016 study reported that 67 Indian companies valued at >US $6 billion made 191 acquisitions across 33 countries from 2000 to 2012 (see tables below from 9, 10).Indian Pharma: Serious Teething Problems With Clinical TrialsVast genetic diversity, large 'treatment-naive' population, ~30% urban dwellers with >67 million living in India's 6 largest cities alone plus cost of conducting a clinical trial in India is < 50% of that in the US, all these factors make India an attractive destination for conducting clinical trials. However recent speed-bumps in the form of serious lack of oversight in clinical trial recruitment and informed consent processes (11, 12, 13) have chilled Indian clinical trial activity. A lessons learned mind-set on the part of global pharma and its local regulators and clinical trial partners would help resume trial activity.Indian Pharma: Dwindling Opportunities For Contract Research For API (Active Pharmaceutical Ingredient) Manufacturing For Europe & USAAlong with China, India leads in API manufacture (see below from 14).In their efforts to reduce manufacturing costs in Europe and USA, in recent years their Big Pharma increasingly off-loaded API manufacturing to cheaper sites located in places like India. This meant increased scrutiny from foreign regulatory authorities like the US FDA. Indian Pharma leads the pack in number of US FDA warning letters (15). While these setbacks can be and indeed are being interpreted several ways, a pragmatic interpretation would be to see them as a steep but necessary learning curve for Indian Pharma to effectively compete in supplying essential drugs to the US and the EU. Indian Pharma got here by becoming an expert mass manufacturer of API. However, shoring up manufacturing to meet their more stringent regulatory standards is beneficial in the long-term as it improves Indian Pharma's QA/QC, data integrity and compliance standards. High profile warning letters are also beneficial in highlighting a glaring shortcoming in the Indian Pharma regulatory landscape, namely long-standing, tremendous shortage of well-trained and qualified drug inspectors (16, 17), something the Drug Controller General of India, G.N. Singh himself conceded in Jan 2014 is a situation that desperately needs improving (18).'You cannot equate the Indian regulator with the US one. We are still evolving and it will take us at least 10 years to reach that level. We do not have resources and infrastructure equivalent to those of US FDA. We have a total staff of 650, compared with US FDA's 13,000. Look at the size of our manufacturing industry. The Indian industry is currently supplying generics to over 214 countries.Also, as a national regulator, the steps that we are taking are voluntary. Manufacturing compliance and quality assurance is a state subject.'To add to Indian Pharma's woes,On 16th July, 2015, the European Commission directed all its member states to suspend national marketing authorization of 700 generic drugs tested and approved by GVK Biosciences (19).An early 2016 decision by the US government's made it mandatory for APIs to be manufactured locally for government procurement. According to Live Mint (20), currently ~88% (9 out of 10) of prescriptions dispensed in the US are for generics. India and China are the largest API suppliers to the US. Of the US $2 to 3 billion worth of API that India exports to the US, ~40% is for government purchase so this decision will definitely hit Indian Pharma exports and companies with holdings or subsidiaries in the US.Thus, Indian Pharma outlook looks bright if it leverages its proven generics expertise into expanding into super generics and biosimilars. Becoming a preferred destination as a clinical trials site and an essential cog in the drug supply chain to the US and the EU, however, need more work in improving its compliance and manufacturing to match their more rigorous standards.Bibliography1. Pharma Industry Promotion | Department of Pharmaceuticals2. http://www.pacificbridgemedical.com/wp-content/uploads/2015/04/India-Pharmaceutical-Regulatory-Report-2013.pdf3. Suri, F. K., and A. Banerji. "Super Generics—First Step of Indian Pharmaceutical Industry in the Innovative Space in US Market." Journal of Health Management (2016): 0972063415625566.4. Duggan, Mark, Craig Garthwaite, and Aparajita Goyal. "The market impacts of pharmaceutical product patents in developing countries: Evidence from India." The American Economic Review 106.1 (2016): 99-135. https://openknowledge.worldbank.org/bitstream/handle/10986/23939/aer.20141301.pdf?sequence=1&isAllowed=y5. Stegemann, Sven, et al. "Improved therapeutic entities derived from known generics as an unexplored source of innovative drug products." European Journal of Pharmaceutical Sciences 44.4 (2011): 447-454. https://www.researchgate.net/profile/Willibald_Stumptner/publication/51690038_Improved_therapeutic_entities_derived_from_known_generics_as_an_unexplored_source_of_innovative_drug_products/links/02e7e52a88a1e8e039000000.pdf6. http://www2.deloitte.com/content/dam/Deloitte/us/Documents/life-sciences-health-care/us-lshc-biosimilars-whitepaper-final.pdf7. Daubenfeld, Thorsten, et al. "Practitioner’s Section." Journal of Business Chemistry 13.1 (2016): 33. http://www.businesschemistry.org/downloads/issues/Issue02-2016.pdf#page=378. The Hindu, Jan 18, 2014. Biocon launches cheaper breast cancer drug9. Trehan, A., Gaikwad, A. Indian Pharma Industry: Trends, Predictions and Challenges. Asia-Pacific Biotech News, 2014: 18: 27-44. Asia Pacific Biotech News - PR NEWSWIRE10. Jayanthi, Bhargavi, S. N. V. Sivakumar, and Arunima Haldar. "Cross-border Acquisitions and Host Country Determinants: Evidence from Indian Pharmaceutical Companies." Global Business Review 17.3 (2016): 684-69.11. Tirumalai Kamala's answer to Should we have an international forum to resolve clinical trial mishaps?12. Tirumalai Kamala's answer to Is it true that Bill Gates faced trial in India for illegally testing tribal children with vaccines?13. Tirumalai Kamala's answer to Do western drug companies test more dangerous drugs on the poor in India, and should they be held accountable?14. CHEManager Europe, April 2012. Will API Manufacturing Move out of India and China? http://thomsonreuters.com/content/dam/openweb/documents/pdf/pharma-life-sciences/misc/12-pharma-cmi0412.pdf15. Business Standard, Aneesh Phadnis, May 5, 2016. Indian drug units violate most US pharma regulators' rules16. Kadam, Abhay B., et al. "Correcting India’s chronic shortage of drug inspectors to ensure the production and distribution of safe, high-quality medicines." (2016). http://www.allysonpollock.com/wp-content/uploads/2016/04/IJHPM_2016_Kadam_CorrectingIndiasDrugInspectorsShortage.pdf17. A report on fixing India's broken drug regulatory framework. Dinesh S. Thakur, Prashant Reddy T. June 4, 2016. http://spicyip.com/wp-content/uploads/2016/06/Report_India-Drug-Regulatory-Framework_June-2016.pdf18. Business Standard, Sushmi Dey, Jan 30, 2014. If I follow US standards, I will have to shut almost all drug facilities: G N Singh19. European Medicines Agency - Human medicines - GVK Biosciences20. Live Mint, Reghu Balakrishnan, Shine Jacob, Feb 6, 2016. No major impact on API import ban in USThanks for the R2A, Kritika Gupta.

FOR IMMEDIATE RELEASEPress Releases are alive and well but evolved in the digital ageMarch 10, 2012 (New York City): The relevancy of the press release as a modern communications tactic continues to be strong, even as the formats and channels for how that information is distributed have expanded the creative and strategic options to create it, says one public relations veteran."The idea of a 'formal' press release as outlined in textbooks has always been the focus for old-fashioned communications purists, PR instructors and HR recruiters evaluating young PR talent," says Ian Edwards, a strategic communications expert with 1,000 years experience. "I have always thought sky writing would make a cool press release."Press releases continue to be vehicles to launch new products, announce corporate developments, help manage crises and provide official comments, among many other communications goals. Formal press releases and formal press kits are still important go-to sources for information available in printed forms at, for example, press conferences or archived in online newsrooms as PDFs.Some rough estimates suggest as many as 3,000 press releases are distributed daily by wire services such as Marketwire and PRWeb (http://blog.journalistics.com/2009/how-many-press-releases-are-sent-out-each-day/). The advent of "owned channels" like blogs and Twitter feeds have provided new, cost-free ways to distribute news."Sure, we need to know what elements make a 'formal' press release to effectively convey a news pitch, but we need to remember that any announcement to the media is an invitation to ask more questions -- however that invitation is created," says Edwards."Before social media, we had to write press releases strategically for news value and creativity that would attract attention in busy newsrooms. Just how formally a press release was formatted depended on the audience and that has not changed today. Publicity stunts are a form of press release. Since social media, we have so many more creative options to bring news announcements to a world that has exploded with new end-user audiences beyond media that might be interested in what companies want to make public."Social media platforms such as blogs offer alternative ways to announce news to key audiences, that might include media and might more importantly reach out to tastemakers who influence more focussed and dedicated audiences. A press release is easily transformed into a blog post that can be scanned by search engines and Google Alerts.A good release that considers SEO and audience needs is probably more important than format, says Edwards, and targeting the right audience with the right message has always been the weakest part of press release development."Reporters have generally always had a professional challenge with press releases," he says. "On one hand, it's helpful to be alerted to real, legitimate news opportunities. On the other, it's frustrating to be spoon-fed news from organizations with agendas that are often more about furthering corporate goals than helping the reporters fulfill their objectives of writing real news. I've found most success with news announcements that have a sense of mutuality -- marrying the goals of clients and media so that the objectives for both are met."-30-For more information:Ian Edwards