• TO PREVENT MIGRAINE, ASSUMING THAT MIGRAINE ARISES FROM THE BRAIN OCCIPITAL CORTEX, EVERY EFFECTIVE PHARMACOLOGICAL AGENT MUST CROSS THE BLOOD BRAIN BARRIER FREELY OR READILY TO INFLUENCE BRAIN NEURONAL FUNCTIONS.
• THERE IS PRACTICAL PHARMACOLOGICAL EVIDENCE AVAILABLE FROM DECADES THAT ALL EFFECTIVE MIGRAINE PREVENTIVE OR PROPHYLACTIC AGENTS DO NOT CROSS THE BLOOD-BRAIN-BARRIER FREELY OR READILY OR EFFECTIVELY.
• HOW DO SUCH MIGRAINE PREVENTIVE AGENTS ACT? (SEE ATTACHED PAPER)
• WHEN IT BECOMES INCONVENIENT FOR RESEARCHERS TO RESPOND OR TO ADMIT THE ERRORS IN THEIR THINKING, THEY RESERVE THE RIGHT NOT TO RESPOND -- AS IF TAKING THE FIFTH AMENDMENT OF THE AMERICAN CONSTITUTION, AS IS AVAILABLE TO THE DRUG MAFIA AND OTHER ACCUSED WHO STAND BY AS POTENTIAL AND/OR HEINOUS CRIMINALS-ON-TESTIMONY.
• SHOULD SUCH AN ESCAPE CHANNEL BE ALLOWED TO ANY MEDICAL RESEARCHER OF ANY NATIONAILTY OR ANY BACKGROUND?
• DO ALL MEDICAL RESEARCHERS -- INCLUDING ALL MEMBERS OF RESEARCHGATE AND OTHER REPOSITORIES OF MEDICAL RESEARCH KNOWLEDGE -- AGREE TO CONDEMN AND BLOCK SUCH NEGATIVE BEHAVIOUR ON THE PART OF AUTHORS OF PUBLISHED PAPERS BY FORCING EDITORS OF MEDICAL JOURNALS TO RETRACT SUCH PAPERS AND BAN SUCH RESEARCHERS FROM TENURE AND FURTHER OPPORTUNITIES TO HIDE AND DISTORT THE HISTORY OF MEDICINE IN ORDER TO SPOIL THE FUTURE OF HUMANKIND IN TERMS OF MEDICAL CARE AND THERAPY?? (PLEASE SEE ATTACHED HYPERLINK BELOW)
• Bigal ME, Krymchantowski AV. Emerging drugs for migraine prophylaxis and treatment. MedGenMed. 2006;8:31. Available at: http://www.medscape.com/viewarticle/528452 Accessed June 15, 2006. [PMCID: PMC1785190] [PubMed: 16926770]
• BIGAL WORKS FOR THE INDUSTRY. TO WIN A VIEWPOINT OR A PATENT OR A FUTURE PIPELINE PRODUCT UNDER THE FDA SCANNER, THE INDUSTRY CAN DO ANYTHING.
• THE ABOVE AUTHORS CHOSE THE FIFTH AMENDMENT-LIKE FACILITY TO REMAIN SILENT. MY ATTACHED PAPER IN MEDGENMED STARTS WITH THEIR DENIAL CLEARLY. THE EDITOR WAS HELPLESS IN THIS MATTER.
• EMASCULATION OF EDITORS IN SUCH MATTERS IS A HORRENDOUS STATE OF AFFAIRS FOR MEDICAL RESEARCH. 
• TO PROGRESS FURTHER BEYOND THE LIMITS OF TECHNOLOGY, SUCH BEHAVIOUR ON THE PART OF MEDICAL RESEARCHERS OF ANY SPECIALIZATION, INCLUDING NEUROLOGY OR NEURO-OPHTHALMOLOGY MUST BE SEVERELY CONDEMNED AND OSTRACISED.
• Several other very respected researchers have refused to offer comment whenever their own work raises more questions than it can answer (see attached paper AND MY RESPONSE AND THE ABSENCE OF ANY REBUTTAL). THIS IS A FORM OF IMPROPRIETY, A STALLING, PLAYING A WAITING GAME, FRUSTATING THE COMMENTATOR, CONSPIRACY BY SILENCE AND IS CERTAINLY NOT A SCIENTIFIC TRAIT.
• SEE THE NEXT EXAMPLE:  (TEV-48125 for prevention of chronic migraine: Suspension of scientific disbelief

Article · September 2016

1st Vinod Kumar Gupta

43.19 · GUPTA MEDICAL CENTRE

Abstract

Bigal et al. presented a fully-humanized monoclonal antibody selectively binding to calcitonin gene-related peptide as a preventive treatment for chronic migraine (CM). [1] To date, all therapies in migraine/CM have been serendipitous or empirical. TEV-48125 therapy is no exception. Such innovations (drugs or devices) drive the science, not the other way around. [2] Given the pathognomonic protean nature of migraine/CM, initial (1-3 weeks) improvement with such novel therapies will always appear statistically significant in a sub-group (~30%), [1] rarely be clinically meaningful for the primary cohort, and even more rarely be clinically meaningful for management over a sustained period (months or years). No randomized clinical trial (RCT), other than patent foramen ovale-closure, is designed to offer long-term data with a one-time intervention. [2] RCTs for patients with migraine/CM are not reproducible largely because of pathognomonic variability in the measured parameters between patients in a given cohort as well in the same patient during serial attacks. Reproducibility of the RCT is the critically limiting clinical touchstone. [3] Surgical procedures are also not free from the placebo effect. [4] The magnitude of the placebo effect of any intervention (including the subcutaneous injection of TEV-48125) [1] may vary with a patient's past experience, current expectation, and the novelty of the intervention. [2,5] 1. Bigal ME, Dodick DW, Krymchatowski AV, et al. TEV-48125 for the preventive treatment of chronic migraine: Efficacy at early time points. Neurology 2016;87:41-48. 2. Gupta VK. Patent foramen ovale closure and migraine: science and sensibility. Expert Rev Neurother 2010;10:1409-1422. 3. Reality check on reproducibility. Nature 2016;533:437. Editorial. 4. Johnson AG. Surgery as a placebo. Lancet 1994;344:1140-1142. 5. Peck C, Coleman G. Implication of placebo theory for clinical research and practice in pain management. Theor Med 1991;12:247-270. 

 (SEE ATTACHMENT)

• SEE THE NEXT EXAMPLE FOR REFUSAL BY ORIGINAL AUTHORS TO COMMENT:  Vagal nerve stimulation and migraine: A therapy? Vinod K. Gupta, Physician & Director, Migraine-Headache Institute New Delhi, India

Article in Neurology 2016 · September 2016

1st Vinod Kumar Gupta

43.19 · GUPTA MEDICAL CENTRE

Abstract in NEROLOGY (AAN)

Re: "Chronic migraine headache prevention with noninvasive vagus nerve stimulation" Silberstein, et al., 87:5 529-538doi:10.1212/WNL.0000000000002918: Silberstein et al. presented an 8-month study of noninvasive vagus nerve stimulation (nVNS) for prevention of headache in patients with chronic migraine (CM). [1] In primary headache management, "prevention" generally indicates mangament of the patient after return to normalcy in terms of neurophysiology as well as clinical symptoms. With CM, patients likely never become normal."Attenuation" of headache, rather than "prevention," may be more appropriate. There was no statistically significant difference in the number of headache days between nVNS-treated and sham cohorts in the randomized phase over 8 weeks. After another 24 weeks of the open phase, for the 15 completers initially assigned to nVNS, the mean change from baseline in headache days after 8 months of therapy was -7.9 days with a wide confidence interval (-11.9 to -3.8) and unmasking of the nVNS device. Silberstein et al. also concluded that important safety issues needed further study, [1] but none emerged in their noninvasive study. No theoretical explanation was offered for the authors' belief that nVNS has a better cumulative efficacy. Silberstein et al. proposed cortical spreading depression (CSD) as the underlying pathophysiological mechanism for CM. [1] The limitations of CSD have been recently detailed, [2,3] and the need to move beyond neuronal and vascular theories of migraine was clearly set out previously. [4,5] 1. Silberstein SD, Calhoun AH, Lipton RB, et al. Chronic migraine headache prevention with noninvasive vagus nerve stimulation: The EVENT study. Neurology 2016;87:529-538. 2. Gupta VK. Cortical-spreading depression: at the razor's edge of scientific logic. J Headache Pain 2011;12:45-46. 3. Gupta VK. CSD, BBB and MMP-9 elevations: animal experiments versus clinical phenomena in migraine. Expert Rev Neurother 2009;9:1595-1614. 4. Blau JN. Migraine: theories of pathogenesis. Lancet 1992;339:1202-1207. 5. Edmeads J. What is migraine? Controversy and stalemate in migraine pathophysiology. J Neurol 1991;238:S2-S5.