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Is a scenario possible wherein the drug exposure achieved in clinical studies surpass or exceed than the exposure achieved in nonclinical toxicity studies conducted of appropriate duration?
And if so, is the dose selection flawed in that particular clinical study?
And to address that kind of a situation, should more nonclinical toxicity studies be performed that test a higher exposure than what is expected in humans?
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It is possible, but highly unlikely base on current regulatory guidelines. For a given dose value, the human can have a better bioavailability and exposure than the animal model used preclinically. However, the preclinical models are dosed at several multiples until toxicity or maximum acheivable dose is reached. Human Ph1 trials start at a fraction of the NOEL reported preclinically. At these starting doses, exposures are compared to the animal data so guidance is available for the escalating dose studies. So it is unlikely that you would ever be in a position that human clinical trials were achieving exposures that were in excess of any reported for preclinical studies. If preclinical studies are not designed correctly, then it is a possible scenario that clinical doses could provide unexpected exposures but in that case the company has wasted much time and money and should rethink their position as a drug company.
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I want to test something after activation of glycolysis, therefore looking forward to drugs that can activate glycolysis easily. Will inhibition of mitochondria naturally activate glycolysis? If so, pls also provide me info about efficient drugs to do it. Thx a million in advance
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Mitochondrial poisons will increase aerobic and anaerobic glycolisis:
Mitochondrial poisons
 Atovaquone is an antimalarial drug used for the treatment of pneumocystis pneumonia and toxoplasmosis and is FDA approved. At the molecular level it is a potent and selective inhibitor of OXPHOS by targeting mitochondrial complex III, inducing aerobic glycolysis and oxidative stress in cancer stem cells[i], [ii].  Atovaquone decreases the pyrimidine synthetic pathway in P falciparum dependent on mitochondria[iii].
Metformin is the most widely prescribed drug for the treatment of diabetes. Its main mechanism of action is inhibition of mitochondrial complex I, increasing the glycolytic pathway through reduction of OXPHOS. Due to lower production of mitochondrial ATP, the AMP/ATP index increases and activates AMPK which further inhibits mTOR[iv]. Used at high doses it may produce lactic acidosis due to increased lactic acid production.
Phenformin is metformin’s predecessor with similar effects on lactic acid production, but is a more powerful inhibitor of the mitochondrial respiratory chain which entails an increased risk of lactic acidosis. This adverse effect led to the withdrawal of this drug from the market[v],[vi],[vii] .  As the effect we are looking for, is precisely a strong inhibition of lactate oxidation, phenformin may be more appropriate for this purpose than metformin although it is more toxic. Regarding cancer cytotoxicity, phenformin also seems to be more powerful than metformin[viii].
Doxycycline is an antibiotic that exerts inhibition of mitochondrial protein synthesis and reduces mitochondrial complex I activity[ix], [x], [xi], [xii].
All four pharmaceuticals described as mitochondrial poisons have in common their inhibitory activity on OXPHOS and increase in lactic acid production through increased aerobic glycolysis.
Metformin, phenformin and doxycycline are weak inhibitors of mitochondrial complex I and with no effect on the rest of the mitochondrial complexes[xiii], so for a more potent inhibition of the OXPHOS process it would be convenient to associate atovaquone as  an inhibitor of complex III and possible synergistic activity with biguanides. This needs experimental testing.
[i] Fiorillo M, Lamb B, Tanowitz HB et al. Repurposing atovaquone: targeting mitocondrial complex III and OXPHOS to eradicate cancer stem cells. Oncotarget 2016; doi: 10.18632/oncotarget.9122
 
[ii] Fry M, Pudney M. . Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4′-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80). Biochem Pharmacol 1992;43:1545-3. http://www.ncbi.nlm.nih.gov/pubmed/1314606?dopt=Abstract
 
[iii] Hammond DJ, Burchell JR, Pudney M.  Inhibition of pyrimidine biosynthesis de novo in Plasmodium falciparum by 2-(4-t-butylcyclohexyl)-3-hydroxy-1,4-naphthoquinone in vitro. Mol Biochem Parasitol 1985;14:97-109. http://www.ncbi.nlm.nih.gov/pubmed/3885032?dopt=Abstract
 
[iv] Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 2006 Nov 1;66(21):10269-73. Epub 2006 Oct 23
 
[v] Stumvoll, M., Nurjhan, N., Perriello, G., Dailey, G. & Gerich, J. E. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N. Engl. J. Med.1995; 333:550–554.
 
[vi] Pernicova I, Korbnits M. Metformin mode of action and clinical implications for diabetes and cancer. Nature Reviews Endocrinlogy 2014;10:143-156. http://www.nature.com/nrendo/journal/v10/n3/full/nrendo.2013.256.html#ref25
 
[vii] Janzer A, German NJ, Gonzalez Herrera KN, Asara JM, Haigis MC, Struhl K. Metformin and phenphormin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells. PNAS 2014; 111(29): 10574-10579. http://www.pnas.org/content/111/29/10574
 
[viii] Miskimins WK, Ahn HJ, Kim JY, Ryu S, Jung Y-S, Choi JY (2014) Synergistic Anti-Cancer Effect of Phenformin and Oxamate. PLoS ONE 9(1): e85576. doi:10.1371/journal.pone.0085576. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0085576
 
[ix] Du Buy HG, Showacre JL. Selective localization of tetracycline in mitochondria of living cells. Science. 1961 Jan 20;133(3447):196-7. http://www.ncbi.nlm.nih.gov/pubmed/13724526
 
[x] Journey LJ and Goldstein MN. The effect of terramycin on the fine structure of HELa cell mitochondria. Cancer Research. 1963;23:551-554. http://cancerres.aacrjournals.org/content/23/4_Part_1/551.long
 
[xi] de Vries H, Kroon AM. On the effect of chloramphenicol and oxytetracycline on the biogenesis of mammalian mitochondria. Biochim Biophys Acta. 1970 Apr 15;204(2):531-41http://www.ncbi.nlm.nih.gov/pubmed/4315017
 
[xii] de Vries H, Arendzen AJ, Kroon AM. The interference of the macrolide antibiotics with mitochondrial protein synthesis. Biochim Biophys Acta. 1973 Dec 7;331(2):264-75.
 
[xiii] Bridges HR, Jones AJY, Pollak MN, Hirst J. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J, 2014;462:475-487. http://www.biochemj.org/content/ppbiochemj/462/3/475.full.pdf
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If a small molecule is shown to be readily absorbed from the GI tract in pre-clinical studies (rat and dog) - what does this really indicate? How can this information assist in the clinical development of a product?
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Hi. (Systemic) absorption and bioavailability are often used interchangeably. However, there may be a difference between absorption and bioavailability. This can occur in particular in the case of  liver first pass: the compound is absorbed from the gut into the portal vein but is metabolized extensively by the liver before it reaches the site of sample collection (usually a venous return). In other words good absorption is required for good oral bioavailability but good absorption does not always guarantee good bioavailability.
You may realize this for example by dosing radioactive compound and observe that radioactivity is well absorbed, despite poor bioavailability assessed by a specific bioanalytical assay. Let's say you saw this in the rat.
This could be of relevance for clinical development. You may for example expect absorption in human to be as good as in your rat experiment (other data is indicative of passive absorption). If humans are expected to have slower hepatic metabolism than the rat (e.g. quantitative assessment based on in vitro rat and human liver microsome or hepatocyte data), then liver first pass could be  expected to be low in human and both absorption and bioavailability may be high in human. Best.
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Im currently working on writing up a report about the potential safety issues to be considered during the clinical drug development of an analgesic.
Any thoughts / papers / journals I could be referred to in this regards, would be of great help.
Many thanks in advance!
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Thanks Nirmala, this is helpful.
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In order to put together an early Phase II study for a proposed anti-inflammatory analgesic (small molecule); where-in the non-clinical pharmacology data shows the compound works in a variety of pain and arthritis models, what are the possible indications that can be proposed for this study?
My thoughts are:
- Since non-clinical pharmacology data shows a positive effect in a variety of pain and arthritis models - would it be safer to propose somatic pain indications? 
Would ankle sprain be a good proposal? (acute pain)
Or should I use Rheumatoid Arthritis itself as an indication (chronic pain).
For some indications, the primary outcomes are well-defined by the regulatory authorities, and so Im keen on going with the one for which it has already been defined. (not sure which one in this case).
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Dear Kanchan,
I believe that the use in Rheumatoid Arthritis will be the most appropriate and easy approach to pursue after conducting comparisons with positive control to this disease.
To propose the drug as for somatic pain will be very hard and needs more advanced experiments to support such proposal.
Regarding acute pain, experiments with potent positive control such as Tramadol & morphine derivatives are needed for comparisons before proposing the agent as a potent pain killer for chronic pain.
I believe that the authority will consider the drug as a Rheumatoid Arthritis agent.
Hoping this will be helpful,
Rafik
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hi what would be the best methods to assess if a drug has crossed the blood brain barrier and to what extent? thanks. 
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I agree with Mr. Al Hajj answer,  Generally is not easy to measure the entry of drugs concentration  in the brain because the presence of BBB.  The characteristics of the drug to crosses the blood brain barrier, BBB, it has to be a small , unionized and fat soluble . Most conjugated ionized  and conjugated and water soluble drugs can't cross the BBC. You can measure the activity of the drug in vivo and such activity has to be dose related; sleep stopping pain etc...
In vitro you can isolated some r receptors of  brain from animals and you can study the extent of the drug bindings 
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I want to know if cholinesterase should be a routine preoperative test, because I can't find it in the latest guidance (ex. NICE guidance).
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Dear Patricia,
I searched this issue.
I added NICE guide.
Sincerely,
Mehmet, MD
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Teneligliptin was launched in India in 2015. Theoretically, it is supposed to be more potent than other gliptins. However, clinical trials comparing its efficacy with other gliptins are not yet published.
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yes, this drog is available in argentina since 2013/2014. I´ve been searching all about and the majority of data is from japan. I´m development a solid form now to introduce a second product in the argentina market.
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I am trying to determine the type and number of animals which are typically used during the exploratory pre-clinical phases of drug development, particular in relation to the type and number of animals used for pre-clinical assessment of a single drug candidate.
Also are there any established regulatory guidelines as to how many animals are required for such pre-clinical work, perhaps as published by the FDA or EMEA?
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Thanks Michal, very helpful. Much appreciated
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Can anyone suggest Models that can reduce the product's cost in Europe (A vision shared recently by EMEA Executive director Prof G Riso)?
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I agree Brian. major factor is different regulations for registration like, monographs, guidelines, clinical requirements, etc.
although ICH has harmonised the registration format, but still there is lots of different requirements, which hampers the timely development and approval of the products.
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hi i wanted to ask, if i am developing a novel drug that targets a gene expressing a signalling protein in the mid brain, how can i test to establish how selective the drug is to binding to the gene?thanks
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It pretty much depends on the molecule you are referring to. In any case, good literature indicated by Beatrice. 
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While selecting a drug and its dosage form for its in vitro dissolution method development and validation by HPLC, what are the things to kept in mind? 
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HiMs.Madhavi
In spite of all as a general consideration feasibility is the major factor you need to keep in mind. It includes what you need and what you have in all aspects and the level of your research along with the outcome which has to be compared with them.
In addition I hope the following link may give you some information related to what  you are looking for.
Wish you Good Luck 
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A new class of cholesterol drugs - the PCSK9 inhibitors - might reduce the risk of heart attacks and strokes, and some trials were recently presented demonstrating these evidences, but we do not have large populacional studies really showing it? What do you think?  Is longer the time for regulatory agencies release this group of medications for regular use of the population?
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PCSK9 inhibitors target and inactivate a specific protein in the liver. Knocking out this protein, called proprotein convertase subtilisin kexin 9, dramatically reduces the amount of harmful LDL cholesterol circulating in the bloodstream. The results of three clinical trials involving PCSK9 inhibitors were presented at the annual meeting of the American College of Cardiology, and simultaneously published in the New England Journal of Medicine, suggest that these may be a very useful drug for dyslipidemia. The trials show that PCSK9 inhibitors are extremely powerful cholesterol-lowering agents. In all three trials, all of the participants took a statin. Half got a PCSK9 inhibitor (either evolocumab or alirocumab) every two to four weeks; the other half got a placebo. After a year, LDL levels were 60% lower in the PCSK9 groups.
As with all drugs, there are downsides. At least for now, PCSK9 inhibitors which are basically developed as monoclonal antibodies, must be given by injection every 2 to 4 weeks. Neurocognitive problems, such as mental confusion or trouble paying attention, were seen in some of the study participants. And regarding cost, CVS officials have estimated that a year’s worth of treatment could cost as much as $7,000. 
PCSK9 inhibitors are still experimental drugs. The three trials presented at the American College of Cardiology meeting were designed to look at how well the drugs lowered LDL, not how well they prevent heart attack, stroke, and other cardiovascular problems. Other trials now underway aim to do just that. The FDA can’t begin to evaluate whether PCSK9 inhibitors should become part of the cholesterol-lowering armamentarium until after the results of these trials have been presented and published, and better information is available about the drugs’ side effects.
Among the ongoing phase 3 trials, one is Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial which is basically a double-blind, randomized, placebo-controlled, multicenter study assessing the impact of additional LDL-cholesterol reduction on major cardiovascular events when evolocumab (AMG 145) is used in combination with statin therapy In patients with clinically evident cardiovascular disease. Estimated time for this study completion is February 2018. Another one is Trial Assessing Long Term Use of PCSK9 Inhibition in Subjects With Genetic LDL Disorders (TAUSSIG) trial whose estimated time foe completion is January 2020. 
If approved, these drugs would probably be used first in people who don’t respond to statins or who develop side effects from them. But because it appears that PCSK9 inhibitors reduce the risk of heart attack and other cardiovascular problems in those taking a statin, combining a statin and a PCSK9 inhibitor may be a good option for people at especially high risk for cardiovascular disease. We’ve never before had medications that can reduce LDL cholesterol levels this much. Time will tell if PCSK9 inhibitors safely prevent heart attack and stroke. Thus, let us hope that the trials will eventually come out with promising results, so that regulatory agencies can grant approval as early as possible to control widespread surge of dyslipidemia and associated cardiovascular and cerebrovascular accidents.
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Does your research promise a significant health-related breakthrough sometime in the future?
I’m trying to compose a timeline that projects new treatments and preventatives over the next century.
I’m interested in preventatives and treatments for all health problems including ones we don't yet suffer from.
The closer these events are, the better we can predict when and if they’ll make an impact, but I'm interested in the lot (and the fuzzy logic behind the predictions).
I've asked a similar question recently and I got a single good answer - but surely there's more than just one forward thinking researcher out there!
1. Have you heard of any health innovations that may become big next 100 years?
2. When are these expected to go 'mainstream' and why then?
3. Any predictions on impact size?
4. Do you have any references? They don’t need to be academic, but academic Is better.
5. Any other thoughts?
6. Do you want to receive this data once I’ve compiled it?
Thanks
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Jan
I know of two potentially major "breakthrough" projects that have been in existence for over a decade  and shown good promise but have not advanced so it's easy to expect they will take another few decades.
One is zolpidem for brain damage, all explained on this website : https://sites.google.com/site/zolpidemtherapy/home  A proportion of patients with brain damage of all causes respond with SPRCT scans showing new brain activity within infarctions plus clinical responses in stroke patients.  This is a unique effect since no other GABA agonist has this effect (such as zopiclone and zaleplon).
A second project is Colostrinin(R) which I suggest you search for by Google.  It is the only project that has worked well in several models of the pathology of Alzheimer's Dementia plus one placebo-controlled clinical trial.  There is a good review of its mechanisms of action by Boldogh and Kruzel in Journal of Alzheimer’s Disease 13 (2008) 303–321.  
Both these treatments are known to be safe. Both are available now at low cost, ie less than a UD dollar a day, so it is a huge tragedy that so many patients are not getting them.  The reasons for being stalled are many but lack of patents is a major one.  High cost of phase 3 type trials is another. Thirdly, investors see pharmaceuticals as very high risk.  Fourthly, academics in basic sciences see them as "old hat" or clinicans are constrained by health care budgets.  Your new breakthroughs will need to avoid all of these pitfalls, I think.
Cheers
Andy Sutton 
.
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We are interested in an investigator-driven treatment study in children in Switzerland and would like to use amoxicillin versus placebo.
We have some problems finding the amoxicillin placebo (suspension and tablets or even better dispersible tablets). Does anyone have any idea?
Thanks for your help.
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good question,
In Spain,some Hosptial Pharmacy unit, manufacture medicines for clinical trials without comercial interest. and i know that exist some independent labs that manufacture medicines for clinical trials
 Kind regards
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What are different chemicals (carcinogens) and its protocols to induce myeloid leukemia in animal model (rat/mouse)? 
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You can find more reference, if you want by tyrosine metabolite p-hydroxyphenyllactic acid.
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I am searching for function of SNP id rs11560324. How to know whether it has been already published?
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dbSNP is a good start.  It could be the SNP you are looking is not published but it is in linkage disequilibrium to a SNP which is functional and have been published.  In this case, I will first look up what are the other SNP in LD to it using SNPA Proxy Search <https://www.broadinstitute.org/mpg/snap/ldsearch.php> to identify those LD SNPs, and then look them up in the dbSNP to see whether they are published.   Hope this is helpful.
Good luck!
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I am interested in seeing if anyone is aware of any specific testing methodologies or assays which might be used to detect specific side-effects in the early stage of drug development? Again does the FDA or EMEA have anything to say on the matter?
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Hello Andrew,
This is a very vast subject. The side-effects may vary from target to target. Therefore, it is more of scientific judgement. One theory, can't be applied to all cases.
There is a lot of literature available on this as how to progress with various in silico, in vitro and in vivo approaches. The ICH and (http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html) and EMEA (http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000397.jsp&mid=WC0b01ac058002956f) guidelines explain the duration of studies or type of sudies required.
I have also a recent publication in Journal of Applied Toxicology (Drug Safety testing paradigm: current progress and future challenges, an overview) on this topic.
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Drug induced Liver Injury is responsible for up to 30+ of project terminations in clinical development. Me and my team are developing a personalized cell model to investigate individual DILI.
Recent Terminations include Lilly's LY2886721 which caused Liver Enzyme Elevations.
Has anyone information on some more terminated candidates and their commercial availability?
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Also, you could check http://www.livertox.nih.gov/ web-site where you could find the hepatoxicity of the drugs on the market and the attached paper for drug-induced hepatoxicity where you could find the drugs recently withdrawn from the market due to the hepatoxicity.
Another web-site for withdrawn drugs and the reason of the withdrawals: http://www.ganfyd.org/index.php?title=Drug_withdrawals
Hepatoxic Drugs:
Statins and Other Lipid Lowering Drugs: Atorvastatin, Fluvastatin, Lovastatin, Pravastatin, Simvastatin, Fenofibrate, Gemfibrozil and Niacin; Oral Hypoglycemics: Acarbose, Pioglitazone, and Rosiglitazone; Anti-seizure Drugs: Carbamazepine, Felbamate, and Valproic Acid; Anti-fungal Drugs: Itraconazole, Ketoconazole, and Terbinafine; Drugs for Tuberculosis: Isoniazid, Pyrazinamide, and Rifampin; Immunosuppressants: Azathioprine, and Methotrexate; Antiretroviral Drugs: Ritonavir, Nevirapine; and others: Acetaminophen, Amiodarone, Diclofenac, Halothane, Leflunomide, Methyldopa.
Of course you could easily find the APIs (active pharmaceutical ingredients) which are hepatoxic but sold as a drug on the market. For the others, you could check commercial availability and sources from SciFinder. I use it very often and it is very helpful.
Best regards,
Esen
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While making dilutions of a drug from stock to working, I have been using cell culture media (which is without serum). I used to make the dilutions fresh, but I cited a protocol which says they made dilutions in complete cell medium, which means they added serum to the drug dilutions. I don't think this should be done, because the drug may get entrapped in serum proteins and interact. Moreover, such dilutions cannot be stored at -20 C. Is there anyone who can enlighten me as to whether the addition of serum is appropriate or not?
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Firstly serum wears off after sometime and thus it is not advisable to prepare drugs in serum for storage. Depending on the solubility of the drug, you should prepare and aliquots higher stock concentration and only dilute with the media in which the cells grow when you are about performing your assay. As said above, it does not make any difference whether the drugs are made with or without serum since in the end, the media of the cells if it contains serum will be much greater than your drug solution. Besides, the cells are supposed to survive naturally in the normal media first before the active ingredients in the drug kills them. Depriving them of a necessary requirement implies hampering their normal growth and might skewed your results.
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I think that analysis of particle size & shape using optical microscope should be included as one of the tests in the official monographs(e.g, BP & USP) for oral suspensions. I have seen during my work in drug quality control field that such test is important and can explain the physical characters of different oral suspensions & can help to confirm that the suspension passes or fails the pharmacopoeial requirements. What do you think ?
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Thank you for your opinion Dr. Teodoro, but my question is that why can't we include such test for oral suspensions while it is already present in the British Pharmacopeia (for example) as a routine test for many injectable and ophthalmic suspensions? moreover, from my experience, it is not a tiring procedure and takes only 1 or 2 drops from the liquid suspension to study the size and nature of particles and can be done on multiple containers (if required) to get reliable statistical data from a certain batch.
Best regards
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Seeing first hand all the different reactions patients have to medications and how these reactions can differ wildly when using the generic version of a medication. How can a medication be called a generic version if the adverse events experienced differ so much from the original medication? Could this be due to the other agents present in the medication and not the principal agent itself?
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Generic drugs are required by law to be bioequivalent to the brand name product, however, they can use different excipients, binders and other inert ingredients. The variable adverse reactions could be due to these changes, even though the generic gives the same blood levels.