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In the article titled "FDOPA-(18F): a PET radiopharmaceutical recently registered for diagnostic use in countries of the European Union", two half-lives are reported for FDOPA.
"6-fluoro-(18F)-L-dopa is removed according to a bi-exponential kinetic process with biological half-lives of 12 hours (67-94 %) and 1.7 - 3.9 hours (6-33 %). Both these half-lives appear to be age-dependent. The 18F-activity is excreted through the kidneys, 50 % with a half-life of 0.7 hours and 50 % with a half-life of 12 hours.
On basis of these data, a biokinetic model for 6-fluoro-(18F)-L-dopa was developed. This model assumes that 100 % of the 18F activity is homogeneously distributed in the body and eliminated through the kidneys with biological half-lives of 1 hour (50 %) and 12 hours (50 %). This model was considered to be independent of age."
What does this mean?
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David Salehi Thank you for your recommendations. I will certainly have a look at them.
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Someone was taking Daflon 500 mg (450 mg Diosmin, 50 mg Hesperidin) twice daily for her varicose veins. Now, the manufacturer makes Daflon 1000 mg (900 mg Diosmin, 100 mg Hesperidin).
Now, the Q is, if she takes the new dosage form 1000 mg once daily, will this dose be equivalent to 500 mg once daily or the pharmacokinetics and the therapeutic effects will be different?
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based on a double-blind, multicenter, RCT comparing 1,000 mg tabs vs 500 mg tabs (same daily dose) in acute hemorrhoid, the authors concluded that "We have been demonstrated that the new single MPFF 1000 mg tablet has clinical acceptability and a good safety profile, comparable to that of MPFF 500 mg tablets. MPFF 1000 mg was as effective as MPFF 500 mg in reducing anal pain and bleeding. The new dose regimen should lead to better treatment adherence and consequently to better management of hemorrhoidal disease."
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I have 2 concentration time curves of a subcut drug implant. the first group has a peak around the 50 day mark where as the second group does not. Both groups received the same implant by the same surgical procedure. If the AUC for group 1 (1018 ng.days.ml-1) is larger than group 2 (800.9 ng.day.ml-1) over the same amount of time, can you assume that the implant in group 2 has more drug left in it compared to group 1?
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The difference between both groups AUC may be due to batch to batch variation if all other factors are kept constant as stated. The reported AUCs for both groups ranges from 800 -1018 ng.days/ml. They may not be statistically different. @ Dr Bellantone, thanks for your contribution, but just to point out that (F) is for bioavailability and not fraction absorbed (fab) just to save confusion in the readership.
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I have in vitro dissolution data for generic drug and I want to predict in vivo pharmacokinetics parameters, please suggest me free software tools or high quality R packages that can achieve this. Also please share suitable keywords I can use to search on this topic other than In- Vitro In Vivo Correlation (IVIVC)!
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Hello,
The best software isn't free. It's expensive. You can try the PKMP trial version https://aplanalyst.com.
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When I viewed the PK parameters of both warfarin and candesartan, I found that both medications have 99% plasma protein binding. I then went to check and confirm there will be PK interaction through resources and I was surprised when I found no interaction! So can it be? Any explanation?
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Hi
Conclusion about no interactions probably cover lack of meaningful PD observations see:
" Candesartan cilexetil produced a 7% decrease in trough plasma warfarin concentration but this had no effect on prothrombin time. "
So in some cases pharmacokinetic interaction can exist but have no impact on clinical findings. Probably this is why you find conclusions about lack of interaction. Finally protein binding in blood plasma not must be most important aspect of interactions between both drugs
from another hand:
" Candesartan had no effect on S-warfarin 7-hydroxylation. In contrast, S-warfarin inhibited candesartan metabolism by the wild-type (K = 17microM) greater than by the Leu359 variant (Ki = 36 microM). These findings suggest that CYP2C9*3 may change not only the metabolic activity but also the inhibitory susceptibility compared with CYP2C9*1. "
Best regards
Tomasz
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Is there any reference/Book/Software that shows only the pharmacokinetic parameters of all medications available? For example, if I want to know the absorption, metabolism of acetaminophen, I should open the monograph in this reference and see all the information I need, the same goes for omeprazole, cetirizine, any medication. Is there such a resource/reference?
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Hi
To be onest from my point of view best are FDA documents related to specific drug submission its better than any database (for example drugbank https://go.drugbank.com/drugs/DB00341) ....
for example
google, key words: fda cetirizine pharmacokinetics accedata
Or maybe such books will be better
Best regards
Tomasz
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  • What is the time taken for steady state to be established in adults for ( Mycophenolate mofetil ) ?
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Please bear in mind that there is a large interindividual variability in the bioavailability and therefore the plasma concentration of parent mycophenolate and active metabolite. The variation can b as large as 30%. You may consider checking the plasma concentration in critical cases.
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I appreciate your comments on the topic above.
Attached is an abstract which suggests the existence of an arteriovenous concentration difference, and that 'peak venous plasma concentrations generally occurred at 1 to 5 minutes after injection'. The abstract also states that 'the plasma concentration-time profile after an intravenous blous injection actually resembles that predicted for a short term intervenous infusion'. Is that your experience?
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please I want to ask in this context is it essential for any intravenously given drug as bolus to start with high concentration followed by gradual decrease in its concentration
as i saw in some research papers that after iv bolus of sedative agent their was gradual increase in concentration
as at 1 was low then at 3 it become higher then decrease
is it is acceptable
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Clinical pharmacokinetic evaluation of plasma samples via HPLC after drug extraction process.
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I am agree with Dr. Grabowski. You should focus on sample extraction methods (unfortunately, it is hit and trial process), if you have satisfactory chromatogram of your drug.
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If someone has been taking Candesartan 4 mg one tablet daily for a year and want to take Diclofenac 25 mg for occassional pain, How can I eliminate the interaction between both (Aside from monitoring blood pressure and renal function)? Is there a way where I can separate the interaction. I read that half life of diclofenac is 2 hours so can he take Candesartan after 2 hours from ingesting Diclofenac or it (Candesartan) already in the blood as he has been taking it for a year, so the interaction will inevitably occur?
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Just have a look at candesartano drug-drug interactions at the link below
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Dear all,
Could you please recent Textbooks on drug-drug interactions covering all or most aspect of this issue.
Thanks
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Hi Ahmed
I think these books may help to find your queries
1. Drug-drug interactions in pharmaceutical development/ [edited by] Albert P. Li : Wiley,2008.
2.Drug-drug interactions /edited by A. David Rodrigues: Informa Healthcare,2008.
3. Drug-membrane interactions: analysis, drug distribution, modeling/ Joachim K. Seydel and Michael Wiese: Wiley,2002.
4. Meyler's side effects of drugs: the international encyclopedia of adverse drug reactions and interactions/ editor, J.K. Aronson: Elsevier,2016.
5. Drug facts and comparisons
6. Drug-Drug interactions with an emphasis on psychiatric medications / Sheldon H Preskorn: Professional Communications,2018.
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Is it after reaching the steady state concentration (3-5days) or it may take more days to reach the maximum effect for atrial fibrillation control?
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Hi,
After administration of one XL capsule, plasma flecainide concentrations gradually increase after a lag time of 2 to 3 hours to reach a peak between the 21st and 25th hour and remain at plateau levels until after the 30th hour.
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Aren't we suppose to see the peak effect after 4-5 half lives of the drug? After reaching the Css? I did view the drug monograph, and it states that the peak effect is seen after 6 hrs not after 4-5 days with once daily dosing?
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ACE-inhibitor may have delayed response due to physiological intermediates (not only due to its long half-life). The physiological mediators of the blood pressure fall (due to angiotensin converting enzyme inhibition) are angiotensin (rapid effect) and sodium (slow effect). It can take at least a week to see the full blood pressure lowering effect because of the long half-life of sodium.
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Dear all,
Following the FDA guidance (attached file), safety of metabolites should be tested depending of its exposure at the steady state in human.
"Human metabolites that can raise a safety concern are those formed at greater than 10 percent of total drug-related exposure at steady state".
My concern is about the calculation of metabolic and total drug exposure. Should I use AUC0-24h ? AUClast ? AUCinf ? Should I consider the half-life of the analytes to choose the best AUC ?
Results can differ a lot depending on what kind of AUC I use.
Thank you for your help
Benoit
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Thank you William. Good point.
Best regards
Benoit
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How is this possible ? One of the images shows that the first dose didn't produce the therapeutic effect !! Aren't we suppose to feel the effect even after the first dose ? Isn't the first dose suppose to cross the MEC ?
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Gee, you'd best ask a clinician that. They get feedback from their patients as to onset of effects. Probably varies amongst the various anxiolytics and patients.
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Isn't Css the same as the plasma therapeutic level ? Because if so, in the case of Acetaminophen, just one dose of 500 mg would reach the Css, and there would be no need for 4-5 half life ?
if we want to reach the Css from one dose(Loading dose), we will use this equation Dose (Oral)=Vd*Css divided by the Bioavailability. Here are the info. The volume of distribution is about 70 L for someone who weigh 70 K.g and the oral bioavailability is about 70%, and the therapeutic level is 10 to 20 mcg/mL so a simple calculation would yield 500 mg to be the dose which is common in practice. So, how is this possible ? Aren't we suppose to reach the Css after 4-5 half life, not just from one dose ? Am I getting this right ? Or there is a difference between the therapeutic level and the Css ?
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Mostafa,
Note that Css is the steady state level that is reached after several half-lives following regular multiple dosing. The therapeutic level is simply the blood concentration that will result in a therapeutic response which (for certain drugs) can be reached just from a single dose.
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Will they have the same magnitude of therapeutic effect ? Or do I have to check for bioequivalence studies before choosing the brand name ?
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I think we need to remember we are treating a patient. If the person really needs a treatment we should not deny them simply because we can't find the same brand. Most of the time the differences between brands are smaller than the differences between individuals, so It is entirely logical to give the patient a trial of a different brand and to watch what happens. So, my recommendation is to switch brands ( my own GP does it all the time) but ensure that the patient knows and is on the lookout for any differences that could be due to a change in pharmacokinetics such as an initially more intense effect (eg: Higher Cmax in an antihypertensive) or delayed effect (Later Tmax).
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Do all drugs need to achieve the steady state concentration after 4-5 half life in order to see the therapeutic effect ? Doesn't ibuprofen produce its effect from a single dose without 4-5 half life ?
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Half life is the time duration required by a drug to get reduced in plasma by half of its initial concentration. For example if the plasma concentration is 100mg now what time it will take to remain 50 mg then 25mg and so on. A drug needs 4-5 half life toget elliminated or excreted completely from body not to acheive a steady state . Actually steady state is an equlibrium mantained by frequent doses of drugs. A single dose may acheive a minimum effective concentration in plasma and effects will be observed but a single dose will not acheive the steady state concentration.
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Take this example (Bisoprolol is the mentioned example ) : assuming that 5 mg is the minimum effective dose
dosing with 5 to 20 mg, and mean peak values range from 16 ng/mL at 5 mg to 70 ng/mL at 20 mg. So 5 mg dose will give a range of concentrations that are therapeutically active ranging from 16 ng/ml to 8 ng/ml , etc.. So how they are equating both terms minimum effective and minimum effective concentration although 5 mg will give a range of concentrations that will be active not like mec which is below which no activity ?
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Minimal effective concentrations is obtained 5mg so the response will be produced but the magnitude of effects is dependent on receptor occupied whileincreasing the dose to 20mg will raise the plasmaconcentrationof the drug that will occupy most of the receptors so the magnitude of effects will be increased .
further you can read from the Katzung basicand clinical pharmacology or further elaborate your question.
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Lets say drug X and drug Y possess the same active ingredient and dose...So my Q is, can all the brand names in the market be used as alternatives to each other with no worries of bioavailability ? or Brand names didn't undergo bioequivalence studies ?
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For any market
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According to the attached image, no therapeutic window is there with regard to diclofenac potassium, because the maximum tolerated dose ( 150 mg/day PO ) is the same as the minimum effective dose ( 50 mg PO 3 to 4 times daily. ) for pain management?
Or there is something I miss, and the minimum effective dose isn't 150 mg (50 three times per day)?
And I have another Q, if there is hepatic impairment, it is said to initiate therapy at the lowest dose, so isn't 50 mg (3 times per day) the lowest dose possible with regard to pain management?
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I think Diclofenac potassium is not at all a drug of choice for oral intake to give relief from pain. It is generally used at local application as a pain reliever due to probable toxicity in oral use.
Paracetamol is the drug of choice for oral use to relief pain, as far my knowledge goes. As the Pain center and Thermo-regulatory center are staying very near in Hypothalamus, interaction in effects are seen in almost all the drugs used in related purposes.
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Would you consider exceeding the "Maximum Dosage" section within websites as overdose? Or there could be overdose even within the normal therapeutic window?
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Acetaminophen toxicity is related to the toxic metabolite that forms when the conjugation enzyme systems in the liver become saturated and N-Acetyl imidoquinone (NAPQI) is formed from the excess drug by the CYP3A4 and CYP2E1 enzymes.
This compound will bind to any available protein and thereby cause serious long term liver damage.
Glutathione can preferentially bind NAPQI if it is available, thereby reducing the levels sufficiently to avoid fulminant liver failure later. To increase the levels of reduced glutathione the patient can be treated with NAC which can also act as a NAPQI scavenger.
Acetaminophen is the most common drug reported for overdosing as it is easily available and also present in many formulations where its presence is not always known.
There are good reviews on acetaminophen toxicity, just search for them on the web.
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How do you calculate?
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Dear Mostafa,
In principle PK (drug concentrations) drives PD (drug effects). The relationship between the two PK/PD can be more or less complex. You may be interested in the following article:
Gabrielsson et al 2010, J Pharmacol Toxicol Methods (2010), 61(2), 146-156: Optimising in vivo pharmacology studies—Practical PKPD considerations
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When modelling parent and metabolite pharmacokinetics it's assumed that the volume of distribution of the metabolite is same as that of the parent drug. Why this assumption?
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In terms of pharmacokinetic modeling, the reason this assumption is made is to avoid issues of model identifiability. If you have access to Peter Bonate's textbook on PKPD modeling and simulation, browse the first chapter to understand this, The underlying concept here is that - Volume is a proportionality constant that relates amount in a compartment to the concentration (Amount/Concentration). E.g., after an IV bolus dose, when we are dealing with the central compartment of the parent, we know the "true" amount of parent drug in that compartment, but the amount of parent being converted into metabolite is at best an estimate given the data we have. As it is an estimate, we never know the "true dose" that is going into the metabolite compartment without which the volume term becomes unidentifiable, and hence it is for convenience assumed to be equal to that of the parent. 
Volume is a proportionality constant that relates amount in a compartment to the concentration (Amount/Concentration). E.g., after an IV bolus dose, when we are dealing with the central compartment of the parent, we know the "true" amount of parent drug in that compartment, but the fraction (fm) of parent being converted into metabolite is at best an estimate given the data we have. As it is an estimate, we never know the "true dose" that is going into the metabolite compartment without which the volume term becomes unidentifiable, and hence it is for convenience assumed to be equal to that of the parent. Note that even if you don't make this assumption during your modeling work, the software will spit out a volume estimate, but you have to acknowledge that  the estimate is Vm/fm, where fm is the fraction of parent drug metabolized to metabolite, 
Two cases where you can estimate the volume of the metabolite - 1) if you know the true clearance of the metabolite, for which one has to conduct a study where the metabolite is given directly as a dose and you measure the "true" clearance of the metabolite. You can then use this "true" metabolite clearance in the parent-metabolite model to estimate the volume. 2) if your parent drug is 100% metabolized, then the fraction fm will be 1 and the volume can be identifiable. 
Note: This discussion above assumes that the parent drug is given via IV route of administration where bioavailability, F is 100%. If F <100 %, it adds to the complexity. 
Hope this helps!
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Hi!
I am testing a new compound on colorectal cancer cell lines and I want to compare it's efficacy with the standard drug utilized in the treatment, which is the 5-FU. What concentrations should I use? I am using plasmatic concentrations found in blood samples collected from patients in treatment 2-3 hours after the infusion, are those concentrations considered clinically relevant? 
Thanks in advance.
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I  think to IC50  you can use in experiment
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I tried to measure my drug sunitinib 0.1mg/kg (0.07mM)samples in mice plasma and used an internal stranded verapamil 50nM and made a calibration standreds from 1nM to 3000nM but the problem is in some samples I GOT NO peaks and also the intercept was negative so please can you help me in addressing the problem
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Dear Ella 
Absence of peaks may be due to column blockage or autosampler needle blockage.check for any carryover or extend your chromatographic run.try to change to any c18 100mm,5micron column.Use 1mm ammonium acetate with acetonitrile as mobile phase ideally it should elute faster in the column using high organic mobile phase.check for your ion source for proper spray.
Good luck
Kannadhasan
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Dear Researchers,
From Pharmaceutical point of view: Could it be possible to have liposomal form of certain protein to be delivered to the brain or not? What is the practical issues related to developing this?
Can we guarantee a 100% of drug protein delivery through BBB?
 
 Best 
Mohammed 
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So far only a very low percentage of administered dose of liposmally entrapped protein can cross the BBB. Liposomes need to be surface decorated with BBB targeting molecules , e.g. antibodies versus transferin receptor or insulin receptor. For further information check literature by W. Pardridge or R. Boado   
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We have started our research on TPMT phenotyping in Azerbaijani population. Alongside with Red blood cell TPMT activity we also perform quantitative determination of TPMT concentrations in serum. There is very short information on quantitaive testing of TPMT concentrations in the litearture. We would be grateful if anybody could provide information about prior experience or report with the aforementioned  method.
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Hi Chingiz, I am curious to know the reason for determination of TPMT in plasma .
As far as I know TPMT is an intracellular enzyme and it's the rationale to get phenotypic information from RBC.
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I'm working with a compound and wanted to determine how much of that parent compound is excreted (unchanged) trough urine and feces after the oral administration. I found some articles have done this work but haven't mentioned the methodology.
If you have any experience and suggestions, please share.
Thank you.  
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Thank you Ahmed.
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I am purifying my mushroom using Anion exchange Column DEAE Sephadex A50. The problem is that when I elute it with 1 M NaCl, the column is compressed. I am not sure if this is normal or should I do something about it. 
Although I am in start of developing protocol but i feel that I might be getting some resin in my product (not sure why my product weigh more as if its actually resin or I haven't completely dried it). I am using Dithenolamine as a buffer (PH=8.4)
If I am getting resin at this stage and I run a LH-20 Size exlusion column of the semi-purified product, Can I get rid of my resin as my resin will weigh far less than my targeted polysaccharide and/or protein complexes. 
Any suggestions?
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The resin will contract when the salt concentration is increased. This is normal. When the salt concentration is lowered, the resin will re-expand.
You should not be seeing any resin in your eluted fractions unless there is a hole in the column support frit or you are using an inadequate type of support for the column bed.
The resin particles are relatively large (40-120 µm when dry), so if they do get into your sample they can easily be removed by passing the sample through a 0.45 µm filter, centrifuging, or just letting them settle out.
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The old version of Winnonlin is not working on my computer. I need it urgently to analyze my data to complete within a due date. If anyone has an idea of downloading the Winonlin software (trial version or free download), please help me.
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I realize that Bitartrate is considerably larger that HCl but would this affect the efficacy of a topical gel? I've tried to find case studies comparing the two salt forms but without any luck. Initial thoughts are the large salt may take longer to absorb through the skin or it could somehow be interfering with the interaction between Epinephrine and adrenergic receptors. Any thoughts, references, or insights would be greatly appreciated. 
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Dear Kurtis,
Both salts have the same mechanism of action, similar pKa (around 9) and close physicochemical properties. The permeation of both salts through skin membranes is similar (log p around -0.5). The skin's pH is 5.5, therefore, it is expected that both salts will exist as the salt form upon their permeation through the skin membranes. No  interaction between epinephrine and adrenergic receptors has been reports upon the use of these two salts. The difference in the molecular weight of the two salts is about 114 Dalton, however, it does not have any significant effect on their permeation. Both salts have molecular weight less than 500 and their permeation is through passive diffusion.
For physicochemical and pharmacological properties, please see the following links:
Hoping this will be helpful,
Rafik
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Hi all, i'll try and keep this short as i can. i have been undertaking an honours project for the past 5 weeks about determining cyp3a4 degradration via mRNA suppression. I have derived a half life value but i want to know how this value and those mentioned previously in literature regarding cyp3a4 can be important for patients as a predictor of drug-drug interactions and clinically. Many thanks for helping. 
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Hi Nadeem,
Choosing the strategy for your clinically-oriented project, it’s less likely to follow recent paper of Ramsden et al (Drug Metab Dispos. 2015 Sep;43:1307-15) related to degradation constant for CYP3A4 achieved by direct suppression of mRNA in a novel human hepatocyte model. They found CYP3A4 mRNA levels rapidly depleted by >90% using either small interfering RNA or addition of interleukin-6, which allowed an estimation of the degradation rate constant for CYP3A protein over an incubation time of 96 hours. The degradation rate constant of 0.0240 ± 0.005 hour(-1) was determined in hepatocytes from five different human donors. In your case, it rather seems more logical to take into account critical factors determining CYPs biosynthesis and catalytic parameters in in vivo situations. Clinically-linked models are much more complicated and (in contrast to in vitro hepatocyte models) primarily affected by an enzyme induction. Unlike enzyme competitive inhibition, enzyme induction is a gradual process. The time required to maximally induce an enzyme is governed by the need to either upregulate or synthesize new enzyme, assuming that the elimination half-life of the inducing drug is less than the enzyme turnover or degradation half-life. Time to maximal induction will be quicker with a short half-life drug such as rifampicin versus a longer half-life medication such as phenobarbital. Therefore, pharmacokinetics of the inducing drug cannot be ignored. In most cases, however, enzyme turnover will be the rate-limiting step in this process. Evidence suggests that CYP3A4 has an enzyme turnover half-life of about 3 days and CYP1A2 about 4 days. This would imply that maximal induction of these important CYPs is likely to take several weeks, although the onset of induction may be evident much sooner. In addition to a time of exposure, both in vitro and clinical studies have demonstrated that the magnitude of induction of various CYP isozymes appears to be at least partially dependent upon the dose of the inducing drug. This dose dependence is seen not only with phenobarbital and carbamazepine, but also with newer agents such as topiramate. Topiramate is frequently cited as a non-inducing medication when, in fact, clinical studies have shown dose-dependent increases in the clearance of ethinylestradiol in female patients, which are clinically relevant at daily doses of 200 mg and above. In vitro experiments have demonstrated concentration-dependent increases in CYP3A4 protein and mRNA with exposure to topiramate. What happens when an enzyme-inducing drug is discontinued? De-induction will be related not only to the half-life of the inducer, but also to enzyme degradation rates. At any given time, the amount of drug-metabolizing enzyme is regulated by a zero order rate of enzyme production and a first-order rate of enzyme degradation. During the process of enzyme induction, enzyme amounts are increased either by increasing the rate of enzyme production or by stabilization (i.e., decreasing the rate of degradation). During the process of deinduction, enzyme amount is decreased (to baseline pre-induction levels) by either decreasing production or increasing enzyme degradation rate. The turnover half-live of CYP3A4 is the primary parameters governing the rate at which one can expect resolution of an induction type interaction following discontinuation of an inducing medication. This implies therefore that the time course for the enzyme to return to baseline or pre-induced activity levels will be gradual. Studies exploring the dissipation of increased CYP3A4 activity following discontinuation of inducers have suggested that this may occur over several weeks for compounds such as St John’s Wort and rifampicin. Pharmacokinetic modeling following discontinuation of carbamazepine suggests a de-induction half-life of approximately 4 days. Using an enzyme-turnover model in patients with epilepsy, it was estimated that CYP3A4 induction should be reduced by about half at 3 days and by 75% at 7 days, and enzyme de-induction would be essentially complete within 2 weeks following complete discontinuation of carbamazepine.
Best wishes,
Ilya
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I want to compare Bioequivalence of test IR and test MR formulation with IR reference formulation. Is it possible to compare both test formulation with reference formulation in single study. ???
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Please find below link for receantly published article
Is it possible to achieve bio-equivalence between an oral solid immediate-release and an analogue enteric-coated formulation?Journal of Pharmacy and Pharmacology
Dannit Licht, Rachel Cohen, Ofer Spiegelstein, Laura Rabinovich-Guilatt, Marina Zholkovsky, Adrian Gilbert, Jennifer B. Dressman and Muhammad Safadi
Version of Record online : 27 JUL 2016, DOI: 10.1111/jphp.12597
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I have done the procedure and took absorbance.
I don't know how to calculate NPSH and Mucus content
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Dear Vara Prasad Saka,
Let me introduce the methods and then the calculations:
Total acid output of gastric juice was determined by titrating with 0.01N NaOH, using phenolphthalein as indicator and was expressed as mEq/4h. Peptic activity was determined using haemoglobin as substrate and was expressed as mmol of tyrosine/4h16. Dissolved mucosubstances were estimated in 90 per cent alcoholic precipitate of the gastric juice. The precipitate thus obtained was either dissolved in 1 ml of 0.1NaOH or 1 ml H2SO4. The former was used for the estimation of protein17, total hexoses18, hexosamine19 and fucose20, while the latter was used for the estimation of sialic acid21.
Assessment of adherent gastric mucus content: Alcian blue binding to gastric wall mucus was determined by the method of Corn et al22. Animals from all groups were sacrificed, the gastric mucosal tissues were scrapped, weighed and incubated in tubes containing 1 per cent alcian blue solution (0.16M sucrose in 0.05M sodium acetate, pH 5.8) for 2 h. The alcian blue binding extract was centrifuged at 3000rpm for 10 min and the absorbance of supernatent was measured at 489nm. Estimation of non-protein sulphydryl (NPSH) groups: Gastric mucosal NPSH was determined by the method of Sedlak and Lindsay23. 200mg gastric mucosal tissues were homogenized in 2.0ml of 20 mM EDTA at 4oC in a homogenizer. To measure NPSH content, 2.0 ml of water was added to 1.0 ml of homotenate which was then treated with 1.0 ml of 10 per cent TCA and centrifuged. From this, 2.0 ml of supernatent was taken and treated with 4.0ml of Tris-EDTA (pH 8.0) and 0.1ml of DTNB in methanol. The contents were mixed well and absorbance read at 412 nm.
Calculations for total acid output of gastric juice:
N1V1 (NaOH) = equivalent of the stomach acidity
N1 = 0.01 N; V1 is the number of 0.01N NaOH used in the titration.
The N1V1 gives the number of equivalents (you can convert the unit to miliequivalent) of the acid (HCl) present in the stomach. You should run the same assay for the control mice and compare between the acidity of the sample to that of the control.
Estimation of non-protein sulphydryl (NPSH) groups:
In this part you should use beer lambert law for calculating the concentration of NPSH: A = epsilon * b * c. where A is the absorbance at lambda 412 nm, b is the cell width = 1 CM and c is the concentration in molar. The extinction coefficient (epsilon) for the liberated NBT at a wavelength of 412 is 13600 M-1CM-1 (Ellman, 1959).
A = 13600 x 1 x c; substituting A with the reading absorbance at 412 nm in the equation gives the concentration (c) in molar.
Please note that you should run sample against blank
For more on this topic, please use the following links:
Hoping this will be helpful,
Rafik
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I have repeated my assay to assess for synergy multiple times, and after plotting the median effect plot, I have calculated the m values and Dm values for both single agents and combination. From this I have calculated the CI values and have plotted the combination index plot. However, each repeat gets slightly different m and Dm values which affects the combination index plots. How can I take my repeats into consideration? I would like to get the mean result from my repeats. I have thought about taking the mean m and Dm values and generating a combination index plot from the mean values, will this be ok?
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Ideally you would want to build run-to-run variation into your uncertainty estimates.
You can probably do that directly by introducing a random effect for run into your statistical analysis, or possibly by resamplng CI values over several runs (i.e. bootstrapped estimate of uncertainty)/
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There are several books talking about Phase I clinical trials establish that this type of clinical trial must be brought in healthy volunteers. Nevertheless, the are clinical trials reports that were carried out with patients... Are there both alternatives correct?
Thanks in advance.
Best regards!
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 Phase I studies assess the safety of a drug or device. This initial phase of testing, which can take several months to complete, usually includes a small number of healthy volunteers (20 to 100), who are generally paid for participating in the study. The study is designed to determine the effects of the drug or device on humans including how it is absorbed, metabolized, and excreted. This phase also investigates the side effects that occur as dosage levels are increased. About 70% of experimental drugs pass this phase of testing.
However for cancer drugs, clinical trials are carried out in patients
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Most people involved in clinical pharmacokinetics are familiar with the 80-125% criterion. This criterion is used to compare two treatments with the purpose of evaluating if the treatments are bioequivalent. But, where did this come from? Why 80-125%? Why not 90-110%? or why not 80-120%?
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Bioequivalence criterion 80-125% are the result of the history of the changes themselves criteria and options bioequivalence account statistically. These strange numbers are the result after log transformation for AUC and Cmax (drug concentration in the blood). If you are not a mathematician, the easiest way read material on Gary Buehler (in file).
I hope this helps :-)
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Hi
does anyone have an idea bout the mechanism of telaprevir mediaed hypersensitivty reaction? is it mediated by hapten or P-I mechanism  ?
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Telaprevir is a HCV NS3-4A protease inhibitor indicated in the treatment of genotype 1chronic hepatitis C in adult and must only be used in combination with peginterferon alfa and ribavirin.
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Dear researchers,
I like to follow the microscopic mass balance approach for predicting intestinal absorption. Three dimensionless numbers viz., dose number, absorption number, and dissolution number can be calculated with the appropriate parameters. Then these dimensionless numbers can be substituted in the differential equations and it can be solved together.
I found an article published in Springer, AAPS PharmSciTech (attached).
I followed the same values and try to solve with R program, I can't able to solve (Authors used Matlab to solve the differential equations). Please give an idea to solve these differential equations.
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Dear Joseph
May be you can try using a function that smoothens the particle size dissolution rate ( variable y1 in your code). In general smoothing functions will perform better than any if else type formalism. 
I also tried methods = "rk4". However, the results dont match. Seems this needs stiff solvers. Let me know if this makes sense to you.
Raja
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if the same drug is given by subcutaneous and intramuscular route, which one would be absorbed faster?
reach faster Tmax?
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Dear Rajesh
The drugs administered intramuscularly may be aqueous solutions or special depot preparations - usually a drug suspension in non-aqueous vehicle, such as ethylene glycol or peanut oil. The drug absorption in aqueous solution is rapid, while the preparation of the deposit is slow. As the  vehicle, diffuses leaving the muscle drug precipitates at the injection site. The drug is then dissolved slowly, providing sustained doses for extended period of time.
3- Subcutaneous (SC)
This route can only be used for medicines that do not irritate the tissue; otherwise you can come intense pain, necrosis and descamasão.
This route of administration, like intramuscular injection, absorption and requires is somewhat slower than the IV route. SC injection minimizes the risks associated with intravenous injection. Small amounts of adrenaline are sometimes associated with a drug so as to restrict it to their area. Adrenaline acts as a local vasoconstitor and decreases drug removal, such as lidocaine, from their place of admiministração. Other drugs using SC administration include solids, such as silastic capsules and programmable mechanical pumps.
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Hello There, I have been doing some researches through my post- graduate students looking at the effect of some medicinal herb  with (and without) the exciting medicines using for Acute Lymphocytic Leukemia (ALL) treatment such as Vincristine on some ALL cell lines. My question is how can we convert or calculate the treatment dose of medicine (for instance Vincristine, which is taken as mg/m2 in adults or mg/kg in pediatrics) to nano molar of Vincristine/mm3 for cell culture? Indeed, how much of this medicine, Vincrictine  per body weight or surface equals with  the amount of Vincristine per one mm3 of cell culture? Because we have been looking for the optimum dose of Vincristine  in cell culture after adding the medicine in ALL-cell lines, which should not be more than  therapeutic dosage in clinic.
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We use a simple rational of clinical dose to use for in vitro cell cultures. We first identify the  concentrations of your drugs (in vivo) in a kinetic manner with time in the circulation, to identify the drug concentration and its degradation/elimination rate. Then based on its half-life we will fix the best peak concentration in the circulation to be used for in vitro. If the first peak does not work we then use the next peak.
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Could somebody with expertise in methods of drug administration point me in the right direction? I'm working with a new polymer which can be customized to degrade in different pH environments along the GI tract, and I was wondering about the challenges faced/applications of current technologies. I can't find much information on pH-sensitive hard shell capsule materials other than hypromellose. Is this a beneficial property? Can it be used for site-specific drug targeting etc?
Any feedback is much appreciated!
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Dear Eaton,
I suggest looking at this from the point of view of pathologies of diseases of the gastrointestinal tract.
For example pancreatitis is treated with very large doses on enzymes because the enzymes are sensitive to pH of the stomach and easily digested. Controlling drug release relative to local pH conditions may allow for discrete drug administration as the capsule travels through the gut and this may allow significantly smaller doses. Of course this example assumes absorption of enzymes would occur after the stomach etc...
Best, Patrick.
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clinical pharmacology 
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 thank you 
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I consulted three elderly patients who used eye drop with dexamethasone after cataract surgery. On the 3rd-4th day there was a significant increase of blood pressure compared with the pre-operative period. Is it possible to reduce the dose for this category of patients?
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Hi,
Dose of  dexamethasone in an eye drop containing dexamethasone is usually 0.1%. This means that there is 1 mg dexamethasone in 1 ml of eyedrop. Each ml makes 20 drops. So each drop contains 0.05 mg. İf patient is using 4 drops a day, it makes 0.2 mg Dexamethasone per day. Even if all of the drug is absorbed into systemic circulation, it is too small an amount to take into consideration for systemic effects.
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In fact, elderly patients are at increased risk of adverse events due to atypical antipsychotic drugs because of age-related changes in pharmacokinetics and pharmacodynamics and current medical conditions, polypharmacy, and potential drug interactions. US Food and Drug Administration black box warnings have clearly shown the potential risks of their use (eg, cerebrovascular accidents, risk of sudden death). Furthermore, metabolic adverse events are extremely dangerous. They are probably linked to an increase in adiposity associated with a variety of adverse physiological effects, including a decrease in insulin sensitivity and changes in plasma glucose and lipid levels.
So, whom could share great experience on this issue?
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Dear Anthony,
very interesting question!
Well, usually antipsychotics are used because of a lack of knowledge of pharmacology (easier to prescribe than reconsider). More than 1/3 antipsychotics are used without support of EBM. In term of inappropriate prescribing (PIP) more than 50 % are included in the nursing homes as PIP. More than 2/3 of antipsychotic polypharmacy (APP) can be reduced to monotherapy (AM).
In special population as elderly parients are, there is necessary to reduced the use of antipsychotic if it is possible. Often patients are treated very long period (e.g. 12 months). Very deep evaluation and dose adjustment is necessary if antipsychotics are used in the elderly patients in dementia. However, another options should be calculated as use of antidepressants (e.g. mirtazapine and trazodone) instead of antipsychotics in patients in dementia.
In real clinical practice in patients with dementia risperidone and quetiapine are used often. Olanzapine should almost not be used in these patients (Daniel you have different opinion). With quetiapine we have an evidence that there are no deaths in compare with placebo in small-medium doses of quetiapine (only quetiapine). In this point of view the use of quetiapine is the safest option in patients in dementia. The use of risperidone should be connected with a great caution. In many patients risperidone is titrated very (tapered) fast and often extrapyramidal symptoms are seen (about 20 % patients have tardive dyskinesia in 2 years treatment). Risperidone has one benefit compared to risperidone (e.g. approved indication in patients with dementia). Another benefit is its efficacy in comorbidity with psychotic episodes, where risperidone is often more efficacy. Very big benefit is sedative action of quetiapine and this action is very useful in these patients. In addition, these patients are often treated with polypharmacy and clinical pharmacist specialist within psychiatry can be involved in the treatment of these patients.
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Many physiological factors affect and alter drug absorption from the g.i. tract. Ionization, the conc. of free and bound drug, solubility, formulation etc. But isn't it true that more there is free unionized unbound portion of a drug available, more of it is rapidly metabolized and exerts its toxicity? Plasma protein binding reduces the free concentration of drug. If more of the active ingredient (herein drug) is present unbound to plasma protein (in free state), does it mean that a much greater amount of it will be rapidly absorbed from the gastrointestinal tract? But why this is reverse in the case with unionized drugs?
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Dear  Sidharta,
The reduction of the amount of free unionized drug due to plasma protein binding enhances its absorption from the g.i. tract because the absorption of a drug from the G.I follows Fick's low (passive diffusion): 
Absorption from the G.I. proportional to  (concentration in the GI (out) -concentration in the blood (in)
If concentration (in) is reduced the absorption is increased.
Hoping this will be helpful,
Rafik 
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We want to improve bioavailability of plant based lipophilic compound. Please let me know various pharmacological mechanism to improve kinetics.
Regards,
Shankar
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Micro-encapsulation technique we use.
Thanks,
Shankar
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Whats the difference between erythromycin base, erythromycin ethyl succinate and erythromycin estolate ? Why does estolate form cause hepatotoxicity in pregnancy while the other two forms are considered safe ?
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it is a hypersensitivity reaction in case of estolate which causes cholestasis.
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Paracetamol suppositories made with PEG 4000 and PEG 6000 as suppository bases undergo dissolution test. After 45 minutes, both batches have mean % of drug release that is higher than 100%.
PEG 4000- 150% and PEG 6000- 120%
Why does the cumulative drug release exceed 100%? Is there error during measuring of absorbance or is it some form of degradation or hydrolysis of the medicine during manufacture/storage?
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Dear Ahmed,
Polymorphs are solid state-of-matter crystal forms? But, for an assay you're dealing with a solution. So the specific absorbance (in solution) will be identical, no matter which polymorph dissolved. You may be thinking of mutorotation, but the assay is by absorbance, not optical rotation.
Rachel, paracetamol is stable in the body until metabolized, which processes usually don't involve attack at the phenol group. So it's likely to be comparably stable once in solution in a dissolution test. As to the possible attack by PEG impurities, you might see http://www.spectra-analysis.com/documents/AppNote016Polyethyleneglycol.pdf , with the caveat that the sample had been "vigorously air oxidized" (hot?). Consider that PEG is used in many preparations, and that it may block chemical carcinogenesis, both of which wouldn't be practical if it generated large amounts of peroxides. I do note that sonication (to disperse or dissolve solids in a solution or semisolid) may degrade PEG, see https://en.wikipedia.org/wiki/Polyethylene_glycol . So don't do that!
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We have designed and synthesized a number of prodrugs for commonly used drugs and looking for a place to conduct toxicity tests for these novel compounds.
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As consultant Toxicology and having 30 years of experience in this field , I am associated with 2 / 3 Toxicological testing laboratories which can provide all tests in very competitive prices .Please contact me on +91 9604878167 or Mail me sudhirborate98@gmail.com / sudhir.borate@pradopreclinical.com 
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Can anybody suggest online free tools or downloadable software for the prediction of ADMET parameters of drugs?
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You could also use admetSAR http://lmmd.ecust.edu.cn:8000/
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I've seeking any peer-reviewed research re: the bio-availability of crystalline methylamphetamine when vaporised and inhaled. There is a lot of grey literature that claims more than 60% or more than 90% of the dose is absorbed into the bloodstream when it is smoked (by someone who knows how to do it properly), and I am not questioning the veracity of this information, however a quick scholar search hasn't yielded any research that actually quantifies bio-availability via this route of administration. If you’re aware of any relevant published research I would be very grateful…
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Here it is, (attached). This study supports the general consensus of opinion, (that ~90% or more of the dose is absorbed via vapourisation/inhalation routes of administration).
There doesn't appear to be very much published research on this topic at all- if any readers are aware of any other studies please let me know.
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I am performing pre-clinical studies in order to develop a novel cancer vaccine. However, I need to get a cell line approved for use as as cell substrate to manufacture my vaccine. Approvals should meet Health Canada specifications. Any resources or details would be greatly appreciated.  
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Thank you for your reply Maxim. I have reviewed documents on cell substrates from the FDA and Health Canada (the regulatory body I am concerned with). However, these documents do not specifically address the steps required or contacts regarding getting a new substrate approved. They contain more general information about GLP, GMP and vaccine development in general. I will try the suggested avenue of contacting a Regulatory Consultant or CRO. Thanks.
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Say if we give 2g/day dose of a supplement to adult humans, how can we extrapolate this dose in rats ?
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Okay, there is no guarantee when extrapolated from animals to humans (rats for example) but the experimentally know the metabolism of the animal model used (pharmacokinetics), sequence action and removal of the test product with biochemical markers and the median lethal dose in addition to the teratogenicity, they are fundamental for comparison with humans. The formula Dobois and recommended input table are useful, but not enough to make the final decision.
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Are there any studies which have used the mother as the mode of drug delivery via breast milk?
How would one go about to determine the amount of drug to administer to the mother to reach the litter?
Krishna et al. 2013 provide a review where they present a formula to calculate human inflant exposure to drug:
The maternal plasma concentration of drug (Cmaternal), area under the concentration-time curves (AUC) of the drug in maternal milk and plasma (M/P AUC) ratio and the volume of milk ingested by the infant (Vinfant):
Dose of infant (mg/kg/day) = Cmaternal (mg/L) x M/PAUC x Vinfant (L/kg/day)
Is this model valid to use in a murine system?
Moreover, is there a model or formula to calculate how much drug would the mother need to ingest (systemic administration through first pass metabolism) to achieve the target dose for an infant?
Reviews, original research papers as references or any interjections/insights are much appreciated.
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This is really interesting, however there would be too many variables that could affect the transfer, and you can not be sure how much drug is delivered.  If there is more than one offspring, one cannot calculate or regulate the amount of milk that each offspring gets from the mother either. 
I also would think that since only a minor fraction of drug is deposited in the milk, the amount of the drug given to mother for desired effect on the offspring could be detrimental or poisonous on the mother.
Good luck
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In order to attain our goal we have  main stage:
Development of therapeutic local action drug forms for skin and nail mycoses and vaginal candidoses and in vitro bio-pharmaceutical study of them; micro-biological studies within the system “ointment-fungous strain” and “suppository-fungous strain”.
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You shall try a similar approach as given in the link
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I want to do a pharmacokinetic study for oral administration of a compound. I calculated conc. vs time. I'm using R program with PK package for non compartmental analysis. With the batch design, I could get the pharmacokinetic parameters like,
- AUC to tlast (μg h ml-1)
- AUC to infinity
- AUMC to infinity
- Mean residence time
- non-compartmental half-life
- Clearance
- Volume of distribution at steady state
I have not performed intravenous route for calculation bioavailability F. In the above the parameters what can be used for oral administration. Somewhere I read clearance and volume of distribution can't be considered for oral administration. Further could some one help me to get the Cmax, Tmax with R program. I'm using Linux OS, R program only suits for me. I can't purchase Gastroplus, Kinetica, and other user friendly softwares.
Please help.
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I would review this first: http://www.boomer.org/c/p1/
It will help clarify the basics of noncompartmental PK analysis. The answers to your questions may be self-evident after reviewing that information.
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If a patient has a penytoin level of 15mg/L and has a Albumin level of 15g/L. He is showing signs of toxicities.
If the average albumin level is 35-50g/L.
What would be the corrected phenytoin level?
My collegue thinks its 37mg/L but surely thats way above the therapeutic range? Thats why im confused, can I have an explanation?
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This a method how to adjust phenytion with the albumin concentration
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Is there any simpler model to check and evaluate a capsuled drug absorption in animal intestine?
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Dear Habibur Rahman and Dr. Perkins, thank you for your answers and could you please, give some more information on this method or a link to any publication is highly appreciated.
Dear Dr. Perkins, we are interested to use enteric coated capsules, which contains a powder inside. Even we can use cavies instance rats. In fact we interested in measuring an intestinal absorption of our compound itself, so as you mentioned, in situ perfused gut model or everted sac method is more useful in this case.
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Does anybody have the pharmacokinetic data that reflects the drug absorption time in mice after oral administration ? Such as 2 hr or 3 hr. In my case the drug that is impermeable to the BBB was orally pre-treated 1 hr before MCAo surgery but the drug still showed the neuroprotective effect. So at this case how can I discuss the result? If the drug absorption time is about 2 hr then we can say BBB rupture and drug is penetrating the brain, or does the drug has indirect neroprotective effect?
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The pharmacokinetics (PK) of drug results from the interplay of the drug properties and the context (species, age, diet, etc), so there is no general answer to your question. If plasma PK is known, you know what concentration-time profile the brain is exposed to. Note that the unbound drug pharmacokinetics are important, as driving BBB transport. Then, BBB transport has a rate (how fast will the drug pass the BBB) and brain distribution will have an extent. The pharmacokinetics of the unbound drug at the target site is what should be linked to the effect.... so there is quiet a bit to be know before drawing firm conclusions...
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and at what concentrations
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Hi Avi. Perhaps you can ask Dr Luna Samat.
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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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I really need to have the partition coefficient of a particular drug in PLGA but I dont know how to find that!
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I knew that.
thanks
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Hi everyone,
I had read many articles which worked on pharmakinetic of a drug. In many of them, they stated that they use computer program 3P97 to calculate the half life and ...
I really appreciated if you help me.
I need some information about computer program 3P97 Pharmaceutical Kinetics Software.
What are these parameters?
C = Ae^−αt+ Be^−βt.
Do you know where I can obtain it?
Is it free?
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1.software 3p97 is programmed by Chinese .And used widely in China to calculate parameters of drugs. accepted by China FDA.
Not free.
Now renamed as DAS, the newest version maybe 2.X.
2. C = Ae^−αt+ Be^−βt.
     two compartment model  describing the disposition of some types drug.
you can find its means in PK textbooks.
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Dear RG experts kindly let me know about a free software to use for my study
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When we review the literature we find many different values used, and none disclose where and how they got the A and E values they employ, or why the value they use is different from others. References appreciated.
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Apart from differences in experimental conditions, the kinetic compensation effect (KCE) can be the reason.
The Arrhenius parameters are usually determined from data corresponding to rather narrow temperature intervals and they are strongly log-linearly correlated (log A = a.E + b). It means that the Arrhenius eqation is an ill-conditioned regression model -- even small errors in data will induce large differences in the kinetic parameters. On the other hand, the rate constants (half lifes, etc.) calculated from such different {A,E} sets are usually close to each other.
Good papers on this phenomenon are
Barrie, P. J. Phys. Chem. Chem. Phys., 2012,14, 318-326. https://dx.doi.org/10.1039/C1CP22666E
Barrie, P. J. Phys. Chem. Chem. Phys., 2012,14, 327-336. https://dx.doi.org/10.1039/C1CP22667C
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We want to do PK study of pure curcumin.
Curcumin is insoluble in H2O but soluble in ethanol, chloroform and DMSO. How can we administer this intravenously? If we use ethanol, what percentage can we give intravenously? 
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I suggest you to observe the lethal effects of curcumin before start of your experiment. 
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Almitrine-Raubasine combination effectively increases both arterial oxygen partial pressure and it is known as effective Osupplier. However, what is the actual mechanism of these two components separately or in combination.
I will highly appreciate your suggestion on this regard. (Pathophysiology, pharmacology, pharmacokinetics ......etc....)
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Hi,
almitrine enhances respiration by acting as an agonist of peripheral chemoreceptors located on the carotid bodies. The drug increases arterial oxygen tension while decreasing arterial carbon dioxide tension in patients with chronic obstructive pulmonary disease. It may also prove useful in the treatment of nocturnal oxygen desaturation without impairing the quality of sleep;
raubasine acts as a α1-adrenergic receptor antagonist with preferential actions over α2-adrenergic receptors
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I successfully implemented a two-compartment (gut-blood) mathematical model for a single oral dose (20 mg/kg) to simulate the SWCNT distribution in the blood using intestinal absorption constant (Ka = 0.033 min^-1/1.98 hrs^-1), volume of distribution ((Vd = D/C0), experimentally determined), and volume of the gut compartment (V1 = 82.5 ml/kg). The methodology might be further applied to build the two-compartment (peritoneum-blood) PBPK model for a single i.p. drug injection if the peritoneum-blood permeation constant is established.
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I haven't.
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I try to analyze a PK study that we've conducted in mice. Since I don't expect the concentrations in the plasma to be very high, I have to increase sensitivity of my detection system. I am using a Micromass quattro micro MS with ESI interface.
The problem is, that I "see" peaks down to 100ng/mL in SIR as well as MRM mode. But below this concentration it's getting hard. My idea was to do a derivatization of the keto function. But somehow nothing seems to work.
Does anyone have an idea what I could try?
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Since your compound has free OH groups, you may try negative mode of ESI.
Making Na adduct will also increase the sensitivity for positive mode of ESI.
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Should a drug in liquid form (Geraniol) be first dissolved in solvent (DMSO/Ethanol) then diluted in media or directly added to media to make different concentrations for an MTT assay? Geraniol directly used in media is showing no effect .
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Drug is in liquid form then what is the need to dissolve in a solvent.why can't make different conc in media directly
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What is the most used technique to calculate chemotherapy dosage? What are emerging techniques, including their pros and cons? Can anybody give me a pointer to reference documents?
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Many chemotherapy (cytotoxic) drugs are prescribed proportional to calculated body surface area, using formulae that are decades old and arguably inaccurate. Some are prescribed at a fixed or capped dose, and some on the basis of pharmacokinetics (eg carboplatin based on predicted AUC). Doses are usually selected on the basis of maximum tolerated dose from earlier clinical trials. There is a substantial literature on this, including good evidence that we often underdose patients for a range of reasons.
Newer agents with different mechanisms of action might not have a defined MTD, or the optimal or biologically effective dose might be different. Drugs such as axitinib, for example, often are titrated until a certain toxicity (hypertension in this case) is achieved, which predicts both therapeutic drug levels for that patient and also correlates with efficacy.
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Pre-clinical drug-drug interaction (DDI) assessment using in-vivo animal models along with in-vitro human systems based assays, aids in early prediction of clinical interactions possibilities and may help to prevent late phase failure of drug in clinic.
But DMEs and transporters of animals vary remarkably from humans, thus limiting their use for clinical predictions. Owing to these limitations "humanized" animal models are developed, which serves as a better model for prediction of metabolism and potential DDI in humans.
Apart from these humanized animal models what are other pre-clinical novel methodologies which are used for investigating/ predicting clinical DDI?
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I'm not aware of any methodologies I would necessarily call novel, however, there are many methods other than humanized animal models that are used. The closest method to being novel that I'm aware of is in silico. Specifically, the software SimCYP which attempts to predict PK based on compound structure. In so doing it also provides information about which transporters and metabolizing enzymes are most likely involved. Using this information you can then make an informed guess about what drugs would likely cause a DDI so that you can better guide subsequent in-vitro testing. This software has been available for a number of years and continues to get better.
There are also a number of in-vitro methodologies such as using human liver microsomes and doing co-incubations with known metabolizing enzyme inhibitors and inducers. Such systems, however, often over predict interactions due to metabolism because there is no cell membrane through which your compound must pass, unlike an intact liver. Along the same lines, there are cell lines transfected with a single or panel of metabolizing enzyme so you can create a metabolism panel. Again, you can use co-incubations. Either of these options require a reasonable amount of additional work in categorizing the actual enzyme/transporter expression levels if you want to use it for allometric scaling.
As for assessing transport, you can always do trans-well assays with epithelial cells, but again you need to categorize the system quite well for allometric scaling. These are all common techniques used in high throughput screening and subsequent pre-clinical testing. There are many many more methods, however, most of them involve these primary techniques or modifications thereof. I hope this helps!
-Zack
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For example, an ixabepilone dose is 40 mg/m2 and the maximum dose is 88mg based on a BSA of 2.2 m2. Therefore, if a person's BSA is 2.5, the dose is capped at 88mg instead of 100mg.
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Thank you for your response. But I'm still puzzled by why 2.2 and not some other number. Is there any pharmacokinetic study out there that reports capping the BSA at 2.2 reduces toxicity in obese patients?
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I am looking for the release parameters of Microtrol beads for Adderall XR so that I may include absorption rate or rate constants in a pharmacokinetic model of Adderall XR. Can you describe the kinetics or provide references?
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Yes. This will be helpful for not only there is some useful content but the names may be useful if I can establish the contacts. Thank you Fakhrul.