Pharmacodynamics - Science topic

Dear Colleague,

I hope this message finds you well. Understanding the pharmacokinetic (PK) differences between rats and mice is essential for interpreting preclinical data and translating findings to human applications. Several factors contribute to these differences, which I detail below:

In conclusion, multiple factors, including metabolic rate, enzyme expression, absorption, distribution, excretion, physiological and anatomical differences, genetic factors, and experimental conditions, contribute to the pharmacokinetic differences observed between rats and mice. Careful consideration and control of these factors are essential for accurate interpretation and comparison of PK data across species.

Should you have any further questions or require additional assistance, please feel free to reach out.

What factors may contribute to the PK differences in rats and mice?

Pharmacokinetic and pharmacodynamic changes occur during pregnancy, impacting drug metabolism, distribution, and response in pregnant patients. Understanding these changes is crucial for safe and effective medication management during pregnancy. Here's an overview of the key alterations:

In summary, pharmacokinetic and pharmacodynamic changes during pregnancy can influence drug metabolism, distribution, and response, posing challenges for medication management in pregnant patients. Clinicians must consider these alterations when prescribing medications, adjusting dosages, and monitoring therapeutic effects to optimize maternal and fetal outcomes while minimizing risks of adverse drug reactions. Close collaboration between obstetricians, anaesthesiologists, and pharmacists is essential for safe and effective medication use during pregnancy.

I,m interested. Sorry for being late.

Respected Prof Faraz Khurshid , I cannot agree with you more. I think PD/PK are really subjects that needs to be emphasized in modern pharmacy training. We really need fundamental and basic scientific training for every pharmacist. Scientific concept is important for clinicians.

I also like evidence-based medicine, I guess this is really an important direction for our future generations. It is the black and white evidence that really underlie our decision and we should record the evidence accordingly so that we are speaking the same language and sharing our knowledge.

It is important that every decision is recorded and traceable, so that we are recognized as a professional and/or expert in a particular area(s).

Dear Siam,

I'm afraid I haven't come across allometry for such cases. In general allometry is used to scale between mammalian species (or individual of different sizes for pediatric applications).

The general idea is that flows (clearance) scales with a factor of about 0.75, so this applies also to dose (which is expected to be a function of clearance). So it follows a relationship of a*BW^0.75.

In absolute terms you could apply the formula with the weight of any species / individual. However, I suspect that the empirical principles mainly established between mammals may not apply to invertebrates.

To note that even between more similar species like mammals allometry does not always work well.

Out of curiosity, how do you apply drugs in insects? Can you actually apply orally or how it it done?

The words selectivity, specificity, and sensitivity (derived from Latin seligere, specificus, sensitivus), can be confusing terms as they are often used synonymously in the medical literature. However, they should not be used

interchangeably as each represents a different phenomenon.

Reference:

Mencher, S. K., & Wang, L. G. (2005). Promiscuous drugs compared to selective drugs (promiscuity can be a virtue). BMC clinical pharmacology, 5(1), 1-7.

@karel

I wish to know if there's any genetic polymorphism/variation in the pharmacology of frusemide. Whether at the level of safety, pk or pd?

Is there anything of concern in this regard sir?

Hi,

Unfortunately, there are no such methods. Current solutions and models do not allow for selective analysis of one or several substances after administering the extract (.... which may contain several substances). Such analysis will only inform about interactions between constituents nothing else. Of course, the extent of these PK interactions will depend on the composition of the extract. What you can do is determine the concentration of the dominant substance in the extract and try to determine its concentration in blood samples or urine. However, the cognitive and scientific value of such an analysis will still be low. If an extract is administered, it is not possible to associate a single substance with a pharmacodynamic effect (PD). Currently, we do not have such data analysis capabilities. The effect of PD after administration of the extract is always the result of interactions between all components of the extract. We currently have neither software nor models that can separate these interactions from each other. Therefore, PK and PD are tested with the use of single selected substances or in systems where interactions with one substance are tested, but not with so many.

All you can do is try to characterize the chemical composition of the extract and describe/analyze the PD effect. Selective analysis of PK or selective PD analysis in your case is not possible.

Best regards

Tomasz

Hi

"enantioselective pharmacokinetics" please check the keyword in google or NCBI.

geometrical isomers have different physicochemical characteristics for example pKa, the same problem cover diastereoisomers.

D-dopa is less absorbed than L-dopa

D-methotrexate is less absorbed than L-methotrexate

cis - lycopene is absorbed to a greater extent than trans - lycopene

L - cephalexin inhibits the absorption of D - cephalexin from the gut

R-methadone has a greater volume of distribution than S-methadone

R - (-) - disopyramide binds less to blood proteins than S - (+) - disopyramide

Cis-cis - mivacurium has a larger volume of distribution than cis-trans, trans-trans

S - propranolol binds more strongly (competes) with plasma proteins than R - propranolol

R - sulbenicillin binds to plasma proteins weaker than S - sulbenicillin

R - latamoxsef binds to plasma proteins more strongly than S - latamoxsef

R-carbenicillin binds to plasma proteins more strongly than S-carbenicillin

R - propafenone delays the metabolism of S - propafenone

S - nitrendipine is an inhibitor of R - nitrendipine metabolism

R - verapamil is less affected by the first-transition effect than S - verapamil

R - ketoprofen in most species is transformed into S ketoprofen (rodent, dog, monkey, horse, cat) the Asian elephant is the only species that converts S into R

A very interesting case is a chiral inversion in the liver (see examples below)

flobufen (Skalova L. et al 2001)

ibuprofen (Doki K. et al 2003)

pranoprofen (Imai T. et al. 2003)

ketoprofen (Lees P. et al. 2003)

fenoprofen (San Martin M.F. et al. 2002)

albendazole (Virkel G. et al 2002)

thalidomide (Erikson T. et al. 2001)

clopidogrel (Reist M. et al. 2000)

D-leucine (Hasegava H. et al. 2000)

thiaprofenic acid (Erb K. et al 1999)

pantoprazole (Masubuchi N. et al. 1998)

styripentol (Tang C. et al. 1994)

lifibrol (Walters R.R. et al. 1994)

Tolperizon (Yokoyama T. et al. 1992)

R-methadone has a longer half-life than S-methadone

R-ibuprofen has a shorter half-life than S-ibuprofen

(-) - mefloquine has a longer half-life than (+) - mefloquine

R - (-) - ketamine inhibits the elimination of S - (+) - ketamine

(+) - terbutaline inhibits tubular reabsorption of (-) - terbutaline

R - sotalolol reduces the renal clearance of S - sotalolol

R - flurbiprofen is excreted from the bile to a greater extent than S - flurbiprofen

R - carprofen is secreted from the bile to a greater extent than S - carprofen

R - sulbenicillin has a lower renal clearance than S - sulbenicillin

R - (+) - propranolol is eliminated more slowly than S - (+) - propranolol

Z - doxepin has a stronger antidepressant effect than E - doxepin

Z - doxepin has a stronger antidepressant effect than E - doxepin

S (-) bupivacaine is less toxic than racemic bupivacaine

Of course, it's only the peak of the iceberg so, please check:

.... now > 1000 results ....

examples with references are available in my free e-book (polish version only)

Best regards

Tomasz

Although I didn't get a single reply to this question for the last 5 days. My own quest to this line of inquiry took me to an interesting study titled ' Adverse drug reactions reporting by undergraduate medical students in a tertiary care teaching hospital of India by Patel et al, 2017. They mentioned that undergraduate medical

students reported a high frequency of Adverse drug reactions (ADRs) with a single drug suspect and probable causality. Moreover, reactions, the ratio of augmented to bizarre reactions was higher among students’ reporting. Students could have easily correlated the augmented type reactions with mechanisms and pharmacological actions of the drugs.

Through this example, we came to know that how understanding the mechanisms of drug action impacted medical students ways of thinking and practising and fostered pharmacotherapeutic skill such as Adverse drug reporting (ADR)

Reference:

Patel PB, Patel TK, Anturlikar S, Khatun S,Bhabhor P, Saurabh MK. Adverse drug reactions reporting by undergraduate medical students in a tertiary care teaching hospital of India: Content and quality analysis in comparison to physician reporting. Perspect Clin Res 2017;8:137-44.

What route of administration are you using? If the oil accumulates, maybe you need to consider another route, adding another maybe solvent to the oil may alter the composition of your vehicle and may need further validation test. You can also try another vehicle or formulate a new one

I believe the concerns for using primates are more of an ethical nature. There is no required regulatory testing for pesticides on primates nowadays. The models that are used are (in decreasing order of use): rat, mouse, rabbit, dog.

All pesticides are tested in mammalian models, including an assessment of kidney toxicity, before they are allowed on the market, so if you are looking to place your research into context and have comparable data available, it would be best to use rat or mouse models.

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.

When drugs enter the circulation, bound drugs with plasma proteins may be formed due to structural differences, while unbound drugs are free drugs. The binding of drugs is mainly through ionic bond, hydrogen bond, hydrophobic bond, and van der Waals force, so it is reversible. The bound drugs are transported through the blood and distributed to the various tissues.

depending on the technique at disposal single threshold values can help

Dear Santiago Mora,

See table on page 10 document below, should be useful for you. Its FDA guidance from 2005. Using that document you can find common denominator between rats and mice based on general allometrical rules and scaling.

https://www.fda.gov/media/72309/download

Best regards

Tomasz

Both in the case of suggestion, involved in the placebo effect, as well as in the transference, it focused on the aspect of the therapeutic relationship. In Freud, this topic is very important in the course of an analysis, to the point where a good part of his work is to unveil it. In some way Freud achieves a journey in which hypnotic suggestion is abandoned as a therapeutic instrument to give rise to free association and the interpretation of transference.

If there is one aspect in which the placebo effect and the transfer can be linked conceptually, that is the one that describes the influence that the psychological relationship between patient and therapist exerts on the process with which it intends to treat a disorder. In that concern it is worth remembering that Freud came to propose "Very often the transference is enough to suppress the most common symptoms, but temporarily and while it lasts, In such a case, the treatment cannot be a psychoanalysis and it is only of suggestion: The name of psychoanalysis applies exclusively to the procedures in which the intensity of the transfer is used against the resistances ". From the foregoing, it can be deduced that Freud recognized the "temporary curative effect" of suggestion, which suggests that, to a certain extent, it resembles transference, even though it is outside the boundaries of psychoanalysis.

It is also necessary to focus on the multiple existing differences. Keep in mind that, within the conflict between Jung, Adler and Freud, the concept of suggestion serves the first two people to oppose the notion of transference. On the conceptual level, suggestion designates a psychological means used to convince the individual of the falsity of his beliefs. It is a vector that goes from the therapist to the patient. Something very different happens in the case of the transference. If you want to represent also through a vector, it would go in the opposite direction, from the analysand to the analyst. Furthermore, the transferred is not a conscious intention (that uses the placebo) but the unconscious desires concerning the external objects.

Dear Dr. Schultz,

thanks for your reply. Are you aware of any organisms that respond to such compound or that harbour the sigma 1 receptor gene?

Best regards,

Antonio

For metal determination in animal tissue, you must use a very energetic digestion; usually HNO3 and H2O2 mixture provide the lowest backgrounds for atomic spectrometry. With these reactants, you need temperatures above 200ºC for about 10 min. This digestion scheme provide lipids break and lower interferences.

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.

Hi,

How can we access the Abstract Book of this conference?

Firstly, I don't think you should disregard side effect profiles when comparing pharmaceutical agents for the same indication. Side effects are a very important factor to consider when selecting among different drugs. They can cause harm to the patient, or they can cause the patient to cease taking the drug.

To compare different otc analgesics, you will have to set up a double-blind trial with placebo control. You will have to decide on the most appropriate dose(s) of each drug. Then you will have to come up with a readout, which in the case of analgesics is the subjective experience of pain upon application of some painful but harmless stimulus. You will have to include enough subjects to achieve sufficient statistical power to detect a difference between the effectiveness of the drugs of the desired size.

There are many reasons why a drug has low oral bioavailability. A major one is poor aqueous solubility. Hence if we can improve the solubility for example using a suitable salt form then we may be able to increase the bioavailability. Other methods include forming a more soluble complex for example with cyclodextrins, using a more soluble polymorphic form or amorphous form of the drug. Drugs in the form of liquids such as vitamin E has low and erratic bioavailability under fasted state and hence should be taken after a meal or formulated as a self emulsifying system which can mimic the intraluminal processing when taken with a meal. Certain compounds are not stable in the harsh gastric environment where the pH is near 1. In this case an enteric coat is useful. Also, some drugs are affected by the absorption barrier comprising P-gP and CYP3A4. The former is a counter transport protein that expels the drug back into the lumen of the GIT whereas CYP3A4 is a metabolizing enzyme that metabolizes a wide variety of drugs. Both act synergistically a s barrier to the absorption of many drugs but both are saturable. Hence if we administer 2 compounds which a substrates of both P-gP and CYP3A4, absorption of both can be enhance if the system is saturated. Piperine may also increase the absorption of certain compounds (mentioned by someone else above) but not helpful to others.

The therapeutic index of cetirizine is not indicated by the recommended maximum dose of 10 mg/day. I belive the recommended dose was chosen to be 10 mg/day since it had the same efficacy as 20 mg/day in several randomized controlled trials. Not due to any toxicity.

When a side effect is listed as “common,” what does that mean? What are the odds of a “rare” side effect happening to me? It was news to me that these terms are actually very specific. The World Health Organization (WHO) defines categories as:

I found these definitions to be comforting. After all, a rare effect that happens to 1 in 1,000 to 10,000 seems safe. Then I pulled out my calculator. As an example, Crestor is one of the most prescribed drugs in America, through June 2015. It “rarely” causes liver damage (among other things). 21 million prescriptions for Crestor were written from July 2014-June 2015. Doing the math reveals that it’s possible that between 2,100 and 21,000 people in the US suffered new onsets of liver damage from taking Crestor each year.

The Kd could be higher than measured EC50 (or IC50). Explanation for this is in inappropriate assay conditions and in theory of "spare receptors".

You can read my last article which deal with it.

Natural products are a very important class of medicinal drugs. Roughly 25% of all drugs are derived from natural sources. For your particular product, a good starting point would be the products history. If people have been taking this product for many centuries (eons?), then the risk of adverse effects is very low. However, standard toxicity tests and carcinogen tests should be performed. Beyond this, I would recommend testing for heavy metals and persistent environmental toxins (pcbs, etc.). Also, there are requirements in the US for vitamins (not sure how much supplements apply). These are listed in the DSHEA standards.

It also can be in situation when API have a long half-life period and expressed two-conpartment PK. In this case absorbtion time will strongly affect on Cmax, but not on AUC.

If you have two formulations with a differece in dissolution and this type of PK you can get same AUC and significant difference in Cmax.

Model in attached file.

You do not specify any particular drug, which is understandable given the number of drugs to consider, so I would offer this general advice. You should inform the patient about possible harmful or dangerous side effects, anything that would affect the efficacy of the medication, and either inform or question about circumstances that would increase the likelihood of an adverse event or lessened medication effectiveness.

For instance, you should inform the patient about side effects that can be harmful (drowsiness, seizures, rash and/or allergic or anaphylaxis, tachycardia, fainting, nausea, etc.).

Also, the best regimens... take with food or on an empty stomach, finish all of the medication, what to do if you miss a dose, etc.

Finally, anything that affects the above. For instance, don't take an antidepressant with certain cold medications (with antihistamines, alcohol as a solvent, etc.). Also, check previous prescriptions for interactions and tell them, even if the prescription is old. (Some patients keep old meds around for a rainy day.) even if you think the patient does not have another med around, verify and/or warn the patient to be careful.

Also, when informing about side effects, tell the patient the symptoms and/or warning signs that he/she should recognize as a possible problem, and what to do. (Call the pharmacist, MD, go to the emergency room for certain symptoms, etc.)

These are all patient, profile and drug specific of course. The role of the pharmacist is to look for potential problems and educate the patient on how to avoid problems, how to react to them, and how to best use the medication for maximum safety and effects.

Hope this helps!

The frequency (whether rare or very rare) speaks to how likely the adverse effect is to be a problem. If an adverse event is rare/very rare, then the benefits of the drug is likely going to outweigh the risk. This is especially when the disease condition is serious.

LexiComp is the as it give an up to date information and I find very handy and user friendly.

Micromedex®

CIOMS generally gives this classification :

The frequency of ADR is often determined during the clinical trials, although clinical trials are more designed to assess efficiency than to detect side effects (as clinical trials do not include more than 3000, it is for example impossible to see very rare ADR).

During those clinical trials ADR are assessed with an imputability method, as it is done in real life with pharmacovigilance.

When a patient has a symptom, those data helps health professionals to see if it could be or not an ADR, and if so stop or not the drugs if needed (and ask an expertise).

No adverse effects are not enough to present bad profile of the drugs. Idiosyncriatic reactions and role of genetics, metabolism in short pharmacokinetics and dynamics both are important.

I suggest you take a look at the public protocols of institutions such as WHO or the European Union

Hi Kim, I don't have much info. in this field, but I can collaborate with you on this project. You can assign me the points needed, and I'll work on it.

Not only the half-life but also the metabolites. If the metabolites are well tolerated then the half-life alone will be a good indicator as long as the body could excrete them all

Side effects or ADRs can occur in any patient at normal doses so make sure to exclude excess doses as they are errors/adverse events and not Adverse drug reactions (ADRs). Secondly, exclude alternative causes (contraindications, enivronmental or genetic causes like G6PD etc).

Search in references for documentation of ADR. Establish a temporal relation for suspected drug causing an ADR and evaluate using algorithm scales like Naranjo scale, inorder to identify whether suspected drug is an actual cause of ADR or not.

Careful evaluation should be done before flagging a medication for allergy as sometimes ADRs or intolerance are misterpreted as allergic reaction.

Very nice topic to discuss and participate

1. Classification using A, B, C, D for other issue is not suit able as these are already adopted by FDA safety categories to use drugs in pregnancy.

2. Even if one uses such classification that will be much more complex because a single drug has multi system side effects .

3. If you consider nausea as class A, Diarrhoea B, Constipation C, Vomiting D, Gastric Ulcer E, Stomatitis F, Metalic test G, Anorexia H, Insomnia I, Dizziness J, Fits K, Vertigo L, Headache M, Treamors N,

3.I mean to say long list of side effects they not be classified as you suggest even it will further complicate pharmacology of drugs to learn and remember

for the first concern of safety between two drug one parameter is LD50. this will allow to find toxicity level of drug and second is ED50. suppose two similar drug has A and B has LD50 1500 mg/kg and 2000 mg/kg. their therapeutic dose should not be reach 0.2 of LD50 that is 300mg/kg for A and 400mg/kg for B. however several possibilities could be there for efficacy of them. nay be B is effective equal to A in less dose that mean we dont need to give 0.2 LD50 of that so this is the mater of experiment which will let you know which drug is more effective and less toxic.

There are assumed to be multiple mechanism, though one of the important mechanism is activation of the fas present in the surface of sertoli cell by increasing expression of fas ligand.

for more details, you can refer to the review (figure 4 ). Here is the link

https://www.researchgate.net/publication/308910902_Review_on_crosstalk_and_common_mechanisms_of_endocrine_disruptors_Scaffolding_to_improve_PBPKPD_model_of_EDC_mixture  

Thanks, Kannan Vadivel for your response. Can you cite any example to support your answer?

Dear Wen,

Now, with the help of the additional info, it's more clear what you intend to do/conclude with the model fitting.

I just took a quick look at your data. Are you able to include the raw data (I mean,  the dissolved amount vs time for the 4 formulations, including the replicates which I guess are available)? and then let us perform the fitting and interpret the results?

There is no better diagnostic tool that plotting the data and look at the resulting charts! Calculations are the second step (at best).

Additionally there is a negative R2 for Form.A, zero order which "seems" quite odd...

Based on the table you sent I can't conclude that Korsmeyer-Peppas is "better" than Higushi just because the average R2 is larger that the other, without looking/analysing the raw data.

Taking the risk of being unfair (because I haven't see the data) to the people who questioned you about the <0.99 R2 I would say that they are most probably not familiarized with drug release/dissolution modelling and came up with that "0.99" value, out of the blue.

Similarly an R2 of 0.80 may be extraordinarily good in some situations or can be unusable and meaningless in others - I'm afraid to disagree but there are no hard general rules of thumb to apply here. These are case based decisions.

Regarding "My understanding is that R-square of >0.99 are required for prediction models, such as calibration curves,"--> NOT TRUE "... but are expected to be lower for experimental data" ---> Not TRUE (but I would in general expect a lower R2 when fitting the model as the dissolution data includes the contribution of a lot more sources of experimental variability than a "simple" calibrationb curve).

An R2 of 0.99 (or larger) reflecfts an unusually very high overall precision (and results from the fitting of a model to the average of a large number of replicate dissolution data). In addition and obviously, the fitted model must be "right" one.

Your last paragraphs reveals that you do understand properly the limitations of R2 and addresses a really important point. That is why I (we) wanted to get the raw data in order to provide an accurate answer.

Again, are you able to share the raw data (time, dissolved amount or %) for each of the 4 formulations (please share the individual profiles not only the average profile, otherwise it will be difficult or even impossible to conclude which is the "best" model to describe the drug release kinetic.)

Regards, Luis

Hi, 

For oral route, try hydroxypropyl beta cyclodextrin, it will increase solubility much better than natural cyclodextrin (beta or alpha cyclodextrins)

If you prefer the co-solvent option, make a ternary mixture (PEG400 30%/Ethanol30%/water40%) it will be better and much tolerated than pure PEG

best regards,

With IP, drug is absorbed into the mesenteric blood supply that is carried directly to the liver such that it is subject to hepatic first pass metabolism; only GI lumenal metabolism/efflux is avoided.  Accordingly, systemic exposure after IP administration is typically less, and sometimes substantially less than that after IV administration if the drug is subject to FPM.

IP is a short-cut/convenience route of administration that you will ultimately end up needing to compare to IV (and to oral if that is an intended route); why not use IV in the first place and avoid the uncertainty?

Thank you Hajra for your response; it is very helpful.

Tricky one. Pretty much every single blood composition parameter is variable on a population level (and over time within a single individual). Probably the least variable in terms of percentage is Na+ concentration. Cl- and Ca2+ are also fairly tightly controlled. But I don't think there's a single compound that will do it. If you're looking for a value to normalise to, your best bet might be a combination of two or three relatively constant parameters

If I understood the question in general from my experience I would have acted like this:

maximum single dose - the largest amount of the drug during the regular treatment regularly causing toxic phenomenon, and has a positive therapeutic effect (typically three to four times is a value medium therapeutic dose)

- maximum daily dose - the largest amount of the drug taken in the time period of 24 hours, does not cause toxic phenomena (typically amounts to three times the maximum single dose) to achieve the desired daily your project maximum tolerance dose (MTD)!

Thank you very much Juan Manuel Serrano-Rodriguez. I will read these chapters.

kind regards

This is a  general question and as mentioned before there is no easy answer. The answer would depend on several aspects. For example is this an academic exercise or a drug discovery project? Second how many compounds are we talking about? Third what are you going to use the data for? Also when you say lypophilic compounds, there is a wide range of lipophilicity. As a general rule, again talking about oral absorption to narrow the discussion down, two factor, in general, that influence oral absorption. First is permeability and second is solubility. Usually compounds with log P of 1-3 has better permeabilty although there are some exceptions. There are software that can usually predict these two parameters fairly well. But you have to do some studies on a few compounds to confirm the prediction. Now bioavailabilty is a composite of oral absorption and first pass effect. The compound could be well absorbed but shows poor oral bioavailabily. You can get an idea about first pass by determining the metabolic stability using in vitro system such as liver microsomes or hepatocytes, although IV clearance in animal is the best estimate of first pass effect. I would suggest that the compounds that shows the best permeability and solubility and low metabolic stability can be tested in a PO/IV study in animals (usually rats or mice). When you do the PO study it will be best to dose it as a solution to avoid compromising bioavailability because of low solubility. There are many relatively safe vehicles you can use to solubilize  hydrophobic compounds (Gad et al., International Journal of Toxicology 2016). One of them I used a lot is 20% aqueous hydroxypropyl beta cyclodextrin for both IV and oral administration..Hopefully this will help

 Thank you so much. In fact I'm trying to test the  inhibatory effect of drug  combinations against cell line in vitro. I maked different combinations and I have the results now i'm trying to present the results in isobolograms, so my question haw can I make it( Drug 1 in absciss, drug 2 in  ordinate like  the figure mentioned before), In fact like this article 

Hi Jingxian,

I'll send you an email.

Regards,

Deji

Hi, 

metformin is usually administered ip in mice at dose ranging drom 50 to 250 mg/kg

1) Metformin inhibits the growth of human pancreatic cancer xenografts.

Kisfalvi K1, Moro A, Sinnett-Smith J, Eibl G, Rozengurt E.                                   Pancreas. 2013 Jul;42(5):781-5. doi: 10.1097/MPA.0b013e31827aec40.

2) Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models. Lengyel E, Litchfield LM, Mitra AK, Nieman KM, Mukherjee A, Zhang Y, Johnson A, Bradaric M, Lee W, Romero IL. Am J Obstet Gynecol. 2015 Apr;212(4):479.e1-479.e10. doi: 10.1016/j.ajog.2014.10.026. Epub 2014 Oct 19.

Hi!

I would recommend to set up your normalization and later analysis using a couple of tool compounds as positive and negative controls. I.e., a regular cell  inhibitor which mechanism of action is not involved with your overexpression target would not be likely shifting your EC50 values neither the curve slope; the other way round, using a pan-killer of your desired target would give you the expected shift.

Once you have established the proper way to analyze your data, then you can proceed your analysis with confidence.

All the best!

not necessarily. The aim pursued will be a therapeutic effect, We will compare the achieved effect using a second drug in relation to a first drug (reference) , if we obtain a better result with another route of administration which is also more comfortable, as example oral route instead intravenous, the result will be still more valued (it's an improvement). We can compare effcicacy/safety  and pharmacokinetics (concetrations) results althought the used routes were not the same. By the other hand if we want to do a comparison for a bioequivalent drug, then:  Yes, we need use the same administration route, because we want another drug able to sustitute the reference drug, with the same conditions and results. 

measuring galutamyl transferasemma g

The attached paper nicely describes the protocol for ECG measures in relation to drug dosing. Hope this helps.

One of the main differences is on p53 expression. In this way, HepG2 cells carry wild-type p53, whereas Hep3B and Huh7 cells have null and point mutations at p53 codon 220 respectively. 

This paper will be of great use for you : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3061558/. 

Good luck. 

Thank you.  This article is what i needed.

Are there any correlation-based methods to at least calculate RES clearance based on size and composition?

So hepatic clearance is very minor for liposomes?

Factors determining the extent of placental transfer:

1.     The molecular weight of the drug:

Most drugs with MW < 500 Da cross the placenta, and most drugs with MW > 1000 Da do not cross the placenta 

 

2.     pH and pKa:

Drugs with a pKa near 7.4 will exist in a partially non-ionized state, and are associated with high placental transfer. Drugs with a pKa > 7.4 are associated with less placental transfer.

Non-ionized drugs tend to cross the placenta more easily than ionized drugs, however the fetus usually has a lower pH than the mother, leading to “ion trapping.”

3.     The extent of drug binding to the plasma protein:

Traditionally it was taught that protein-bound drugs did not cross the placenta, however as these medications exist in equilibrium with non-bound versions, it appears that this is not true

4.     Lipophilicity :

While liphophilicity is generally advantageous with regards to placental transfer, extreme lipophilicity may impede transfer as highly lipophilic substances can accumulate in the placenta

 

5.     Volume of Distribution:

Vd = total drug / [drug]plasma. In pregnant women, who have increased plasma volume (and body fat), Vd increases.

 Hi Dr.Hansang Row 

I think you must make the Safety Pharmacology Test, the single dose toxicity test, as well as the tolerance Test. Please follow this attached paper as a detailed method

i have solved this problem of quercetin. if you are using pure quercetin. then you can dissolve it in 60% DMSO and then decreasing concentration further, wht i have done i have reduced concentration of DMSO to 1 %, then. for final experiment. If you need help of my calculations Do ask i will help.

Drug interacting with simvastatin could work but there is also a lot of non-medicated products that will interact with simvastatin as well, such as grapefruit 

Hi Renato

As I know

Half life of  Phentolamine 19 minutes, also you can certify  from drugbank.

Regards

This is an interesting problem with a surprising answer. I downloaded the free compusyn software without much trouble. Looked at the video available on the compusyn website. Unfortunately the demo shows the professor using already saved data. After searching for an hour for a guide for compusyn, there was apparently none...so how to enter data? Well, you fill in the title of the experiments,

1. click new drug. 2. inputs your drug name and units for the dose (uM). 3. Enter the first  SET of dose+effect values. dose = 100, effect = 0.96 (e.g. 96% cells killed etc). 4. Press ENTER on your keyboard for data to be saved,  5. Type next set of dose/ effect data, Press Enter.  repeat process until all dose-response values are saved. 5. press finished. 6. to enter dose/response data for drug#2, repeat whole process starting by cllcking "new single drug". I found it possible to enter data for two single drugs, data for the combination (fixed ratio) or else combination of drug one (at IC50) + range of values for drug 2. The "enter" key is not on the program interface but uses..you keyboard. It was worth the trouble, as managed to complete the whole analysis within about one hour once, the problem of "entering data" had been surmounted. Best W.

As suggested by Tanja there is no specific or general answer for this. It very much depends on the permeabilities and bioavailbilities of the compound in question, which relies on the chemical properties of the compound. In a VERY general sense, a subcut admin can be similar to an i.v. if the right vehicle is used, however an i.v. is usually a bolus and s.c. is more slowly absorbed from the sub cut deposit. If you are giving oral, then the oral bioavailability is important (e.g. If the compound has a ED50 of 1mg/kg i.v. in vivo, and it has a 20% oral bioavailability in the species you are using, then you should give 5mg/kg oral to obtain the plasma ED50). But remember that oral dosing, as well as the majority of i.p administered compounds will be subject to first pass metabolism in the liver... An i.p dose is difficult to judge from an i.v. dosage regime, and may be comparable to sub cut, but this depends on the vehicle/excipient in which the drug is dissolved/delivered...

The best you can do is start with the maximal effective dosage found in an i.v. case and use then same dose in an i.p. and s.c., OR tailor the dosage for oral depending on its F%.. If there is NO i.v. data, or pharmacokinetic data, available then use a conservative dosage and try to perform a dosage-response study to determine the best dose required. Certainly i.v. bolus has the highest bioavailability by definition (i.e. F%=100), so any plasma/blood exposure below that, as seen in s.c., i.p. and oral dosing for instance, is likely (but NOT definitively) be LOWER than that given the same dose in the other route. Any drug will usually have a slower absorption from an s.c., oral or i.p route than i.v., and therefore will not reach the same Cmax, AND have a later Tmax as i.v.: therefore a longer total blood exposure is expected, even though the same total amount may be absorbed (i.e. 100% (F) in the best of cases).

All this based simply on how much is absorbed from the 'other route' to the blood, compared to i.v. (i.e. as is F% for oral, the F% exists for all routes). The total amount absorbed depends heavily on it's permeability through different in vivo biological barriers (i.e. gut/blood vessel walls) and metabolic stability. This in the end is dependent on

1/ the PK/PD of the compound (which relies on it's physicochemical properties)

2/ the vehicle/excipient used and

3/the species chosen (an how it compares to previously collected data).

I'm sorry for the long-winded answer, but I hope it helps with some insight.

Good luck!

Hi Reagen,

Can't offer too much help about the assays, but biphasic will not work for your data (biphasic needs the drugs at similar effects at both curves, e.g. 100% to 50%, then 50% to 10%), as your drugs appear to have opposing functions at various concentrations (e.g. drug A at high nM conc appears to offset its own effect at low nM conc). A possible better model will be bell curve (http://www.graphpad.com/guides/prism/7/curve-fitting/index.htm?reg_bellshaped_dose_response.htm), which will give you EC50 1 and 2.

There is no standard method of coating plates on an impactor. The coating by reducing re-entrainment of particles aims to reduce variability. But the type of coating largely depend on the type of formulation or in other word on the characteristics of the DPIs. MIcronized lactose or more classical coarse lactose based formulations do not require particular coating. At variance ultrafine powders not requiring deaggregation mechanisms may be "resistant" to any type of coating and the NGI is not the ideal impactor. In these cases Andersen of MSLI are much reliable.

To come to you question you may compare variability without coating and after different coating systems.

At the links below you can some information I hope you will find useful. One of the link is on a paper on this topic I found here on Research Gate.

Hi Jinhu, in an ideal case, these two approaches should give the same result. However, when the affinity of antibody to the beads is not ideal, using the direct method is recommended. I guess in your situation it should be fine, if the indirect method is already working for you.