What is the maximum safe dose for a drug based on its cyto-toxicity and dosage?

[Jennifer100]

If you had the following information on Cyto-Toxicity of a drug:

the relative viability on (human) cell lines are high (Above 90%) even under higher concentrations of the compound (hundreds of micro-molar). Cyto-toxicity should be minor concern.

What would you assume to be the maximum safest dose of that drug? (For a daily dose, and also for a one-time-only dose) Based only on the above information.Im only asking for the best educated guess based on the above info that you can come up with, since you obviously could never know how safe the drug was without years of testing

For example, would it be highly probable that 250 mg would be safe? Or would it be fairly impossible to make any good guesses only using the above information

 

[mtc1973]

Human cell lines are mostly cancer cell lines - and extremely good at transporting drugs out of them - and have a much higher toxic/lethal dose than 'real' cells. Therefore, you could never infer from a cell line the information you are trying to infer.
There just is no way to infer - hence why the process includes years of testing.

 

[Jennifer100]

if you are just looking to find out more info on what the odds are that a specific amount of a specific compound would kill a human is it more efficient to test the compound on a dog or a rat? What I mean is, why would testing on a rat be more efficient than testing on a dog? (To get information on that) Is it just that there are more rules in place against testing on dogs? What animal would be more efficient to test on than a dog or a rat?

 

[nismaratwork]

I don't see any way around what mtc1973 said, none. Pharmacokinetics/dynamics are just not that simple... which is why we still test and STILL end with recalled drugs.

 

[Jennifer100]

what are the reasons that people prefer to test drugs on beagles rather than other dogs? What are the pros of testing drugs on beagles instead of other dogs?

 

[mtc1973]

Standard genetic line - like any other animal model. You use a model that has been bred so that all members are simiar and carry similar genetic code - that way experiments are less confounded by genetic variability. The dog doesn't matter as long as they have been bred carefully. You could take a mongrel and back cross it and breed it to a genetically similar breed (and I don't mean to a beagle!) - but that has been done already with pedigree dogs so why reinvent the wheel. Also beagles are naturally social and love packs - very little fighting between them when housed together because of their very social nature. It means keeping them in large groups communally is logistically easier.

 

[nismaratwork]

I'd add, they have a BBB that is closer to human than some other breeds, such as Collies.

 

[Jennifer100]

why not use a goat, or pig, or something instead of a dog?
assuming they were fine with being housed together and that the ones you are using are have genetic code that is similar to each other's

 

[Jennifer100]

Specifically what did you mean by BBB? Did you mean they have closer genes to a human than a collie does?

 

[Jennifer100]

also can they just put the drugs into meat and feed it to the dog that way- or does giving the drug to the dog with food change the drug somehow?

 

[nismaratwork]

why not use a goat, or pig, or something instead of a dog?
assuming they were fine with being housed together and that the ones you are using are have genetic code that is similar to each other's

Goats are not used in such a fashion, but pigs are very close to being perfect human analogues for GI and Vascular issues. In fact, drugs are tested on a number of animals.

As for BBB: Blood Brain Barrier; Collies have a notoriously permeable one. I was illustrating why a standard genetic line in any given animal is key as a control/test.


For the record... I hate the idea of animal testing, but that doesn't stop me from knowing the protocols. Usually, cell lines, mice, pigs and dogs, and then if necessary primates, and finally humans. Never forget that last one, because for all the rest, every drug is a fundamental test of its long-term effects in an unpredictable population.

 

[Jennifer100]

If anthraquinone derivatives, or a different component of a compound, are being used to achieve a certain effect but that effect is very sensitive to a slight modification of the anthraquinone derivatives, or another component, of a compound that is being used to achieve that effect,
what does that mean?

Does it mean the compound would not be consumed orally, because the stomach would modify that compound? Does that mean the compound can't be eaten with food food, because if it was on top of food or mixed in or something that would modify the compound? Would the stomach modify the compound enough that it wouldn't work- would it have to be adminstered through iv, or nothing? Or does that just relate to things like the temperature of the compound? I am just confused about what "sensitive to a slight modification" means in that context

 

[nismaratwork]

If anthraquinone derivatives, or a different component of a compound, are being used to achieve a certain effect but that effect is very sensitive to a slight modification of the anthraquinone derivatives, or another component, of a compound that is being used to achieve that effect,
what does that mean?

Does it mean the compound would not be consumed orally, because the stomach would modify that compound? Does that mean the compound can't be eaten with food food, because if it was on top of food or mixed in or something that would modify the compound? Would the stomach modify the compound enough that it wouldn't work- would it have to be adminstered through iv, or nothing? Or does that just relate to things like the temperature of the compound? I am just confused about what "sensitive to a slight modification" means in that context

Hmmmm... is this an academic question, or a 'homework-help' question? How to proceed really depends on that, because there is an easy answer, but if this is meant to be a learning experience, you can still get help here... just not the flat-out answer.

I will say this... One of the uses for anthraquinone is a laxitive... what does that tell you?

 

[Jennifer100]

its an academic question not a homework help question;
but would it mean the compound would have to be administered via the blood, and not through eating it? Would that also mean it couldn't be taken with food? Since the effect is sensitive to modifications to components of the compound? I am just confused by what that means

Or does it just mean, don't change the temperature and other things about the components of the compound since the effects could be changed by modification to the components of the compound?

 

[nismaratwork]

its an academic question not a homework help question;
but would it mean the compound would have to be administered via the blood, and not through eating it? Would that also mean it couldn't be taken with food? Since the effect is sensitive to modifications to components of the compound? I am just confused by what that means

Or does it just mean, don't change the temperature and other things about the components of the compound since the effects could be changed by modification to the components of the compound?

It's very hardy, and very bioavailable; up to 91% throgh oral administration. In short, this just means that you need to match your desired outcome with this multi-use drug, to serum levels.

Lets say you're using this to treat asthma... well you'd use oral administration to achieve around ~80%-~90% availability which is what you want, and doesn't present a metabolic risk. As the dose of this rises, the available compound for treating asthma (anthraquinone 2-carboxylic acid) has an inverse relationship to dosage given orally.

So, if you need to have a very HIGH level maintained, you'd need to buffer it, or administer it through other means.

 

[Jennifer100]

what are the reasons to not use purebred huskies when testings drugs/compounds on dogs?

 

[Jennifer100]

Is it true that the more genetically similar the animal is to humans, the more it can tell you about how toxicity of a drug will affect a human? therefore, would testing on cats and dogs yield more accurate results than testing on rabbits, when it comes to testing on animals to try to predict human toxicity of a drug?

 

[Ryan_m_b]

Is it true that the more genetically similar the animal is to humans, the more it can tell you about how toxicity of a drug will affect a human? therefore, would testing on cats and dogs yield more accurate results than testing on rabbits, when it comes to testing on animals to try to predict human toxicity of a drug?

It really depends on the drug. Ideally you want to be as close as possible with genetics to a human but you also want to be as close as possible in proteomics. Some species are less related genetically but are better at simulating specific systems or tissues. Other species such as drosophila have only 50% genetic similarity and 70% protein (if i remember that correctly, its been a long while since I've worked in a drosophila lab!) but are useful for development and genetic studies. They're also quite good because they breed in large numbers and through generations very quickly.

Drug testing is a very wide field, it's not really as simple as "test the closest to human". If we had humans that we tested on there's a lot of work we couldn't do, such as how genetic diseases progress across generations unless you want to go to the expense and time of breeding thousands of people for hundreds of years.

I wish we didnt have to test on animals but there is no alternative at the moment. Hopefully over the next several decades our progress with tissue engineering and regenerative medicine will provide us with fully formed in vitro tissues/organs to test on instead.

 

[Jennifer100]

What are the reasons to not test drugs on cats instead of dogs? Don't dogs and cats have around the same amount of genetic difference to humans?

(Although obviously there's a lot of variables like what drug is involved)

Which is better; cats or dogs (If you're taking into account specifically the proteomics of cats versus the proteomics of dogs)

 

[Ryan_m_b]

I'm not entirely sure however I do know that cats are primarily used in neuroscience research whilst dogs are more used for drug testing. As you point out the variables of what you are trying to test make a difference, also note that genetic difference is far from being the sole contributor.

As we have already conducted decades of research on cats and dogs (and drosophila/mice/rats for that matter) we already have a detailed understanding of how their biology matches/differs from ours and have designed standardised protocols for dealing with them. If we were to switch to another animal it would take further decades of research to get to a point where the use of said animal rivals that of a cat or dog.

Which is better; cats or dogs (If you're taking into account specifically the proteomics of cats versus the proteomics of dogs)

A quick search didn't give me any indication that the proteome of dogs and cats has been fully mapped. Even if it had depending on what you want to test would decide what you wanted to use. If drug X affects the Shapes system# and that system is both inherit in dogs and cats then your choice of what to use changes to include costs, ease of access, systemic effects etc etc etc

I'm afraid there is no simple answer to your question, we can't make a list of "best animals to use" and rank them. What animal to use depends on what you are testing (does it even have to be an animal? What about plants/bacteria/cell culture?), what animal models currently exist and a multitude of other concerns.

#(--> = activates --| = stops) Square --> Circle --> Triangle --| Circle

 

[Jennifer100]

how much better is a rabbit to test (to determine potential toxicity of a drug on humans) on than a rat? In terms of its genetic similarity to humans and how much worse is a rabbit to test (to determine potential toxicity) on than a cat or a dog? in terms of its genetic similarity to humans (in regards to just genetic similarity to humans; I know that there's other variables involved in animal testing)
because for example I read this

http://wiki.answers.com/Q/Are_rabbits_part_of_the_rodent_family
Contrary to popular belief rabbits are not part of the rodent family although they look very similar. They are part of the Lagomorph family, which are more closely related to horses due to similar methods on how their digestive systems function.

Read more: http://wiki.answers.com/Q/Are_rabbits_part_of_the_rodent_family#ixzz1IFKO1opJ

 

[Ryan_m_b]

I'm sorry but I'm going to have to quote my previous answer to answer this question

I'm afraid there is no simple answer to your question, we can't make a list of "best animals to use" and rank them. What animal to use depends on what you are testing (does it even have to be an animal? What about plants/bacteria/cell culture?), what animal models currently exist and a multitude of other concerns.

May I ask why you are asking? No offence but it seems like you are reeling off one question after the other without reading the answers

 

[Jennifer100]

Is there no alternative to testing drugs/compounds etc on animals that is just as good as testing drugs/compounds etc on animals? because I read this on wikipedia


there is no alternative to testing drugs compounds etc that's as good as testing drugs compounds etc on animals right? Since I read this on wikipedia

http://en.wikipedia.org/wiki/Alternatives_to_animal_testing

Two major alternatives to*in vivo*animal testing are*in vitro*cell culture techniques and*in silico*computer simulation.**Others say that they cannot replace animals completely as they are unlikely to ever provide enough information about the complex interactions of living systems.[2]*Other alternatives, not subject to this criticism, involve the use of humans for skin irritancy tests and donated human blood for pyrogenicity studies.

 

[Ryan_m_b]

Two major alternatives to*in vivo*animal testing are*in vitro*cell culture techniques and*in silico*computer simulation.**

It depends on what you are testing but the answer is essentially no, there is no current replacement for animals. Cell culture does not represent the workings of an organism well as they do not create interacting 3d, representative models. However there is a drive to improve our ability to grow human tissues and organs in vitro for testing but we are a long way from being able to do that.

Whenever someone mentions in silico I cringe at their lack of understanding. We can't even simulate how proteins fold with much accuracy or speed, to simulate the entire human body (you would need to do it atom by atom) would require computing power far in excess of anything of our wildest dreams. A bigger problem of that is that any computer simulation that realistic would be able to feel pain, have emotions and thoughts. You've moved the ethical problem from in vivo organisms to in silico

 

[Jennifer100]

If you order what is most genetically similar to humans in this way

Rats Less so than rabbits, rabbits less so than cats and dogs, cats and dogs less so than primates...


where would intelligent parrots, dolphins etc go? Approx? Would they be between cats & dogs & Primates?

 

[Ryan_m_b]

If you order what is most genetically similar to humans in this way

Rats Less so than rabbits, rabbits less so than cats and dogs, cats and dogs less so than primates...


where would intelligent parrots, dolphins etc go? Approx? Would they be between cats & dogs & Primates?

"Intelligence" isn't a measure of how genetically close something is to humans. Cats, dogs, primates and rodents are all more similar to us than birds because they are mammals like us. Dolphins are also mammals so they would be closer to us than birds but as our common ancestor was so long ago we are closer to cats, dogs, primates and rodents (who we diverged from far more recently)

When you ask how genetically similar something is you are essentially asking "how long ago did our evolutionary lineages diverge"

 

[Jennifer100]

What animals are closer to humans genetically than dogs cats and pigs but less close to humans than primates; and what animals are closer to humans genetically than dogs cats pigs and primates?

 

[Ryan_m_b]

Google "mammalian phylogeny". You can find all sorts of diagrams showing the relatedness of organisms, here's two I found that may help you

http://whozoo.org/mammals/mammalianphylo.htm

http://bit.ly/h0xKAC

 

[Jennifer100]

because collies have such a notoriously permeable blood/brain barrier; how much worse is it to test the toxicity of a drug on collies and/or dogs with some collie in them, than it is to test on other breeds? (just looking for opinions/approxiamete info)

 

[Ryan_m_b]

It depends on what you are testing for. If you want to test a drug and it kills the collie due to CNS toxicity then you would want to account for how the drug may behave differently in other animals.

 

[Jennifer100]

I noticed from reading that:

Beagles have a blood brain barrier that is closer to humans than collies
Collies have a notoriously permeable blood brain barrier
So in that regard beagles are better for testing than collies

But what are the upsides and downsides of testing on dogs that are:

jack russel terrier
Huskey
Australian Shepherd
Heeler

and dogs that are a mix of those? For example do huskies also have a notoriously permeable blood brain barrier?

 

[Jennifer100]

Do you mean that, if the effect of a compound is sensitive to modifications of the compound and/or components of the compound; that as the dose of compound rises, the available compound for treating what you're trying to treat has an inverse relationship to dosage given orally. and that as a result, if you need to have a very HIGH level maintained, you'd need to buffer it, or administer it through other means.

Or were you just referring to a specific drug when you said that and not answering my question, specifically, about what a compound (or components of a compound) being sensitive to modifications meant thanks