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Prodrug Strategies for Brain Targeted Delivery of Antiparkinson Agents

The brain is one of the least accessible organs for the delivery of drugs. The mechanisms that protect the brain from foreign substances also restrict the entry of many therapeutic agents in the treatment of fatal CNS diseases such as brain tumors, HIV, encephalopathy, epilepsy, cerebro-vascular diseases and neurodegenerative disorders. Despite its relatively high blood flow, blood–brain barrier (BBB) is a strong hurdle that has to be crossed for efficient delivery of any bioactive agent into the brain.

The development of new drugs for the brain has not kept pace with progress in the molecular neurosciences, because the majority of large-molecule drugs and greater than 98% of small-molecule drugs do not cross the BBB. More than 99% of worldwide CNS drug development is devoted to CNS drug discovery with <1% of the efforts devoted to CNS drug delivery.

The available strategies for CNS drug delivery include intra-ventricular drug infusion, intra-cerebral implants, BBB disruption, liposomal delivery, carrier /receptor-mediated transport and prodrugs.

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterized by bradykinesia, postural instability, rigidity and tremor due to specific loss of dopamine neurons in the substantia nigra pars compacta. Dopamine deficiency appears to be responsible for the motor deficits of the disorder but PD cannot be treated directly with dopamine or related catecholamines due to their extensive first pass metabolism and poor permeability across the BBB. L-dopa, a prodrug of dopamine, still remains the most clinically useful drug for treatment of PD but suffers from many drawbacks. To improve pharmacological and pharmacokinetic properties of dopamine and L-dopa, numerous attempts have been made for their targeted delivery to brain through prodrug approach.

This presentation will highlight current status of antiparkinson therapy, drawbacks of BBB, need for brain targeted delivery, various prodrug strategies and recent trends for efficient delivery of antiparkinson drugs to brain.

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Comments

hi.
thats a nice work done by u hrushikesh.my question is that seligilline its a MAOB inhibitor.why cant it be used in single.can u say the reason why it is used in combination with L-dopa?

Dear Sridivya Palacharla
selegiline undergo extensive hepatic metabolism to give metabolites as meamphetamine and subsequently amphetamine and thus potentiates the pharmacological actions of L-Dopa. Also these metabolites produce hypertensive crises so its use in single doses is avoided.
The only reason behind use of this drug in combination with Levodopa is this retards breakdown of dopamine and enhances and prolongs the anti Parkinsonism effect of Levodopa and may reduce on-off effects. Also its is used in those patients with a declining response to Levodopa.

That is good,in your presentation that some peptides are linked with L-dopa as a prodrug.Such linking increases the molecular size. But how can they overcome BBB.

What are the newer prodrug strategies for treating the parkinsonism

Dear Sir,
Nice observation. Now if u can have a close look over that slide, Peptides of no 10,11 & 20 you will come to know that those amino acids are of small molecular weight and only those were more effective than LD. In general, the peptides were relatively non-toxic and resulted in a low degree of stereotypic behaviour than LD. In short Levodopa is modified into Pseudonutrient structure, able to transport by neutral amino acid transporter.
There are various prodrug strategies for treating the parkinsonism which i have mentioned in the presentations and apart from those certain newer approaches are Neurotropin Chimeric peptides, Nerotropin pegylation, Implantation of electrode inside nigrostriatal region along with levpodopa therapy.

Lakshmi's picture

Sir,
Could you please clarify the following points:
1. In the flochart given in your presentation you have mentioned that the active drug released in systemic circulation would be immediately excreted in urine. Does it mean that only the drugs with a very short plasma half life are used in such systems?
2. Prodrugs are basically designed to increase the lipophillicity of the drug. but highly lipophyllic drugs are distributed more to fatty tissues due to thier abundance in the body. How can this be overcome?

Dear V.Lakshmi Indira

Nice Questions. The ans to your 1st question is as follow:
We are specifically interested in targeted drug delivery system to BBB. The question regarding half life of drug comes as and when drug will get penetrate inside the brain, but almost many times we are facing problem about penetration of these drugs in to brain as there are lot of barriers present. The Flow chart shown gives you information regarding how we can achieve drug delivery to Brain by Use of Dihydropyridine - Pyridinium Salt Redox System. Not only short half life drugs but also long acting drugs can be delivered to CNS or BBB through this carrier system.

Ans to 2nd question:
It’s true what u have said. Now in order to Enhance BBB permeability we sometimes need drugs manipulation. According to Pharmacokinetic rule for brain drug delivery or Lipinski’s “rule of five “ if we can achieve Log P value of the drug between 1.5 to 2.5 along with molecular weight threshold of drug between 400 to 600 Dalton, then most probably we can overcome this problem. So modify the drug in such a way that it will fulfil maximum requirements regarding penetration into brain and or try some specific Carrier mediated transport systems which I have mentioned in the presentations.

Sirisha Pingali's picture

hi..
you have mentioned abt the enzyme which destroy the drug reaching brain..Where are these enzymatic sites exactly present?

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Dear Sirisha Pingal,
Thanks for your kind interest.
The BBB, which segregates the brain interstitial fluid (ISF) from the circulating blood, is located at the level of the brain capillaries, where there is a convergence of different cell types: endothelial cells, pericytes, astrocytes and microglias (perivascular macrophages). The brain microvessel endothelial cells (BMEC) that form the BBB, display important morphological characteristics such as the presence of tight junctions between the cells, the absence of fenestrations and a diminished pinocytic activity, that together help to restrict the passage of compounds from the blood into the extracellular environment of the brain. The BMEC express a variety of enzymes, both cytosolic and on the extracellular membrane which also contribute to the restrictive nature of the BBB

Amol Malpani's picture

Dear Hrushkesh,
Can you explain something about physiological strategies for delivery of drug through BBB?
Regards,
Amol

Physiological strategies are cationic antibodies, Pseudonutrient and chimeric peptides. Pseudonutrient system i have mentioned in the presentation.

aukunjv's picture

Enough homework was not done!! New examples could be selected and cited. Dopa is older I guess!!

Respected Jithan Aukunuru Sir,
Its true that DOPA is older but still there is no any good option other than Dopa. There are certatin new strategies now a days used in Parkinson's treatment but all those needed combination therapy along with dopa. There is one Electrode implantation therapy is used now a days in that electrode is implanted in the nigrostraital region and it is used to stimulated dopa nerves to release dopa but along woth dopa therapy it is proved to be more effective. there are so many eg like this but Dopa has no any better option.

abherids86's picture

Hi

Nice presentation with good explanation.
Can to pro-moieties with hugely different effective doses administered together?

Thank You

hi thaks for nice question,
the answer is that,
No not at all. One needs to think chemistry also. Don’t look molecule directly through formulation point of view. If you can see basic chemistry, consider the molecule has a free –COOH gr then u can attach only one carrier to that drug to form amide or ester etc. That is you need to think mole is to mole ratio release from drug.
thanks

aukunjv's picture

Personal question!!

If you were to select liposomes, nanoparticles and prodrugs for brain targeting, what would you select considering cost, practicality and success? Development of prodrugs could consume lot of money compared to other forms. Is it not?

Respected Sir,
brain targeting delivery can be achieved using liposomes also. But the liposomes hold up a great disadvantage with them when used. The problem is that they get avidly uptaken by the mononuclear phagocyte system due to which they rapidly get eliminated from the circulation leading to reduced availability of liposome-entrapped drug to the targeted site. The major problem associated with nanoparticles is cytotoxicity and degradation. Liposomal delivery to BBB is rather more costly than synthesizing a prodrug with a proper knowledge of chemistry and functional groups. (You can refer this book Brain drug targeting: the future of brain drug development By William M. Pardridge)
if the compound is not chemically modifiable, then only these liposomes can be think but we should see chemical possibilities first because chemically modification has lot of advantages over these physical modifications. So i will prefer Prodrug concept.

anis0019's picture

Dear Hrushkesh,

Good Explaination...
What are the measures to improve biologically inactive prodrug?

Thanks!!!

Read it carefully.
Definition
Prodrugs are Chemically modified inert drug precursors which upon biotransformation convert to active moiety and show biological effects.
Ideal properties of Prodrugs
 Inert and nontoxic.
 It should not have intrinsic pharmacologic activity.
 Rapidly transform, chemically or enzymatically, into active form where desired.

Prodrugs are not active at all. They are metabolized to active drug upon metabolism. Prodrugs are biologically inactive so there is no question for its improvement measures. If at all prodrug is active then it won’t be call as a prodrug it will completely new compound.

ayushsinghal's picture

Mr.H.Kara,
Before going forth towards my question i would highlight few things that i felt lacking from my point of view as a viewer in your presentation.

1) No where i found any kind of limitations or drawbacks of any of the drug delivery system.
for inf: because of erratic oral absorption and gastrointestinal tract metabolism of LD, so that relatively little arrives in the bloodstream as intact drug.

2)Conclusion as such is of 4-5 points or max. a slide full. but yours is not just conclusion but its a summary.

Now moving towards question sections:-
1) What is the reason behind the fact that only very few drugs such as LD methyl ester (SIRIO®) have found clinical application in the field on antiparkinson therapy?

2)Is there any synthetically formulated CMT ? if yes please mention a few ones.

3)Is the nasal drug delivery a 100% safer one without any drawbacks???If no please mention which are those...

Thank you...

Ayush A. Singhal RPCP, CHANGA GUJARAT http://www.pharmainfo.net/ayushsinghal/biography

Respected sir,
If u can refer the slides again then you can see that i have mentioned the problems associated with L-Dopa and Dopamine which itself will give you idea regarding the drug delivery problems.
Sir actually there are only 4 points i have mentioned in the slide and those are BBB problem, Lack of view towards CNS drug delivery, prodrug strategies in this area, & future developments in Prodrug strategies in BBB drug delivery.

Now answering to your questions.
1. Now if u can see the chemistry or structure of L- Dopa there is free carboxylic acid group. And in brain this –COOH gr is decarboxylated to give us Dopamine which is essential in Parkinson’s treatment. LD has number of drawbacks which I have mentioned in the slides. Now on slides I have mentioned carboxy esters, phenol esters. Now if we can able to mask free COOH gr in the form of ester then we can achieve better bioavailability bcz that ester will 1st hydrolyse to acid and then acid is decarboxylated to Dopamine. Methyl ester is easy to prepare and also small molecule as compared with other esters to deliver to BBB.
2. Yes there are some drugs which are formulated as CMT. The use of L-DOPA for the brain targeting of dopamine, which does not cross the BBB, is a classical example of modification of the drug structure, with the aim of obtaining a prodrug as a “pseudonutrient” substrate for LAT 1. Nipecotic, kynurenic and diclophenamic acids were chosen as model compounds, being potentially able to induce therapeutic effects against important CNS pathologies - such as epilepsy, neuronal disorders, Parkinson’s and Alzheimer’s diseases - but unable to reach the brain from the bloodstream so with conjugation with Vit C and through SVCT2 system.
3. Limitations of nasal drug delivery system are very few drugs can be introduced through nasal delivery system as there are lot of barrier (mucus), polarity of the drug also matters much in this system.

anuja raut's picture

Dear Hrishikesh,

I have concluded from your ppp that only drugs with short plasma half lives can be used in this system. This might be a dwawback to this system. Right?

Are there any measures to overcome this?

Thanks

Dear Anuja

If you are talking about DOPA then yes dopa has short life. As Dopa is having prime importance in Parkinson’s treatment one has to think its basic problems as and when it enters to body. But it doesn’t necessarily mean that only Dopa like short half live drugs can be given in this system. If you have enough knowledge about chemistry, free functional groups in the molecule then one can achieve longer half-life drug delivery to brain without thinking of any formulation pattern. You use those carriers with which drug can penetrate inside the brain and have longer duration of action of that drug. If you can able to synthesize mutual prodrugs then u can have DOPA along with Carbidopa, Or DOPA with entacapon. Now let me tell you the marketed drugs having such combination are only physical mixtures.

Thanks

shilpa.sambana's picture

nice presentation,

You have mentioned the drug delivery through nasal route to target the brain
in such case what could be the way of delivery as nasal sprays or any other system.

And also depending on the system of delivery would there be any side effects to the lungs or pulmonary system.

thank you,

shilpa.s

shilpa.sambana st Ann's college of pharmacy

Thanks for such a nice question.
In my presentation I have explained you how Antiparkinson drugs have shortcoming and how prodrugs are suitable for delivery to BBB so as to overcome those shortcomings. Now regarding Drug delivery through nasal route what we have come across regarding Anti Parkinson’s prodrug is as follows.

Less than 1% of orally L-DOPA administered reaches the brain unchanged, being transformed to dopamine during first-pass metabolism. Dopamine induces, at peripheral, side effects such as nausea, vomiting and cardiac irregularities. L-DOPA is therefore a good candidate for nasal administrations, but, unfortunately, this drug is not very soluble. In the aim to improve the efficacy of liquid nasal formulations (> 10 mg in 100 μL), L-DOPA has been transformed in its butyl ester, giving a pro-drug more lipophilic and water soluble than the parent compound. The DOPA structure has been indeed changed from a zwitterionic form to an amine salt. In rat in vivo studies substantiated that after nasal administration, this prodrug resulted rapidly adsorbed into the systemic circulation and converted to L-DOPA without significant formation of dopamine. Moreover, an improvement of L-DOPA adsorption into CNS was detected in comparison with equivalent intravenous doses. It would appear that the utilization of water soluble prodrugs of L-DOPA via the nasal route may have therapeutic success in the treatment of Parkinson’s disease.

We are having more interest in Development of new molecules through prodrug concept rather than its formulation part. There might be some side effects regarding pulmonary system when nasal sprays are being used. But my job is not formulation but it’s of discovering new drug and tries to use various carriers (if required) along with it through different routes of administration.

Thank you.
Hrushikesh

Thank you sir,for such a nice explanation.But i want to know regarding the way of this dopamine administration through nasal way either as nasal drops or nasal sprays or else these ways are still in research level ....

regards

shilpa.s

shilpa.sambana st Ann's college of pharmacy

Dear Shilpa

Yes administration of dopa through nasal way by using various techniques are still in the research pipeline soon we will come to know about those techniques.

Thanks
Hrushikesh

thank you very much sir for your clarification

regards,

shilpa.s

shilpa.sambana st Ann's college of pharmacy
shilpa.sambana's picture

Can you please provide the branded names of the mostly used drugs for parkinson disease and also Alzeimer's disease

thank you,

shilpa.s

shilpa.sambana st Ann's college of pharmacy

Dear shilpa,
These are branded drugs used in Parkinson's treatment which are prodrugs.

Prodrug(s). Brand Name
Levodopa and Carbidopa. Timodate Forte (Torrent Pharma)
Levodopa Syndopa (Sun Pharma)
Levodopa and Entacapone Parkinate (Biddle)

chitrakaladhuri's picture

A nice presentation. Can you please listed few herbal drugs used in Parkinsonian state & their over all efficiency in treating the disorder with the possible hurdles . And its possibility of use as a modified prodrug.

Hi Chitrakala
Thank you so much for such a nice question. The ans is as follows.

Prodrugs concept can be used in case of Herbal drugs (not directly) because one should know the exact chemical structure responsible for giving Anti parkinson’s activity from that herb, for that we should study in detail evrey single chemical constituent of that herb So if that compound is known we can think for its prodrug provided all conditions to be satisfied by the drug candidate.

These are certain herbal drugs

Mucuna pruriens
Seeds contain L-DOPA (4-3,4-dihydroxy phenylalanine), glutathione, lecithin, gallic acid, glycosides, nicotine, prurenine, prurenidine, and dark brown viscous oil. It is a source of minerals According to Ayurveda, seeds are astringent, laxative, anthelmintic, aphrodisiac,
alexipharmic and tonic.

Vicia fava beans
Fava beans in Parkinson disesase :
Some small studies have shown that the levodopa in fava beans can help control the symptoms of Parkinson disesase, just as medications containing levodopa do. In fact, a few
people report that the effects from fava last longer than the effects from medications. Some researchers believe fava beans may contain other substances besides levodopa
that could be helpful for PD symptoms. However, although some people report good effects, others find no antiparkinson effect from fava beans at all; and still others report adverse effects, such as nausea and dyskinesia. Much more research needs to be done to determine how effective fava beans may be.

Ginseng
Ginseng roots have been found recently to help protect against cancer, cardiovascular
disease, and stress. These health-promoting effects are thought to be a result of high levels of antioxidants in ginseng called ginsenosides. In a recent study, researchers sought to find out whether ginseng, particularly the ginsenosides, could protect rats from a toxin that severely impairs movement and loss of neurons in the brain, they found that the leaves and stems preparation, which has greater levels of the panaxadiols (35.8% of Rb1, Rb3 and Rd), had the brain-protecting effects whereas the root preparation
26.9% of Rb1, Rb3 and Rd) had no protective effect. For the researchers, “the results suggest that the Rb extract may prevent [nerve damage] in Huntington's disease or other neurological disorders.

Ayahuasca
ayahuasca brew contains four main alkaloids, it is DMT which is the primary source of the
hallucinatory/entheogenic experience. DMT is a potent short-acting hallucinogen that is present in various species of plants found in temperate and tropical regions. Ayahuasca is interesting because it combines DMT, which is inactive when taken orally, with beta-carbolines. These tricyclic compounds have proserotonergic and prodopaminergic properties but lack hallucinogenic activity. However, beta-carbolines are potent inhibitors of the MAO enzyme. This MAO inhibiting activity prevents the oxidative deamination of DMT allowing it to exercise its effects on the central nervous system.
Zanthoxylum schinifolium
A methanol extract of the plant showed potent inhibitory activity against monoamine oxidase (MAO) in a mouse brain. Activity-guided separation and purification of the extract yielded lacinartin as an active coumarin compound. Lacitarin showed significant inhibitory effects on MAO in adose dependant manner. An enzyme kinetic study revealed that lacitarin inhibited MAO activity by a non-competitive mode and thus could help in Parkinson’s disease.

Ergot
Ergot Derivatives and Parkinson’s Disease: Recent studies involving
ergot derivatives in the treatment of Parkinson’s disease have investigated their effects on dopamine receptors. Most dopamine agonists employed at present are ergot derivatives.

If you still want detail information pls let me know i can give it.

Thanks
hrushikesh

Thanks for providing these details...& its interesting to know the controversial statements regarding the effect of Fava beans.

Good topic I must say!

It is said that in advanced Parkinson's disease, as far as the drug side effects are concerned, much depends on precise dosage and timing of dugs taken. If this is to be considered, would it be advisable to design the dosage form consisting your prodrug moieties in the form of pulsatile drug delivery? Would it pass through the BBB in this case if suitable polymers are used?

Parkinson's being A PLETHORA OF SYMPTOMS, wouldn't it be prudent to minimise the side effects?

Also, what can be done about the adverse effects of antiparkinson drug withdrawal?

Thanks and good luck to you for your future work on this topic!

Dear Rujuta,

Thanks for such nice question and interest in this field. The answers are as follows.

1. Yes you can use pulsatile drug delivery system if suitable drug moiety and carrier we are able to find it out. It will be better case for that person too because missing a dose for parkinate person can prove to be fatal. Actually this concept along with prodrug is being in the pipeline of research work. We can hope that this concept would be fruitful.
2. What you have said is absolutely correct and that is what we are trying in Targeted drug delivery bcz unless and until drug is showing side effects at non targeted site we can’t think for targeted delivery.
3. Frankly speaking and as you must have read Parkinson cannot be cure totally and that is most unfortunate case. So drugs are given to these people are just supportive or extending life of that day by day. The problem of drug withdrawal in such case is thus because problematic and you can’t avoid it completely so the only option is try to minimize those effects by giving different drugs time to time or give the combination of drugs in which ones adverse effect can be counterbalanced by other drug. But nothing can be done more than this for withdrawal problems. But yes we can hope that one of us can come with this problem being solved.

Regards
Hrushikesh

Dear Hrushikesh,

As you have mentioned the use of herbal drugs,they have got the side effects of increasing the temperature,increasing the viscosity of the body fluids,thereby imbalance in the biological system.How can this be treated or mention its therapeutic effects and advantages in case of a modified prodrug?

Regards,
K.S.Kumar Upadhyayula.

Dear K.S.Kumar Upadhyayula,

Thanks for nice question.

Its right what you have mentioned about herbal drugs problem. But let me tell you that For the treatment of Parkinson Doctors DON'T prescribes herbal drugs. They all prescribes Levodopa combination drug which are of synthetic origin. Researchers have just done study over different kinds of herbs of Anti-Parkinson's activity. Prodrugs concept can be used in case of Herbal drugs (not directly) because one should know the exact chemical structure responsible for giving Anti parkinson’s activity from that herb, for that we should study in detail evrey single chemical constituent of that herb So if that compound is known we can think for its prodrug provided all conditions to be satisfied by the drug candidate.

Pls Don't say modified prodrug bcz Prodrugs are itself modified from one active drug as the active drug has some limitations.

Dear Hrushikesh,

Thank you for clarifying my query,and thank you for correcting me.Keep doing and all the best.

Regards,
K.S.Kumar Upadhyayula.

good presentation
can transdermal delivery system used in tretment of parkinson's disease?????? if yes give some market products with mechanism of action.
thanks

reply
priyanka

Hi Priyanka

Thanks for nice question. The answer is as follows.
No. Not at all. We can’t use Transdermal patches for brain targeting. Hardly drug reaches to brain as it had lot of barriers and we need some physiological carriers or highly lippophiic drug with recommended molecular weight or chemical delivery system has to be used. I have not come across any Transdermal Patches used in Brain delivery. Pls refer my presentation slide heading Blood brain barrier targeting strategies, So that you will come to know how hard is the delivery to brain and what can be used in delivering to brain.

Thanks
Hrushikesh

nikdream's picture

Thats nice presentation. Can you give detail information about the Bradikinesia?

Nikhil

hi Nikhil

Bradykinesia: Slowed ability to start and continue movements, and impaired ability to adjust the body's position. Can be a symptom of neurological disorders, particularly Parkinson's disease, or a side effect of medications.
The word bradykinesia is logically derived from two Greek roots: bradys, slow + kinesis, movement = slow movement, slow motion, slow moving.
In medicine (neurology), bradykinesia denotes "slow movement" (etymology: brady = slow, kinesia = movement). It is a feature of a number of diseases, most notably Parkinson's disease and other disorders of the basal ganglia. Rather than being a slowness in initiation (see hypokinesia) bradykinesia describes a slowness in the execution of movement. It is one of the 3 key symptoms of parkinsonism, which are bradykinesia, tremor and rigidity. Bradykinesia is also the cause of what is normally referred to as "stone face" (expressionlessness) among those with Parkinsons. A very detailed explanation of this topic can be found at http://www.wemove.org/bradykinesia

Regards
Hrushikesh

kavita_a_iyer's picture

Dear Hrushikesh,
A very interesting topic and presentation.

My questions are: Having been "locked" in the brain and exerted its therapeutic action, how does the drug then get eliminated from the body? Won't the prolonged presence of the drug in the brain have a potentially harmful effect?

Regards,
Kavita Iyer

Dear Kavita Iyer

Nice question. Thank you very much for a nice comment. The answers are as follows.
1. You must have studied synthesis of Dopamine and its metabolizing pattern or any drug which is used delivering to brain or to body, the same or either way it will get metabolised inside body and then it will get eliminated from body easily. In case of brain after get locked in it will surely get metabolised sooner or later depending upon characteristic of drug and those metabolised products will remove from brain through its own transport system.
2. Prolonged presence of the drug in the brain do not have a potentially harmful effect as you are must be aware that how much drug I am delivering to brain and what is the therapeutic or desired dose of that drug suitable for Brain. Yes Potential harmful effects will be seeing only when drug had harmful metabolising products. This Case happened with one drug called as MPTP. You can refer Medicinal Chemistry book by Foye. (6th edition)

Regards
Hrushikesh

ganesh.nirma's picture

hi,

It is the lucid and fantastic presentation.

Are prodrug modification can over come all the adverse effects which the drug causes when given as such??

What about the meatabolites elimination from the brain, can they cause damage to brain due to their abundance??

Regards
ganesh.

Hi Parihar

Nice question. Thank you very much for a nice comment. The answers are as follows.

1. Prodrug modification can surely decrease the percentage of damage created by own drug or it may reduce the side effects of that drug moiety by some folds but yes we can't overcome all the side effects which drug causes. Let me tell you one eg that NSAIDS have anti inflammatory pain killer activity but it has major side effects of gastric ulcer and then prolong use of it causes peptic ulcer but we have actually studied this effect and when we compared out NSAIDS prodrug we have got the ulcer index which was several fold lesser than actual that NSAIDS and we have filed Patent.

2. In case of brain after drug get locked in it will surely get metabolised sooner or later depending upon characteristic of drug and those metabolised products will remove from brain through its own transport system. Prolonged presence of the drug in the brain do not have a potentially harmful effect as you are must be aware that how much drug I am delivering to brain and what is the therapeutic or desired dose of that drug suitable for Brain. Yes Potential harmful effects will be seeing only when drug had harmful metabolising products. This Case happened with one drug called as MPTP. You can refer Medicinal Chemistry book by Foye. (6th edition)

Regards

Hrushikesh

abherids86's picture

How rate of prodrug cleavage influence prodrug application?
thank you

Hi ABHERI

Thanks for such a nice question. The answer is as follows.

Prodrugs are Chemically modified inert drug precursors which upon biotransformation convert to active moiety and show biological effects.
Now body has several enzymes which are responsible for cleaving the bonds of the chemical structure. Prodrugs can be prepared by several chemical linkages through Ester, amide, ether, succinyl,etc . Now esterases are present in all parts of the body, Amidases are present more in the colonic region. Now if you have synthesize the ester prodrug then As soon as it will enter into body it will start biotransformed to original drug molecule. But in case of Amide bonds and if you want colon targeted drug delivery then (with preper carrier and hypothesis )that prodrug will get almost 100% biotransformed to colonic region.

Another for PROLONGATION OF DURATION OF ACTION prodrug can be utilized.

Frequent dosing reqired for drugs having short life this can be overcome by use of both controlled release and prodrug apporaches. two rate controlling steps in the enhancement of duration of action are:
1. The rate of release of prodrug from site of application or administration in to systemic circulation, and
2. The rate of conversion of prodrug into active drug in the blood.

Hope your query has solved. if want more info regarding these two points let me know.

Thanks
hrushikesh

anis0019's picture

What is the principle behind the use of prodrugs to mask taste?
thanks

Dear Anisur,

one of the reason for poor patient compliance in case of Children is the bitterness, acidiy or causticity of the drug. Two approaches can be used to overcome the bad taste of drug. First is the reduction of drug solubility in saliva and other is to lower the affinity of drug towards the Taste receptors thus making the bitterness imperceptible. Eg

Parent drug Prodrug with improved taste
Chloramphenicol Cholramphenicol Plamitate ester.
Clindamycin Clindamycin palmitate ester

Hope your quarry has been solved.

Hrushikesh

A very nice presentation and a novel topic.
My question is- What are the possible side effects associated with the use of this system?

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