Chloroquine was, for many years, the workhorse against P. falciparum malaria. Around fifties (give or take a decade) resistance appeared in Cambodia and spread around the globe (if my memory serves me right there are at most 4 independent sources of malaria Chloroquine (CQ) resistance, being the Cambodia one the first to appear). Currently CQ clinical efficacy is deemed too low and CQ use is frowned upon. CQ is extremely cheap, therefore economically sustainable in Africa. The more current Artemisinin (ART) based drugs (ART, a short lived drug commonly used in combination with other - longer lived - drugs) are too expensive for most countries where malaria is a public health threat (thus requiring subsidies from external sources).
CQ is still used as a first line drug at least in Guinea-Bissau (On Google Scholar search for “kofoed bissau chloroquine”), even in the presence of resistance. A change of drug regimen (i.e. how the drug is used) seems to make its clinical efficacy go up and without increasing the spread of resistance. This is interesting from both a theoretical and practical point of view (being able to reuse CQ would be great given its price and wide availability). This is roughly the scope of my current theoretical study.
I am developing a Groovy model to specify CQ resistance. The fundamental concepts are:
On the drug side there are Compounds (e.g., Chloroquine) and Drugs (a drug is composed of one or more compounds, for instance, the widely used SP is composed of Sulfadoxine and Pyrimethamine. Chloroquine (as a drug) is composed of… Chloroquine - A single compound drug).
On the parasite side there are enzyme (protein) mutations. A mutation might help the parasite in tolerating a certain drug.
So here is my current piece of Groovy code to model CQ resistance:
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 | cq = compound(name: "Chloroquine", abbreviation: "cq", halfLife: 45.d) CQ = drug(name: "Chloroquine", abbreviation: "CQ") CQ.includes cpd: cq, qty: 300.mg, bioavail: 1.2 regimen = regimen() regimen.take drug: CQ, qty: 2, at: 0.h regimen.take drug: CQ, qty: 1, at: 6.h regimen.take drug: CQ, qty: 1, at: 1.d regimen.take drug: CQ, qty: 1, at: 2.d CRT = protein("CRT") CRT.mutatingAmino 76, Lys, Thr cqEffect = effect( name: "General", formula: {3.8 / (1 + km1/cq) }, parameters: [km1: 68.0] ) cqResistance = resistance( effect: cqEffect, mutations: [CRT.mutation(76)], parameters: [km1: 204.0] ) |
Chloroquine has a terminal half life (roughly the time that the body takes to eliminate half of the drug concentration) of 45 days (line 1). Actually, it is quite difficult to estimate half lives (and they vary from case to case). CQ is estimated to be between 1 and 2 months (extremely long).
A typical CQ pill has 300 mg of the substance (line 4).
A possible CQ regimen is, for an adult, 2 pills on the first day. 1 pill 8 hours later, 1 pill the 1 and 2 days after. Lines 6-10.
Resistance is related, among many other things to codon 76 of the CRT (Chloroquine resistance transporter) lines 12-13.
Looking at the code until line 13 I would say that is pretty readable and an elegant representation the problem. From line 13 onwards I think the same holds, but for now I will not discuss pharmacokinetics (I also refrained from explained the simplistic bioavailability parameter on line 4).
In the next posts I will concentrate on line 17, a formula for the pharmacokinetics (PK is mainly the killing effect of the drug on the parasite) of CQ. Sometimes I will be more of a computer geek and concentrate on the Groovy side of things, sometimes I will discuss more the underlying biology and pharmacology.
By the way, and going in the geek direction, why do optional parenthesis become mandatory inside list? i.e., I can do
DHFR.mutation 108
But I need parenthesis here:
[DHFR.mutation(108)]
The same seems to be happen when calling functions scoped inside a script (in the DSL example above, line 1 requires parenthesis).
By the way, that DHFR thingy above? DHFR is an enzyme involved in malarial resistance to SP, the other widely deployed cheap drug. SP acts in a less obvious way, and that will require changes to the DSL (to have relationships among effects), but that is further down the road.
Appendix:
One interesting Scala syntactic goodie that Groovy could plagiarize is this:
import org.jfree.chart.plot.{PlotOrientation, XYPlot}From the snippet above you might infer that charts will be appearing in future posts 
3 Comments to "Chloroquine malaria treatment and Groovy (DSL tactics in Groovy 2)"
Please share your thoughts
Filed in: bioinformatics, declarative programming, groovy, malaria
cool.
one further option would be to replace the lines
regimen.take drug: CQ, qty: 2, at: 0.h
with
take drug: CQ, qty: 2, at: 0.h
by either wrapping them in
regimen.with {
take drug: CQ, qty: 2, at: 0.h
…
}
or by using a MethodClosure as an alias
def take = regimen.&take
take drug: CQ, qty: 2, at: 0.h
…
BTW: how about
takeAt 0.h, 2 * CQ
?
cheers
Dierk
One of the fantastic things about Groovy is that there is always some good feedback coming in. Thanks!
Regarding the last solution… I suppose is a case of “monkey patching” numbers (so that * can be used in that way)?
As per the thread going on the groovy users mailing list, I am a bit concerned about monkey patching (which I already use a lot).
[…] history is one of torment: …&39SA is a haven for smugglers&39 Independent Onlinewww.guardian.co.ukChloroquine malaria treatment and Groovy DSL tactics in Groovy 2 Chloroquine was, for many years, the workhorse against P. falciparum malaria. Around fifties give […]