Sunday, October 11, 2009

Drugs, Genes and ADHD

The Effects Specific "ADHD Genes" Have on Dosing ADHD Medications:

Below is a list of five of the most common medications for ADHD. In order to break down or metabolize these drugs, however, a series of steps must take place for effective absorption, delivery and clearance of these drugs. This process, however, requires a series of enzymatic steps. Generally, when a physician prescribes these drugs, he or she considers factors such as the patient's age, gender, symptom severity and past medication history. However, lost in the shuffle is a lesser-known, but often equally critical factor: the particular genes of the individual. It is these genes which play a large role as to how well these enzymes function (alongside other factors such as the person's nutritional status, as most vitamins and minerals act as chemical "helpers" to these enzymes, and deficiencies can lead to lower enzyme function and sub-optimal metabolic efficiency).


Unfortunately for prescribing physicians, the landscape of enzyme capabilities among the general population is far from uniform. Some individuals naturally possess enzymes or enzyme systems (which are coded for and dependent on the genetic makeup of the particular individual)which are more efficient than others (often by multi fold differences). If these enzymes are essential to drug metabolism (including ADHD medications), then a potentially crucial piece of information may be missing from the physician's repertoire of assessment tools for medicating at the proper dosage.


Much to the dismay of many a frustrated parent of an ADHD child, this often begins the laborious process of adjusting medication dosages through a glorified "guess and check" process. However, due to the need for a relatively small window of effective dosing (especially for psychotropic drugs such as those prescribed for ADHD and related disorders) and unforgiving margins of error in the optimization process, bits of information, such as a child's genetically-dictated levels of drug-metabolizing enzymes could be extremely useful. With the increasing efficiency, lowering costs of and wider availability of genetic screening methods, we may soon be able to predict a child's enzyme levels by their genetic makeup and facilitate the dosing of (and eliminating much of the guess-work from) their medications for ADHD or other disorders, saving both time and money while on the medication circuit.


Given the powerful role of enzymes and enzyme systems (and the specific genes which encode for them) for the delivery, metabolism and clearance of these medications, we should take a look at some of the genetic variations of these enzymes and the implications they may having in assisting the diagnosing physician in the near future for more effectively dosing ADHD medications.


Here are 5 common ADHD drugs (including one which is not prescribed but often used as a "self-medication" tool among the ADHD population), and the genetically-dictated enzymes which can play a role in their metabolism and dosing patterns and levels.

ADHD Drug #1: Strattera (Atomoxetine)

Key enzymes involved and gene of interest: SLC6A2, CYP2D6

We have already investigated another gene believed to have an impact on dosing with Strattera, the SLC6A2 gene. However, in that earlier post, we alluded to another gene responsible for the metabolism of the non-stimulant ADHD drug Atomoxetine. This gene is called CYP2D6. The CYP2D6 gene codes for an important enzyme of the same name (which is an important enzyme produced in the liver). The gene is located on the 22nd human chromosome (the 22q13.1 genetic region to be more specific if you are familiar with genetic markers).

Approximately a dozen different genetic forms (or alleles) of this CYP2D6 gene are seen in individuals of European ancestry. These forms are often designated by a star followed by a number, such as *1 or *4. While these numbers are used for naming purposes, it is worth noting that most individuals of European descent appear to carry either the *1 (the most common), the *2 or the *4 form of this gene. Additionally, *3, *6, and *10 forms are each found in about 1-2 percent of the population.

Interestingly, the *10 form of this gene is found in higher levels in individuals of East-Asian descent. A Chinese study found that a higher frequency of this *10 form in the population (the *10 form shows up in over half of the Chinese population, about 10 times more frequently than in whites), resulted in slower rate of drug metabolism of the ADHD medication Strattera (Atomoxetine) by the CYP2D6 enzyme.

Relevance of the CYP2D6 gene to medicating ADHD with Strattera: The *10 form of the CYP2D6 produces less enzymatic activity than the most common *1 form. This can result in about a 50% increase in Atomoxetine concentration in the blood and duration before clearance, which was seen in the Chinese study. As a result, for individuals with the exclusive *10 form (such as seen in much of the East Asian population), slightly lower or less frequent dosing levels of atomoxetine might be needed to get the same therapeutic effects. This is in agreement with another study suggesting a 50 to 75% dosage reduction of Atomoxetine for those with hepatic impairment (liver dysfunction), as the CYP2D6 enzyme is produced in the liver.

Additionally, this population may be at a slightly greater risk of side effects with the drug due to a slower clearance and greater buildup of the drug. Of course other genes and additional factors in the Atomoxetine pathway certainly play a role, but these genetic variations can still play a significant role in medication dosing strategies.

ADHD drug #2: Adderall (Mixed amphetamine salts)

Genes of interest: Catechol O-Methyltransferase (COMT) gene, Dopamine Transporter Gene (DAT)

In previous posts, we have spoken extensively about a gene called COMT, short for Catechol O-Methyltransferase and its role on dosing for amphetamine-related ADHD medications such as Adderall and Vyvanse. This previous discsussion on COMT and ADHD medication dosing can be found here.

However, there are a few other genes worth noting here for their potential roles in dosing with amphetamine-based ADHD medications such as Adderall. One of these is the Dopamine Transporter gene (DAT), which is located on the 5th human chromosome. This gene also goes by other names such as DAT1 or SLC6A3. The DAT gene codes for an important protein called the Dopamine Transporter protein, which is responsible for shuttling the important brain chemical dopamine in and out of neuronal cells.

A number of stimulant drugs used to treat ADHD and related disorders work, at least in part, by interacting with this dopamine transporter (DAT) to correct a dopamine imbalance (in general, individuals with ADHD often have too little dopamine in the regions between brain cells or neurons in key regions of the brain. Many stimulant ADHD drugs remedy this by blocking the shuttling of dopamine back into the cells, keeping adequate amounts in these "gaps").

Interestingly, on a side note, the DAT gene has been implicated (in conjunction with another dopamine-related gene called DRD4) in IQ levels an behavior problems.

Like the genes mentioned above, DAT exists in a wide number of different forms across the human gene pool. Some forms appear to increase ones predisposition to ADHD and various neurophysiological or behavioral disorders and have earned the moniker "high risk alleles" (remember, an "allele" is simply a specific form of a gene which varies within the population).

A study on families of ADHD children found that a specific form of the DAT gene which included a 480 base pair repeat (simply a repeating section of DNA which is 480 DNA "letters" long) allele was associated with greater severity of ADHD symptoms, especially in the combined ADHD subtype (which includes high levels of both inattentive and hyperactive/impulsive symptoms as opposed to a predominance of one).

Potentially, individuals with ADHD who carry this "high-risk allele" of the DAT gene (which is a substantial portion of the general population) may require slightly higher levels of medication dosage with amphetamine-based stimulants than their "lower-risk" counterparts. These differences may be even more pronounced if the individual carries the "Val" form of the COMT gene, mentioned in a previous post (given the current body of research on the subject, the contributions of the COMT gene dwarf those of the DAT gene with regards to governing amphetamine dosage levels).

ADHD drug #3 Vyvanse (lisdexamfetamine dimesylate)

Gene of Interest: Trypsinogen

Due to its chemical proximity to amphetamines (Vyvanse is essentially an "inactivated" form of the drug Dexedrine, which is an isolation of one of the potent components of Adderall). A special chemical "tag" is linked to the active part of the drug, which must be chemically cleaved to release the active form of Vyvanse (think of it as essentially breaking a seal to free up the drug) into its functional amphetamine-based product. Naturally, the genes listed above (and the enzymes which they encode) which metabolize amphetamines are of substantial interest for potentially influencing the effectiveness of ADHD treatment with Vyvanse as well.

However, the actual cleaving process of releasing the active component of Vyvanse is equally as important. If the drug is not freed, then it cannot be effectively metabolized.

Several enzymes which are called upon to metabolize the other ADHD drugs in this post do NOT appear to have a significant effect on Vyvanse. These include CYP2A6, CYP2B6 (both for nicotine), and CYP2D6 (for Strattera). This is good news for those who are already taking medications, as Vyvanse's relative independence of these drug-metabolizing enzymes means fewer adverse drug-drug interactions.

As far as genetics go, the genes coding for the breakage of de-activating chemical tag placed on Vyvanse may be of most importance, especially since this breakage (or "hydrolysis") is believed to be the slowest (or rate-determining) step in metabolizing Vyvanse for ADHD. The de-activating "tag" attached to Vyvanse is none other than the amino acid lysine. While the exact mechanism of cleaving this link is not fully known, one enzyme in particular may be extremely relevant to this process.

Trypsin is an extremely common digestive enzyme produced predominantly in the pancreas. It is responsible for breaking up chemical linkages much like that of the one used to de-activate Vyvanse. Thus, a genetically-governed deficiency of the trypsin enzyme could lead to a severely hampered absorption (and subsequent metabolism and clearance of the ADHD drug Vyvanse).

Trypsin is actually coded for by a series of enzymes, often referred to as Trypsinogen, which located on the 7th human chromosome (in the "q35" region of the chromosome to be more exact). Individuals with pancreatic deficiencies, including pancreatitis have been tied down to having mutations in this trypsinogen gene.

Therefore, while this genetic region on the 7th chromosome hasn't been sufficiently studied with regards to Vyvanse (at least to the best of this blogger's current knowledge), this blogger personally believes that aberrations in the region of the Trypsinogen gene on this 7th human chromosome may be a worthwhile place to look for genetic response-based differences to the ADHD medication Vyvanse.

ADHD drug #4: Concerta/Ritalin/Daytrana/Biphentin (methylphenidate)

Genes of Interest: Carboxylesterase 1 (also referred to as "CES1"), DAT (refer to ADHD drug #2: Adderall section for DAT's genetic location)

Carboxylesterase 1: Although the affected form of this enzyme, which is coded for by a gene on the 16th chromosome, is relatively rare, some key studies have indicated that deficiencies in the CES1 enzyme can be coded from specific forms of this gene. These rare, low-functioning gene-mutation forms of Carboxylesterase 1 result in extremely poor methylphenidate metabolism, resulting in a buildup of abnormally high levels of the drug in individuals with this enzymatically-deficient form.

In addition to their effects on amphetamines such as Adderall or Dexedrine, variations (often referred to in the literature as "polymorphisms") in the DAT gene also play a role in the response to methylphenidate. A Korean study found that a specific allele (the 10-repeat allele, which is the same form as the "high-risk" 480 base-pair allele mentioned earlier in the amphetamines section) predicted a poor response to methylphenidate.

Interestingly, however, several Irish studies suggest the exact opposite: the "high-risk" 10-repeat 480 base pair form of the DAT gene may produce larger amounts of the DAT protein (which shuttles essential dopamine out of the gaps between the cells, the opposite effect of what one wants if they suffer from ADHD), so the higher levels of expression of this transporter may make it a better candidate for methylphenidate.

Another Irish study may help resolve some of this discrepancy. It found that individuals with the so-called "high-risk" form of the DAT gene mentioned above exhibit a more positive response to treatment with methylphenidate with regards to treating their attentional symptoms based on the left side of the brain. Left sided inattention can be a reflection of brain damage or brain asymmetry, the latter being a common trait in the ADHD population. It should be worth noting that methylphenidate has been an effective treatment method for improving cognitive processes for those suffering from traumatic brain injuries.

Given the fact that in the amphetamine section we mentioned that the DAT gene was more connected to the Combined ADHD subtype (the original article specifically stated that the association did not hold for the strictly inattentive ADHD subtype). If this holds true, then we may have discovered a potentially significant gene/medication/ADHD subtype association.

It is this blogger's current hypothesis that the "high-risk"/480 base pair/10-repeat allele form of the DAT gene might predispose one to a MORE FAVORABLE response to methylphenidate treatment if inattention is the most persistent ADHD symptom (as in the predominantly inattentive ADHD subtype). Conversely, if the hyperactive/impulsive behavior either predominates or is largely present in an individual (such as in the hyperactive/impulsive or combined ADHD subtypes, respectively), then the "high-risk" label holds for this particular gene type, and the methylphenidate response potential goes down.

In other words, if large amounts of hyperactivity are present (which is the case in most ADHD children, as the combined subtype is by far the most common form), then this "high-risk" form of the DAT gene hampers methylphenidate's effectiveness, whereas if hyperactivity is largely absent, then the response to methylphenidate is actually more favorable. If this hypothesis were to hold true, then we could screen youngsters for this form of the gene and keep them far away from methylphenidate if they were bouncing off the walls, whereas if the exhibited more of an inattentive "space cadet" type of behavior then methylphenidate might be a good first choice of pharmaceutical treatment. Of course this theory could be completely off-base, but given this blogger's current knowledge and exposure to the current literature, this may be a plausible explanation.

Another possible explanation for this discrepancy between Irish and Korean studies: We have already seen that specific forms of certain genes can be found at considerably higher levels such as the *10 form of the CYP2D6 gene mentioned above with regards to the East Asian population. Keep in mind that this gene form was associated with the metabolism of Strattera (which exhibits a significantly different mode of operation than do stimulants such as methylphenidate or mixed amphetamine salts). However, there are a number of so-called ADHD genes which have been implicated with the disorder. The current thought here is that some genes exhibit a more powerful influence on physical or behavioral traits than do others. In other words, some genes simply act more "powerfully" than others. This is known as epistasis ("Epistasis" roughly means "standing upon").

***As a side note, please don't confuse "epistasis" with the whole dominant/recessive "big A/little a" (Aa) gene thing you probably learned about in middle school biology. Dominant/recessive refers to different forms of the SAME gene, whereas epistasis refers to DIFFERENT genes. For example, let's say, hypothetically that there was a rare gene for green hair located on the 20th human chromosome. However, a more "powerful" gene, say on the 14th chromosome codes for brown hair. This brown hair gene in this case would be epistatic, meaning that it would overpower the effects of the green hair gene altogether. This phenomena is quite common in genetics.

Getting back to our discussion, this blogger hypothesizes that there may be one or more other unidentified genes in either the Korean or Irish population which are epistatic to the DAT gene with regards to the methylphenidate response. If this was true, then it's quite possible that the effects of these hypothetical yet-to-be-identified genes might "mask" or override the effects of the DAT gene, and that the association with the "high-risk allele" may be largely coincidental rather than causative. Given the state of the current research on current "heavyweight" genes such as the COMT gene mentioned earlier, it is entirely possible that the overall level of contribution among specific "high-risk" DAT alleles might be less significant than many of these studies seem to indicate.

Of course the discrepancy could just as easily be attributed to small sampling sizes, slight differences in experimental methods or uncontrolled variables in the experiment (or a complete lack of true association between methylphenidate and the DAT gene at all, although given the current body of literature, this last assertion seems highly unlikely).

ADHD drug #5: Nicotine:

Genes of interest: CYP2A6, CYP2B6

I have included this drug due to the high rates of smoking among those with ADHD. As with alcohol, nicotine is often widely used as a form of self-medication for those with ADHD. Some research even suggests that individuals with ADHD exhibit a different response to nicotine and that nicotine withdrawal may produce different patterns in certain critical brain regions between ADHD'ers and the general population. Interestingly, there are some genetic regions which may tie into this behavior.

With regards to nicotine metabolism, 2 genes appear to stand out in particular: CYP2A6 and CYP2B6 (note the similarity in nomenclature between these and the gene/enzyme mentioned above for Strattera metabolism CYP2D6. This is not an accident, as all three of these belong to the same "superfamily" of enzymes and carry many similar chemical and functional similarities). Out of these, the CYP2A6 (hereafter abbreviated as "2A6") enzyme is responsible for the lion's share of nicotine metabolism. It is coded for by by a gene of the same name, located in the "q13.2" region on the 19th human chromosome.

Like the 2D6 gene for Strattera, the 2A6 gene can exist in multiple different forms. Some 2A6 gene forms produce higher levels of the 2A6 enzyme than others. Other forms of 2A6 are less efficient, which results in a slower breakdown and clearance of nicotine. As a result, the nicotine stays in the body longer, and less of it is typically required. As a result individuals with these less efficient forms (called "slow metabolizers") of the 2A6 genes are less likely to develop nicotine addictions.

The relevance of these 2A6 genes on ADHD: The stimulating effects of nicotine are believed to be a major contributing factor to the higher prevalence of smoking among the ADHD population. If this is true, then slow metabolizers of nicotine may not derive the full effect of nicotine self-medication for attentional deficits, at least not as immediately as the fast metabolizers. On the flipside, they have lower cravings (like with virtually all stimulant drugs, the speed and rate of uptake and clearance of nicotine is a major factor in its addiction potential) and are exposed to less tobacco and often find it easier to quit smoking.

At least two alleles or forms of the 2A6 gene (using the "star/number" nomencalture us used in 2D6 for Strattera earlier in this blog), have been shown to coincide with slower rates of nicotine metabolism. They are 2A6*2 and 2A6*4 (these two forms are actually referred to as "null alleles" meaning that the 2A6 enzyme they code for has no activity).

Additionally, there are noticeable differences in the frequencies of these forms across different ethnicities among the global population. For example, these "slow metabolizing" gene/enzyme forms of are found in higher percentages in individuals of Asian ancestry (around 20%) compared to those of European descent (around 8%).

With regards to ADHD behavior, it is likely that people possessing these *2 or *4 forms of the CYP2A6 gene, may be less likely to use nicotine as a self-medication tool for their ADHD, or at least use the drug in lower doses, due to its lesser effects. On the flipside, however, there is another allele of the 2A6 gene, referred to as CYP2A6*1B. This version of the 2A6 nicotine metabolism gene actually promotes greater activity of the nicotine metabolizing enzyme, and speeds up the processing and clearance of the drug. As a result, individuals who possess this relatively rare CYP2A6 form may be more prone to more frequent use and abuse of nicotine, and individuals with ADHD who attempt to self-medicate with this drug may cycle through their nicotine more rapidly if they carry this *1B form of the gene.

Interestingly, another drug, bupropion (Wellbutrin), which is an anti-depressant often used off-label to treat more "depressive" forms of ADHD is a relatively common anti-smoking drug. Given the fact that a number of ADHD'ers who typically do not respond well to stimulants, but do respond to Wellbutrin may fall in this smoking category, it is possible that the fast metabolizers (i.e. the *1B individuals), may be good candidates for Wellbutrin, not only to stop smoking, but possibly also to treat unwanted ADHD symptoms.

Alleles of the CYP2B6 gene and enzyme with regards to nicotine and ADHD:

Shifting gears for a minute, we see that the CYP2B6 gene (as well as the enzyme which it encodes) also may also play a unique role in ADHD. The CYP2B6 gene is located on the 19th human chromosome (in the 13.2 region of the 19th, to be more specific). For individuals who lack CYP2A6 enzyme activity because of the reduced-activity or even "null" alleles, the enzyme CYP2B6 can metabolize nicotine in its place (it turns out that CYP2D6, the enzyme responsible for Strattera metabolism can also do the trick). For those who need to metabolize nicotine, but lack an effective CYP2A6 enzyme system, this is good news (however, this "B6" enzyme only functions at about 10% of the level of the "A6" enzyme, so B6 is not a very efficient "backup" for A6).

Beyond its role as a "backup" for the CYP2A6 enzyme, CYP2B6 may also be of clinical significance with regards to ADHD and similar disorders. In contrast to "A6", whose enzymes are predominantly generated in the liver, the CYP2B6 generated enzymes are expressed in brain tissue. With regards to the differences in neurochemistry and neurological functioning of the ADHD brain, the role of CYP2B6 is therefore potentially noteworthy.

Additionally, as we have discussed in earlier posts regarding ADHD and alcoholism, the 2B6 enzyme apparently also plays a role in alcoholism, and individuals who express higher levels of this genetically-encoded CYP2B6 enzyme in their brains may be more sensitive to alcohol, nicotine and other centrally acting drugs. The study even suggests that individuals with high levels of this gene-coded enzyme may be more prone to damages induced from these common chemical agents, including possible higher susceptibility to cancer.

For reference (using the "star" notation again), genetic forms of CYP2B6 which typically yield higher levels of this enzyme in the brain include the CYP2B6*4 (which shows up in about a third of the European popluation) form and the CYP2B6*9 (which is present in about a quarter of those of European descent) form. Again, don't worry too much about the specifics of these "starred" variants, just know that if you were to get a genetic screen and had one of these two enzymatic forms, you may be more sensitive to nicotine as a self-treatment ADHD "medication".

What this means is that ADHD individuals who harbor the higher-expressing "*4" and "*9" forms of the CYP2B6 enzyme in their brains may be more sensitive to chemical agents such as nicotine, and these same individuals may be more likely to suffer the toxic effects of this popular form of ADHD "self-medication".

In conclusion, we should note that some of these genes (such as DAT) have been well-studied and have repeatedly shown to be associated factor in proper dosing of ADHD medications. Others, however, such as the trypsinogen gene for Vyvanse are more at the theoretical level at the moment. However, this blogger believes that in the next couple of decades, (due in part to our expanding knowledge of the human genetic code and functional genomics), genetic screens will become foutinely more commonplace as a necessary tool for both prescribing and dosing medications. With regards to this general trend, psychotropic medications for disorders such as ADHD should be no exception.

48 comments:

  1. I am 20 years old and currently taking 56mg of Concerta (as well as 20mg Lexapro) once daily. Though it has been extremely helpful, I still feel as if something is off. I was prescribed 25mg of Adderall XR twice a day when I was 14, and this dosage was awful -- though I am assuming it was because of the high dosage and not much "build up" time, but straight from 15mg once a day to 25mgXR twice a day in less than 2 weeks.


    That said -- I have contemplated trying Vyvanse instead of Concerta, but because of my awful experience with Adderall in the past, I am extremely hesitant. I have read through much of this blog and am just curious about your opinion, having researched this topic rather thoroughly.

    I may be accounting for variables not related to my medication, but lately I have felt as if, within 30 minutes of taking my Concerta, my inattentiveness and distractability is notably decreased, however, hyperactivity seems to increase. I am slightly more fidgety (though, it may be that I don't NOTICE how fidgety I am when I am off the meds) and I feel as if I am more active and possibly even more talkative.

    My biggest problem with Concerta is cloudiness at the end of the day. I am a full time college student and work 20hrs/wk in a law firm. Because of this, my days are not over until about 6-7 pm, and the Concerta is usually wearing off by around 5pm -- unless I take it around noon, but that requires my morning classes to be full-blown ADHD mode (no meds).

    If you don't mind, your opinion would be greatly appreciated.

    (In case you are wondering, I do have a psychiatrist overseeing my medication, but he has not been very helpful at ALL over the last couple of months -- I basically pay a $25 co-pay once a month for him to write my prescription and send me on my way without answering any of my questions...pretty sick of it)

    Thanks so much!

    ReplyDelete
  2. It can't work in reality, that's exactly what I think.

    ReplyDelete
  3. This can't have effect in reality, that's what I think.

    ReplyDelete
  4. so often happens all medications usually have side effects and are nothing nice

    ReplyDelete
  5. I have spoken to many former substance users whose longing is not for the drug, but for the lifestyle. https://www.levitradosageus24.com/

    ReplyDelete
  6. Your comments on the role of CYP2D6 in metabolising ADHD medications are quite misleading.
    The vast majority of ADHD medications are affected by CYP2D6. Dexamphetamine (and consequently lisdexamphetamine's active metabolite) are CYP2D6 substrates. So are methylphenidate and clonidine. And many of the antidepressants an ADHD sufferer is likely to encounter to treat comorbid depression are also CYP2D6 substrates.
    The impression your article gives its readers - that atomoxetine is the main drug affected by CYP2D6 - is misleading and erroneous.

    ReplyDelete
  7. Your blog post are really impressive and interesting. Thanks for sharing the valuable information.
    Ayurvedic Treatment in Kerala

    ReplyDelete
  8. Excellent information on your blog,thank you for taking the time to share with us.I really appreciate sharing this great post.Keep up your work.Thanks for sharing this great article. Great information thanks a lot for the detailed article.
    psychotropic genetic testing

    ReplyDelete
  9. I think the admin of this web site is in fact working hard for his site, since here every material is quality based information.

    Happy New Year Images 2018

    Happy New Year Quotes 2018

    Happy New Year Gif 2018

    New Year Wishes 2018

    Happy New Year Pictures 2018

    ReplyDelete
  10. After looking at a number of the blog articles on your site, I seriously like your way of blogging. I added it to my bookmark webpage list and will be checking back in the near future.

    Merry Christmas Images For Facebook

    Christmas Wallpaper For Facebook

    Merry Christmas Images 2018

    Merry Christmas Gif For Facebook

    Funny Christmas Quotes For Facebook

    Merry Christmas Poems For Facebook

    ReplyDelete
  11. excellent put up, very informative. I wonder why the opposite experts of this sector do not understand this. You must continue your writing. I’m sure, you’ve a great readers’ base already!
    Happy Rose Day Images And Quotes 2019
    Happy Purpose Day Images And Quotes Free Download
    Happy Chocolate Day Images And Quotes Free Download
    Happy Teddy Day Images And Quotes Free Download
    Happy Promise Day Images And Quotes Free Download

    ReplyDelete
  12. I’m really amazed with your posting skills as well as with the layout on your blog site. Very informative and well written post! Quite interesting and nice topic chosen for the post Nice Post keep it up.Excellent post.

    ReplyDelete
  13. I generally like the blog and I really respect your content.
    Phrases are my favorite.
    I will bookmark your site and continue to explore new data.
    magic photo recovery crack
    imazing crack
    devonthink pro server crack
    driver toolkit crack license key free

    ReplyDelete
  14. I loved as much as you will receive carried out right here.
    The sketch is attractive, your authored material stylish.
    nonetheless, you command get got a shakiness over that you wish
    be delivering the following. unwell unquestionably come further formerly
    again as the same nearly a lot often inside case you shield this hike.

    sidify music converter crack

    ReplyDelete
  15. I like the result, I found what I wanted, and you completed a 4-day hunt!
    God bless your husband and wish you a happy day. day
    iobit malware fighter pro
    cleanmymac crack
    ytd video downloader pro 2020
    snagit 2019 crack

    ReplyDelete
  16. I am bold enough among many others to state that there is now a potent cure to this sickness but many are unaware of it. I discovered that I was infected with the virus 3 months ago, after a medical check-up. My doctor told me and I was shocked, confused and felt like my world had crumbled. I was dying slowly due to the announcement of my medical practitioner but he assured me that I could leave a normal life if I took my medications (as there was no medically known cure to Herpes). I went from churches to churches but soon found that my case needed urgent attention as I was growing lean due to fear of dying anytime soon. In a bid to look for a lasting solution to my predicament, I sought for solutions from the herbal world. I went online and searched for every powerful trado-medical practitioner that I could severe, cos I heard that the African Herbs had a cure for Herpes syndrome. It was after a little time searching the web that I came across one Dr Itua(A powerful African Herbal Doctor), who offered to help me at a monetary fee. I had to comply as this was my final bus-stop to receiving a perfect healing. My last resolve was to take my life by myself, should this plan fail. At last it worked out well. He gave me some steps to follow and I meticulously carried out all his instructions. Last month, to be precise, I went back to the hospital to conduct another test and to my amazement, the results showed that negative,Dr Itua Can As Well Cure The Following Desease…Cancer,Hiv,Herpes,Shingles, Hepatitis B,Liver Inflammatory,Diabetes,Fibroid,Parkinson's,Alzheimer’s disease,Bechet’s disease,Crohn’s disease,Cushing’s disease,Heart failure,Multiple Sclerosis,HypertensionFatal Familial Insomnia Factor V Leiden Mutation ,Epilepsy Dupuytren's disease,Desmoplastic small-round-cell tumor Diabetes ,Coeliac disease,Creutzfeldt–Jakob disease,Cerebral Amyloid Angiopathy, Ataxia,Arthritis,Amyotrophic Lateral Scoliosis,Autism,Fibromyalgia,Fluoroquinolone ToxicitySyndrome Fibrodysplasia Ossificans ProgresS sclerosis,Seizures,Adrenocortical carcinoma.Asthma,Allergic diseases,,Copd,Glaucoma., Cataracts,Macular degeneration,Cardiovascular disease,Lung disease.Enlarged prostate,Osteoporosis.
    Dementia.,Lyme Disease,,Non Hodgkin Lymphoma,Skin Cancer,Uterine Cancer,Prostate Cancer Dercum,Lupus,Hpv,Weak Erection,Infertility,fibromyalgia,Chronic Diarrhea,Get Your Ex Back,Als,SYPHILIS,Colo-Rectal Cancer,Blood Cancer,Breast CANCER,Lung Cancer,Prostate Cancer,Autism,Brain Cancer,Genetic disease,Epilepsy, Parkinson's disease..You can free yourself of this Herpes virus by consulting this great African Herbal Doctor via this email: drituaherbalcenter@gmail.com / . or call and whatsapp him on +2348149277967 He will help you and his herb medication is sure. he has the cure on all disease .You can talk to me on INSTAGRAM..tashamoore219.

    ReplyDelete
  17. I think this is one of the most important pieces of information.
    My. I am delighted to study your article.
    But I want to comment on a few common issues: the site tastes great, the articles are really cool.
    anytrans crack
    edius pro crack
    avs video editor crack
    light image resizer crack
    hma pro vpn crack

    ReplyDelete
  18. Excellent, sent, informative. I wonder why the opposition experts in this area do not know. You have to continue
    write. I'm sure you already have a huge number of readers!
    guitar pro crack

    ReplyDelete
  19. Faisalabad is one of the biggest cities in Pakistan and the hub of the textile industry. It is widely acknowledged as the Manchester of Pakistan due to its large industrial role. The quality of the fabrics produced in this city has no parallel. In fact, the fabric is something of a specialty of Faisalabad. Many people from all over the country flock to this city for a spot of cloth shopping. We aim to provide you all of the best of Faisalabad at our store.latest lawn collection 2016 with price , latest lawn dress design 2016

    ReplyDelete
  20. Hi, I’m so glad I found your blog, I stumbled upon you when
    I was already viewing other content on Google, I’m here now and want
    to thank you for this great post. And the surrounding entertainment sites
    please continue to maintain good work.
    techtool pro crack
    autodesk infraworks
    spyhunter 5 crack
    diskgenius professiona crack

    ReplyDelete
  21. It's in fact strong for you basically all window programming set up. This web page is confounding its article are vital and captivating. I took pleasure in and bookmark this on my chrome. This is in which you could get all damaged programming in a like way positioned in a smooth manner.
    https://letcracks.com/

    ReplyDelete
  22. It's in fact robust for you essentially all window programming set up. This page is confounding its article are vital and captivating. I took pride in and bookmark this on my chrome. This is wherein you could get all damaged programming in a like way positioned in a smooth manner.
    https://cracksmad.com/

    ReplyDelete
  23. Nice article and explanation Keep continuing to write an article like this you may also check my website Crack Softwares Download We established Allywebsite in order to Create Long-Term Relationships with Our Community & Inspire Happiness and Positivity we been around since 2015 helping our people get more knowledge in building website so welcome aboard the ship.
    Lightburn Crack
    Astute Graphics Plugins Elite Bundle Crack

    vfxAlert Pro Crack

    PassFab Android Unlocker Crack

    PCUnlocker Cracked ISO Enterprise Crack

    Adobe XD Crack

    Retouch Pro Crack

    ReplyDelete
  24. VideoProc 4.2 Crack is powerful software which is used to edit, crop, cut and adjust the video. It can also merge, convert and compress the videos. It is best for the videos it has many features which the user can apply on the video according to their taste.
    https://cracksway.com/videoproc-crack/

    ReplyDelete
  25. Playing good has never been exciting than in the new FIFA Mobile Apk Build and manage your team, playing head to head, and keep coming back for daily updated content. Whether you are a savvy veteran or just starting on a soccer pitch, the FIFA game goes bigger & better than ever, entirely redesigned and built exclusively for a device with a download under 100MBs.
    https://apksway.com/fifa-mobile-apk/

    ReplyDelete
  26. Bomber Friends Mod Apk is the application that perfectly justifies the name, as it provides you with the opportunity to play with your friends and engage in the battlefield in the virtual world, which lets you, throwing bombs on each other. The last Bomber surviving is declared the winner, but the story doesn’t end for people who have been bombed out early in this game.
    https://apkzamn.com/bomber-friends-mod-apk/

    ReplyDelete
  27. Hi, friends, I have created my channel on youtube and I need your support I need subscribers so I am requested to you to subscribe to my channel on youtube which is created on pubg mobile video game so please subscribe to my channel as more as you can. Requesting once again. Thanks a lot.
    https://www.youtube.com/channel/UCCP1h3LWgmvyqBU1t7Tk0Lw/

    ReplyDelete
  28. I've been reading about your articles and subjects for the past two days, and I'm still reading! On each line, wondering about your words was really powerful. In each of your subjects, techno-based information has been gathered.
    ESET NOD32 AntiVirus Crack

    Flixgrab Premium Crack

    VIPRE Advanced Security Crack

    ArtRage Crack

    ABBYY FineReader Crack

    ReplyDelete
  29. Have you ever heard of second life (sl for short). It is basically a online game where you can do anything you want. Second life is literally my second life (pun intended lol). If you want to see more you can see these Second Life websites and blogs the time to study or pay a visit to the content or web-sites we have linked to

    무료야설
    휴게텔
    마사지
    건전마사지
    카지노

    ReplyDelete
  30. it's easy to understand, thanks
    much more. Very good information. Fortunately, I stumbled upon your site (crashed).
    I ordered the latest book! I have visited various blogs, but music videos are available on this very good site. Your style is very different from my other people's style.
    reading things from. Thank you for posting if you have
    Chance, imagine I just booked this site.
    zonealarm free antivirus crack
    lizardsystems wi fi scanner crack
    file viewer plus crack
    format factory crack

    ReplyDelete
  31. This design is spectacular! You most certainly know how to keep a reader amused.
    Between your wit and your videos, I was almost moved to start my own blog (well, almost…HaHa!) Excellent job.
    I really enjoyed what you had to say, and more than that, how you presented it.
    Too cool!
    microsoft security essentials crack
    corel paintshop pro crack
    usb disk security crack
    pcloud crack

    ReplyDelete

  32. Usman Gull is a Pakistani SEO expert who has worked with many companies over the years to help them reach their goals. He specializes in helping websites reach high rankings on search engines such as Google, Yahoo and Bing. He also has expertise in content writing, link building, and other aspects of SEO. Usman Gull is highly experienced and will work hard to ensure that your website receives maximum visibility and reaches its full potential. He is available for hire through the Upwork platform.
    https://usmangull.com/

    ReplyDelete