Adjuvant Treatment for Phenylketonuria: Future Research Needs: Future Research Needs Paper Number 21
Adjuvant Treatment for Phenylketonuria: Future Research Needs: Future Research Needs Paper Number 21
Overview
Phenylketonuria (PKU) is a metabolic disorder in which an inability to properly metabolize the amino acid phenylalanine (Phe) leads to a buildup of Phe in the blood, causing neurotoxicity and resulting in intellectual disability, delayed speech, seizures and behavior abnormalities. PKU is typically diagnosed at birth following abnormal newborn screening results. With adherence to a Phe-restricted diet, poor outcomes can be mitigated. Nonetheless, management of PKU can be difficult and onerous for the patient and the family, leading to interest in identifying new ways of managing this lifelong condition. The mainstay for treatment of PKU is a diet that restricts the intake of Phe to control the Phe concentration in the blood. In 2007 the United States Food and Drug Administration approved sapropterin dihydrochloride (Kuvan®, formerly known as Phenoptin) for the treatment of PKU under the stipulation that studies regarding the drug's efficacy and long-term safety continue. Sapropterin dihydrochloride (hereafter, BH4) is presumed to work by enhancing residual enzyme activity present in some individuals with PKU. In addition to a Phe-restricted diet and BH4, another potential treatment for PKU is large neutral amino acids (LNAAs). In theory, LNAAs decrease the brain Phe concentration by competing with Phe for shared amino acid transporters to cross the blood-brain barrier. The Vanderbilt Evidence-based Practice Center completed an Agency for Healthcare Research and Quality (AHRQ)-funded systematic review of adjuvant treatments (BH4, LNAAs) for PKU. The report focused on Key Questions related to outcomes and harms of adjuvant treatment with BH4 and LNAAs in individuals with PKU, including pregnant women with PKU, and effects in subgroups (defined by demographic, clinical, genotypic, and adherence-related variables such as age, disease severity, genetic mutations, and dietary status). Key Questions also addressed evidence for optimal Phe levels for minimizing cognitive impairment. Overall, evidence was graded as insufficient to moderate to address treatment-related questions. Dietary management remains the mainstay of treatment for PKU, and maintaining control over the lifetime is an appropriate goal. Nonetheless, there is potential to support patients in achieving their clinical goals and possibly liberalizing their diet with adjuvant therapy. BH4 has been shown in two RCTs and two open label trials to reduce Phe levels in some patients, with significantly greater reductions seen in treated versus placebo groups. Overall, harms associated with the drug were minor. To date, there are no data to directly establish the potential effects of BH4 on longer term clinically important outcomes, including cognition, executive function, and quality of life. Thus, while the strength of evidence is moderate for a large, positive effect of BH4 on reducing Phe levels over the short term in some groups of patients showing initial responsiveness, evidence for the effect of BH4 on longer term clinical outcomes is low, and based on indirect associations, including a meta-analysis of the relationship of Phe levels and IQ. In theory, supplementation of a Phe-restricted diet with LNAAs might have a beneficial effect on cognition as LNAAs may competitively inhibit transportation of Phe through the bloodbrain barrier, thereby offering protection by potentially decreasing brain Phe levels. However, there was insufficient evidence to suggest that LNAAs could be a viable treatment option for reducing Phe levels or increasing Phe tolerance. Increasing Phe is clearly associated with decreased IQ, with a probability of IQ less than 85 exceeding the population probability (approximately 15 percent) at blood Phe over 400 µmol/L and leveling off at about 80 percent at 2000 µmol/L (moderate strength of evidence). This finding supports the typical target goal for blood Phe levels in individuals with PKU (120 to 360 µmol/L).Description
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- Used - Acceptable: All pages and the cover are intact, but shrink wrap, dust covers, or boxed set case may be missing. Pages may include limited notes, highlighting, or minor water damage but the text is readable. Item may but the dust cover may be missing. Pages may include limited notes and highlighting, but the text cannot be obscured or unreadable.
Note: Some electronic material access codes are valid only for one user. For this reason, used books, including books listed in the Used – Like New condition, may not come with functional electronic material access codes.
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Estimated delivery times:
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- Expedited Shipping: 3-5 business days
Shipping method varies depending on what is being shipped.
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You may return most items within 30 days of delivery for a full refund.
To be eligible for a return, your item must be unused and in the same condition that you received it. It must also be in the original packaging.
Several types of goods are exempt from being returned. Perishable goods such as food, flowers, newspapers or magazines cannot be returned. We also do not accept products that are intimate or sanitary goods, hazardous materials, or flammable liquids or gases.
Additional non-returnable items:
- Gift cards
- Downloadable software products
- Some health and personal care items
To complete your return, we require a tracking number, which shows the items which you already returned to us.
There are certain situations where only partial refunds are granted (if applicable)
- Book with obvious signs of use
- CD, DVD, VHS tape, software, video game, cassette tape, or vinyl record that has been opened
- Any item not in its original condition, is damaged or missing parts for reasons not due to our error
- Any item that is returned more than 30 days after delivery
Items returned to us as a result of our error will receive a full refund,some returns may be subject to a restocking fee of 7% of the total item price, please contact a customer care team member to see if your return is subject. Returns that arrived on time and were as described are subject to a restocking fee.
Items returned to us that were not the result of our error, including items returned to us due to an invalid or incomplete address, will be refunded the original item price less our standard restocking fees.
If the item is returned to us for any of the following reasons, a 15% restocking fee will be applied to your refund total and you will be asked to pay for return shipping:
- Item(s) no longer needed or wanted.
- Item(s) returned to us due to an invalid or incomplete address.
- Item(s) returned to us that were not a result of our error.
You should expect to receive your refund within four weeks of giving your package to the return shipper, however, in many cases you will receive a refund more quickly. This time period includes the transit time for us to receive your return from the shipper (5 to 10 business days), the time it takes us to process your return once we receive it (3 to 5 business days), and the time it takes your bank to process our refund request (5 to 10 business days).
If you need to return an item, please Contact Us with your order number and details about the product you would like to return. We will respond quickly with instructions for how to return items from your order.
Shipping Cost
We'll pay the return shipping costs if the return is a result of our error (you received an incorrect or defective item, etc.). In other cases, you will be responsible for paying for your own shipping costs for returning your item. Shipping costs are non-refundable. If you receive a refund, the cost of return shipping will be deducted from your refund.
Depending on where you live, the time it may take for your exchanged product to reach you, may vary.
If you are shipping an item over $75, you should consider using a trackable shipping service or purchasing shipping insurance. We don’t guarantee that we will receive your returned item.
Overview
Phenylketonuria (PKU) is a metabolic disorder in which an inability to properly metabolize the amino acid phenylalanine (Phe) leads to a buildup of Phe in the blood, causing neurotoxicity and resulting in intellectual disability, delayed speech, seizures and behavior abnormalities. PKU is typically diagnosed at birth following abnormal newborn screening results. With adherence to a Phe-restricted diet, poor outcomes can be mitigated. Nonetheless, management of PKU can be difficult and onerous for the patient and the family, leading to interest in identifying new ways of managing this lifelong condition. The mainstay for treatment of PKU is a diet that restricts the intake of Phe to control the Phe concentration in the blood. In 2007 the United States Food and Drug Administration approved sapropterin dihydrochloride (Kuvan®, formerly known as Phenoptin) for the treatment of PKU under the stipulation that studies regarding the drug's efficacy and long-term safety continue. Sapropterin dihydrochloride (hereafter, BH4) is presumed to work by enhancing residual enzyme activity present in some individuals with PKU. In addition to a Phe-restricted diet and BH4, another potential treatment for PKU is large neutral amino acids (LNAAs). In theory, LNAAs decrease the brain Phe concentration by competing with Phe for shared amino acid transporters to cross the blood-brain barrier. The Vanderbilt Evidence-based Practice Center completed an Agency for Healthcare Research and Quality (AHRQ)-funded systematic review of adjuvant treatments (BH4, LNAAs) for PKU. The report focused on Key Questions related to outcomes and harms of adjuvant treatment with BH4 and LNAAs in individuals with PKU, including pregnant women with PKU, and effects in subgroups (defined by demographic, clinical, genotypic, and adherence-related variables such as age, disease severity, genetic mutations, and dietary status). Key Questions also addressed evidence for optimal Phe levels for minimizing cognitive impairment. Overall, evidence was graded as insufficient to moderate to address treatment-related questions. Dietary management remains the mainstay of treatment for PKU, and maintaining control over the lifetime is an appropriate goal. Nonetheless, there is potential to support patients in achieving their clinical goals and possibly liberalizing their diet with adjuvant therapy. BH4 has been shown in two RCTs and two open label trials to reduce Phe levels in some patients, with significantly greater reductions seen in treated versus placebo groups. Overall, harms associated with the drug were minor. To date, there are no data to directly establish the potential effects of BH4 on longer term clinically important outcomes, including cognition, executive function, and quality of life. Thus, while the strength of evidence is moderate for a large, positive effect of BH4 on reducing Phe levels over the short term in some groups of patients showing initial responsiveness, evidence for the effect of BH4 on longer term clinical outcomes is low, and based on indirect associations, including a meta-analysis of the relationship of Phe levels and IQ. In theory, supplementation of a Phe-restricted diet with LNAAs might have a beneficial effect on cognition as LNAAs may competitively inhibit transportation of Phe through the bloodbrain barrier, thereby offering protection by potentially decreasing brain Phe levels. However, there was insufficient evidence to suggest that LNAAs could be a viable treatment option for reducing Phe levels or increasing Phe tolerance. Increasing Phe is clearly associated with decreased IQ, with a probability of IQ less than 85 exceeding the population probability (approximately 15 percent) at blood Phe over 400 µmol/L and leveling off at about 80 percent at 2000 µmol/L (moderate strength of evidence). This finding supports the typical target goal for blood Phe levels in individuals with PKU (120 to 360 µmol/L).Description
Condition Guidelines
Books - New and Used
The following guidelines apply to books:
- New: A brand-new copy with cover and original protective wrapping intact. Books with markings of any kind on the cover or pages, books marked as "Bargain" or "Remainder," or with any other labels attached, may not be listed as New condition.
- Used - Good: All pages and cover are intact (including the dust cover, if applicable). Spine may show signs of wear. Pages may include limited notes and highlighting. May include "From the library of" labels. Shrink wrap, dust covers, or boxed set case may be missing. Item may be missing bundled media.
- Used - Acceptable: All pages and the cover are intact, but shrink wrap, dust covers, or boxed set case may be missing. Pages may include limited notes, highlighting, or minor water damage but the text is readable. Item may but the dust cover may be missing. Pages may include limited notes and highlighting, but the text cannot be obscured or unreadable.
Note: Some electronic material access codes are valid only for one user. For this reason, used books, including books listed in the Used – Like New condition, may not come with functional electronic material access codes.
Shipping & Delivery
Shipping Fees
- Stevens Books offers FREE SHIPPING everywhere in the United States for ALL non-book orders, and $3.99 for each book.
- Packages are shipped from Monday to Friday.
- No additional fees and charges.
Delivery Times
The usual time for processing an order is 24 hours (1 business day), but may vary depending on the availability of products ordered. This period excludes delivery times, which depend on your geographic location.
Estimated delivery times:
- Standard Shipping: 5-8 business days
- Expedited Shipping: 3-5 business days
Shipping method varies depending on what is being shipped.
Tracking
All orders are shipped with a tracking number. Once your order has left our warehouse, a confirmation e-mail with a tracking number will be sent to you. You will be able to track your package at all times.
Damaged Parcel
If your package has been delivered in a PO Box, please note that we are not responsible for any damage that may result (consequences of extreme temperatures, theft, etc.).
If you have any questions regarding shipping or want to know about the status of an order, please contact us or email to support@stevensbooks.com.
Returns & Refunds
You may return most items within 30 days of delivery for a full refund.
To be eligible for a return, your item must be unused and in the same condition that you received it. It must also be in the original packaging.
Several types of goods are exempt from being returned. Perishable goods such as food, flowers, newspapers or magazines cannot be returned. We also do not accept products that are intimate or sanitary goods, hazardous materials, or flammable liquids or gases.
Additional non-returnable items:
- Gift cards
- Downloadable software products
- Some health and personal care items
To complete your return, we require a tracking number, which shows the items which you already returned to us.
There are certain situations where only partial refunds are granted (if applicable)
- Book with obvious signs of use
- CD, DVD, VHS tape, software, video game, cassette tape, or vinyl record that has been opened
- Any item not in its original condition, is damaged or missing parts for reasons not due to our error
- Any item that is returned more than 30 days after delivery
Items returned to us as a result of our error will receive a full refund,some returns may be subject to a restocking fee of 7% of the total item price, please contact a customer care team member to see if your return is subject. Returns that arrived on time and were as described are subject to a restocking fee.
Items returned to us that were not the result of our error, including items returned to us due to an invalid or incomplete address, will be refunded the original item price less our standard restocking fees.
If the item is returned to us for any of the following reasons, a 15% restocking fee will be applied to your refund total and you will be asked to pay for return shipping:
- Item(s) no longer needed or wanted.
- Item(s) returned to us due to an invalid or incomplete address.
- Item(s) returned to us that were not a result of our error.
You should expect to receive your refund within four weeks of giving your package to the return shipper, however, in many cases you will receive a refund more quickly. This time period includes the transit time for us to receive your return from the shipper (5 to 10 business days), the time it takes us to process your return once we receive it (3 to 5 business days), and the time it takes your bank to process our refund request (5 to 10 business days).
If you need to return an item, please Contact Us with your order number and details about the product you would like to return. We will respond quickly with instructions for how to return items from your order.
Shipping Cost
We'll pay the return shipping costs if the return is a result of our error (you received an incorrect or defective item, etc.). In other cases, you will be responsible for paying for your own shipping costs for returning your item. Shipping costs are non-refundable. If you receive a refund, the cost of return shipping will be deducted from your refund.
Depending on where you live, the time it may take for your exchanged product to reach you, may vary.
If you are shipping an item over $75, you should consider using a trackable shipping service or purchasing shipping insurance. We don’t guarantee that we will receive your returned item.
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