Our Experience with PreKUnil Tablets

by Kirsten K. Ahring, Clinical Dietician, The Neuropediatric Department, The John F. Kennedy Institute, Glostrup, Denmark

From the Winter 2002 issue of National PKU News

Over the past several years, a group of researchers and clinicians at the J.F.K Institute in Glostrup, Denmark have been experimentally using a tablet, called PreKUnil, as a partial substitute for traditional PKU treatment for a select group of patients. Since many people have already heard bits and pieces about this new treatment, I think it is important to provide everyone with the facts that are available and to outline the questions still remaining about this potential adjunct therapy. Kirsten Ahring, clinical dietitian, writes about the experiences of her group at the J.F.K Institute with PreKUnil tablets. This continues a discussion started in the fall issue of National PKU News, Brain Phe and PKU by Dr. Richard Koch.

Note: PreKUnil tablets may be available in the U.S. in 2003, however there is still much more research needed before this adjunct treatment can be shown to be effective and safe for long-term usage. Please see the commentaries about this article by Dr. Richard Koch and Virginia Schuett, National PKU News editor.

Newborn screening for PKU in Denmark began in 1965 and was centralized at the J.F.K Institute in 1967. The first group of well-treated teenagers started to face social and psychological problems associated with maintaining the diet in 1982. Some teens were not able to follow the strict diet.

Since 1985, the J. F. K. Institute has treated some of our young adults ages 15 years and older with PreKUnil tablets and a liberalized diet. Of 180 suitable-age patients in our clinic, 60 are using the PreKUnil tablet treatment. The basic concept of the pills was inspired by the work of Dr. Arnold E. Anderson (Arch. Neurol., Volume 33, 1976). (Find the link at www.nilab.dk, web site for the distributor of PreKUnil tablets).

Theoretical Basis for the Tablets

When amino acids (AAs) diffuse through the wall of "blood brain barrier" (BBB) blood cells into nerve cells, phenylalanine competes with the other large neutral amino acids (LNAAs) for the same bonding sites on carriers. These carriers take the amino acids across the BBB into the brain. The LNAAs besides phenylalanine include tyrosine, tryptophan, leucine, isoleucine, histidine, methionine and threonine. The amount of these amino acids in the blood thus has a very important influence on how much phe is transported into the brain. High levels of these other large neutral amino acids in the blood reduces the uptake of phenylalanine by simple competition, and vice versa.

Two of these LNAAs have a special function. As more tyrosine and tryptophan reaches the nerve cells, important neuro-transmitters are produced. Tyrosine is transformed into the neurotransmitters dopamine and noradrenaline; tryptophan is transformed into serotonin. These neuro-transmitters are stored in small vesicles until they are released; then they transfer nerve signals to receptors of adjacent nerve cells.

The PreKUnil tablets that we have developed contain high amounts of LNAAs. Each tablet contains 256 mg L-tyrosine plus L-tryptophan, and 244 mg of a combination of the L-form of arginine, leucine, histidine, methionine, isoleucine, valine and threonine. The idea is that the blocking effect of the LNAAs will prevent excess phe from crossing the BBB and therefore prevent abnormally high quantities from entering the brain. This supplement does not prevent high blood phe levels. But high blood phenylalanine levels have not been proven to be harmful. This is based on clinical observations of late- diagnosed patients, who for years have been eating a normal diet and have high phe levels. Their brains are damaged, but no other side effects, such as liver or renal failure, have been found.

Since there are no proven harmful effects of high blood phe levels per se, we allow a liberalized diet together with the PreKUnil tablets. Our theory is that while blood phe levels will remain elevated during treatment with PreKUnil tablets, brain phe levels will remain normal or near-normal.

Research and Development

To avoid imbalance between essential amino acids we found it was necessary also to supply other essential amino acids. By the time the first patients started to participate in longterm clinical research, we had already changed the mixture to include other LNAAs and the name was changed to Tyro-Tryp-S. Tyro-Tryp-S was then used for longterm clinical research on a larger patient group. That brand name was difficult to register and was changed to PreKUnil™ in 1992. Starting in 1986, using this supplement became a standard regime for PKU patients in our clinic who were older than 15 years and who were not willing or able to continue the traditional strict diet regimen.

We did a follow-up study of patients on the LNAA regime, from the mid-1980's to approximately 1990. The study included 16 patients with PKU, ages 15 to 27, who were followed during a transition from a conventional diet regimen to the alternative regimen consisting of a semi-free diet and LNAA supplementation. The group was compared to a similar group on the regular PKU diet. The study showed that the plasma amino acid concentrations after a meal were the same with either regimen, with the exception of 4 amino acids that did not show the same elevation following a meal in the PreKUnil group.

Long-Term Follow-Up

In 1987, we started neuropsychological follow-up studies to assess performance of PKU-patients on the traditional PKU diet compared to those on the modified regimen. First, a group of teenagers and young adults with PKU were fed the modified diet regimen and then had a CSF amino acid profile measured. Results showed no significant differences in amino acid profiles between conventional therapy and PreKUnil tablet treatment. The group on the modified diet again showed increased concentration of CSF neurotransmitter metabolites.

A study that started in 1987 at the J. F. K. Institute included 45 patients with a minimum age of 15, divided into two groups with 23 in Group 1 (traditional PKU diet ) and 22 in Group 2 (PreKUnil treatment). Group 2 patients were given new diet guidelines, which are very relaxed compared to standard treatment (see example at right).

A team of dietitians, doctors, nurses and psychologists followed each individual closely. Patients were advised to divide the daily dosage of PreKUnil tablets into 3 and eat them along with a mixed meal in order to obtain optimal benefits of the amino acid composition. A higher level of blood phe was allowed with this kind of treatment. A new maximum level was set at 1500 µmol/l (25 mg/dl), compared to 900 µmol/l (15 mg/dl) on a traditional PKU diet. Blood samples were analyzed every three weeks. All patients were tested psychologically prior to the study, and 6 and 12 months after the start of treatment.

There was a significant difference between the blood phe levels in Group 1 and Group 2, as expected. However, we found no significant difference in the psychological test performance of the patients in the two groups. The patients were followed and given neuropsychological tests again at ages 16, 17 and 18. IQ was measured at age 14 and again at age 25. No change in IQ was found for those patients who reached the age of 25. This data has been partly presented over the years at various meetings. A review article is planned for this winter, written by the psychologist who did the testing. A study also was published (Lou, H.C. et al, Acta Pćd. 83:1312-14, 1994) showing that MRI is unchanged in PKU when patients are on a relaxed diet with PreKUnil supplements.

We started a project in Denmark in March 2001, offering all late-diagnosed PKU patients the PreKUnil treatment. Out of 60 patients, 20 are participating. They will receive PreKUnil treatment for 6 months and placebo treatment for 6 months.

PreKUnil Treatment Program

When our 15-year old patients with PKU come for their annual visit, we inform them about the PreKUnil tablet treatment option, but encourage them to stay on a strict low protein diet if compliance is good and they feel good about it. If not, we provide information about PreKUnil, discussing the advantages and disadvantages of changing treatment regimens. For example, it can be a great disadvantage for a young woman of child-bearing age to get used to PreKUnil tablet treatment, only to have to go back on a strict maternal PKU diet since the higher blood phe levels with PreKUnil treatment would be harmful to the developing fetus.

We ask for a diet record after 3 months and for blood samples every 1 to 2 weeks in the beginning, then every 3 weeks. We have regular contact over the telephone and ask patients to contact us if they experience abnormal symptoms.

How Does PreKUnil Treatment Differ from Typical Treatment?

The main difference between PreKUnil treatment and ordinary treatment is as follows:

• Traditional PKU Treatment:
  Approximately 80% of total dietary protein comes from the amino acid powder (formula) and only 20% from the diet.
• PreKUnil Treatment:
  20% of protein comes from the PreKUnil tablets and 80% from the diet.

The tablets contain essential amino acids (LNAAs), including high dosages of tyrosine and tryptophan. Too much tyrosine can cause headaches, which limits the amount of tablets that can be consumed. The main purpose of the tablets is to create the "phe blocking" effect described earlier. The tablets must be combined with a certain amount of natural protein in order for the diet to contain sufficient protein. That is the reason why a semi-free diet is necessary in the PreKUnil treatment program.

The number of tablets required is based on body weight (body weight in kg x 0.38888 = number of tablets). Maximum dosage is 30 tablets, with a typical range of 25-30, divided into 3 portions during the day. The tablets cover approximately 0.2 g protein/kg/day. The recommended intake is 1 g protein/kg/day, so the rest (0.8 gm protein/kg/day) must come from dietary protein.

Who Can Use PreKUnil Tablets?

Since we allow blood phe levels up to 1500 µmol/l (25 mg/dl) during PreKUnil treatment, this treatment can only be used for certain groups of patients:

• It is not for children. We don't know how high blood phe could effect brain development.
• It is not for Maternal PKU. Blood phe levels must be kept between 150-300 µmol/l (2-6 mg/dl) for normal fetal development.
• We believe it is ideal for young adults, when compliance is poor.
• We believe it could be ideal for late diagnosed patients, where compliance is low and drinking formula can be a burden for the patient and caretakers. Our research underway will help us assess the suitability of PreKUnil treatment for this population.

In our experience, compliance among teenage PKU patients is often poor. We believe it is much better to take the PreKUnil tablets, establishing the blocking effect of the blood brain barrier (BBB), and then accept a blood phe level up to 1500 mmol/l rather than having the young people feeling guilty about not drinking formula, or cheating with forbidden foods, and then being "punished" with high blood phe levels. Most important, the adolescents feel well and are happy taking the PreKUnil tablets.

We believe that the data collected from our patients over the years shows that PreKUnil is safe. The patients have been examined by doctors and psychologists, had MRI and CSF tests done as well as a variety of other tests, and have been in close contact with our clinic. As we were developing the tablets, however, the technique to measure brain phe using Magnetic Resonance Spectroscopy was not available to confirm that the therapy is effective in lowering brain phe in the face of high blood phe. Dr. Richard Koch at Los Angeles Children's Hospital is now doing a small preliminary study to assess this.

Sample "Prekunil Diet"