A safety trial of high dose glyceryl triacetate for Canavan disease.

Canavan disease (CD MIM#271900) is a rare autosomal recessive neurodegenerative disorder presenting in early infancy. The course of the disease is variable, but it is always fatal. CD is caused by mutations in the ASPA gene, which codes for the enzyme aspartoacylase (ASPA), which breaks down N-acetylaspartate (NAA) to acetate and aspartic acid. The lack of NAA-degrading enzyme activity leads to excess accumulation of NAA in the brain and deficiency of acetate, which is necessary for myelin lipid synthesis. Glyceryltriacetate (GTA) is a short-chain triglyceride with three acetate moieties on a glycerol backbone and has proven an effective acetate precursor. Intragastric administration of GTA to tremor mice results in greatly increased brain acetate levels, and improved motor functions. GTA given to infants with CD at a low dose (up to 0.25 g/kg/d) resulted in no improvement in their clinical status, but also no detectable toxicity. We present for the first time the safety profile of high dose GTA (4.5 g/kg/d) in 2 patients with CD. We treated 2 infants with CD at ages 8 months and 1 year with high dose GTA, for 4.5 and 6 months respectively. No significant side effects and no toxicity were observed. Although the treatment resulted in no motor improvement, it was well tolerated. The lack of clinical improvement might be explained mainly by the late onset of treatment, when significant brain damage was already present. Further larger studies of CD patients below age 3 months are required in order to test the long-term efficacy of this drug.

Metabolic acetate therapy for the treatment of traumatic brain injury.

Patients suffering from traumatic brain injury (TBI) have decreased markers of energy metabolism, including N-acetylaspartate (NAA) and ATP. In the nervous system, NAA-derived acetate provides acetyl-CoA required for myelin lipid synthesis. Acetate can also be oxidized in mitochondria for the derivation of metabolic energy. In the current study, using the controlled cortical impact model of TBI in rats, we investigated the effects of the hydrophobic acetate precursor, glyceryltriacetate (GTA), as a method of delivering metabolizable acetate to the injured brain. We found that GTA administration significantly increased the levels of both NAA and ATP in the injured hemisphere 4 and 6 days after injury, and also resulted in significantly improved motor performance in rats 3 days after injury.

A double-blind, vehicle-controlled study of the safety and efficacy of Fungoid Tincture in patients with distal subungual onychomycosis of the toes.

Onychomycosis is one of the most common causes of nail disease and one of the hardest to treat among fungal infections. A double-blind, vehicle-controlled study has been conducted to evaluate the safety and efficacy of Fungoid Tincture (Pedinol Pharmacal, Inc), for the treatment of fungal infection of the toenails. Ten patients with distal subungual onychomycosis were treated for twelve months with topical Fungoid Tincture. Another ten patients with the same ailment were treated with the vehicle alone. Once a month, clinical and global evaluation of the target nail was done, in addition to trimming and debridement of the nails. After twelve months of treatment, 90 percent of patients applying Fungoid Tincture showed negative results on culture. There were minimal adverse effects.

Parenteral nutrition with short- and long-chain triglycerides: triacetin reduces atrophy of small and large bowel mucosa and improves protein metabolism in burned rats.

The effect of total parenteral nutrition with combinations of long-chain triglycerides (LCTs) and triacetin, the water-soluble triglyceride of acetate, on structural components of the gastrointestinal tract and protein metabolism was assessed in burned (30% body surface area) rats. Rats received isovolemic, isocaloric, and isonitrogenous diets that delivered 672 kJ.kg-1.d-1 (160 kcal.kg-1.d-1), 9.6 g amino acids.kg-1.d-1, and 30% nonprotein calories as 90% triacetin/10% LCTs, 50% triacetin/50% LCTs, or 100% LCTs for 7 d. Daily and cumulative nitrogen balances and whole-body leucine kinetics and fractional protein synthetic rates in rectus muscle and liver were determined on the last day of nutrition. DNA, protein, and total weight were determined in mucosal scrapings from segments of jejunum and colon. Plasma acetate concentrations were substantially higher in both triacetin groups. Parenteral nutrition with 50% triacetin and 50% LCTs promoted a positive nitrogen balance similar to that of 100% LCTs, increased protein in rectus muscle and liver, smaller and more numerous mucosal cells in jejunum and colon, and increased colonic mucosal weight compared with the other groups. Triacetin did not appreciably affect whole-body and tissue leucine kinetics. The equicaloric provision of triacetin and LCTs improved protein utilization and structural components of the small and large bowel and reduced the development of intestinal mucosal atrophy associated with conventional parenteral nutrition in burn injury.

Open-label study of the safety and efficacy of Fungoid tincture in patients with distal subungual onychomycosis of the toes.

Onychomycosis is the most frequent cause of nail diseases. An open-label study has been conducted to evaluate the safety and efficacy of Fungoid Tincture, a topical antifungal agent approved by the Food and Drug Administration for the treatment of onychomycosis of the toes. Ten patients with culture-proven distal subungual onychomycosis were treated twice daily for twelve months with topical Fungoid Tincture. Another ten patients with the same condition were treated with the vehicle alone. At monthly intervals, the target nail was trimmed, the nail bed debrided, and global clinical assessment recorded. After twelve months of therapy, all patients applying Fungoid Tincture showed negative findings on fungal culture. The vehicle alone benefitted several patients, and may have antifungal activity. Adverse effects were minimal, with mild peeling occurring in seven patients and erythema noted in one.

Experimental short-bowel syndrome: effect of an elemental diet supplemented with short-chain triglycerides.

To determine whether short-chain triglycerides (SCTs, 1:1 triacetin:tributyrin, wt:wt) enhance intestinal adaptation in short-bowel syndrome (SBS), male Sprague-Dawley rats underwent 60% distal small-bowel resection with cecectomy and received either a chemically defined diet (CD) or a CD containing 40% of nonprotein energy as either medium-chain triglycerides (MCTs) or SCTs. After 12 d the SCT group had significantly increased jejunal mucosal weight compared with the MCT and CD groups and had significantly increased segment weight and mucosal protein compared with the CD group. In the colon the SCT group had significantly increased segment and mucosal weights and mucosal protein and DNA compared with both the MCT and CD groups. Body-weight change and measurements of serum ketones, albumin, glucose, and triglycerides revealed no significant differences among groups. SCTs improved jejunal and colonic adaptive growth and maintained comparable nutritional status in SBS when compared with CD alone or CD with MCTs.

[Cervix ripening using drugs before oxytocin labor induction. Clinical study of a new prostaglandin E2 triacetin gel]. / Medikamentöse Zervixreifung vor Oxytocin-Geburtseinleitung. Klinische Studie mit einem neuen Prostaglandin E2-Triacetin-Gel.

In an open randomized clinical study, 50 of 100 gravidae with a low Bishop score (less than or equal to 5) at term were treated with prostaglandin E2 (0.5 mg PGE2 in 2.5 ml Triacetin gel. Prepidil, intracervically) 12 hours before the indicated i.v. oxytocin induction. In 50 patients labor was induced intravenously without any pretreatment. In 46 of 50 pretreated women (92%) there was an increase in the Bishop score of at least three points, and of only two points in the remaining four. In the control group no significant increase in the Bishop score was measurable. Sixteen patients delivered within the first 12 hours after PGE2 gel administration, before oxytocin induction. Three women in the untreated control group also delivered during this pre-observation period. In 14 (64%) of 22 women in whom cervical priming with PGE2 was performed and 26 (57%) of 47 patients in whom it was not the first intravenous oxytocin induction was successful. The frequency of cesarean sections was 10% (n = 5) in the PGE2 gel group and 12% (n = 6) in the oxytocin group. The oxytocin dose needed to induce labor was significantly lower after cervical priming. No severe side effects were observed during and after PGE2 treatment, in either the mothers or the children.

Clinical evaluation of endocervical prostaglandin E2-triacetin-gel for preinduction cervical softening in pregnant women at term.

In an open randomized clinical trial 100 pregnant women with low Bishop Scores at term were treated either with intracervical Prostaglandin (PG) E2 (0.5 mg in 2.5 ml triacetin-gel) 12 hours before labor induction with intravenous oxytocin or with oxytocin infusion alone. In 46 of the 50 pretreated patients (92%) the Bishop Score progressed at least 3 points, in four cases only 2 points. The mean Bishop score in the untreated patients increased insignificantly. After PGE2-gel administration 16 patients delivered during the 12 hour interval compared to 3 in the group without pretreatment. The first induction attempt was successful in 14 (64%) of the 22 patients that were left to be induced after cervical softening and in 26 (57%) of the 47 women without cervical priming. The Cesarean section rate was 10% (n = 5) in the PGE2-gel group and 12% (n = 6) in the control group. Dosage of oxytocin required for labor induction was significantly lower after cervical softening. No serious fetal or maternal side effects were observed after PGE2 pretreatment.