Nasal absorption of hydroxocobalamin in healthy elderly adults
Cobalamin (vitamin B12) deficiency is especially common among elderly people. Studies indicate that as many as 15% are cobalamin deficient. The treatment of choice is the administration of cobalamin by intramuscular injections [3, 4]. Usually, the patient is put on a lifetime regimen of monthly maintenance injections. Intramuscular injections, however, have disadvantages: they are inconvenient, painful and the frequent need for the assistance of health professionals makes the patient dependent and increases the cost of treatment considerably. These drawbacks could encourage noncompliance. A more convenient and cost-effective alternative would be advantageous to health care in general and patients in particular.
The search for alternative routes of cobalamin administration began soon after cyanocobalamin was isolated and introduced for parenteral use in 1948. Nasal inhalation, insufflation or instillation of cyanocobalamin were proposed in the early 1950. The formulations for nasal inhalation or instillation consisted of low concentrations of cyanocobalamin in isotonic saline solution or lactose powder. Although these formulations were reported to be effective in the treatment of pernicious anaemia, none of these proposals found a follow-up in clinical practice, in industry or in the scientific literature. Recently a gel for nasal cyanocobalamin instillation has become commercially available. The gel, in a dose of 400–500 μg cyanocobalamin, has been claimed to be safe and effective. We are not aware of studies that show the safety and efficacy of the nasal gel in treating cobalamin deficiency. A practical problem with the use of a gel is that it sometimes dries up and sticks to the unit-dose tubes. In the sixties oral cyanocobalamin administration for the treatment of pernicious anaemia was proposed. Despite the claim that doses of 150 μg to 1000 μg daily are effective, it is rarely used.
A disadvantage of all these forms of treatment is that they contain cyanocobalamin while hydroxocobalamin is the drug of choice. Since the fifth World Health Organization Model List of Essential Drugs, hydroxocobalamin, and not cyanocobalamin, has been the cobalamin included in the list. Hydroxocobalamin binds more extensively to plasma proteins and has a longer half-life in the body than cyanocobalamin. As a result, hydroxocobalamin is better retained in the body and therefore requires less frequent dosage. Moreover, cyanocobalamin is contraindicated in patients with tobacco and tropical amblyopia and optic neuropathy in pernicious anaemia. A plea for the withdrawal of cyanocobalamin has been made.
Recently, a formulation for the nasal administration of hydroxocobalamin has been developed. Here we present the results of our exploratory study on the absorption of nasally administered hydroxocobalamin in healthy elderly adults. To our knowledge this is the first report to document nasal hydroxocobalamin absorption in humans.
Subjects
Healthy elderly adults were recruited from the general population by means of advertisements in local newspapers. The following exclusion criteria were applied: use of vitamin supplements containing cobalamin, use of nasal medication, or acute or chronic rhinitis. Ten subjects were selected, six females and four males, age 71.6±4.6 year (mean±s.d.).
Protocol
The study protocol was approved by the Committee for Experimental Research with Humans of the University Hospital Nijmegen. All subjects gave written informed consent. On the first test day subjects were randomly allocated to a dose of 750 μg or 1500 μg hydroxocobalamin. On the second test day (after 163±10 days, range 147–175 days) subjects received the alternate dose. Blood samples were obtained through an indwelling cannula inserted into a forearm vein of each subject. After a blood sample was collected the cannula was flushed with 1 ml of heparinized salt solution (150 IE heparin in 0.9% NaCl solution) in order to maintain patency. Before each blood sample was collected the first 1–2 ml blood were discarded. EDTA-plasma was collected before and after drug administration at the following time points: 0, 10, 20, 30, 40, 60, 120, 180 and 240 min.
The hydroxocobalamin formulation contained 750 μg hydroxocobalamin per 70 μl in a preserved solution and the nasal spray device was a metered pump (Valois, France, VP 7/70). The investigator administered 750 μg (one puff) or 1500 μg (one puff in each nostril) hydroxocobalamin nasally. The nasal dispenser was weighed before and after administration of the drug to ensure that the dose had actually been given.
The plasma cobalamin concentration was determined by competitive radioisotope binding technique using purified hog intrinsic factor as cobalamin binder (Solid Phase DualCount, Diagnostic Products Corporation, Los Angeles, California). The within-assay coëfficient of variation was 3.1–3.5% and the between-assay coëfficient of variation was 3.3–6.7%. The assay has a detection limit of 37 pmol l−1. In case the plasma cobalamin concentration fell outside the range of the assay, i.e. >1700 pmol l−1, the samples were diluted with zero-diluent and assayed again.
Filed under: Clinical Pharmacology