I. BRONDZ
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questionable. Ephedrine is a sympathomimetic amine
commonly used as a stimulant, appe tite suppressant, con-
centration aid, and decongestant, and to treat hypotension
associated with anesthesia. It has a similar structure to
amphetamine and methamphetamine. Inclusion of ephe-
drine in the formulation of Tuxidrin was considered ne-
cessary for masking the harm that was observed to be
caused by unrestricted, prescription-free use of Tuxi. The
latter had led to an elevated number of allergy and po ssi-
ble asthma cases in the Norwegian population relative to
the popu lation in n eig hboring Swed en. In Sw eden , wher e
the dominant antitussive medication, Cosylan, was avai-
lable as a prescription-duty medication, the allergic reac-
tivity was six times lower than in Norway.
Furthermore, it is not only opiates that are under regu-
lation. In Ireland, New Zealand, the USA, and most other
countries, the N-oxides of opium alkaloids are covered
under laws and regulations for narcotics control. Phol-
codine in high concentrations in medical forms is also
under narcotics control laws and regulations as a mor-
phine d e r ivati ve.
As stated by Findlay in [4], pholcodine “has been for-
mulated in many combination medications (45)—some
rational and some quite irrational pharmacologically…”
Pholcodine has been included in many problematic medi-
cal formulations, especially liquid mixtures with pH le-
vels at which pholcodine quickly degrades. It has been
shown that the opiate in the liquid medical form Cosylan
does not degrade to morphine or oxidize to N-oxide [1],
but in Tuxi, the opiate derivative pholcodine does. The
degradation of pholcodine to morphine is strongly de-
pendent on the pH of the medium [1]. The pH of the
Tuxidrin formulation was optimized (relative to that of
Tuxi) in order to retard the degradation of pholcodine to
morphine; however, its pH was not optimized to retard
the degradation of pholcodine into other oxidation pro-
ducts. It is therefore of interest to examine Tuxidrin for
the presence of contaminants (see Figures 1 and 2).
As is mentioned in [1], and earlier in [5], N-oxides of
some opium alkaloids are less toxic than original alka-
loids, and often have higher specific activity than the
original alkaloids alone. The toxicity of morphine-N-
oxide was studied, as described in [5]. The authors of [5]
stated: “The intravenous and subcutaneous acute toxici-
ties of morphine-N-oxide (mno) in mice were respectively
3.2 and 8 times less than that of morphine. Amiphenazole
or tacrine reduced the acute toxicity of mno but not that
of morphine in mice. The chronic toxicity of mno was
examined in mice and rats. Daily oral doses of 100
mg/kg did no t significantly affect gr owth or condition, or
produce gross or microscopic lesions in mice treated for
3 weeks or rats treated for 3 months. No teratogenic ef-
fect of mno or of bromolysergic acid diethylamide was
observed in rats”.
Figure 1. There is a chromatogram of Tuxidrin. Tuxidrin
(hostedempende, slimløsende) mixture, produced by Weifa
(Norway), was purchased from the Norwegian Medicinal
Depot in Oslo, Norway.The peaks and retention times are as
follows: pholcodine at 6 min, N-oxide of pholcodine at 6.5
min, 10-hydroxy-pholc odine at 11 min, and ephedrine at 14
min. The mass spectra of the substances corresponding to
the peaks were recorded by MS with inline to HPLC. The
spectra of substances related to pholcodine are given below;
the mass spectra of pholcodine, N-oxide of pholcodine, and
10-hydroxy-pholcodine are shown in Figure 4, the spectrum
of ephedrine is not presented. Conditions used for HPLC-
MS are described in the Materials and M ethods section.
Figure 2. The percentage of oxidation products present in,
calculated as a percentage of the total amount of pholcodine.
The blue line is the concentration of pholcodine-N-oxide
and the green line is the concentr ation of 10-hydroxy- phol-
codine. Temperature: 60˚C. Duration of accelerated degra-
dation: 62 days.
The N-oxides of pholcodine mimic quaternary ammo-
nium ions; but, they are not equivalent. However, re-
searchers have not yet studied the tendency of quaternary
ammonium ions of degradation contaminants in medical
formulations containing pholcodine to provoke allergies.
The major allergenic epitopes in IgE-mediated anaphy-
laxis to neuromuscular blocking agents (NMBAs) of de-
gradation contaminants in medical formulations contain-
ing phol codin e were not studied.
10-hydroxy-pholcodine should possess the same al-
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