Chemistry Reference
In-Depth Information
4.4.4
Toxicology
Toxicological studies conducted in different animal species indicated less severe
undesirable side effects associated with cholinergic activation for HA than for other
AChEIs such as physostigmine and tacrine.
42,79
In mice, the LD
50
doses were
4.6 mg per os (p.o.), 3.0 mg s.c., 1.8 mg i.p., and 0.63 mg i.v. Histopathological
examinations showed no changes in liver, kidney, heart, lung, and brain after
administration of HA for 180 days, in dogs (0.6 mg/kg i.m.) and in rats
(1.5 mg/kg p.o.). No mutagenicity was found in rats, and no teratogenic effect
wasfoundinmiceorrabbits.
80
4.4.5
Effects on Miscellaneous Targets
It was reported that HA inhibited nitric oxide production from rat C6 and human
BT325 glioma cells.
81
The actions of HA on the fast transient potassium current
and the sustained potassium current were investigated in acutely dissociated rat hip-
pocampus neurons by Li et al.
82
HA reversibly inhibited the transient potassium
current, being voltage independent and insensitive to atropine. In fact, the inhibition
on the fast transient potassium current might form a potential toxic effect of HA in
AD treatment. In this context, HA seems safer than tacrine, as the latter was much
more potent in the inhibition of the transient potassium current. The results sug-
gested that HA may act as a blocker at the external mouth of the A channel.
82,83
Human studies have confirmed the analgesic action of AChEIs, such as physos-
tigmine and neostigmine. The antinociceptive effect of HA was also investigated in
the mouse hot plate and abdominal constriction tests by Galeotti et al.
84
The results
showed that HA could produce the dose-dependent antinociception in mice, without
impairing motor coordination, by potentiating endogenous cholinergic activity. HA
is endowed by muscarinic antinociceptive properties mediated by the activation of
the central M
1
muscarinic receptor. So HA and other AChEIs could be employed as
analgesic for the relief of painful human conditions.
84
In conclusion, as an AChEI, HA possesses different pharmacological actions
other than hydrolysis of synaptic ACh. HA has direct actions on targets other
than AChE. These noncholinergic roles of HA could also be important in AD treat-
ment. The therapeutic effects of HA are probably based on a multitarget mechanism.
4.5
CLINICAL TRIALS
Scores of clinical studies with HA have been reported thus far. Favorable efficacy of
HA was demonstrated in the treatment of more than 1000 patients suffering from
age-related memory dysfunction or dementia in China. An early study conducted
on 100 patients with probable AD oral HA (0.15-0.25 mg, t.i.d.) showed significant
improvement in all rating scores evaluated by the Buschke Selective Reminding
task. An inverted U-shaped dose response curve for memory improvement was
observed.
48,85,86
The most frequently occurring side effects with HA were related
Search WWH ::
Custom Search