Indication:
Incontinence
Summary-
Studies to date suggest that terolidine is safe and effective agent in the treatment of urinary incontinenence. Its unique combination of both anticholenergic and calcium blocking activity provide an advatage over presently available treatments. However, further studies are required to clarify long term safety and to identify those patients who most likely to benefit from from terolidine therapy.
Forest Labs acquired U.S. Lincensing right for oral tablets from KabiPharmacia in December 1987. Kabi temporarily discontinued the sale of terolidine world wide following reports of an association with PVT. Clinical trials in US have been put on hold at the request of FDA .
Forest submitted an NDA on August 30, 1989. An anticipated approval date for the drug,
which will be marketed as Micturin , is now unknown.
Adverse Reaction:
Side effects-
Up to 50% of patients in some studies reported side effects during the first 3 months of
therapy vs 35% with placebo.
Most side effects were mild, anticholenrgic -related and decreased in frequency (34%),
between 3 and 6 months of continuous therapy.
The most commonly reported was dry mouth, 27%, during first 3 months, 19% beteween
3 and 6 mths.Other side effects reported during the first 3 months include,-
blurred vision 15%, tremor 14%, weight gain 11%, tachycardia 4%, ankle edema 2%,
The incidence of these side effects decreased between 3 and 6 months. One study reported a small increase (2mg Hg) in resting diastolic blood pressure after 6 months.
Other side effects include vertigo. headache, nausea, polymorhic ventricular tachycardia
(PVT, reported in other countries )
Pharmacology/ Pharmacokinetics:
Pharmacology-
Terolidine is a secondary amine which has non-selective anticholinergic and calcium
blocking effects. Although originally investigated as an anti-anginal agent, terolidine
is presently undergoing evaluation in the treatments of patients with bladder incontinence
Terolidine provides an advantage of anticholnergic and calcium blocking effects within
the same plasma concentration range, with anticholinergic effects, predominating
at lower plasma concentrations and calcium entry blocking blocking action
predominating at higher plasma concentrations. .
The motor nerve supply to the bladder and urethra is from the parasympathetic system,
the neurotransmitter active in this system is acetyl choline. Therfore, anticholnergic
agents have been used to treat incontinence , but side effects often limit their usefulness
In addition to parasympathetic activity, it appears that calcium entry from the extra celular
space is important in the contratile activity of urinary tract smooth muscle. Calcium blocker
reduce freqency and amplitude of detrustor contrations and improve bladder capacity,
however, the side effects associated with their use have prevented their use in treating
incontinence
Pharmacokinetics-
Terolidine is well absorbed after oral administration with a bioavailabilty of app 90%.
Peak serum levels occur 2 to 8 hours (average 4 hours) after administration. altough
therapeutic levels have not been established a steady state concentration of 0.6mg/L
is generally tolerated. Higher concentrationof 0.8 to 1.1mg/L can be maintained in some
patients without serious adverse effects
The volume distribution is 500L app 80% to 85%, is bound to serum proteins, and the half life is app 60 hours. Due to long long half-life the maximal clinical effect will not be seen until about 10 days after initiation of therapy
Clinical studies-
Terolidine 12.5mg to 25mg twice daily was effective in the treatment of some patients with
urge urinary incontinence. Patients treated with terolidine have a decrease both in
pre-micturation symptoms such as urgency in urinary frequency.
One study reported a decrease in voluntary micturation from a mean of 10.8 to 7.9/day after 6 months of treatment. Another group reported a decrease in involuntary micturation from
2.5 to 1.5/day with greater effects in these patients with higher base line micturation frequency
An increase in bladder capacity has been observed in several studies with one group
reporting an average increase from 252 to 335ml after 6 months of therapy
A preliminay study suggest that terolidine may be effective in children 6 to 14 years of age
involved in bladder traing program to correct urgency or urge incontinence
