Tolerability profile of a new nasal decongestant--tinazoline hydrochloride (Go-7996 B) : open and double-blind studies in human male volunteers.
Tinazoline hydrochloride is a new nasal decongestant, showing potent and long-acting vasoconstrictor activity on several vascular beds in dogs, guinea-pigs, cats, and rabbits. Chemically, it is 4,5-dihydro-2- (3-indolyl) mercaptoimidazole [Fig. 1] It was synthesized at CIBA-GEIGY Research Centre, Goregaon. The vasoconstrictor effect has been shown in animals to be due to a stimulation of the 1-adrenoceptors and the compound does not exhibit any B-adrenoceptor agonist activity. It was also found to be several times more potent than the commercially available nasal decongestants and has a longer duration of action. Tinazoline HCl did not inhibit the ciliary movement in the fragments of guineapig trachea. In acute toxicity studies. the oral LU50 in rat was around 550 mg/kg and in mouse 258 mg/kg. The subacute toxicity studies in rats and local toxicity studies in dogs and rabbits showed that the compound was safe for human pharmacological studies.
In the present investigation, the local naso-pharyngeal, systemic and organ function tolerability of tinazoline HCI was evaluated in ambulant and hospitalized healthy human volunteers, by open as well as randomized, placebo-controlled double-blind studies.
All the subjects in the tolerability study were hospitalized in the clinical pharmacology unit of the K.E.M. Hospital, Bombay. Twenty five hospital inpatients, all males, ranging in age from 17 to 50 years, weighing from 39 to 59 kg, with a height from 145 to 173.5 cm and who had recovered from minor intercurrent illness, volunteered for phase 1 studies. Careful history, physical examination and laboratory investigations were carried out to exclude any severe systemic disease. For the placebo-controlled double-blind naso-pharyngeal tolerability study, ten healthy male volunteers between the ages of 32 and 51 years and having an average body weight of 62.3 kg (Range: 30-71 kg.) and an average height of 162.2 cm (Range: 160-177.5 cm) were studied on an ambulant schedule. For the nasal pH experiment, 7 volunteers were studied. An informed written consent was obtained from each volunteer.
Baseline symptoms for naso-pharyngeal, cardio-vascular and systemic tolerability were graded and recorded basally and after the nasal drops to avoid non drug adverse reactions. The nasopharyngeal tolerability was judged by nasal pain, burning, stinging, rhinorrhoea, sneezing, bad taste, smell and dryness. The cardiovascular tolerability was studied by a basal and serial record of blood pressure and pulse rate in supine and standing positions and by the symptoms of palpitations and giddiness. The systemic tolerability was assessed by a check-list of headache, nausea, tremors, weakness and other symptoms.
The following laboratory investigations to monitor organ function tolerability, were carried out basally, and 24, hours, and 3 days after tinazoline HCl administration according to the standard methods: haemoglobin, haematocrit, white cell count (total and differential), platelet count, erythrocyte sedimentation rate, serum uric acid, serum enzymes (transaminases and alkaline phosphatase), serum bilirubin (total and direct), serum cholesterol, fasting blood sugar, blood urea nitrogen, routine urine analysis and stool examination. An electrocardiogram for standard and chest leads was taken before and after tinazoline in five volunteers.
Nasal pH study
The subjects were resting in a supine position with a pillow under the head. The electrodes were checked at the beginning and end of the experiment with a standard buffer of pH 6.5. The differences in potential induced by the differences in temperature of the nasal mucosa as compared to the room temperature were compensated for by a temperature adjustment on the electrometer. The glass pH electrode was placed on the floor of the nasal passage in contact with the inferior turbinate. After the reading was taken the electrode was withdrawn and rinsed. Tinazoline HCl, 0.027c and 0.04% solutions of pH 6.2 were administered-3 drops nasally-in a randomized order. Five minutes later, the pH recording was repeated.
For the open tolerability studies, tinazoline nasal drops were instilled-2-3 drops per nostril-eight hourly for three to four days. Both 0.04% and 0.08% concentrations were used. For the pH study 0.02% and 0.04% concentrations were used.
For the double-blind trials, tinazoline and an identical placebo (same solvents and excipients without the active ingradient) were used. The drug and placebo were instilled three times in a day for 2 days in a randomized cross-over design. No other concomitant drugs or nasal drops were permitted during these studies.
Open tolerability studies
With 0.04%, solution of tinazoline, the nasopharyngeal tolerability was good in 15 volunteers. A mild unpleasant taste complained of by some volunteers was due to an excipient PEG 300. The other mild and transient complaints were burning sensation of nasal mucosa in 2 subjects and mild nasal dryness in 3 subjects. No adverse effects were observed on supine and standing blood pressure values and heart rate in 14 subjects. In one subject with iron deficiency anaemia, the symptom of palpitations occurred with a tachycardia of 90 per minute in standing position. One subject complained of mild and transient headache.
With 0.08% formulation of tinazoline in 10 subjects, the local nasopharyngeal tolerability was good. Unpleasant taste due to PEG 300 was no longer present in this formulation with PEG 6000. Mild burning of the nasal mucosa was reported by two subjects. Mild and transient unpleasant smell was reported by 5 subjects. There were no adverse effects on blood pressure and heart rate. The systemic tolerability of tinazoline was good.
The laboratory investigations, carried out in 10 volunteers, did not show any adverse effect on organ functions. [Table - 1] shows the basal and post-treatment mean values of the investigations carried out. The values were within normal limits. The electrocardiograms did not show any adverse effects of tinazoline in 5 subjects who were studied basally and after the drug.
[Table - 2] shows the nasal mucosal pH values in 7 volunteers, before and after tinazoline. The mean pH change was -0.178 with 0.02% formulation and +0.033 with 0.04% formulation. There was no marked reduction in nasal mucosal pH with tinazoline.
Tinazoline and placebo were well tolerated. Mild and transient symptoms reported by 10 subjects are shown in [Table - 3] The incidence of mild symptoms with tinazoline was comparable to that observed with the placebo. The difference between the overall symptoms in the two groups was not statistically significant.
As there were six observations (3 per day) on placebo and tinazoline and the severe side-effect is graded as 3, the maximum score on each side-effect for any given volunteer, can be 18. Hence the maximum possible score on any side effect in a given period of 2 days was 180 (n = 10). [Table - 4] shows the comparative indices of tinazoline and placebo. With Student's paired `t' test applied to individual scores, there is no statistical difference between the two groups. The scores of allied and miscellaneous symptoms were also added up: (1) pain + burning + stinging, (2) rhinorrhoea + sneezing and (3) headache + unpleasant taste + others. There was no significant difference between the placebo and tinazoline.
The nasopharyngeal, cardiovascular and general tolerability of tinazoline HCl was found to be good, as observed from the open and the double-blind studies. There were no adverse effects on the bone-marrow, kidney, liver and metabolic functions as judged by the laboratory investigations. The nasal mucosal pH was also not significantly altered.
It has been stated by several investigators that good tolerability of nasal decongestants must be assured by proper studies in human volunteers and patients.,  It has been emphasized that not only the active ingredient but the vehicles and other additives must also be evaluated for nasopharyngeal tolerability. In the present study, unpleasant taste was traced to PEG 300, which was replaced with palatable PEG 6000. The placebo contained all the excipients, solvents, etc. without the active ingredient; it was studied in a double-blind manner for nasopharyngeal tolerability. It was found that tinazoline and placebo were comparable in their tolerability profile. Hence, tinazoline HCl is recommended for safety and efficacy studies in patients with nasal congestion.
We thank Prof. C. K. Deshpande, Dean, Seth G.S. Medical College and K.E.M. Hospital for the permission to use the clinical facilities. We also thank Prof. T. R. Govindachari, Prof. R. S. Grewal, Prof. D. Subrahmanyam, the ex-Directors and the present Director respectively, of CIBA-GEIGY Research Centre, for their encouragement and advice. We are also grateful to Dr. S. Selvavinayakam and Dr. C. L. Kaul for their help in the nasal pH studies. We thank Dr. Kirit Vora and Dr. N. K. Desai for supervising the investigations to monitor organ functions.