A Randomised Double Blind Trial

A randomised control trial in a tertiary institute evaluated camylofin dihydrochloride, a potent antispasmodic, in active phase of labour. The efficacy of camylofin in accelerating active phase of labour, rate of cervical dilatation; its effects on second and third stage of labour and side effects were studied. 100 primigravidas were randomised into 2 groups; 50 patients each in the study and control group received 50 mg camylofin or placebo intramuscularly, respectively. Primary outcome was the time from onset of active labour (3 cm cervical dilatation) to full dilatation, which was 3 hours 35 minutes and 5 hours 34 minutes in the study and control group respectively (p < 0.001). Secondary outcome was the rate of cervical dilatation, which was 1.92 cm/hour and 1.18 cm/hour in the study and control group respectively (p < 0.001). Side effects of camylofin were dryness of mouth (9%) and vomiting (5%). The second and third stages of labour were unremarkable in both groups. Camylofin dihydrochloride is a potent antispasmodic in accelerating active phase of labour and cervical dilatation.

INTRODUCTION

The problems and hazards of prolonged labour, both for the mother and foetus, have been recognised for many years. The mother is exposed to a higher risk of infection, ketosis and obstructed labour, while the foetus faces the dangers of infection, asphyxia and excessive cranial moulding. Professor O’Driscoll at the National Maternity Hospital, Dublin (1973), introduced the concept of “active management of labour”,1 and this has influenced obstetricians to change their outlook regarding first stage of labour.

Attempts to accelerate labour and thereby shorten its duration without jeopardizing maternal or foetal outcome is welcome to both the patient and the obstetrician. Uterine activity and the rate of cervical dilatation are the two basic factors that determine the duration of labour. Various drugs have been tried over the last few decades, which accelerate labour either by increasing the uterine activity or by accelerating cervical dilatation. Oxytocin and prostaglandins are used to intensify uterine contractions. Sedatives and belladonna alkaloids have been tried to hasten cervical dilatation, but many have adverse effects on the mother or the foetus.2 Drotaverine and valethamate bromide have been used to accelerate cervical dilatation but many have anticholinergic side effects like dryness of mouth, tachycardia and vomiting.

An ideal antispasmodic for acceleration of cervical dilatation should have a prompt and long lasting action, no adverse effects on uterine contractility, and be free from the risk of uterine inertia. It should also have minimal side effects in the mother and the foetus. Camylofin dihydrochloride, an Isoamyl N- (â diethyl-aminoethyl)- á-aminophenyl- acetate is a powerful antispasmodic and we evaluated its efficacy in labour in a randomized controlled trial with these points in view.

MATERIAL AND METHODS

A randomized double blind trial was conducted in a tertiary care institute to evaluate the effect of camylofin dihydrochloride as compared to control in shortening the duration of active phase of labour, its efficacy accelerating the rate of cervical dilatation, its effects on second and third stage of labour and side effects in the mother and foetus.

Inclusion criteria for the study were primigravidas in the age group of 18 to 35 years with gestational age 37 to 40 weeks, with singleton foetus in vertex presentation, in active phase of labour. Active phase of labour was defined as 3 cm or more cervical dilatation with uterine contractions.

Exclusion criteria were any antenatal pregnancy complications like preeclampsia, eclampsia or other medical disorders of pregnancy, suspected cephalopelvic disproportion, premature rupture of membranes and patients requiring induction or augmentation of labour. Patients where artificial rupture of membranes had occurred or where oxytocic drugs were used were also excluded.

Institutional ethics committee approval was obtained for the trial. Written informed consent of the patient was taken. 100 primigravidas were randomized into 2 groups, where 50 patients in the study group received 50 mg camylofin dihydrochloride intramuscularly and 50 patients in the control group received placebo intramuscularly. The drug or the placebo was administered as a single dose in active phase of labour at 3 cm cervical dilatation. The results were obtained and analysed after decoding the data on completion of the trial.

Patient’s vital parameters, foetal heart rate and progress of labour were monitored and recorded. Side effects in the form of dryness of mouth, nausea, vomiting and tachycardia in the mother were recorded. Both mother and baby were closely observed for 24 hours following delivery.The results were analysed using ‘t’ test.

RESULTS

The study and the control group were well matched in terms of maternal age and gestational age. The average maternal age was 23 years in the study and 25 years in the control group. The average gestational age was 39.1 weeks and 38.4 weeks in the study and control group respectively. Both these were not statistically significant.

The primary outcome measure was the time from onset of active labour (3 cm cervical dilatation) to full cervical dilatation. The average time was 3 hours 35 minutes in the study group and 5 hours 34 minutes in the control group, which was statistically significant (p < 0.001). The average duration of active phase of first stage of labour was shortened by almost 2 hours in patients receiving camylofin dihydrochloride, as seen in Table 1.

The secondary outcome measure was the rate of cervical dilatation in cm/hour. This was 1.92 cm/ hour in the study group, which was almost double as compared to 1.18 cm/hour in the control group (p < 0.001). Time required for 1 cm cervical dilatation in the study group was 31 minutes whereas it was 48 minutes in the control group. The rate of cervical dilatation was thus accelerated by 17 minutes/cm in patients receiving camylofin dihydrochloride, as also seen in Table 1.

Other outcomes studied were the effects of camylofin on second and third stage of labour and side effects in the mother and the foetus. The mean duration of second and third stage of labour in the two groups was not statistically significant. The mean total duration of labour from the active phase was 4 hours 42 minutes in the study group and 6 hours 31 minutes in the control group. A significant

Duration	Study group n=50	Control group n=50
Active phase of first stage	3 hrs 35 mins	5 hrs 34 mins
Second stage	42.16 mins	43.56 mins
Third stage	15.22 mins	13.08 mins
Total duration of labour	4 hrs 42 mins	6 hrs 31 mins

reduction of about 2 hours in the study group was mainly due to the effect of camylofin in accelerating the first stage of labour (Table 2).

The mode of delivery was not altered by the study medication. The incidence of full term normal delivery was 92% and 88% in the study and control group respectively, and the incidence of outlet forceps was 4% in both groups. Caesarean section was performed in 4% of the study group and 8% of the control group.

No change in uterine activity was noted in the study group. There were no major complications encountered in the third stage nor was there any significant difference in the amount of blood loss in either group. Cervical tears occurred in one case each in both the groups, in patients who underwent forceps delivery.

The average Apgar scores were comparable in the two groups. There was only one admission to the neonatal intensive care unit in both the groups for respiratory distress. There was no foetal or neonatal mortality.

Dryness of mouth (9%) was the most common side effect seen in the study group. The other side effects were nausea (5%), vomiting (6%), drowsiness (1%) and transient tachycardia (1%).

DISCUSSION
Brock et al studied the chemical structure and pharmacological properties of camylofin dihydrochloride in detail. Camylofin has a direct papaverine like spasmolytic action on the smooth muscle and a mild atropine like anticholinergic action, making it one of the most potent antispasmodics. It inhibits the enzyme phosphodiesterase, which in turn causes increase in concentration of cyclic AMP and smooth muscle relaxation. Due to its phosphodiesterase enzyme-IV isoenzyme selectivity, this drug does not interfere with uterine contractility.

Camylofin dihydrochloride primarily acts on smooth muscles (intestine, ureter, cervix) whereas its influence on glands, eyes, heart and circulation is slight and of no clinical significance. It has very mild anticholinergic side effects like dryness of mouth, dilatation of pupils, paralysis of accommodation and palpitations. It has a wide margin of safety. The ratio of the effective therapeutic dose to the toxicity dose in animal studies varies from 1:40 to 1:150.5

Since the past 50 years, camylofin dihydrochloride in a dose of 25 mg administered intramuscularly or intravenously has been used as a potent and safe antispasmodic in cases of biliary colic, renal and ureteric colic, dysmenorrhoea, peptic ulcer and chronic enterocolitis. It has also been used in the treatment of angina pectoris when the usual sedative therapy or nitrites are ineffective. Kruger et al6 and Penzold et al7 in two independent studies showed that camylofin in the dose of 20-40 mg intramuscularly or intravenously resulted in relief of anginal pain in 10-15 minutes.

In modern obstetrics, a drug that offers convenience and assures shortening of first stage of labour without compromising the mother of foetus, is a welcome drug. In primigravidas the cervix normally dilates at the rate of 1 cm/hour. Camylofin dihydrochloride accelerates labour by regulating the autonomic system and thus the disordered progress of labour is normalised. This facilitates the cervical effacement and dilatation.8,9 It does not interfere with uterine contractility. Camylofin dihydrochloride remains a preferential cervical dilator because of the absence of major side effects and symptoms of intolerance. Hence it is a new indication of an old drug.

Available literature review indicates that camylofin dihydrochloride is highly effective in shortening the duration of active phase of labour. Etterich et al2 studied 9702 parturients, where 2800 cases received spasmolytic agent(s). They showed the duration of active phase of labour to be 4 to 5 hours in the study group as compared to 6 to 12 hours when other spasmolytics were used. Asholter et al10 in a study of 300 primigravidas and 300 multigravidas found the duration of active phase in primigravidas to be 5 hours 6 minutes when no spasmolytic was used which was reduced to 4 hours 4 minutes with other spasmolytics and was further reduced to 3 hours 52 minutes with camylofin. Similar reduction in active phase was seen in multigravidas and best results were seen in the camylofin group. Guseck et al11 found a positive improvement in cervical dilatation in 53 to 120 patients (44%). There were no adverse effects on the mother or foetus. In our study the average duration of active phase of labour was 3 hours 35 minutes in the study group as compared to 5 hours 34 minutes in the control group. The average duration of active phase was significantly shortened by 2 hours
in the study group. Hence the results of our study are comparable to other reports in literature (Table 3).

TABLE 3
Literature reivew

Authors	Duration of active phase of labour
	Study group	Control group
Etterich M et al2	4 hrs - 5 hrs	6 hrs - 12 hrs
Asholter et al10	3 hrs 52 mins	5 hrs 6 mins
Present study	3 hrs 35 mins	5 hrs 34 mins

CONCLUSION
Camylofin dihydrochloride has beneficial effects in facilitating cervical dilatation and shortens the duration of active phase of first stage of labour significantly without any undesirable effects on the foetus. It has no effect on the second and third stage of labour and no effect on uterine activity. The side effects are minimal with no change in caesarean section rate and the neonatal outcome is favourable. There are no major side effects or symptoms ofintolerance. Camylofin dihydrochloride remains a preferential cervical dilator and its use can thus be advocated in accelerating the first stage of labour.

ACKNOWLEDGEMENTS
The Dean, KEM Hospital for allowing us to conduct the trial and use hospital data.

Khandelwal Laboratories Pvt. Ltd. sponsored the trial and we gratefully acknowledge the support of Dr. Gupta, Medical
Consultant Khandelwal Laboratories Pvt. Ltd.

REFERENCES

1. O’Driscoli K, Stronge JM, Minogue M. Active management of labour. British Medical Journal 1973; 3 : 135-8.

2. Etterich M, Mall-Haefeli M. The effect of spasmolytic agent on parturition. Gynaecologia 1959; 147 : 512-21.

3. Drotaverine hydrochloride versus valethamate bromide in acceleration of labour. Sharma JB. Int J Gynaecol Obstet
2001; 74 (3) : 255-60.

4. Arulkumaran S, Chua S. Management of the first stage of labour. In: S Arulkumaran, SS Ratnam, K Bhaskar Rao Eds.
The management of labour. Scotland: Orient Longman Ltd. 1996: 21-42.

5. Brock N. Pharmacology of avacan. Dtsch Med Wochenschr 1951; 76 :474-80.

6. Kruger HH, Krentz C. Clinical experiences with avacan, a new antispasmodic. Arz: Wochenschr 1951; 6 : 232-8.

7. Penzold FA. Contribution to spasmolysis (Clinical experiences with the new antispasmodic Avacan). Dtsch
Med Wochenschr 1951; 76 : 479.

8. Losche G. The use of synthetic antispasmodics in obstetrics. Med Welt 1951; 20 : 1582-90.

9. Boldt W, Gocht W. The use of Avacan for facilitating and accelerating parturition. Dutsch Med J 1952; 3 : 330-4.

10. Asholter et al. Acceleration of parturition by Avacan. Die Medizinische 1953; 36 : 1164-6.

11. Guseck E. Conservative acceleration of parturition by Avacan. Journal Suisse de Medicine 1952; 82 : 882-6.

To Section TOC

	Active Phase of Labour		Cervical Dilatation
	Mean	Range	Rate	Time for
	Duration	(hours)	(cm/hr)	1 cm dilatation (min)
Study group	3 hours	1 hour	1.92	3 minutes
n=50	35 minutes	45 minutes	cm/hour
Control	5 hours	5 hours	1.18	48 minutes
group	34 minutes	9 hours	cm/hour
n=50