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Biomedical subjects

M Akerlund

Publications and source records attributed to M Akerlund.

At least 55 records · Page 3Linked to original sources
PubMed1990

Induction of labor in intrauterine fetal death with 16-phenoxy-prostaglandin-E2-methylsulfonylamide (sulprostone)--effects on uterine contractility, coagulation and kallikrein-kinin systems.

Thirty-two patients with intrauterine fetal death after the 20th week of pregnancy were treated with 1-3 intramuscular injections of 500 mg of 16-phenoxy-PGE2-methylsulfonylamide (sulprostone). Intrauterine pressure records demonstrated onset of contractions within 20 min of injection and all women aborted-delivered after in mean 11 h (4-31 h). No effect on routine hematologic and plasma parameters, kallikrein-kinin and factor XII systems was observed. It is concluded that 16-phenoxy-PGE2-methylsulfonylamide is an effective and safe oxytocic agent for the induction of labor in case of intrauterine fetal death with minimal effects on the coagulation system.

Adult↗
PubMed1989

Effect of an oral contraceptive in primary dysmenorrhea--changes in uterine activity and reactivity to agonists.

Mechanisms for the therapeutic effect of oral contraceptives in dysmenorrhea were studied by recording intrauterine pressure on the first day of menstrual bleeding in women with moderate to severe symptoms and after three weeks of oral contraceptive therapy (150 micrograms levonorgestrel + 30 micrograms ethinyl estradiol, daily). Spontaneous uterine activity and reactivity to intravenous injections of vasopressin (6 pmol/kg body weight; n = 8) or prostaglandin F2 alpha (12 nmol/kg body weight; n = 9) at the two sessions were compared. During the first recording when all women had dysmenorrhea, the uterine activity and reactivity to both agonists were pronounced. After therapy, when the women felt essentially no pain, a statistically significant decrease in spontaneous uterine activity in terms of total pressure area, frequency and amplitude of contractions was observed. The agonist injections induced less pain at the second recording, although the magnitude of responses, superimposed on the much smaller uterine activity at this time, were not significantly different from those at the first recording during dysmenorrhea. The mechanism of pain relief by oral contraception in dysmenorrhea could be a lesser impact of the decreased contractile activity on uterine blood flow, abolishing the local ischemia. A reduced uterine reactivity to agonists might also to some extent contribute to the therapeutic effect.

Adult↗
PubMed1989

Oxytocin receptor blockade: a new principle in the treatment of preterm labor?

The concentration of myometrial and decidual oxytocin receptors increases dramatically in normal women in late pregnancy, causing enhanced uterine sensitivity to physiologic levels of oxytocin. Similar increase in myometrial oxytocin receptors has been found in women in preterm labor, indicating a role for oxytocin also in idiopathic preterm labor. A newly synthesized oxytocin analogue, 1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-oxytocin, has been found to be a competitive inhibitor of oxytocin. The present study was conducted to test its efficacy in suppressing uterine contractions during preterm labor in women. Twelve patients with established, uncomplicated preterm labor between 27 and 33 weeks of gestational age were given intravenous infusions of the analogue for 1.5 to 13 hours during continuous external cardiotocographic monitoring. In nine patients inhibition of uterine contractions was achieved and further progression in cervical scores was arrested. In three patients, all at 27 weeks of gestational age, no significant tocolytic effect was observed during a 1.5-hour infusion of the analogue and the patients were then given ritodrine intravenously. No side effects were observed in any of the patients. These preliminary findings support the concept that an increased concentration of uterine oxytocin receptors is an important etiologic factor in uncomplicated preterm labor and therefore oxytocin receptor blockade may be a therapeutic alternative for this condition.

Adult↗
PubMed1989

The effect of magnesium on calcium uptake and contractility in the human myometrium.

High concentrations of magnesium (12 and 24 mM) in the extracellular medium markedly inhibited both spontaneous activity and K+-induced contracture in strips of nonpregnant human myometrium. Net calcium influx measured by the uptake of 45Ca2+ in the myometrium was considerably decreased by high concentrations of magnesium. This was true for both resting (unstimulated) and K+-stimulated uptake of 45Ca2. While calcium uptake in K+-stimulated tissues exposed to 24 mM magnesium was significantly lower than in those exposed to 12 mM, no difference was found in the unstimulated tissues. These data indicate that the tocolytic action of magnesium most probably results from the inhibition of calcium entry into myometrial cells.

Adult↗
PubMed1989

Comparison of ketoprofen and naproxen in the treatment of dysmenorrhoea, with special regard to the time of onset of pain relief.

In a double-blind, crossover study in 39 women with dysmenorrhoea, the effects of oral treatment with single doses of 100 mg ketoprofen and 500 mg naproxen were compared with regard to time for onset of pain relief and overall effect on symptoms. Assessments of pain severity using a visual analogue scale and an activity-related scale were made at 15-minute intervals for 2.5 hours. The results showed that ketoprofen was significantly more effective at 60 and 45 minutes, respectively, after intake of medicine and the differences remained significant until 120 and 105 minutes, respectively. Reduction in original pain by 50%, the patient's view on the overall effect after each treatment as well as a comparison of effects at the end of the study all differed significantly in favour of ketoprofen. No significant differences were found between treatments in the need for additional analgesic therapy after the 2-hour observation period or in the incidence of side-effects, which was low with both medications. It is suggested that ketoprofen could have a therapeutic advantage over naproxen, particularly in patients in whom menstrual pain develops rapidly.

Adolescent↗
PubMed1989

The influence of a combined oral contraceptive on uterine activity and reactivity to agonists in primary dysmenorrhea.

The mechanisms underlying the therapeutic effect of an oral contraceptive (150 micrograms levonorgestrel and 30 micrograms ethinyl estradiol daily for 21 days) in primary dysmenorrhea were studied by recordings of uterine activity and reactivity to lysine (L) vasopressin (VP) and prostaglandin (PG) F2 alpha on the first day of menstruation in 14 women before and after one period of oral contraceptive treatment. During the first session, when all women had moderate to severe dysmenorrhea, intra-uterine pressure recording showed an intensive uterine activity, and bolus injections of LVP (6 pmol/kg body weight; 6 subjects) or PGF2 alpha (6 or 12 nmol/kg body weight; 4 subjects in each group) increased contractile activity and discomfort. After oral contraceptive treatment, spontaneous uterine activity, measured as total pressure area, decreased significantly (p = 0.02 and p = 0.03 in the VP and PG groups, respectively). The mean uterine responses to LVP and PGF2 alpha were on average smaller after oral contraceptive treatment and the women experienced minimal discomfort after this injection. It is suggested that inhibition of uterine activity could be an important mechanism for the therapeutic effect of gestagen-dominated oral contraceptives in primary dysmenorrhea and that reduced uterine reactivity to agonists might contribute to this effect.

Adolescent↗
PubMed1988

Effects of vasopressin on the human non-pregnant uterus: studies with analogues of different vasopressor potencies.

The uterotonic effects of arginine8-vasopressin (AVP) have been studied on uterine strips from non-pregnant women. Concentration-dependent contractions could be recorded over a 10 min period in the presence of AVP (5.5.10(-10)-3.10(-7) M); the most reproducible recordings were obtained with tissue from the inner part of the myometrium. Analogues of AVP and oxytocin (OT), modified at positions 1 (2-hydroxy-3-mercaptopropionic acid, deamino-3-mercaptopropionic acid), 2 (Phe), 4 (Arg, Val), 7 (Sar) or 8 (Orn) were synthesized and tested for uterotonic activity on human and rat uterine strips, and for vasopressor and antidiuretic activity in the rat in vivo. There was a positive correlation between the activity of these analogues on non-pregnant human myometrial tissue with that in the rat vasopressor assay (r = 0.86, P less than 0.01) but none with their activity in the antidiuretic assay. For example, [Mpa1,D-Arg8]vasopressin had more than twice the antidiuretic activity of AVP but less than 0.2% of its pressor or human uterotonic potency (Mpa = 3-mercaptopropionic acid). Correspondingly, the specific pressor analogue [Hmp1,Phe2,Orn8]OT was as potent as AVP on the human uterus, but had less than 3% of its antidiuretic activity (Hmp = 2-hydroxy-3-mercaptopropionic acid). There was no correlation between the uterotonic activities of AVP or its analogues when non-pregnant human and rat tissues were compared, indicating that rat uterine tissue is a poor guide when testing analogues intended for clinical use in non-pregnant women.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Uterine blood flow and myometrial activity at menstruation, and the action of vasopressin and a synthetic antagonist.

Local endometrial blood flow was measured by a thermistor technique and myometrial activity by intrauterine pressure recording in 10 women before and during menstruation. The effect of lysine vasopressin infusion (1 pmol/kg body-weight per min) and of bolus injection of a synthetic oxytocin analogue, 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin (10 nmol/kg body-weight), were studied. Spontaneous variations in blood flow were seen synchronous with clearly demarcated uterine contractions, the myometrial activity being significantly increased in early (day -1 to day +2) compared with late (day +3 to day +5) menstrual phase. The vasopressin infusion decreased blood flow, stimulated uterine activity and caused slight to moderate dysmenorrhoea-like pain. These effects were completely inhibited by the injection of the oxytocin analogue. In-vitro studies on uterine arteries confirmed that the analogue also inhibited the vasopressin-induced constriction of the uterine arteries. This antagonist was more effective than two other analogues, 1-deamino-2-D-Tyr(OEt)-4-Val-8-Orn-oxytocin and 1-deamino-2-Tyr(OEt)-oxytocin. The counteracting effect of 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin on the vasopressin-induced decrease of blood flow and increase of contractions supports the therapeutic value of the drug in primary dysmenorrhoea and preterm labour.

Adult↗
PubMed1987

Inhibition of uterine contractions of premature labour with an oxytocin analogue. Results from a pilot study.

A competitive inhibitor of the action of oxytocin on the uterus, 1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-oxytocin, was studied for the first time in 13 patients with established, uncomplicated premature labour. Intravenous infusion of 10-100 micrograms/min of the analogue was given for 1-10 h and the effect was monitored by external cardiotocography. In all women an inhibition of uterine activity was observed, and in the majority of patients infused with 25 micrograms/min and a total dose of about 5 mg or more of the drug total inhibition of uterine contractions was achieved. There were no effects on the maternal and fetal pulse rates, nor were there any other side-effects. The results of this preliminary study support the concept of an increased concentration of uterine oxytocin receptors being aetiologically important in uncomplicated premature labour. They also suggest that the present oxytocin antagonist could be an interesting therapeutic alternative in the condition, primarily because of the marked selectivity of its effect.

Clinical Trials as Topic↗
PubMed1987

Plasma concentrations of vasopressin and a prostaglandin F2 alpha metabolite in women with primary dysmenorrhoea before and during treatment with a combined oral contraceptive.

Oral contraceptives reduce menstrual pain but the interaction with vasopressin and prostaglandin F2 alpha, two uterine stimulants related to the condition, is unknown. Ten women with a history of moderate to severe dysmenorrhoea were studied. Repeated blood samples were taken during a first menstrual cycle without treatment, during the first 21 days of a second cycle when they received an oral contraceptive (150 micrograms levonorgestrel and 30 micrograms ethynyloestradiol) and on the first or second day of the bleeding following hormonal withdrawal. Measurements were made of plasma concentrations of arginine vasopressin, 15-keto-13,14-dihydroprostaglandin F2 alpha, oestradiol-17 beta, progesterone, ethynyloestradiol, levonorgestrel, FSH, LH and prolactin, and serum osmolality was measured. Seven of the women rated their discomfort as moderate to severe on the first two menstruations, but as none or light at the withdrawal bleeding; with the rating scale for degree of pain that was used, this decrease in pain was significant (P less than 0.001). The plasma concentration of vasopressin in these seven women showed significant variation, with the highest concentrations being obtained at the beginning of the two painful menstruations (3.76 +/- 0.76 and 1.75 +/- 0.30 (S.E.M.) pmol/l) and at ovulation in the control cycle (1.91 +/- 0.58 pmol/l). During treatment the concentrations were consistently low, except on the first day of withdrawal bleeding (2.33 +/- 0.35 pmol/l). The concentrations of the prostaglandin F2 alpha metabolite showed less variation, but again the values at withdrawal bleeding (271 +/- 39 pmol/l) were not different from those obtained over the painful menstruations (255 +/- 24 and 217 +/- 25 pmol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1987

Can primary dysmenorrhea be alleviated by a vasopressin antagonist? Results of a pilot study.

In order to study the etiological role of vasopressin in primary dysmenorrhea the therapeutic effect of an antagonist of vasopressin action on the uterus (1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin) was investigated in 14 patients with moderate to severe symptoms. The women participated in the study at two menstruations and each time one intravenous bolus injection of the analogue (10 micrograms/kg body weight) and one of the placebo (saline) were given, randomized and double-blind with at least a 2 hour interval. The effect was monitored by overall ratings and by pain diagrams described by the patients. In the former parameter the vasopressin antagonist was significantly more effective (p less than 0.01). In the pain diagrams, however, a significant reduction of symptoms occurred both after the analogue administrations and after placebo given as second injection. The results support a causative role of vasopressin in primary dysmenorrhea, but further studies with higher doses and/or other routes of administration or delivery systems are required in order to delineate the therapeutic value of vasopressin antagonists in the condition.

Adolescent↗
PubMed1986

Involvement of prostaglandins in the effect of cupric ions on the human uterus.

The effect of cupric ions on the human uterus and the involvement of prostaglandins (PGs) in mediating this effect was studied by recording of isometric contractions of isolated myometrial strips and pieces of uterine arteries, and by intrauterine pressure recordings in women before the onset of menstruation. In vitro, CuCl2 in concentrations of 10(-4) M and higher caused a significant inhibition of myometrial contractile activity, but no effect on the artery preparations was seen. Furthermore, the contractile response of myometrial strips to PGF2 alpha and PGE2 (10 ng/ml) decreased in the presence of CuCl2 in concentrations of 5 and 50 mumol. In vivo, instillations of 0.3, 1.0 and 2.0 mM of CuCl2 in 0.7 ml of saline solution into the uterine cavity caused a dose-dependent stimulation of uterine activity, but after pretreatment with naproxen, 500 mg orally, the effect of these substances was abolished. After naproxen treatment, but during infusion of PGF2 alpha (5 micrograms/min), the response to the CuCl2 solutions was partially restored. It is suggested that cupric ions, at high concentrations, have an inhibiting effect on myometrial activity. The stimulatory effect of low doses of CuCl2 seen after instillation into the uterine cavity is largely exerted via initiation of synthesis and release of endometrial PGs.

Arteries↗
PubMed1986

Vasotocin analogues which competitively inhibit vasopressin stimulated uterine activity in healthy women.

Three analogues of posterior pituitary hormones, 1-deamino-2-D-Tyr(OEt)-4-Val-8-Orn-vasotocin(dE-VVT), 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-vasotocin(dE-TVT) and 1-deamino-2-D-Tyr(OEt)-oxytocin(dE-OXY) were compared for their inhibitory effects on vasopressin (VP)-induced uterine activity in healthy women. At menstruation, during recording of intrauterine pressure (18 recording sessions in 11 women), intravenous infusion of lysine vasopressin (LVP, 1 ng/min/kg/body weight) induced an increase of the uterine activity and dysmenorrhoea-like symptoms. Intravenous injections of all analogues (10 micrograms/kg body weight) caused relief of symptoms and inhibition of uterine activity, dE-TVT was the most effective and dE-OXY was least active. With dE-TVT almost complete inhibition of contractions was seen during the first 10 min after injection. The duration of effect was also greatest with that analogue (40-50 min). Only dE-OXY had an agonist effect on spontaneous uterine activity. Pharmacokinetic studies of intravenous dE-TVT (10 ng/kg body weight) showed that the plasma half-life was approximately 16 min and the clearance 30 l/h. The bioavailability of 100 ng/kg given intranasally was about 5.5%. Further studies are recommended.

Adult↗
PubMed1986

Pharmacokinetics in the human of a new synthetic vasopressin and oxytocin uterine antagonist.

The pharmacokinetics in the human of 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-vasotocin (dE-TVT), was studied after iv and intranasal administration in 11 subjects at 12 experiments each route. The plasma concentration of the analogue was analysed by means of an arginine vasopressin antibody, which cross-reacted with dE-TVT to 4.7%. When given intravenously as bolus injection (10 nmol/kg/body weight), the total body clearance amounted to 0.623 +/- 0.099 (SEM) l/h kg and the half-life to 16.2 +/- 2.4 min. After intranasal administration (100 nmol/kg/body weight), the bioavailability was 10.5 +/- 2.9%. Peak concentrations in plasma appeared 2-8 min after iv and 10-45 min after intranasal administration. At the end of an observation period of 2 h measurable amounts in plasma were still found in one of the iv and seven of the intranasal experiments. It is concluded that the moderately long half-life is suitable for the treatment of hospitalized patients in premature labour where promising results with intravenous infusion (50 micrograms/min) of dE-TVT have been obtained. It is still uncertain whether or not the absorption of dE-TVT is sufficient for intranasal administration to out-patients with uterine hyperactivity in late pregnancy and to patients with primary dysmenorrhoea, where significant relief of symptoms were seen after iv administration (10 micrograms/kg body weight).

Administration, Intranasal↗
PubMed1986

Synthetic antagonists of the myometrial response to vasopressin and oxytocin.

With the aim of developing inhibitors of vasopressin- and oxytocin-induced uterine activity, 17 analogues of 1-deamino-oxytocin were synthesized by the solid-phase method. Modifications were made at positions 2, O-methyltyrosine (Tyr(OMe] and O-ethyltyrosine (Tyr(OEt],D-Tyr,D-Tyr(OEt),D-Trp; 4, Val,Thr and 8, Orn,Cit,Arg,D-Arg. The analogues were tested for antiuterotonic activity in vitro and in vivo in the rat and in vitro on myometrial strips from non-pregnant women and pregnant women at term. Their selectivity was also investigated in blood pressure and antidiuretic bioassays in rats. Results were compared with those from an original antiuterotonic analogue 1-deamino-2-Tyr(OEt)-oxytocin (d(OEt)-oxytocin). In the rat in vitro and in vivo all analogues possessed higher antiuterotonic activity than d(OEt)-oxytocin. The negative logarithm of the molar concentration of the antagonist which reduced the effect of a dose of agonist to that of half the dose (pA2) was between 7.6 and 8.9 for all the new inhibitors compared with 7.2 for d(OEt)-oxytocin. The highest pA2 value was found for 1-deamino-2-Tyr(OMe)-8-Orn-oxytocin (8.9 +/- 0.2, S.E.M.) and 1-deamino-2-Tyr(OEt)-4-Thr-8-Orn-oxytocin (8.9 +/- 0.6). In myometrium from non-pregnant women the most potent peptide was 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin (17.2 +/- 2.0 times more potent that d(OEt)-oxytocin). In myometrium from pregnant women the inhibitory effects of the majority of the analogues were less pronounced.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗