Testing the tyrosine/catecholamine hypothesis of oral contraceptive-induced psychological side-effects: a controlled study on triphasil.

BACKGROUND: This study was conducted to probe the existence of oral contraceptive (OC)-induced psychological side effects that might be undetectable by psychometric testing. METHODS: Triphasil was administered during six complete menstrual cycles to young never-OC-users. Plasma Tyr and Trp/Sigma-respective competitor neutral amino acids (NAA) ratio and concentrations of other amino acids (AA), known to be involved in the functioning of the central nervous system (CNS) and the synthesis of neurotransmitters, in particular, were used as biochemical markers to assess this likelihood. Factors known to influence plasma AA concentrations such as cortisol and pyridoxal phosphate (PLP, active form of vitamin B6), both modulators of AA intestinal absorption, were examined. RESULTS: Dietary supply of amino acid substrates (precursors) and blood levels of coenzyme/cofactor (vitamin B6 and iron) involved were adequate in both groups and were kept constant throughout the treatment. The rise in plasma cortisol, known to be stimulated under the action of estrogen, was significant (p < 0.05) after the first menstrual cycle and remained higher (although not significantly) than mean baseline and reference normal values at the end of the 6-month OC treatment. Plasma Trp/Sigma-specific competitor NAA ratio remained unchanged whereas Tyr/Sigma-specific competitor NAA ratio was significantly (p < 0.02) reduced after the sixth artificial menstrual cycle. CONCLUSION: Although plasma AA biochemical markers cannot accurately assess CNS activity, they seem to be more sensitive than a comprehensive psychometric testing (MMPI) in assessing OC-induced psychological changes.

Nutritional and psychological status of young women after a short-term use of a triphasic contraceptive steroid preparation.

The present study was aimed to assess the psychological status of young healthy women after the administration of a triphasic contraceptive steroid preparation for six complete menstrual cycles. Subjects had never used oral contraceptives (OC) and had neither a familial history of depression nor psychological disturbances. OC-induced psychological disturbances were interpreted for years as evidence of pyridoxine (vitamin B6) deficiency. Other nutritional deficiencies, namely in cobalamin, folate and iron, can disturb the functioning of the central nervous system. In addition, a deficiency of any of these nutrients can lead to several anemia-induced symptoms that are highly susceptible to influence the psychological status. For ample evidence, nutritional status was then evaluated in parallel to psychological testing. Blood iron and vitamin levels of interest were found to be adequate and could not have biased the response to a psychological test (MMPI). This study showed that a 6-month Triphasil treatment did not modify significantly the psychological status of subjects. To our knowledge, this is the first psychological study on young never OC-users taking an identical triphasic contraceptive steroid preparation to investigate early psychological side-effects due to OC, at a similar time of the menstrual cycle, when nutritional status was also evaluated.

Early effect of a low dose (30 micrograms) ethinyl estradiol-containing Triphasil on vitamin B6 status. A follow-up study on six menstrual cycles.

The objectives of the study were to follow-up six artificial menstrual cycles induced by Triphasil in order to determine: 1) the time of apparition of B6 metabolic side-effects, in the eventuality they occur, and 2) the existence or non-existence of a normalization process and if so, when it is initiated. The choice of this triphasic OC preparation was based on its current popularity among modern gynecologists. Among the selected twenty-three young women who had never used oral contraceptives (OC), fourteen consented to try a new contraceptive method. Their nutritional status including anthropometric, hematologic, biochemical and dietetic (including vitamin B6 intake) parameters was found to be adequate. A functional enzymatic test coupled to a direct measurement of vitamin B6 was employed to obtain a complete assessment of their vitamin B6 status. By using both approaches, only one case (7%) of deficiency due to OC was evidenced. This well-controlled study revealed that a short-term use of a relatively low dose estrogen-containing OC (30 micrograms) did not alter PLP concentrations in plasma and erythrocytes in the majority of our young subjects consuming adequate diets. However, a disturbance in vitamin B6 metabolism was detected. PL levels in both blood components have increased steadily and did not subside to pretreatment values at the end of the experiment. In conclusion, the single use of the PLP vitamer can be misleading as demonstrated by other investigators. To assess B6-status during oral contraception, in addition to a functional enzymatic test, it may be necessary to include the other aldehydic form of vitamin B6, to fully establish and comprehend hormone-induced adverse effects on this metabolism, particularly those of progesterone/progestin that have not yet been explored.

Effects of indomethacin and etodolac on coronary blood flow and other cardiovascular variables in propranolol-treated dogs.

Indomethacin has been reported to induce coronary vasoconstriction in patients treated with beta-adrenoceptor blockers and nitrates. In the present investigation, the possibility that coronary blood flow was affected by a direct or indirect interaction between nonsteroidal anti-inflammatory drugs and propranolol was studied in the anesthetized dog. During beta-adrenoceptor blockade by propranolol, both indomethacin and etodolac failed to decrease coronary blood flow. When administered alone at doses sufficient to inhibit prostaglandin synthesis, indomethacin and etodolac did not reduce the coronary blood flow. It was concluded that there was no interaction between propranolol and the nonsteroidal anti-inflammatory drugs used. The results also suggested that the role of prostaglandins in the regulation of the coronary circulation remains an open question.

Cetamolol: cardiovascular effects of a new cardioselective beta-adrenoceptor blocker possessing partial agonistic activity and lacking membrane-stabilizing activity.

The cardiovascular effects of cetamolol, a new beta-adrenoceptor blocker, were studied in the anesthetized dog and cat and in the conscious dog and monkey. The compound was compared with other beta-blockers known to possess various degrees of cardioselectivity, partial agonistic effects, and membrane-stabilizing activity. In the anesthetized open-chest dog, cetamolol and pindolol produced similar cardiovascular effects in that the partial agonistic activity predominated over the blockade of beta-adrenoceptors. The partial agonistic activity of pindolol was greater than that of cetamolol. Unlike pindolol, cetamolol had no significant vasodilating property. However, the beta-blocking effects of these two drugs predominated in the anesthetized closed-chest dog, conscious dog and monkey. Atenolol, nadolol, and propranolol, which lack partial agonistic activity, produced cardiovascular changes characteristic of this type of beta-blocker in the animal preparation in which they were tested. In the anesthetized cat, comparison of the mean effective doses for the heart rate and blood pressure responses induced by isoproterenol showed that cetamolol was more cardioselective than metoprolol but less than acebutolol and atenolol. Evidence of the cardioselectivity of cetamolol was also obtained in the anesthetized closed-chest dog, although the degree of cardioselectivity of both cetamolol and atenolol was less marked than in the cat. When given orally to the conscious dog and monkey, cetamolol appeared to be well absorbed. The peak effect was observed after 1-2 h and persisted for the 5-h test period. It is concluded that cetamolol is a potent beta-blocker with a moderate degree of partial agonistic activity and cardioselectivity in in vivo experiments.

Cetamolol: a new cardioselective beta-adrenoceptor blocking agent without membrane-stabilizing activity.

Cetamolol, a new beta-adrenoceptor blocker with partial agonist activity and cardioselectivity, was studied in vivo to determine its membrane-stabilizing effects. Comparisons were carried out with atenolol, pindolol, practolol, propranolol, timolol, dexpropranolol, lidocaine, and procaine. The following results indicated that cetamolol lacked membrane-stabilizing activity: (i) failure to cause local anesthesia on the rabbit cornea and motor nerve of the rat tail; (ii) ineffectiveness in reversing ventricular arrhythmias induced by coronary artery litigation in dogs; (iii) failure to reduce cardiac automaticity in catecholamine-depleted dogs as determined by the rate of a subatrial rhythm during ventricular (vagal) escape; and (iv) lack of a significant increase in atrioventricular conduction time in vagotomized or atropinized dogs in contrast to the effect in normal dogs indicating a reflex effect of cetamolol. Other results include a restoration of sinus rhythm in dogs with ventricular tachycardia induced by ouabain, and a dose-related decline in the force of cardiac contraction in anesthetized dogs at doses from 3 to 15 mg/kg, which occurred after an initial increase in force owing to intrinsic sympathomimetic activity. Although the mechanisms for the latter two effects are not clear at this time, explanations other than membrane-stabilizing activity have been considered in view of the other findings. It is concluded that cetamolol lacks membrane-stabilizing activity even at inordinately high doses.

Positive inotropic and antiarrhythmic actions of actodigin in dogs (1).

The effects of actodigin were studied in dogs with decreased cardiac contractility or atrail flutter. When injected at 30 min invervals into dogs with barbiturate-induced heart failure, actodigin caused a marked positive inotropic action of short duration. Actodigin's pronounced but fleeting effect appears to be related to the novel attachment of its steroid nucleus alpha to the carboxyl function in the lactone. Cardiac glycosides with a conventional beta linkage of the lactone ring to the steroid nucleus (e.g., AY-22,248) had positive inotropic actions which were both slower in onset and cumulative when injected every 30 min. Apparently because of its short duration of action, actodigin was not as cardiotoxic as its isomer, AY-22,248. Lastly, a sustained atrail flutter was induced by intercaval crush and faradic atrial stimulation. Both actodigin and ouabain converted this arrhythmia to normal sinus rhythm.