The antinociceptive efficacy of morphine-ketamine-magnesium combination is influenced by the order of medication administration.

OBJECTIVE: Ketamine and magnesium, both N-methyl-D-aspartate (NMDA) receptor antagonists, enhance the antinociceptive effects of opioid analgesics in different animal models of pain, as well as in humans. This study aimed at evaluating whether magnesium sulphate added to morphine-ketamine combination produces a higher level of analgesia. MATERIALS AND METHODS: Analgesic activity was assessed by tail-immersion test in male Wistar rats (200-250 g). RESULTS: Magnesium sulphate (0.5-60 mg/kg, s.c.) and ketamine (5-30 mg/kg, i.p.) administered alone did not produce any effect. Magnesium sulphate (5 and 60 mg/kg) and ketamine (5 and 30 mg/kg) increased the antinociceptive effect of morphine (2.6 mg/kg, i.p.). Magnesium sulphate (5 mg/kg) increased the antinociceptive effect of the morphine (2.6 mg/kg)-ketamine (2.5 or 5 mg/kg) combination when magnesium sulphate was added to morphine after, and not before ketamine. It is also demonstrated that magnesium sulphate prolonged the duration of the antinociceptive effect of the morphine-ketamine combination. Low dose of morphine (2.6 mg/kg), ketamine (5 mg/kg) and magnesium sulfate (5 mg/kg) given together did not cause motor impairment that could be verified on a rotarod test. The antinociceptive effect of the triple combination was readily antagonized with naloxone (3 mg/kg, s.c.), a nonselective antagonist of opioid receptors, indicating that the effect is mediated via opioid receptors. CONCLUSIONS: This study revealed that the efficacy of the morphine-ketamine-magnesium sulphate combination in tail-immersion test in rats is influenced by the order of medication administration; a higher level of activity is demonstrated only when ketamine is added to morphine before magnesium sulphate.

Impact of age, weight and concomitant treatment on lamotrigine pharmacokinetics.

WHAT IS KNOWN AND OBJECTIVE: Lamotrigine metabolism may be substantially altered with concomitant administration of valproic acid and/or carbamazepine. Such alterations may require the adjustment of lamotrigine dose to ensure optimal treatment efficacy and safety. METHODS: The extent of lamotrigine interactions was investigated dependent on age, gender, weight and dose of concomitant carbamazepine and/or valproic acid in 65 patients with epilepsy. Lamotrigine plasma steady-state oral clearance (CLss/F) and area under the curve (AUCss) were calculated from the dose of drug, average steady-state concentration (Css) and interval of administration. Multiple regression analysis was used for the identification and quantification of factors that influenced lamotrigine pharmacokinetics. RESULTS AND DISCUSSION: Age and dose of carbamazepine and valproic acid had significant influence on lamotrigine CLss/F and AUCss. Carbamazepine was associated with a dose-dependent increase and valproic acid with a dose-dependent decrease of lamotrigine metabolism rate. The effect of carbamazepine was more pronounced. Younger patients were expected to metabolize lamotrigine more rapidly whereas overweight patients may be less susceptible to interactions. Gender had no influence on lamotrigine pharmacokinetics. WHAT IS NEW AND CONCLUSION: The efficacy and safety of lamotrigine may be altered by concomitant administration of carbamazepine and valproic acid. The models developed may be useful for estimating doses of lamotrigine for individual patients to minimize clinically significant interactions. Therapeutic monitoring is advisable when those drugs are used concomitantly.

Opioidergic mechanisms are not involved in the antihyperalgesic effects of carbamazepine and oxcarbazepine.

The mechanisms of the analgesic action of carbamazepine and oxcarbazepine, in particular the role of opioid receptors, have not been established precisely. The systemic effects of naloxone, an opioid receptor antagonist, on the antihyperalgesic effects of carbamazepine and oxcarbazepine were examined in the model of inflammatory hyperalgesia induced by the intraplantar (i.pl.) administration of concanavaline A (Con A, 0.8 mg/paw) into the rat hind paw. Naloxone (3 mg/kg; i.p.) did not alter the antihyperalgesic effects of either carbamazepine or oxcarbazepine. These results indicate that the opioid system of pain modulation does not play a significant role in the antihyperalgesic effects of carbamazepine and oxcarbazepine.

Peripheral anti-hyperalgesia by oxcarbazepine: involvement of adenosine A1 receptors.

In this study we determined whether oxcarbazepine (OXC) could produce local peripheral antinociceptive effects in a rat model of inflammatory hyperalgesia, and whether adenosine receptors were involved. When coadministered with the pro-inflammatory compound concanavalin A, OXC (1000-3000 nmol/paw) caused a significant dose- and time-dependent anti-hyperalgesia. Caffeine (1000-1500 nmol/paw), a nonselective adenosine receptor antagonist, as well as 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (10-30 nmol/paw), a selective A1 receptor antagonist, coadministered with OXC, significantly depressed its anti-hyperalgesic effect. Drugs injected into the contralateral hind paw did not produce significant effects. These results indicate that OXC produces local peripheral anti-hyperalgesic effects, which is mediated via peripheral A1 receptors.

The synthesis and preliminary pharmacological evaluation of 4-methyl fentanyl.

The synthesis of 4-methyl fentanyl, a prototype of a novel class of fentanyl analogues has been effected in 5 steps, starting from N-ethoxycarbonyl-4-piperidone (approximately 20% overall yield). In the key step, N-phenylation of secondary aliphatic amide intermediare was achieved by a novel reaction, using diphenyliodonium chloride for the phenyl group transfer. Preliminary pharmacological results indicate that 4-methyl fentanyl is a super potent narcotic analgesic, about four times more potent than fentanyl.

The cardiovascular effects of the administration of L-NAME during the early posthemorrhagic period.

1. The effects of the various doses of NG-nitro-L-arginine methyl ester (L-NAME, 10 and 30 mg/kg) on some cardiovascular and biochemical parameters during the early posthemorrhagic period were studied in anesthetized rabbits subjected to hemorrhagic hypovolemia. 2. Hemorrhagic shock was produced by intermittent bleeding of 40% of the estimated blood volume for 15 min. Blood samples were taken before and after bleeding (0, 15 and 60 min). Simultaneously, the mean arterial pressure (MAP) and the heart rate (HR) were measured. Hemorrhaged rabbits were treated by L-NAME10 or L-NAME30 (10 or 30 mg/kg, i.v. bolus injection, respectively) or the corresponding volumes of saline (0.6 ml, i.v. bolus) immediately after the end of bleeding. 3. The observed cardiovascular parameters (MAP, HR) were significantly reduced after the end of bleeding in all rabbits. 4. The rise of the MAP was significantly more pronounced 30 min after the injection of L-NAME30 in comparison with the corresponding values in the saline (S) group. In contrast, L-NAME10 produced only a small, insignificant increase in the MAP in hemorrhaged rabbits. 5. The L-NAME30-induced rise of the MAP was accompanied by a severe bradycardia, hyperkalemia and an aggravated metabolic acidosis, more severe than the corresponding disturbance of the acid-base status in the S group. The changes in the acid-base parameters were observed both in arterial (pH, excess base) and in venous blood (pH) of hemorrhaged rabbits. 6. In conclusion, the i.v. bolus injection of L-NAME30 (immediately after the end of bleeding) produced a significant increase in the MAP during the first hour after the injury, but the presumable inhibition of the endothelial constitutive nitric oxide synthase during the early posthemorrhagic period resulted in severe cardiovascular and metabolic disturbances.

Physostigmine and modulators of nitric oxide system on the mean arterial pressure of the spontaneously hypertensive rat.

1. A slow intravenous infusion of L-arginine (3 mg kg-1) lasting one hr produced significant hypotension in urethane-anaesthetized spontaneously hypertensive rats (SHRs). 2. A slow intravenous infusion of NG-nitro-L-arginine methyl ester (L-NAME) (3 mg kg-1 h-1) did not produce any significant change in the mean arterial pressure during infusion. After stopping infusion of L-NAME, a slowly developing increase of the mean arterial pressure was observed during the following 40 min. 3. The pressor response to physostigmine (20, 40 and 80 micrograms kg-1, IV), injected during a slow intravenous infusion of either L-arginine or L-NAME, was not changed. 4. L-arginine and L-NAME depressed the pressor responses to physostigmine, if physostigmine was injected after the end of a 1-hr infusion. 5. Acute pretreatment with increasing doses of physostigmine markedly affected the blood pressure response to L-arginine (i.e., L-arginine-caused hypotension was more pronounced), but only slightly that to L-NAME. 6. In conclusion, L-arginine, as a donor of NO, produced hypotension by itself and also decreased, but not significantly, the central cholinergically-mediated hypertension (CCMH) produced by physostigmine. It is quite possible that the peripheral NO released by L-arginine antagonized the increased adrenergic activity in the CCMH. This does happen in normotensive rats, but to a lesser degree than in SHRs, as shown in the current experiments. 7. Also, our results show that inhibition of endogenous NO biosynthesis using L-NAME does not necessarily lead to pressor response in vivo, at least in SHRs. It is concluded that L-arginine-nitric oxide pathways operate in SHRs, as well as in normotensive Wistar rats, but their role in modulating cholinergically-mediated regulation of the mean arterial pressure is less pronounced in SHRs than in normotensive animals.

[Adverse drug reactions in children]. / Nezeljena dejstva lekova kod dece.

Small children, older than one year of age, can bear as many drugs as mature people can. They can bear some drugs even better than older people, but show unusual sensitivity towards certain drugs. The occurrense of dose-dependent adverse drug effects can be influenced by pharmacokinetics (limited biotransformation-inactivation and elimination of drugs). Only a few drugs can cause adverse effects occurring almost exclusively in children. Even if rare, pediatric adverse drug reactions may be life-treatening. It should be pointed out that many drugs are restricted for children, and many drugs, in spite of the fact that are in clinical practice for several decades, contain no approval for use in children.

[Pharmacology--new therapy. Calcium channel blockers: new aspects of therapeutic use of diltiazem]. / Farmakologija--novine u lecenju. Lekovi blokatori kalcijumskih kanala: novine u terapijskoj primeni diltiazema.

The calcium antagonist, diltiazem is effective in the treatment of patients with various types of angina pectoris, as well as with essential and renovascular arterial hypertension. Sustained-release diltiazem in dose of 180 mg once daily is effective as sustained-release diltiazem in dose of 90 mg twice daily. Besides, in patients with stable angina pectoris and essential arterial hypertension the monotherapy with sustained-release diltiazem in dose of 180 mg is similarly effective as beta blockers and thiazide diuretics. However, monotherapy with sustained-release diltiazem is at least effective as monotherapy with sustained-release verapamil. Comparative clinical investigations showed that diltiazem is more effective than propranolol in decreasing ischemic attacks, whereas the risk of bradycardia is smaller. On the other hand, nifedipine (dihydropyridine calcium antagonist) is more effective than diltiazem in lowering ischemic electrocardiographic changes, incidence of attacks and improving working capability. The efficacy of diltiazem, nifedipine and verapamil is similar in the treatment of patients with spastic angina pectoris, whereas the least effective is propranolol. As far as the arterial hypertension is concerned, clinical investigations showed that the efficacy of diltiazem and nifedipine is similar. Side effects are relatively rare (1.8-9.6% patients) and depend on the dose (nausea, fatigue, dizziness, headache and itching).

The effect of physostigmine on the haemorrhagic hypovolemia in anaesthetized rabbits.

1. The effects of physostigmine (70 micrograms kg-1, intravenously) on mean arterial blood pressure, blood volume and survival were studied in anaesthetized rabbits subjected to haemorrhagic hypovolemia. 2. It was found that physostigmine increased the mean arterial blood pressure, increased the residual blood volume, decreased the haematocrit values and increased the survival of the animals. 3. The increase of blood pressure might be due to a general adrenergic activation produced by physostigmine, whereas the increase in plasma volume might be due to changes in pre- to postcapillary resistance ratio. 4. The beneficial effect of physostigmine might also be due to antagonism of humoral factors known to aggravate the hypovolemia (e.g. endogenous opioids).

Modulating effect of adenosine on the hypertensive response to physostigmine.

The purpose of this work was to study the neuromodulatory role of adenosine on the hypertensive response to physostigmine in the rat. It was found that increasing doses of adenosine, injected intravenously, produced a biphasic blood pressure response, consisting of an initial and short-lasting hypotension, followed by a prolonged hypertension. The hypertensive phase of this response was significantly depressed or even abolished by phentolamine, whereas the hypotensive phase was depressed but not abolished by atropine. If injected intravenously, but immediately before physostigmine, adenosine produced a potentiation of the blood pressure response to physostigmine. This was even more evident if adenosine was injected directly into the carotid artery immediately before the intravenous injection of physostigmine. Neither aminophylline nor 8-phenyltheophylline affected this potentiating action of adenosine. This finding might indicate that this potentiating action does not involve the already known adenosine receptors, or that this action is realized through some other type of receptors and mechanisms not sensitive to xanthine derivatives. It is concluded that adenosine might have a general modulating presynaptic effect on various transmitting processes, including those which take place in the central nervous system during the hypertensive response to physostigmine in the rat.

Transmitter interactions in the central cholinergic control of blood pressure regulation.

There are at least five mechanisms by which the central nervous system regulates neural and humoral systems that control the blood pressure (BP). Particular attention has been paid to central cholinergic-adrenergic interactions in the regulation of BP. Physostigmine and other anticholinesterases which penetrate the blood-brain barrier, both carbamates and organophosphates, produce an increase of BP. This effect can be abolished by atropine, but not by methylatropine. The available evidence indicates that physostigmine and other AChE inhibitors initially produce an activation of central muscarinic receptors, which subsequently leads to an increase of the peripheral adrenergic activity. The hypertensive response to physostigmine is possible only if a functionally competent ChE is present in the brain. This effect of physostigmine is regularly associated with a dose-related increase in the neural activity in the preganglionic fibers of the cervical sympathetic nerve. BP rise after physostigmine is significantly less in immunosympathectomized animals and almost completely abolished after chemical sympathectomy. Physostigmine significantly increased the plasma concentration of catecholamines. After electrocoagulation of the locus coeruleus, not only did a significant decrease occur in the basic level of noradrenaline in plasma, but there was also a strong depression of the noradrenaline plasma response to physostigmine and immobilization. Physostigmine increased lipolysis and glycogenolysis, whereas neostigmine did not produce any change. Several directly acting cholinergic agonists alter the functions of the cardiovascular system when injected directly into the cerebral ventricular system, or directly into various brain regions. The most probable sites of action of AChE inhibitors and directly acting cholinergic agonists are the locus coeruleus, the nucleus tractus solitarii and the rostral ventrolateral medulla (RVLM). The primary activation of the cholinergic synapse is believed to take place in RVLM. Met-enkephalin, Leu-enkephalin and beta-endorphin, when applied exogenously, depress or even abolish the hypertensive effect of physostigmine. The same type of response was obtained after application of substances which inhibit the enkephalin-degrading enzymes (bestatin, phosphoramidon). Thus, the exogenous or endogenous enkephalins activate the opioid receptors in the brain and at the same time produce a depression of the cholinergic-adrenergic interaction in the central nervous system, which is a prerequisite for the hypertensive response to physostigmine. The functional role of the central cholinergic mechanisms in BP control under physiological conditions has not been established with certainty. These mechanisms might have a more significant role under pathological or homeostatic disturbances. For example, physostigmine showed a life-saving effect in acute hypovolemic shock in rabbits.

[Comparative effects of dihydropyridine inhibitors of calcium penetration on spontaneous contraction of the isolated heart atria in the guinea pig]. / Effets comparatifs des inhibiteurs dihydropyridiques de la pénétration calcique sur les battements spontanés des oreillettes isolées du Cobaye.

All DHPs (nifedipine, nicardipine, nitrendipine) produced a concentration-dependent depression of the isometric contraction and of the atrial rate of the isolated, spontaneously beating atria of the guinea-pig. The depressive actions of nifedipine and nitrendipine were completely antagonized by the addition of calcium, aminophylline and isoprenaline. Aminophylline partially, calcium almost completely and isoprenaline completely antagonized the depressive action of nicardipine on the isometric contraction. Only isoprenaline antagonized the effect of DHPs on the atrial rate of the isolated, spontaneously beating atria of the guinea-pig. It is possible that all these substances restore the contractibility of the atria by compensating the calcium balance, previously changed by DHPs, or by producing an increase in the intracellular cyclic AMP content (aminophylline and isoprenaline).