Opposite effects of GABAA and NMDA receptor antagonists on ethanol-induced behavioral sleep in rats.

The effects of the GABAA receptor antagonists, pentylenetetrazol, bicuculline, and picrotoxin, the glycine antagonist, strychnine, and the NMDA receptor antagonist, memantine, on ethanol-induced behavioral sleep and body temperature were investigated. Pentylenetetrazol, bicuculline, and picrotoxin given prior and following ethanol reduced the behavioral sleep and potentiated the hypothermia caused by ethanol. However, convulsions appeared when bicuculline, but not pentylenetetrazol and picrotoxin, were given following ethanol. After the reversal of unconsciousness in rats without convulsions the animals remained awake throughout the experiments without motor incoordination, hyperexcitability, and sedation, but they were in hypothermia within 12 h. The glycine antagonist, strychnine, given prior or after ethanol had virtually no effect on ethanol-induced behavioral sleep and hypothermia. Ethanol given prior or following strychnine failed to antagonize strychnine-induced convulsions. The NMDA receptor antagonist, memantine, given following ethanol potentiated the behavioral sleep and had virtually no effect on hypothermia induced by ethanol. It is suggested that the ethanol-induced behavioral sleep may be attributed to its ability to enhance the GABAergic mechanisms and to inhibit NMDA-mediated excitatory responses. However, the ethanol-induced hypothermia may be ascribed solely to the facilitation of GABAergic transmission. Further, it is postulated that a bidirectional inhibitory system subserves the regulation of behavioral sleep and convulsions. However, one-way inhibitory system underlies the ethanol-induced hypothermia.

Single 8 mg dose of oral ondansetron failed to prevent FAC chemotherapy-induced acute nausea and vomiting.

The aim of this open, nonrandomized, monocentric study was to evaluate the efficacy of a single daily dose of 8 mg oral ondansetron in the prophylaxis of acute nausea and vomiting in chemotherapy-naive breast cancer patients receiving their first cycle of chemotherapy with 5-fluorouracil, doxorubicin and cyclophosphamide (FAC). Forty-five female patients were recruited, median age 42 years. The number of emetic episodes and the grade of nausea were recorded. 51% of patients achieved complete, and 9% major control of acute emesis. 33% of patients experienced no acute nausea, and in 18% nausea was mild. Complete protection from nausea and vomiting (complete prophylaxis) was obtained in 12/45 (27%) of patients. Treatment success (no vomiting with no more than mild nausea) was achieved in 18/45 (40%) of patients. We conclude that the efficacy of a single dose of 8 mg oral ondansetron in controlling acute nausea and vomiting induced by FAC chemotherapy is not high enough to justify its use as a sole antiemetic agent in outpatients.

[Tamoxifen: modern drug therapy of estrogen-dependent breast tumors]. / Tamoksifen: savremena medikamentozna terapija estrogenzavisnih tumora dojke.

Tamoxifen is an antiestrogen drug which is used for adjuvant therapy of patients with estrogen positive receptors in breast cancer. It is a competitive antagonist of estrogen receptors for endogenous and exogenous estradiol, but its anticancer effects cannot be explained only by its action on estrogen receptors. Its main effects are anticancer and endocrine, but it also effects on antithrombin III, HDL cholesterol and biosynthesis of prostaglandins. Low incidence of side effects is its main advantage, but not having causal effects its disadvantage.

The role of alpha-adrenergic mechanisms within the area postrema in dopamine-induced emesis.

Intracerebroventricular injection of dopamine (0.5-4.0 mg) produced dose-dependent and short-lasting emesis (1-8 min) in cats, which was abolished after ablation of the area postrema. Relatively selective alpha 2-adrenoceptor antagonists (yohimbine and idazoxan) and a mixed alpha 1- and alpha 2-adrenoceptor antagonist (tolazoline), but not a non-selective alpha 1-adrenoceptor antagonist (prazosin), injected intracerebroventricularly inhibited the emesis induced by intracerebroventricular dopamine. However, dopamine receptor antagonists (chlorpromazine, droperidol, spiperone, domperidone, triflupromazine, sulpiride and metoclopramide), an antimuscarinic drug (atropine), a ganglionic blocking agent (mecamylamine), an opioid receptor antagonist (naloxone) and a 5-HT receptor antagonist (methysergide), all injected intracerebroventricularly, had no significant effect on emesis evoked by intracerebroventricular dopamine. The emetic response to intracerebroventricular dopamine was attenuated in cats pretreated with intracerebroventricular reserpine, 6-hydroxydopamine, alpha-methyl-p-tyrosine and hemicholinium-3. It is postulated that dopamine-induced emesis is mediated through the release of noradrenaline acting at alpha 2-adrenoceptors and that it depends on the integrity of monoaminergic and possibly cholinergic structures within the area postrema. It appears, therefore, that the emetic effect of intracerebroventricular dopamine is mediated by adrenergic rather than dopaminergic mechanisms in the area postrema, at least in the cat.

[Granulocyte colony-stimulating factor: biologic effects and possibilities of therapeutic use]. / Stimulantni faktor granulocitnih kolonija: bioloska dejstva i moguca terapijska upotreba.

This review is a brief overview on recent advances in biology as well as in the potential clinical application of recombinant methionil human granulocyte colony-stimulating factor (r-metHuG-CSF). Biologically active human granulocyte colony-stimulating factor is a recombinant human protein expressed in Escherichia coli. It is localized on membrane of stroma cells in molecules of extracellular matrix. R-metHuG-CSF increases the number of circulating neutrophils, and to a much lesser extent macrophages. The clinically relevant uses of r-metHuG-CSF at present lie in two general areas: neutropenia and febrile netropenia present in patients with non-myeloid malignant diseases induced by anticancer agents. R-metHuG-CSF produces dose-dependent and reversible side effects such as: musculoskeletal pain, urinary disorders, retention of fluid, pericarditis, dyspnea, hypoxia and hypotension.

[5HT-3 receptors: characteristics and therapeutic implications of a new subtype of 5-hydroxytryptamine receptors]. / Terapijski znacaj novog tipa pet-hidroksitriptaminskih receptora.

5HT-3 receptors, as well as their selective agonists and antagonists have been recently discovered. They are localized exclusively on the nervous elements of the peripheral and central nervous system, and are involved in the regulation of emesis, in pain, motility and secretion of the gut, and possibly in some functions of the central nervous system. At present, the 5HT-3 antagonists are used in the therapy of emesis induced by cytostatic drugs, radiation and in some intestinal disorders. Further experimental and clinical studies are needed to evaluate the use of 5HT-3 antagonists in the therapy of pain (migraine), some cognitive, and affective disorders and addiction.

[Gastrointestinal motility disorders and drugs: opioids, calcium antagonists, nitrates, peptides, prostaglandins and 5-hydroxytryptaminergic drugs (part II)]. / Poremecaji motiliteta gastrointestinumskog trakta i lekovi opioidi, kalcijumski antagonisti, nitrati, peptidi, prostaglandini i pet-hidroksitripitamin.

The review describes gastrointestinal receptors which are of therapeutic interest for the treatment of motility disorders. It updates the present knowledge of opioid, dihydropyridine, peptide, prostaglandin and 5-hydroxytryptamine receptors, their subtypes, cellular sites and functional role as drug targets. On the basis of this pharmacological concept, drugs, mainly agonists and antagonists, are evaluated in proven and potential indications. In view of the very complex regulation of motility, our understanding of receptors is still fragmentary, and our tools to treat motility disorders do not fulfill all therapeutic requirements. This review tries to point out the areas of particular need for further basic research and the prospects of further drug development.

[Gastrointestinal motility disorders and drugs: cholinergic, anticholinergic, adrenergic, antiadrenergic and prokinetic drugs (part I)]. / Poremecaji motiliteta gastrointestinumskog trakta i holinergicki, antiholinergicki, adrenergicki, antiadrenergicki i prokineticki lekovi (prvi deo).

The review deals with gastrointestinal receptors which are of therapeutic interest for the treatment of motility disorders. It updates the present knowledge of muscarinic, adrenergic and dopaminergic receptors, their subtypes, cellular sites and functional role as drug targets. On the basis of this pharmacological concept, drugs, mainly agonists and antagonists, are evaluated in proven and potential indications. In view of the very complex regulation of motility, our understanding of receptors is still fragmentary and our tools to treat motility disorders do not fulfil all therapeutic requirements. This review tries to point out the areas of particular need for further basic research and the prospects of further drug development.

[Biologic effects and possible therapeutic use of the granulocyte-macrophage colony-stimulating factor. Modern treatment of leukopenia]. / Bioloska dejstva i moguca terapijska uptreba stimulantnog faktora granulocito-makrofagnih kolonija. Savreno lecenje leukopenija.

This review is a brief overview of recent advances in biology as well as in potential clinical application of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Biologically active rhGM-CSF is a recombinant human protein expressed in Escherichia coli. GM-CSF is produced by nontransformed (T-lymphocytes, trophoblasts, keratinocytes, osteoblasts, tracheal epithelial cells, renal mesangial cells, endothelial cells, macrophages, fibroblasts, smooth muscle cells) and transformed (murine plasmocytoma, bladder carcinoma HIBY cell line, anaplastic carcinoma of the gall bladder, Yoshida sarcoma cell line, HC3T3-osteoblast cell line) cells. RhGM-CSF increases the number of circulating neutrophils, monocytes and eosinophils and increases chemotactic, microcidal killing and cytotoxic activity of monocytes and granulocytes. The present clinically relevant uses of rhGM-CSF two general areas: restoration of haematopoietic dysfunction by raising cell counts from suppressed to normal levels, and augmentation of host defence against infection. Thus, rhGM-CSF reduces risk of infections. In addition, rhGM-CSF may increase tumour cell destruction in some malignant diseases. RhGM-CSF produces dose-dependent toxicity consisting of myalgic fever, fluid retention and serosal effusions.

Differential inhibition by ethanol of norepinephrine- and clonidine-induced emesis in cats.

The effect of acute ethanol administration into the cerebral ventricles on the unanesthetized cat upon emesis produced by norepinephrine and clonidine injected similarly as well as upon emesis evoked by copper sulfate given orally was compared and investigated. Ethanol inhibited the norepinephrine- and clonidine-induced emesis. The inhibitory effect of ethanol occurred after a transient and inconsistent emetic action of the drug. Norepinephrine-induced emesis was about 12 times more sensitive than clonidine-induced emesis to the inhibitory effect of ethanol. In addition, norepinephrine-, but not clonidine-induced emesis was abolished after ablation of the area postrema. On the contrary, intracerebroventricular ethanol had virtually no effect on emesis caused by intragastric copper sulfate. The inhibitory effect of ethanol is ascribed to an action on alpha-2 adrenoceptors within the area postrema and on imidazoline-preferring sites and/or muscarinic cholinoceptors outside the area postrema, but not on the emetic region of the brainstem reticular formation. It follows then that ethanol can differentiate alpha-2 adrenoceptors from imidazoline-preferring sites and/or muscarinic cholinoceptors in the brain of the cat.

[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).

Selective effect of ethanol on norepinephrine- and nicotine-induced emesis in cats.

The effect of acute ethanol administration into the cerebral ventricles of the unanesthetized cat upon emesis produced by norepinephrine and nicotine injected similarly was investigated. Ethanol inhibited the norepinephrine- and nicotine-induced emesis. The inhibitory effect of ethanol occurred after a transient and inconsistent emetic action of the drug. Ethanol was about 10 times more potent inhibiting the emesis caused by nicotine. On the other hand, intracerebroventricular ethanol had virtually no effect on emesis produced by intragastric copper sulfate. The inhibitory effect of ethanol is ascribed to an action on alpha-noradrenergic and nicotinic receptors in the area postrema. Differential responses to ethanol most probably reflect the microenvironment of alpha-noradrenergic and nicotinic synapses in the area postrema of the cat.

[Thyrotropin-releasing hormone: distribution, role and importance]. / Oslobadjajunci hormon tireotropina: rasprostanjenost,uloga i znacaj.

TRH is one of the first hypothalamic releasing hormones which has been identified and applied in humans. It is a tripeptidamid which belongs to the family of neuropeptides together with endorphins, neurotensin and substance P. TRH is widely distributed not only in hypothalamus, but also in extrahypothalamic parts of CNS as well as in many peripheral tissues and organs. TRH receptors are one of the first discovered peptide receptors in the brain. TRH coexists with other neurotransmitters and neuromodulators in brain neurons. In addition to its endocrine function in the regulation of TSH secretion, it also releases prolactin, FSH and NOR. Moreover, its extrapituitary actions have not yet been fully elucidated. Although TRH receptors are identified in CNS, it is not yet known whether it is a neurotransmitter or a neuromodulator. In particular, its relationship with cholinergic, noradrenergic, dopaminergic, serotonergic and opioid systems as well as other putative neurotransmitters in the brain, has been discussed. Finally, TRH is used as a diagnostic means in some endocrine and nonendocrine disorders.

The potentiation of cardiodepressant and hypotensive effects of bradykinin by enalapril and captopril both in vitro and in vivo.

1. Bradykinin (cumulative concentrations of 0.007-0.09 micrograms ml-1) produced a dose-related, but statistically insignificant depression of the isometric contraction of the isolated, spontaneously beating atria of the guinea-pig. The same concentrations of bradykinin did not change the atrial rate, but a tendency to a slight decrease was observed. 2. Enalapril (4.06 or 13.54 mumol l-1), produced a dose-related potentiation of the effect of the highest concentration of bradykinin on the isometric contraction. 3. Captopril (equimolar concentrations) also potentiated the effect of the highest concentration of bradykinin on the isometric contraction. This effect of captopril was not dose-related. 4. Both enalapril and captopril did not change the effect of bradykinin on the heart rate. 5. Bradykinin induced dose-related hypotensive responses in anaesthetized cats (0.03-1.0 microgram/kg b.w., i.v.) with a tendency towards bradycardia. 6. Enalapril (0.3 and 1.0 mg/kg b.w., i.v.) significantly potentiated bradykinin-induced hypotension and bradycardia. However, the potentiating effect of enalapril was not dose-dependent. 7. Captopril (0.1, 0.3 and 1.0 mg/kg b.w., i.v.) significantly potentiated bradykinin-induced hypotension and bradycardia. Also, the potentiating effect of captopril was not dose-dependent. 8. The failure of ACE inhibitors to potentiate the cardiodepressant and hypotensive effects of bradykinin in a dose-dependent manner is explained with some other mechanism(s) independent of ACE inhibition.

Ablation of the area postrema and emesis.

The emetic action of dopamine, norepinephrine, epinephrine, nicotine, dimethylphenyl-piperazinium (DMPP), and 4-m-chlorophenylcarbamoyloxy-2-butynyltrimethylammonium (McN-A-343) injected intracerebroventricularly (i.c.v.) to the unanesthetized cat was investigated and compared. ED50 values (mg) were as follows: nicotine, 0.011; epinephrine, 0.047; norepinephrine, 0.57; DMPP, 0.9; dopamine, 1.66; and McN-A-343, 4.42. The most potent was nicotine, whereas the least active McN-A-343. On the other hand, DMPP produced the longest emetic response, about 30 min, while McN-A-343-induced emesis lasted up to 1 min. The ablation of the area postrema abolished the emetic response to i.c.v. dopamine, norepinephrine, epinephrine, nicotine, and DMPP. However, the emetic response to i.c.v. McN-A-343 was significantly reduced in cats with an ablated area postrema. Taken together, the results obtained show that the area postrema is almost always involved in the central regulation of emesis and that the area postrema represents, in most cats, a common site of confluence of different inputs subserving the emesis.

The area postrema and the hypertensive effect of angiotensin.

The intracerebroventricular administration of angiotensin II in pentobarbital-anesthetized cats produced dose-dependent increases in the arterial blood pressure without significant changes in the heart rate. The ablation of the area postrema significantly reduced, but did not abolish, the pressor effect of angiotensin injected into the cerebral ventricles. It follows, then, that the central pressor effect of angiotensin is dependent on the integrity of the area postrema and that this central site, at least in part, contributes to the pressor action of endogenous angiotensin.

Area postrema: cholinergic and noradrenergic regulation of emesis. A new concept.

In unanaesthetized cats the biochemical mechanisms and the functional characteristics of the emetic action of injection of noradrenaline and McN-A-343, a ganglionic muscarinic stimulant into the cerebral ventricle (i.c.v.) through chronically implanted cannulae were investigated. Both produced dose-dependent and shortlasting emetic response. The emesis evoked by noradrenaline was abolished, whereas the emesis induced by McN-A-343 was not completely blocked after ablation of the area postrema. Further, the emetic response to noradrenaline as well as to McN-A-343 was attenuated or blocked in cats pretreated with 6-hydroxydopamine (i.c.v.) and hemicholinium (i.c.v.); it was abolished in cats pretreated with reserpine (i.c.v.). On the other hand, the emetic response to i.c.v. noradrenaline and to i.c.v. McN-A-343 was not virtually altered in cats pretreated with bretylium (i.c.v.), alpha-methyl-p-tyrosine (i.c.v.) and 5,6-dihydroxytryptamine (i.c.v.). It is postulated that noradrenergic neurones as well as cholinergic axon terminals within the area postrema are necessary for the emetic action of noradrenaline, whereas cholinergic axon terminals within the area postrema subserve the emetic response to McN-A-343. A functional link between cholinergic terminals and noradrenergic neurones as well as a modulatory role of noradrenergic afferents on cholinergic afferents mediating emesis within the area postrema is further proposed. Thus, noradrenergic neurones might represent a common site of confluence of different inputs subserving the emesis in the area postrema. Finally, cholinergic terminals sometimes bypass this area and synapse in the emetic regions of the brainstem regulating emesis.

[TRH dissociates the aggressivity of vegetative and motor phenomena induced by carbachol in the cat]. / La TRH dissocie l'agressivité des phénomènes végétatifs et moteurs induits par le carbachol chez le chat.

In these experiments interaction of thyrotropin releasing hormone (TRH) and carbachol injected into the cerebral ventricles of unanaesthetized cats has been investigated. Intracerebroventricular (i.c.v.) carbachol as well as i.c.v. TRH produced emotional behaviour, autonomic and motor phenomena. The most impressive feature of i.c.v. carbachol was the aggressive behaviour, whereas that of i.c.v. TRH the autonomic changes. In cats treated with i.c.v. TRH, the aggressive behaviour, but the autonomic and motor changes of i.c.v. carbachol was potentiated. Since there is evidence that carbachol acts mainly on muscarinic M-2 receptors, the potentiation by TRH of aggressive behaviour, but not the autonomic and motor changes induced by carbachol could indicate heterogeneity of central muscarinic M-2 receptors.