In vitro alterations in dental enamel exposed to acidic medicines.

OBJECTIVE: To evaluate the effect of acidic medicines (Klaricid(®), Claritin(®), and Dimetapp(®)) on surface enamel in vitro. METHODS: Enamel blocks (n=104) were randomly distributed into two groups: G1 (pH-cycling simulating physiological oral conditions) and G2 (erosive conditions). Each group was divided into four subgroups, three to be immersed in the medicines and the control in deionized water. Specimen surfaces were evaluated for roughness and hardness at baseline and again after the in vitro experimental phase, which included 30 min immersions in the medicines twice daily for 12 days. Scanning electron microscopy (SEM) was also performed after the in vitro experimental phase. RESULTS: All medicines produced a significant reduction in hardness in G1 after 12 days (P<0.05). The three medicines promoted greater roughness after both pH-regimens - G1 and G2 (P<0.01), except for Claritin in G1. Scanning electron microscopy analysis showed erosive patterns in all subgroups. Dimetapp(®) showed the most erosion and Klaricid(®) the least, in both groups. CONCLUSION: Dimetapp(®) (lowest pH and viscosity) and deionized water (control) showed the most pronounced erosive patterns. Klaricid(®) (highest pH and viscosity) presented an in vitro protective effect against acid attacks perhaps due to its mineral content and viscosity.

Effects of serotonin on memory impairments produced by ethanol.

Subjects treated with low or high doses of ethanol demonstrated impaired memory, particularly in tests involving the recall of poorly learned information. Zimelidine, an inhibitor of serotonin reuptake, reversed this ethanol-induced impairment. The serotonin neurotransmitter system may mediate learning and memory in humans and may determine some of the effects of alcohol on higher mental functions.

H1-antihistamines and oxidative burst of professional phagocytes.

OBJECTIVES: We analysed and compared the effect of five H1-antihistamines on stimulated oxidative burst at extra- and intracellular level of isolated and stimulated human polymorphonuclear leukocytes. DESIGN: Oxidative burst of isolated human neutrophils was studied by means of luminol and isoluminol enhanced chemiluminescence. RESULTS: The following rank order of potency for H1-antihistamines to decrease chemiluminescence was evaluated extracellularly: dithiaden> loratadine> chlorpheniramine> brompheniramine> pheniramine and at intracellular site: loratadine> dithiaden. CONCLUSION: H1-antihistamines differ substantially according to their chemical structure in suppressing oxidative burst both at extra- and intracellular site of isolated stimulated human neutrophils.

Subcutaneous brompheniramine for cutaneous analgesia in rats.

Brompheniramine as an antihistamine blocked sodium channels, and local anesthetics by blocking sodium channels produced the local anesthetic effects. The authors aimed to assess local anesthetic quality and duration of brompheniramine when compared to the local anesthetic mepivacaine. After rats were shaved and injected subcutaneously on the dorsal skin, the panniculus reflex, induced via applying a noxious pinprick to the skin (injected area), was scored. The dose-response curve and nociceptive block duration of brompheniramine were constructed and compared with mepivacaine. The cutaneous analgesic effects in both brompheniramine and mepivacaine groups were concentration-dependent. On the basis of the amount required to produce a 50% block effect (ED50, 50% effective dose), the drug's potency was brompheniramine (0.89 [0.82-0.96] µmol) better than mepivacaine (2.45 [2.17-2.76] µmol) (P < 0.01). Full recovery time of brompheniramine was more prolonged than mepivacaine's (P < 0.01) on infiltrative cutaneous analgesia when comparing ED25s, ED50s and ED75s. Our preclinical data demonstrated that subcutaneous brompheniramine induces dose-relatedly analgesic effects, and brompheniramine induces prolonged analgesic duration when compared with mepivacaine. Brompheniramine also provokes better cutaneous analgesia than mepivacaine.

Transient receptor potential vanilloid-1-mediated calcium responses are inhibited by the alkylamine antihistamines dexbrompheniramine and chlorpheniramine.

American guidelines, unlike European guidelines, support the use of antihistamines as a first line of treatment for some causes of chronic cough. Transient receptor potential vanilloid-1 (TRPV1) is an ion channel activated by the tussive agents capsaicin, resiniferatoxin, and protons. It is predominantly expressed by C-fiber and some Adelta -fiber sensory neurons and is thought to be a cough receptor. By measuring increases in intracellular calcium as an indicator of TRPV1 activation, the authors sought to determine whether antihistamines could antagonise TRPV1 permanently expressed in HEK and Pro5 cells and TRPV1 endogenously expressed in rat dorsal root ganglia neurons. In human TRPV1-expressing HEK cells (hTRPV1-HEK), diphenhydramine and fexofenadine failed to inhibit capsaicin-triggered calcium responses. However, both dexbrompheniramine and chlorpheniramine significantly inhibited capsaicin-evoked responses in hTRPV1-HEK. Dexbrompheniramine also inhibited activation of rat TRPV1 expressed in HEK and Pro5 cells, without interfering with TRPA1 and proteinase-activated receptor-2 (PAR(2)) activation. Finally, in rat dorsal root ganglia neuron preparations, dexbrompheniramine dose-dependently inhibited capsaicin-evoked calcium responses. Thus, the inhibition of TRPV1 activation by dexbrompheniramine may provide one potential mechanism whereby this antihistamine exerts its therapeutic effect in chronic cough.

Enhanced prostaglandin synthesis after ultraviolet injury is mediated by endogenous histamine stimulation. A mechanism for irradiation erythema.

Acute ultraviolet light B (UVB) injury is associated with dermal mast cell histamine release. The possibility that histamine-stimulated prostaglandin (PG) synthesis could be a mechanism for irradiation erythema was therefore examined using human skin explants. Explants responded to UV irradiation (120 mJ/cm2) with a fivefold increase in synthesis of prostaglandins E2, F2 alpha and 6-keto PGF1 alpha. Incubating explants with the H1 antihistamines brompheniramine (50 microM) or pyrilamine (30 microM) inhibited PG release from irradiated explants 63 +/- 4.9% (mean +/- SEM) 6 h after UV exposure. Antihistamines did not affect PG synthesis in control explants. Irradiation increased the histamine concentration in explant conditioned medium only 50% over basal values, suggesting that irradiation enhanced histamine responsiveness. Explants were therefore incubated with exogenous histamine. In irradiated explants, PG synthesis was stimulated threefold by 3 microM histamine. Unirradiated explants' PG synthesis was unaffected by histamine. Enhanced histamine sensitivity was also examined in epidermal cell cultures. In irradiated cultures, histamine sensitivity was again markedly potentiated: as little as 1 microM histamine stimulated significant PGE2 release and the response to 10-30 microM histamine was increased six to eight times compared with that of unirradiated cultures. These studies demonstrate that endogenous histamine stimulates PG synthesis in human skin after UV injury by potentiation of histamine-induced prostaglandin release. Potentiated agonist responses induced by UV exposure may contribute to the effects of UVB irradiation injury and in particular to irradiation erythema.

Extra- and intracellular formation of reactive oxygen species by human neutrophils in the presence of pheniramine, chlorpheniramine and brompheniramine.

BACKGROUND: Allergic inflammation was found to be accompanied by activation of neutrophils. Since this resulted in increased formation of reactive oxygen species, the antioxidative activity of antiallergic drugs was considered to decrease the risk of tissue damage. However, if the drug-induced inhibition of radical formation occurred intracellularly, it could disturb regulation of neutrophil functions and decrease bactericidal activity of these cells. Separate analysis of extra- and intracellular activity of antioxidative drugs is thus of particular importance. OBJECTIVE: To differentiate the effects of three antiallergic H1-antihistamine drugs (pheniramine, chlor- and brompheniramine) on radical formation outside and inside human neutrophils. METHODS: Formation of reactive oxygen species was determined in vitro using the chemiluminescence method. The chemiluminescence signal, initiated by phorbol-12-myristate-13-acetate, was enhanced either with isoluminol (extracellular) or with luminol in the presence of extracellular scavengers, superoxide dismutase and catalase (intracellular). RESULTS: The antihistamines tested displayed dual activity - they inhibited the extracellular and potentiated the intracellular chemiluminescence. Chlor- and brompheniramine were found to be more effective than pheniramine. CONCLUSION: Compared to other H1-antihistamines (such as dithiaden or loratadine, active both extra- and intracellularly), the observed inhibition caused by the pheniramines tested was unique since it occurred selectively outside neutrophils. This might indicate the ability of these drugs to minimise toxic effects of extracellular radicals without affecting intracellular oxidant production involved in regulation of neutrophil functions and in microbial killing.

Electroconvulsive treatment and lithium carbonate. Their effects on norepinephrine metabolism in patients with primary, major depressions.

Effects of electroconvulsive treatment (ECT) and lithium carbonate on norepinephrine metabolism were investigated in eight patients with primary, major depressions. A series of 12 ECTs reduced urinary norepinephrine and normetanephrine output significantly, and showed a tendency to reduce urinary vanillylmandelic acid output as well as whole-body norepinephrine turnover. Treatment with lithium carbonate significantly reduced urinary norepinephrine, normetanephrine, 3-methoxy-4-hydroxyphenylglycol, and vanillylmandelic acid output as well as whole-body norepinephrine turnover. These findings point to a common effect of antidepressant treatments since they are similar to results produced by administration of three other types of antidepressant drugs: clorgiline, a specific monoamine oxidase A inhibitor; desipramine, a relatively specific norepinephrine reuptake Inhibitor; and zimelidine, a relatively specific serotonin reuptake Inhibitor. These drugs reduce total production of norepinephrine and/or its major metabolites in depressed patients. Thus, five antidepressant treatments with different mechanisms of action have a common overall effect on the system.

Alteration of norepinephrine metabolism with desipramine and zimelidine in depressed patients.

Twelve patients with a major affective disorder were treated during the depressed phase of their illness with desipramine hydrochloride and/or zimelidine hydrochloride, and urinary excretion rates of norepinephrine and its major metabolites were examined. During treatment with desipramine, daily urinary excretion of norepinephrine, 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid was reduced, but urinary normetanephrine excretion was not significantly changed. In all patients, the proportion of urinary norepinephrine metabolites represented by normetanephrine was increased during desipramine treatment. Independent of treatment outcome, desipramine seemed to decrease total formation and metabolism of norepinephrine, which was reflected in decreases in the excretion rate of the catecholamine and its metabolites. These results are consistent with known actions of desipramine on the disposition of norepinephrine and represent alterations in the rate of norepinephrine formation and metabolism, resulting from inhibition of norepinephrine reuptake. Zimelidine, a new antidepressant, which is a relatively specific serotonin-uptake inhibitor, significantly reduced only urinary MHPG excretion without appearing to alter "whole-body" norepinephrine turnover. This effect of zimelidine on norepinephrine metabolism was unexpected. Current and previous findings concerning clorgyline, a relatively specific monoamine oxidase A inhibitor, suggest that three pharmacologically distinct classes of antidepressants, norepinephrine and serotonin-reuptake and monoamine oxidase type A inhibitors, all reduce central norepinephrine turnover in depressed patients.

Effects of antidepressant treatments on dopamine turnover in depressed patients.

Effects of five antidepressant treatments--clorgyline, desipramine hydrochloride, electroconvulsive treatment, lithium carbonate, and zimelidine hydrochloride--on urinary outputs of dopamine, dihydroxyphenylacetic acid, and homovanillic acid (HVA) were investigated in unipolar and bipolar depressed patients. Clorgyline and lithium carbonate, which stabilized mood in bipolar patients, reduced the urinary output of HVA and whole-body dopamine turnover. Electroconvulsive treatment and zimelidine were without major effects, whereas desipramine had variable effects on these indexes of dopamine metabolism. Three patients, two receiving desipramine and one receiving clorgyline, who had increased HVA output during the drug treatments, became severely agitated and delusional.

Histaminergic systems and sleep. Studies in man with H1 and H2 antagonists.

Effects of H1 (mepyramine, mequitazine, triprolidine and brompheniramine) and H2 (cimetidine and ranitidine) antagonists on sleep were studied in healthy man. There were no effects of mepyramine (50 and 100 mg), and the only effect of mequitazine (5 and 10 mg) was a reduction in the number of awakenings. Triprolidine (10 and 20 mg) and brompheniramine (4 and 8 mg) did not alter wakefulness during sleep or the total sleep time, but rapid eye movement sleep was reduced. There were no effects of ranitidine (150 and 300 mg), but slow wave sleep was increased by cimetidine (200 and 400 mg). It is tentatively suggested that the histaminergic system is concerned with the mechanisms which favour vigilance during the wakeful state, and the balance between wakefulness and slow wave activity during sleep. Effects of some H1 antihistamines on rapid eye movement sleep are believed to be due to their monoaminergic rather than their histaminergic activity.

Attenuation of pethidine-induced antinociception by zimelidine, an inhibitor of 5-hydroxytryptamine reuptake.

1 The effect of selective inhibition of 5-hydroxytryptamine (5-HT) re-uptake by fluoxetine and zimelidine on morphine- and pethidine-induced antinociception was studied in rats. The hot plate (55 degrees C) and tail flick test procedures for measurement of analgesia were employed to assess antinociception. 2 Pretreatment with fluoxetine and zimelidine potentiated the antinociceptive effect of morphine (4.5 mg/kg, as base); zimelidine was without effect on a lesser dose of morphine (3.0 mg/kg, as base). 3 Pretreatment with zimelidine but not fluoxetine, significantly attenuated pethidine-induced antinociception (24 mg/kg, as base) and prevented the expression of pethidine-induced antinociception at a lesser 10 mg/kg (as base) dose of pethidine. 4 These and other results support (a) a role for 5-HT in the expression of morphine-induced antinociception, and (b) a different mode of antinociceptive action of morphine and pethidine. The role of 5-HT in pethidine-induced antinociception remains unclear.

Zimelidine: a review of its pharmacological properties and therapeutic efficacy in depressive illness.

Zimelidine is a new antidepressant, which is structurally unrelated to the tricyclic and tetracyclic antidepressants. The pharmacological profile of zimelidine is different to that of other antidepressants in that it appears to owe the major part of its activity to the inhibition of serotonin uptake within the central nervous system. It appears that the demethylated metabolite, norzimelidine, may be responsible for most of the pharmacological activity. Studies to date suggest that zimelidine has overall efficacy comparable with that of amitriptyline, desipramine, maprotiline and doxepin in depressive illness, but at dosages which have achieved a similar overall clinical improvement zimelidine does not cause sedation, and anticholinergic side effects are mild and occur infrequently. Preliminary evidence suggests that zimelidine is effective against concomitant anxiety in depressed patients, and that it may also be useful in treating phobic anxiety. Zimelidine appears less likely to cause serious cardiotoxicity, in therapeutic dosages or an overdosage, than the tricyclic antidepressants, but it has not been studied in patients with cardiovascular disease. Sleep disturbance has occurred significantly more frequently during zimelidine therapy than during therapy with other sedative antidepressants, but whether this simply reflects the absence of sedation with zimelidine, or an effect on sleep as such, is presently unclear. Zimelidine appears to be effective and well tolerated in elderly patients. Thus, some aspects of the drug's profile (e.g. apparent low incidence of anticholinergic effects or drowsiness) may offer potential advantages in some patients; however, clinical experience with zimelidine to date has been limited, and further well designed studies are required to define the role of the drug more clearly in treating depressive illness compared with other antidepressants, and particularly to define whether some types of depression may respond more readily to zimelidine than to other antidepressants.

Fluoxetine and two other serotonin uptake inhibitors without affinity for neuronal receptors.

Fluoxetine and nine other antidepressant drugs which interact with brain receptors for neurotransmitters were studied in vitro using radioligand-binding techniques and transmitter-coupled adenylate cyclase assays. Tricyclic antidepressant drugs (desipramine, imipramine, clomipramine, amitriptyline and doxepin) had marked affinity for alpha-adrenergic, muscarinic cholinergic and histaminergic H1 receptors, and lesser affinity for serotonin and dopamine receptors. Mianserin was relatively similar to some of the tricyclic compounds, whereas trazodone had less affinity for most receptors except serotonin and alpha-adrenergic receptors. Fluoxetine had little affinity for any of these receptors, and the same was true for zimelidine and fluvoxamine, two other selective inhibitors of serotonin uptake. None of the compounds showed much affinity for beta-adrenergic receptors, opiate receptors, gamma-aminobutyric acid receptors, or benzodiazepine receptors. The present findings with fluoxetine are consistent with the virtual absence of anticholinergic or other side effects often observed with tricyclic antidepressant drugs in animal models or during the treatment of depressed patients.

Interaction of EEG sleep, antidepressants, and affective disease.

The major sleep characteristics of depression are summarized and new EEG sleep studies of antidepressants, including preliminary data on desipramine and zimelidine, are described. The relationship of steady-state plasma amitriptyline levels to REM sleep and the use of EEG sleep measures as predictors of clinical response to tricyclics will also be discussed. The effects of antidepressant agents on sleep are immediate and pronounced, and studies of these drug-induced effects may also represent a rational method for drug classification.

Effects of acute doses of zimelidine on REM sleep in rats.

Sleep EEG (7 h) were obtained from 11 rats given 5, 10, and 20 mg/kg zimelidine, and a control dose of saline. Zimelidine significantly suppressed REM sleep, lengthened REM latency, and reduced total sleep time (TST) in a dose-dependent manner. Sleep latency was not affected except at the highest dose of zimelidine. Slow-wave sleep (SWS) was not affected at any dose. The results are discussed in terms of their implication for the use of zimelidine in the clinical treatment of depression.

Effects of amitriptyline and zimelidine in combination with ethanol.

Six healthy male volunteers took part in this three-period crossover study. In each session, a dose of trial drug -- either placebo, zimelidine 200 mg, or amitriptyline 75 mg -- was given at 09.00 h. Ethanol (50 g) was taken orally at 1200 h. Blood samples were taken for measurement of drug and ethanol concentrations, and body sway and subjective sedation were determined. No differences in the pharmacokinetics of ethanol were seen between the three treatment sessions. Amitriptyline and ethanol showed marked sedative effects, and the results suggest that these two effects may be additive. The combination of amitriptyline and ethanol results in a particularly marked increase in body sway. No sedative nor alerting effect of zimelidine was seen, nor was any interaction between zimelidine and ethanol apparent.

Effects of zimelidine and desipramine on serotonin and noradrenaline uptake mechanisms in relation to plasma concentrations and to therapeutic effects during treatment of depression.

The selective inhibitors of neuronal 5-hydroxytryptamine (5-HT) and noradrenaline (NA) uptake, zimelidine and desipramine, were compared in a double blind crossover study of 40 inpatients with endogenous depression. The clinical effects of these two drugs and some biochemical variables related to the monoamine systems were studied during 4 weeks' treatment. Patients with a low pretreatment level of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) (less than 20 ng/ml) responded significantly better to zimelidine treatment than those with a high pretreatment level (greater than 20 ng/ml). In the group treated with desipramine no difference in therapeutic outcome was obtained between patients with low and high pretreatments levels of 5-HIAA in the CSF. Attempts to correlate the steady state plasma concentrations of zimelidine, norzimelidine and desipramine with the therapeutic effect were unsuccessful. The plasma concentration of norzimelidine demonstrated a significant (P less than 0.05) positive correlation with age. The mean value of the uptake of 14C-5-HT in the patient's platelets, when measured before the treatment, was significantly (P less than 0.05) lower than found in a control group. Zimelidine, mainly via its metabolite norzimelidine, caused a pronounced inhibition of uptake of 14C-5-HT in platelets, decrease in whole blood 5-HT and inhibition of accumulation of 14C-5-HT in rat hypothalamic synaptosomes incubated in the patients plasma. Desipramine produced a slight inhibition of accumulation of 14C-5-HT in rat synaptosomes, but a marked inhibition of uptake of 14C-5-HT in the patient's platelets and a decrease in whole blood 5-HT. The accumulation of 3H-NA in rat synaptosomes incubated in the patient's plasma was strongly inhibited by desipramine treatment but only slightly affected by zimelidine.

Long-lasting cardiovascular depressor response following sciatic stimulation in spontaneously hypertensive rats. Evidence for the involvement of central endorphin and serotonin systems.

A naloxone-reversible long-lasting depressor response induced by a prolonged low frequency stimulation of the sciatic nerve in conscious spontaneously hypertensive rats (SHRs) was reported in a previous paper. In the present study pharmacological tools were used to further investigate the neurotransmitters involved in this phenomenon. Naloxone infusion (20--25 mg/kg/h following a bolus dose of 10 mg/kg i.v.) attenuated significantly the depressor response, while dexamethasone pretreatment had no such effect, suggesting an important role of the brain endorphin system, but not of the pituitary beta-endorphin, in this depressor response. Since the concomitant increase in pain threshold produced by the sciatic stimulation exhibited a different time course of development and naloxone reversibility, it is suggested that the depressor response and the hypalgesic effect produced by the same stimulation are mediated via different types of opiate receptors in the brain. On the other hand, PCPA abolished the post-stimulatory depressor response whereas 5-HTP and zimelidine had additive effects on the sciatic stimulation-induced depressor response, suggesting the involvement of central serotonin systems in the mechanism of the response. The interaction between the central endorphin and the serotonin systems in the mediation of the post-stimulatory depressor response is discussed.

Differential effects of fluoxetine and zimelidine on the uptake of 5-hydroxytryptamine and tryptamine by cortical slices and on responses of cortical neurones to stimulation of the nucleus raphe medianus.

Intravenous administration of fluoxetine inhibited the uptake of tryptamine and 5-hydroxytryptamine by cortical slices. In contrast, zimelidine inhibited the uptake of 4-hydroxytryptamine only. In vivo, inhibitory and excitatory response of cortical neurones to stimulation of raphe medianus were potentiated by fluoxetine whereas only excitatory responses were enhanced by zimelidine. The results are consistent with the suggestion that the inhibitory effects of raphe stimulation are mediated by tryptamine and the excitatory responses by 5-hydroxytryptamine.