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The pharmacokinetics of pheniramine and its two metabolites (N-desmethyl pheniramine and N-didesmethyl pheniramine) were determined in six healthy male subjects after intravenous (n = 3) or oral (n = 3) administration (30.5 mg of pheniramine - free base). Serum and urine levels were measured by HPLC. After i.v. administration, serum concentrations of pheniramine between 231 and 894 ng/ml were reached and after oral administration peak serum concentrations between 173 and 274 ng/ml were reached after 1-2.5 h. AUC values up to 72 h were 3035-4662 (i.v.) and 3507-5768 (ng/ml X h) (oral). The terminal half-lives were estimated to range between 8 and 17 h (i.v.) and 16 and 19 h (oral). Serum levels of the N-desmethyl derivative remained very low (up to 21 ng/ml), but were still detectable after 72 h. Serum levels of the N-didesmethyl derivative were below the detection limit. The amount of pheniramine excreted in the urine for up to 120 h varied between 5.7 and 11.6 mg and 10.2 and 13.2 mg after i.v. and oral administration respectively. Unlike the serum, considerable fractions of the drug occurred as metabolites in urine. Values were 8.1-16.4 mg (i.v.) and 7.4-13.3 mg (oral) for N-desmethyl pheniramine, 0.4-2.9 mg (i.v.) and 0.2-0.8 mg (oral) for N-didesmethyl pheniramine.
OBJECTIVES: To assess the relative clinical toxicity of pheniramine compared with other antihistamines taken in overdose and its relative use for self-poisoning. DESIGN: A prospective follow-up cohort study of antihistamine self-poisonings. Local pharmacists were surveyed to ascertain the approximate market share of pheniramine. SETTING: Newcastle, Australia. SUBJECTS: 102 patients giving rise to 118 consecutive admissions to hospital for antihistamine self-poisoning after ingestion of pheniramine (43) or other antihistamines (75). MAIN OUTCOME MEASURES: Generalised seizures, delirium/psychosis, sedation, QRS width, mean blood pressure. RESULTS: Pheniramine accounted for only 3.0% of antihistamine items dispensed, 5.5% of defined daily doses (DDDs) dispensed, but 33.9% of antihistamine self-poisonings. Fourteen admissions were complicated by seizures and 43 by delirium/psychosis. Patients admitted after ingestion of pheniramine were more likely to have generalised seizures (13 of 43) than those ingesting other antihistamines (one of 75). Other complications (sedation, need for ventilation, prolongation of QRS interval, change in blood pressure) were comparable. A very high proportion of the pheniramine group had a history of drug or alcohol abuse (79.9%). This included 60.5% with a history of antihistamine abuse. The figures for those who ingested other antihistamines were 46.7% and 6.7% respectively. CONCLUSIONS: Pheniramine is taken in overdose more frequently than other antihistamines relative to its market share. It is also more likely to be abused than other antihistamines. In overdose, it appears to be more proconvulsant than other antihistamines. Consideration should be given to the use of alternative antihistamines in patients at risk of seizures. In the light of these findings, regulatory authorities should review the over-the-counter availability of pheniramine.
Cardiovascular toxicity including ventricular extrasystoles associated with pheniramine overdosage has been documented in the absence of factors recognised to aggravate this toxicity. The presence of pheniramine and the absence of other compounds was established using analytical techniques. It is concluded that patients with pheniramine overdosage should be treated exercising the same precautions as with tricyclic overdosage. Several sudden and unexpected deaths have occurred due to pheniramine overdosage in both adults and children. The cause of death in each case was not known. The purpose of this report is to document clinical features of pheniramine overdosage, in particular previously unsuspected cardiovascular toxicity manifesting as clinically significant ventricular arrhythmias. Pheniramine was positively identified in the overdosed patient, and the presence of other agents excluded.
A double-masked, randomized, parallel group, placebo-controlled study demonstrated the efficacy of Naphcon-A (naphazoline HCl 0.025% and pheniramine maleate 0.3%). Seventy-two patients with a documented positive skin test or radioallergosorbent test were recruited. Three groups of 24 patients each received 1 drop of Naphcon-A instilled in one eye, and 1 drop of either naphazoline, pheniramine, or placebo in the other eye. After the instillation of test medication, a titrated dose of ragweed antigen was administered bilaterally, and ocular signs and symptoms were evaluated 10, 30, and 120 minutes later. All patients (excluding 4 who had persistent symptoms attributable to ragweed) were rechallenged with ragweed antigen at 120 minutes to assess the duration of action of the test medications. Naphcon-A was significantly more effective than placebo, naphazoline, and pheniramine in reducing redness. Naphcon-A and pheniramine were equally effective in relieving itching.
The quantitative determinations of codeine phosphate, guaifenesin, pheniramine maleate, phenylpropanolamine hydrochloride, and pyrilamine maleate in a liquid dosage form are described. All active and inactive ingredients (sodium benzoate and FD&C Yellow No. 5 dye) can be separated with high-pressure liquid chromatography except the two antihistamines, pheniramine maleate and pyrilamine maleate. Pheniramine maleate is determined colorimetrically, and pyrilamine maleate is determined either by difference or spectrophotometrically. The methods are simple short, accurate, and precise. The standard deviations are reported.
In this work, a method for the determination of the antihistaminic drugs loratadine and pheniramine from human serum is presented. Serum samples are extracted under basic conditions with hexane-n-amyl alcohol (95:5, v/v), the analytes are reextracted into diluted hydrochloric acid and, after basification, are once again extracted into the organic phase. The samples are measured by GC-MS. The limits o detection of the assay are 0.5 ng/ml for loratadine and 2 ng/ml for pheniramine. The R.S.D.s in the day-to-day precision test for loratadine are 7.0% at 20 ng/ml and 12.4% at 2 ng/ml. for pheniramine, the R.S.D. are 6.4% at 300 ng/ml and 10.2% at 20 ng/ml.
A series of hybrid compounds combining the pharmacophores of both pheniramine-type histamine H1 receptor antagonists and roxatidine-type H2 receptor antagonists have been synthesized and tested for histamine antagonism at the isolated ileum (H1) and the spontaneously beating right atrium (H2) of the guinea pig. The 'polar group' of the H2 antagonist moiety (cyanoguanidine, nitroethenediamine or urea) and the side chain amino group of the H1 antagonist portion have been linked by a polymethylene spacer or by a piperazine system. The incorporation of a flexible spacer (2-7 methylene groups) resulted in H1 antagonists achieving up to 2.4 times the activity of pheniramine. Depending on the nature of the polar group the highest H2 antagonist potency resides in compounds with spacers ?2 methylene groups. Nitroethenediamine 24c with a seven-membered chain and a chlorpheniramine substructure proved to be approximately equipotent with pheniramine at the H1 and with ranitidine at the H2 receptor (pKB values 7.82 and 7.1, respectively).
Pheniramine is efficiently adsorbed by Norit Medicinal Activated Charcoal in vitro. Administration of activated charcoal after pheniramine ingestion in dogs resulted in significantly lower blood levels. Norit or another proven effective activated charcoal would be of value in first-aid treatment of pheniramine poisoning.
A case of unintentional fatal intoxication of a 10 month-old baby with the anti-histamine Pheniramine (Avil) is reported. On the face value and without an autopsy this case parallels familiar cases of SIDS and had for this reason been certified as such. Autopsy, however, revealed 32 partly dissolved tablets which proved to be Phenyramine. High concentrations of Pheniramine were found in body fluids and various tissues. According to official investigations, the tablets were offered to the baby by his 3 1/2 year old sister who probably believed they were sweets.
In mice, apomorphine (10 mg/kg s.c.) does not induce a compulsion to gnaw, but pretreatment with antihistamines, viz. pheniramine, chlorpheniramine and mepyramine, in doses ranging from 30 to 60 mg/kg i.p. caused gnawing activity. Mepyramine showed significantly less effect when compared to the other two agents. Antihistamines are known to influence the activity of biogenic amines in central nervous system. The potentiation of apomorphine-induced gnawing by antihistamines might depend upon the reciprocal balance between dopaminergic and cholinergic systems. This was tested by blocking biosynthesis of biogenic amines or by blocking their receptors. The potentiation of gnawing was antagonised by physostigmine (0.25 mg/kg) or blocked by pretreatment with alpha-methyl-p-tyrosine (alpha-MPT) (4 X 150 mg/kg) and bis-(4-methyl-1-homopiperazinylthiocarbonyl)-disulphide (FLA) (40 mg/kg), while p-chlorophenyl alanine (p-CPA) (3 X 100 mg/kg) had no effect. Similarly, phenoxybenzamine (30 mg/kg) and haloperidol (1.0 mg/kg) inhibited gnawing activity, but methysergide (10 mg/kg) had no effect. Furthermore, pretreatment with tetrabenazine (20 mg/kg) and L-Dopa (200 mg/kg) did not affect gnawing activity. It is concluded that both pheniramine and chlorpheniramine potentiate apomorphine gnawing by upsetting the cholinergic and dopaminergic balance in favour of dopaminergic dominance.
1. Two strains of the filamentous fungus Cunninghamella elegans (ATCC 9245 and ATCC 36112) were screened for their ability to metabolize three alkylamine-type antihistamines; brompheniramine, chlorpheniramine and pheniramine. 2. Based on the amount of parent drug recovered after 168 h of incubation, C. elegans ATCC 9245 metabolized 60, 45 and 29% of brompheniramine, chlorpheniramine and pheniramine added respectively. The results from strain ATCC 36112 were essentially identical to those of strain ATCC 9245. 3. The metabolic products of N-oxidation and N-demethylation were isolated by reversed-phase hplc and identified by analysing their mass and proton nmr spectra. For all three antihistamines, the mono-N-demethylated metabolite was produced in the greatest amounts. The chloro- and bromo-substituents appeared not to affect the route of metabolism but did influence the relative amounts of metabolites produced. 4. Circular dichroism spectra of the metabolites and the unmetabolized parent antihistamines showed each to be a racemic mixture of the (+) and (-) optical isomers. In addition, comparison of the metabolism of racemic chlorpheniramine to that of optically pure (+) chlorpheniramine showed no significant differences in the ratios of metabolites produced. There was therefore no metabolic stereoselectivity observed by the fungal enzymes.
We describe a case of central anticholinergic syndrome with choreiform movements after an overdose of pheniramine aminosalicylate. The symptoms and signs of the condition were reversed by the intravenous administration of the cholinesterase-inhibitor tetrahydroaminacrine. We also discuss the concept of adrenergic-cholinergic imbalance in relation to this case and recommend the use of centrally acting anticholinesterase agents in the treatment of specific cases of drug overdose.
Compounds with combined histamine H1- and H2-receptor antagonist activity were synthesized by connecting H1- and H2-receptor substructures via cyanoguanidine, urea, or nitroethenediamine moieties. Loss of the strongly basic side-chain nitrogen results in a decrease of H1-receptor activity compared to single reference compounds. At the guinea-pig right atrium (H2-receptor model) compounds with mepyramine or cyclizine structure are also less active than the single references tiotidine, ranitidine, or lamtidine. Nevertheless substances with a pheniramine like partial structure proved to be potent histamine H2-receptor antagonists at the atrium model (about 27 times more active than cimetidine).
Histamine (5 X 10(-6) to 10(-3) M) depressed the spontaneous motility of the isolated rat uterus in a dose-dependent manner. Under these conditions uterine cyclic AMP was raised up to 92%. Both effects, uterine relaxation and cyclic AMP accumulation after 2 min could be inhibited dose dependently by the H2-antihistaminic compound metiamide (1.7 X 10(-6) M to 1.7 X 10(-4) M). By contrast, the H1-antagonist pheniramin (4.4 X 10(-5) M) was ineffective. It was concluded that the histamine-induced inhibition of rat uterine motility is mediated by cyclic AMP which is formed in response to stimulation of H2-histaminergic receptors.
Hybrid molecules combining the crucial structural features of both pheniramine-type histamine H1 receptor antagonists and guanidinothiazole-type H2 receptor antagonists have been synthesized and tested for in vitro pharmacological activity at the isolated ileum and the spontaneously beating right atrium of the guinea-pig. In the title compounds the basic side chain nitrogen of the H1 antagonist and the so-called 'polar group' (cyanoguanidine, urea, or nitroethenediamine) of the H2 antagonist moiety have been linked by a polymethylene spacer. The new substances displayed high affinities to both histamine receptor subtypes and a dual type of antagonism (surmountable/insurmountable) characterized by a shift of the concentration response curves to the right accompanied by a depression of the maximal response to the agonist if the antagonist concentration was >/=100 nM. Highest combined histamine antagonist activities were found in the nitroethenediamine series with pKB values ranging from 8.16 to 9.04 in the ileum (H1) and 7.0-8.08 in the atrium (H2)
Thin-layer chromatography (TLC)-densitometry was used to separate, identify, and quantitate chlorpheniramine maleate (CPM) and pheniramine maleate (PM) when present in combination with other drugs in pharmaceutical preparations of tablets, syrups, eye and ear drops, etc. CPM or PM was extracted (tablets, capsules, etc.) or diluted (liquid preparations, if needed) with 80% ethanol and isolated from other ingredients by TLC on silica gel G using cyclohexane-chloroform-methanol-diethylamine (4.5 + 4.0 + 0.5 + 1.0, v/v) as the mobile phase. Separated CPM and PM were detected under shortwave ultraviolet light and quantitated by scanning densitometry at 260 nm. Recoveries of CPM and PM were 100.09+/-0.77% and 100.09+/-0.87%, respectively.
Analytical CE and HPLC methods were developed for the chiral separation of halogen-substituted 3-phenyl-3-(2-pyridyl)propylamines 1-4 (1: 3-(4-fluorophenyl) approximately, 2: 3-(3,4-difluorophenyl) approximately, 3: 3-(4-chlorophenyl) approximately, 4: 3-(3,4-dichlorophenyl) approximately ), 3-(4-fluorophenyl)-3-(2-thiazolyl)propylamine (5), and 3-(4-fluorophenyl)-3-(1-benzylimidazol-2-yl)propylamine (6), which are building blocks for the preparation of very potent arpromidine-type histamine H(2) receptor agonists. All amines were enantioseparated by CE with resolutions of at least 1.8 using alpha-, beta-, or gamma-cyclodextrin (CD) as chiral selectors. With heparin as buffer additive for CE the optical antipodes of 1-4 and 6 were separated with resolutions > or = 1.8. On RP-18 columns the separation of the (+)-(S)-acetylmandelic acid amides of racemic 2 (R = 0.9, alpha = 1.07) and the thioureas prepared by addition of 6 to 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate (R = 2.0, alpha = 1.20) was successful, whereas the diastereomeric ureas prepared from 3 and (+)-(S)-1-(1-naphthyl)ethyl isocyanate could not be resolved. Separation of the diastereomeric isoindoles prepared from 1-5, o-phthaldialdehyde and 2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranoside was achieved on a RP-18 phase (R > or = 0.4, a > or = 1.02). Direct separation of the enantiomers of 3 and 4 was achieved on a Cyclobond I column (R > or = 0.9, alpha > or = 1.07). alpha- and beta-CD were also useful as mobile phase additives for HPLC (3 and 4: RP-18 column, beta-CD, R > or = 0.4, alpha > or = 1.03; 3: RP-18 column, alpha-CD: R = 0.5, alpha = 1.04).