Bioavailability assessment of a brompheniramine taste-masked pediatric formulation in a juvenile porcine model.

A brompheniramine taste-masked pediatric formulation was developed as part of the National Institutes of Health Pediatric Formulation Initiative to help address low patient compliance caused by the bitter taste of many adult formulations. To confirm that the taste-masked formulation can provide a similar pharmacological effect to the previous marketed adult formulations, a juvenile porcine model was used to screen the model pediatric formulation to compare the bioavailability between the marketed brompheniramine maleate and the taste-masked maleate/tannate formulation. Pigs were dosed orally with both formulations and blood samples were obtained from 0 to 48 h. Plasma samples were prepared and extracted using solid-phase extraction. The mass spectrometer was operated under selected ion monitoring mode. The selected ion monitoring channels were set to m/z 319.1 for brompheniramine and m/z 275.2 for the internal standard chlorpheniramine. Calibration curves were linear over the analytical range 0.2-20 ng/ml (r2 > 0.995) for brompheniramine in plasma. The intra- and inter-day accuracies were between 98.0 and 105% with 5.73% RSD precision. The bioanalytical method was successfully applied to a preclinical bioavailability study. The bioavailability profiles were not significantly different between the two formulations, which demonstrates that taste-masking with tannic acid is a promising approach for formulation modification for pediatric patients.

Determination of brompheniramine enantiomers in rat plasma by cation-selective exhaustive injection and sweeping cyclodextrin modified electrokinetic chromatography method.

A method consisting of cation-selective exhaustive injection and sweeping (CSEI-sweeping) as online preconcentration followed by a cyclodextrin modified electrokinetic chromatography (CDEKC) enantioseparation has been developed for the simultaneous determination of two brompheniramine enantiomers in rat plasma. In this method, analytes were electrokinetically injected at a voltage of 8 kV for 80 s in a fused-silica capillary. Prior to the injection, the capillary was rinsed with 50 mM phosphate buffer of pH 3.5, followed by a plug of a higher conductivity buffer (150 mM phosphate pH 3.5, 20 psi, 6 min) and a plug of water (0.5 psi, 5 s). Separation was carried out applying -20 kV in 50 mM phosphate buffer, pH 3.5, containing 10% v/v ACN and 30 mg/mL sulfated-ß-cyclodextrin (S-ß-CD). Analytical signals were monitored at 210 nm. The detection sensitivity of brompheniramine enantiomers was enhanced by about 2400-fold compared to the normal injection mode (hydrodynamic injection for 3 s at 0.5 psi, with a BGE of 50 mM phosphate buffer containing 20 mg/mL S-ß-CD at pH 3.5), and LLOQ of two enantiomers were both 0.0100 µg/mL. In addition, this method had fairly good repeatability and showed promising capabilities in the application of stereoselective pharmacokinetic investigations for brompheniramine enantiomers in rat.

Brompheniramine and Chlorpheniramine Pharmacokinetics Following Single-Dose Oral Administration in Children Aged 2 to 17 Years.

Two pediatric studies characterized brompheniramine and chlorpheniramine pharmacokinetics in a total of 72 subjects, aged 2 to 17 years. A single age-/weight-based oral dose, ranging from 1 to 4 mg, was administered with 2 to 6 oz of water at least 2 hours after a light breakfast. Plasma samples were obtained before and for 72 hours after dosing and analyzed using high-pressure liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods; relationships with age were assessed using linear regression. Results indicated that for brompheniramine and chlorpheniramine, Cmax was similar across age groups, although it tended to occur earlier in the youngest group. AUC was ∼15% to 30% higher in the oldest age group. As expected, CLo and Vz /F increased with age; however, following allometric scaling, no age-related differences existed. Because the increase with age for both parameters was similar, no age-related differences in t1/2,z existed (∼15 hours). Overall, the single doses were well tolerated. Sedation was the most common reported AE and appeared to be more prevalent in the 2- to 5-year-old group. Overall, these results indicate that an age/weight dosing nomogram using a 4-fold range of doses achieves similar Cmax and AUC.

Immunoassay screening of diphenhydramine (Benadryl®) in urine and blood using a newly developed assay.

Diphenhydramine (DPH) is a common over the counter antihistamine that produces drowsiness and has the potential to cause driving under the influence of drugs-related accidents. To date there are no commercially available immunoassay screening kits for its detection in biological fluids such as urine and/or blood. We describe a newly developed enzyme-linked immunosorbent assay (ELISA) screen and report on its utility in the analysis of authentic specimens taken from volunteers. The assay is specific for detection of DPH and does not detect closely related antihistamines like brompheniramine, chlorpheniramine, and doxylamine. There is a varying amount of cross-reactivity seen with certain tricyclic compounds, due to similarities in side chain structure with DPH. Intra- and interday precision of the assay were determined to be less than 10%. The assay is highly sensitive and has a working range from 1 to 500 ng/mL for urine and 1 to 250 ng/mL for blood. The assay was further validated with authentic urine and blood specimens obtained from volunteers and coroner's laboratories.

Analytical characterization and rapid determination of 2-(diphenylmethyl)pyrrolidine in blood and application to an internet product.

The increased availability of new psychoactive substances ("legal highs") from retail shops or internet sources has caught the imagination of consumers, law enforcement and scientific communities. The present study describes the identification of 2-(diphenylmethyl)pyrrolidine (DPMP, desoxy-D2PM) as the key constituent found in an internet product called "A3A New Generation". Analytical characterization of this new generation "legal high" product was based on gas chromatography (EI/CI) ion trap mass spectrometry and liquid chromatography (HPLC) using electrospray ionization tandem mass spectrometry and diode array detection. A quantitative method was also developed and validated for the detection of DPMP in human whole blood using HPLC single wavelength ultraviolet detection (210 nm). Evaluation of standard method validation parameters was found to be satisfactory. The circulation of DPMP on the market is another example of psychoactive substances described decades ago in the patent literature which are beginning to be rediscovered by recreational drug communities. The ability to unambiguously identify and detect this psychoactive compound should therefore be of interest to those who are exposed to the recreational drugs field.

Fatal cold medication intoxication in an infant.

The case history and toxicological findings of an infant fatality involving pseudoephedrine, brompheniramine, and dextromethorphan are presented. Concentrations of brompheniramine and dextromethorphan were measured in both postmortem blood and liver specimens using a gas chromatograph equipped with a nitrogen-phosphorus detector. Brompheniramine and dextromethorphan were 0.40 mg/L and 0.50 mg/L, respectively, in the blood sample and 0.16 mg/kg and 0.57 mg/kg in the liver sample. The concentration of pseudoephedrine in blood and liver specimens was measured using gas chromatography-mass spectrometry and was determined to be 14.4 mg/L in the blood and 16 mg/kg in the liver. Additionally, a baby bottle allegedly administered to the infant was collected as evidence and sent to the Medical Examiner's Office for evaluation. The amounts of total brompheniramine, dextromethorphan, and pseudoephedrine remaining in the baby bottle were 1.4 mg, 9.4 mg, and 40 mg, respectively.

The clinical pharmacology of brompheniramine in children.

BACKGROUND: Brompheniramine has been widely used in the treatment of allergic rhinitis and other disorders during the past 4 decades. There are no published studies of its clinical pharmacology in children. OBJECTIVES: This study was performed to test the hypothesis that brompheniramine would have a prompt onset of action and a 24-hour duration of action in children. METHODS: Before brompheniramine 4 mg was ingested, and at intervals from 0.5 to 30 hours thereafter, blood samples were obtained for quantitation of plasma brompheniramine concentrations by means of HPLC. Concurrently, epicutaneous tests with histamine phosphate were performed; wheals and flares were traced at 10 minutes, and the areas were measured by using a computerized digitizing system. RESULTS: In 14 children, mean age 9.5 +/- 0.4 years (SEM), the peak brompheniramine concentration was 7.7 +/- 0.7 ng/mL, and the time at which peak concentrations occurred was 3.2 +/- 0.3 hours. The terminal elimination half-life was 12.4 +/- 1.1 hours, and the oral clearance was 20.2 +/- 2.1 mL/min/kg. Compared with predose areas, the wheals and flares produced by histamine phosphate 1 mg/mL were significantly decreased from 0.5 to 30 hours and from 1 to 30 hours, respectively (P <.05), with mean maximum inhibition at 12 (52% +/- 9%) and 6 hours (72% +/- 10%), respectively. CONCLUSIONS: In children a single dose of brompheniramine produces prompt, long-lasting peripheral H1 -blockade. Revised dosage regimens may be needed in this population.

A double-blind comparison of zimelidine and desipramine in endogenous depression.

Zimelidine, a specific 5HT uptake inhibitor (final dose 225 mg), and desipramine, mainly a noradrenaline uptake inhibitor (final dose 150 mg), were given in random order to 24 in- and out-patients fulfilling the Research Diagnostic Criteria for Major Depressive Disorder, definite or probable endogenous type, for a 3-week treatment period. Nonresponders were crossed over to the other drug for another 3 weeks. There was a nonsignificant trend towards more overall improvement on desipramine. Some patients in both groups showed very little change during 3 weeks, indicating a bimodal distribution of response to either drug. Several nonresponders improved markedly upon direct crossing over to the other drug. There were few and mild side effects on both drugs, with no significant difference between them. No significant correlation was found between improvement and plasma concentrations of zimelidine, norzimelidine, or desipramine, whereas a significant positive correlation was found between improvement and platelet serotonin uptake inhibition (measured in fresh platelets incubated in diluted plasma from the patients) in zimelidine-treated patients.

The pharmacokinetics and antihistaminic effects of brompheniramine.

We studied the pharmacokinetics and antihistaminic effect of brompheniramine in seven normal adults. The mean peak serum brompheniramine concentration of 11.6 +/- 3.0 ng/ml occurred at a mean time of 3.1 +/- 1.1 hr. The mean serum half-life value was 24.9 +/- 9.3 hr, the mean clearance rate was 6.0 +/- 2.3 ml/min/kg, and the mean volume of distribution was 11.7 +/- 3.1 L/kg. The mean wheal size was significantly suppressed (p less than or equal to 0.1) at 3, 6, and 9 hr after the brompheniramine dose when mean concentrations ranged from 10.2 +/- 2.9 to 7.0 +/- 2.2 ng/ml. Significant suppression (p less than or equal to 0.05) of mean flare size was found from 3 to 48 hr after the brompheniramine dose, when mean concentrations ranged from 10.2 +/- 2.9 to 2.5 +/- 0.6 nl/ml. The mean pruritus score was significantly suppressed at 9 and 12 hr (p less than or equal to 0.1) and at 24 hr (p less than or equal to 0.05). Brompheniramine had a long half-life and large volume of distribution in normal adults. It also had a prolonged antihistaminic effect in the skin as evidenced by suppression of the wheal and flare response to histamine and by suppression of pruritus.

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.

An examination of possible interactions between zimelidine, a serotonin uptake inhibitor, and ethanol ingested conjointly in human subjects.

Non-alcoholic male subjects were given either a placebo or zimelidine (100, 200 or 300 mg, p.o.) 2 h prior to consumption of alcohol (1 g/kg) or a non-alcoholic mixer. Slight increases in heart rate and diastolic blood pressure induced by alcohol were unaffected by pretreatment with zimelidine. Alcohol, zimelidine, and the combination of the two, did not affect any of the hematologic measures except for serum potassium levels. The latter were reduced slightly but not in any discernible pattern. Blood alcohol concentrations were not changed by zimelidine pretreatment. Conversely, blood concentrations of zimelidine and its metabolite norzimelidine were also relatively unaffected by alcohol consumption. In general, the results indicate that the simultaneous administration of zimelidine and alcohol to human subjects does not produce any observable adverse effects.

Safety data on zimelidine hydrochloride following an overdose.

Zimelidine, a new antidepressant, has proved to be a potent and selective inhibitor of 5-HT uptake into central 5-HT neurons. Due to its structural differences from the tricyclic antidepressants, it has also been suggested that it may have a different pharmacological profile, and be devoid of anticholinergic and noradrenaline potentiating properties. During the treatment with zimelidine hydrochloride, as a part of an open trial, one of our patients, a 38-year-old chronically depressed woman, overdosed herself with more than 10 times the actual therapeutic dose of zimelidine with no undesirable side effects. Previous studies have indicated that zimelidine in comparison with imipramine and chlorimipramine has no, or at most, a slight effect on peripheral adrenergic neurons, and has less pronounced anticholinergic properties than imipramine. The findings of our overdose case provide some support for these findings.

A double blind comparison of zimelidine and amitriptyline in endogenous depression.

In a randomized double-blind group comparison study of 40 patients with endogenous depression zimelidine appeared to be as effective an antidepressant as amitriptyline at 4 and 6 weeks using the Hamilton Rating Scale (HRS) and the Montgomery and Asberg Depression Rating Scale (MADRS). At 2 weeks there was a significantly better response (P less than 0.05) on zimelidine compared to amitriptyline on the clinician's global scale and 4 out of 10 items on the MADRS suggesting an early onset of action. A significant better response to zimelidine was seen on the item somatic anxiety (HRS) while the effect on sleep and appetite was better in the amitriptyline group. There were significantly more side effects, raw and corrected, in the amitriptyline-treated group. High steady state plasma concentrations of norzimelidine (greater than 800 nmol/l) which were significantly correlated with age (r = 0.8) were associated with a significantly poorer response suggesting that a lower dose than 200 mg in older patients may be appropriate.

Zimelidine to geriatric patients: a pharmacokinetic and clinical study.

To evaluate the clinical efficacy, tolerance and pharmacokinetic properties of zimelidine in elderly people, twelve hospitalized depressed patients with a mean age of 80 years were included in a clinical trial. Zimelidine was administered twice daily at a dose of 50 mg during the first week, 75 mg during the second week and 100 mg during the third to sixty week. The patients also received a single oral test dose of 75 mg of zimelidine during an initial placebo week. All patients that completed the study improved according to the rating scales used. The drug was well tolerated, and adverse reactions were few and of mild or moderate severity. No influence of clinical importance was noted on hematology, liver and kidney functions, ECG, blood pressure or pulse rate. The mean elimination half-lives of zimelidine and norzimelidine were found to be 15 h and 35 h, respectively, which were longer than the half-lives earlier obtained in younger patients. The blood levels (AUC) in the geriatric patients were about twice those obtained earlier in healthy volunteers. The AUC values for both zimelidine and norzimelidine increased in close proportion to the increase in dose and, thus, the pharmacokinetics of zimelidine was apparently not dose-dependent in the dose interval used. The results obtained may indicate a reduction in the rate of metabolism for zimelidine in the elderly, possibly combined with increased total bioavailability of the drug. A reduction of the regular zimelidine dose may be recommended in the treatment of elderly patients.

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.

Changes in endorphins and 5-hydroxyindoleacetic acid in cerebrospinal fluid as a result of treatment with a serotonin reuptake inhibitor (zimelidine) in chronic pain patients.

Both the endorphin and the serotonin systems seem to be involved in pain perception, and a significant positive correlation between the levels of endorphins and 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) has been established. In the present study, 20 chronic pain patients were treated with zimelidine, a rather selective inhibitor of serotonin reuptake, or placebo. Zimelidine produced a significant pain relief and a significant reduction of the levels of endorphins and 5-HIAA in CSF, while no significant changes occurred during placebo treatment. The results indicate that both the endorphin and the serotonin systems are involved in pain perception and that the systems are functionally related.

Plasma levels of zimelidine and norzimelidine in endogenous depression.

A new serotonin uptake inhibitor zimelidine was studied in 16 endogenously depressed inpatients, who received 150 mg/kg orally during 3--6 weeks in a phase II-type study. Plasma concentrations of zimelidine and its main metabolite norzimelidine were determined twice a week. Ten patients obtained a well-defined steady-state plasma level within 1--2 weeks, while three patients still had increasing concentrations of both substances or only norzimelidine within the investigation period. In two patients, biochemical affection of the liver could be demonstrated during the treatment; one associated with moderate clinical symptoms (dizziness and fever), the other without clinical symptoms. Both patients recovered upon cessation of the zimelidine treatment. In the former patient, very high concentrations of zimelidine at the time of hepatic symptoms were demonstrated, while the latter patient was within the average concentration range. Other adverse reactions were mild and few, particularly with respect to anticholinergic effects. With the applied, probably suboptimal, dosage the therapeutic response was only satisfactory in five cases.

Comparative pharmacokinetics of zimelidine and desipramine in man following acute and chronic administration.

Single dose and steady-state pharmacokinetics of zimelidine and desipramine were compared in eight depressed patients who were subjects in a double-blind crossover study. Within the same patient, there was no relationship between the pharmacokinetics of desipramine (pharmacokinetically similar to all other tricyclic antidepressants) and those of zimelidin, a bicyclic antidepressant. The weight-corrected dose of zimelidine gives a reasonable index of the concentration of its active metabolite norzimelidine, which predominates over zimelidine by a ratio of approximately 3 to 1. The variation in steady-state concentration of norzimelidine for a given dose of zimelidine in adults is about twofold and can be reduced by correcting for weight.