Zolpidem Research Articles

Estimating the cost of strategic entry delay in pharmaceuticals: The case of Ambien CR

With the Hatch-Waxman Act of 1984, the FDA included an unchallengeable exclusivity period for newly approved drugs, independent of patents. This potentially generates an incentive for firms to strategically delay the introduction of new versions (reformulations) of drugs until just before patent expiration of the original drug. This way the reformulated drug competes mainly with newly introduced generics of the original drug. If instead, the reformulated drug was to be introduced well before the original drug’s patent expires, the reformulated drug would compete only with the original drug. While the pattern of strategic delay is well documented in the literature, its effects on consumers and firms are not. Reformulations may increase utility through improved efficacy and through fewer doses per day or a more even molecule decay rate. However, as suggested in the press and literature, it is also possible that the adoption of reformulated products is mostly the result of advertising rather than product-related benefits. Using detailed prescribing and pricing data from the prescription sleep aid market, I document significant adoption of the reformulation Ambien CR and show that it is not only driven by advertising. I use these estimates to evaluate two different policies designed to induce earlier entry of Ambien CR. I find that there are large potential gains in consumer surplus and in revenue.

Estimating the Cost of Strategic Entry Delay in Pharmaceuticals: The Case of Ambien CR

With the Hatch-Waxman Act of 1984, the FDA included an unchallengeable exclusivity period for newly approved drugs, independent of patents. This potentially generates an incentive for firms to strategically delay the introduction of new versions (reformulations) of drugs until just before patent expiration of the original drug. This way the reformulated drug competes mainly with newly introduced generics of the original drug. If instead, the reformulated drug was to be introduced well before the original drug’s patent expires, the reformulated drug would compete only with the original drug. While the pattern of strategic delay is well documented in the literature, its effects on consumers and firms are not. Reformulations may increase utility through improved efficacy and through fewer doses per day or a more even molecule decay rate. However, as suggested in the press and literature, it is also possible that the adoption of reformulated products is mostly the result of advertising rather than product-related benefits. Using detailed prescribing and pricing data from the prescription sleep aid market, I document significant adoption of the reformulation Ambien CR and show that it is not only driven by advertising. I use these estimates to evaluate two different policies designed to induce earlier entry of Ambien CR. I find that there are large potential gains in consumer surplus and in revenue.

Learning and Memory Deficits in Male Adult Mice Treated with a Benzodiazepine Sleep-Inducing Drug during the Juvenile Period.

Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, is also known to be important for brain development. Therefore, disturbances of GABA receptor (GABA-R) mediated signaling (GABA-R signal) during brain development may influence normal brain maturation and cause late-onset brain malfunctions. In this study, we examined whether the stimulation of the GABA-R signal during brain development induces late-onset adverse effects on the brain in adult male mice. To stimulate the GABA-R signal, we used either the benzodiazepine sleep-inducing drug triazolam (TZ) or the non-benzodiazepine drug zolpidem (ZP). We detected learning and memory deficits in mice treated with TZ during the juvenile period, as seen in the fear conditioning test. On the other hand, ZP administration during the juvenile period had little effect. In addition, decreased protein expression of GluR1 and GluR4, which are excitatory neurotransmitter receptors, was detected in the hippocampi of mice treated with TZ during the juvenile period. We measured mRNA expression of the immediate early genes (IEGs), which are neuronal activity markers, in the hippocampus shortly after the administration of TZ or ZP to juvenile mice. Decreased IEG expression was detected in mice with juvenile TZ administration, but not in mice with juvenile ZP administration. Our findings demonstrate that TZ administration during the juvenile period can induce irreversible learning and memory deficits in adult mice. It may need to take an extra care for the prescription of benzodiazepine sleep-inducing drugs to juveniles because it might cause learning and memory deficits.

Fall-Related Injuries in Older Adults Taking Nonbenzodiazepine Sedative Hypnotics

An estimated 25% to 40% of older adults have insomnia, treated most commonly with medication. In this population, benzodiazepine hypnotics and zolpidem

PENGOLAHAN LIMBAH CAIR LABORATORIUM DENGAN BERBAGAI WAKTU RETENSI

According to the Indonesian Government Regulation Number 85 Year 1999 about the processing of B3 waste, the laboratorys waste water classified to B3 (Bahan Berbahaya Beracun). Based on this, then conducted laboratory research on wastewater treatment using chemical processes, biology and physics with a variation of time are 5 hours, 10 hours and 15 hours. Test parameters studied were Iron (Fe) and Mangan (Mn). The Goal of this study was to determine the effectiveness of the decrease in the concentration of iron (Fe) and Mangan (Mn) using a combination of processing by the processing chemistry, biology and physics with a variation of residence time is 5 hours, 10 hours and 15 hours. Based on initial test data, the initial concentration is known to Iron (Fe) is 46.4 mg / l while the initial concentrations of manganese (Mn) is 3,91 mg / l, where the concentration exceeds the ambien. From the results revealed that the decrease in Fe content of the most effective outcome of the time of 15 hours is able to reduce up to 99,78% Fe with a concentration of 0,1 mg / l, while the decrease in Mn content of the most effective results on the time of 15 hours, able to reduce up to 86,70% Mn with a concentration of 0,52 mg / l.

Treatment of general anxiety disorder by using of pregabalin – case report

Introduction Pregabalin is a chemical analog of the neurotransmitter gamma-aminobutyric acid (GABA). Its anticonvulsive, anxiolytics and analgetic effect is based on reducing of quantity of several neurotransmitters – especially glutamate, noradrenaline and substance P. Objective Generalized anxiety disorder is a quite common psychiatric disorder, affecting approximately 8% of the population. Pregabalin is effective in the treatment of GAD. Its efficacy is comparable to sertraline. The first positive effects on symptoms of anxiety are described after one week of an admistrating. Anxiolytic dose of pregabaline varies from 450 to 600mg per day. Pregabalin could be used potentially in patients with benzodiazepines adictions. There is hypothesis that pregabaline moderates withdrawal symptoms. Aims This poster presents a case report of the patient who suffers from generalized anxiety disorder with comorbid somatoform disorder and severe hypnotic (zolpidem abuse) Methods Short-termed hospitalisation at the detoxification unit to reduce doses of zolpideme. The attempt to use pregabaline to treat an anxiety and to decrease withdrawal symptoms. Results Patient who has been treated by antidepressants without any effect so far, is now showing a good response to pregabalin. Conclusion Decreasing symptoms of anxiety and somatoform pain compared to the beginning of the treatment. Complete discontinuation of using zolpidem without the withdrawal symptoms.

Locus Coeruleus and Tuberomammillary Nuclei Ablations Attenuate Hypocretin/Orexin Antagonist-Mediated REM Sleep.

Hypocretin 1 and 2 (Hcrts; also known as orexin A and B), excitatory neuropeptides synthesized in cells located in the tuberal hypothalamus, play a central role in the control of arousal. Hcrt inputs to the locus coeruleus norepinephrine (LC NE) system and the posterior hypothalamic histaminergic tuberomammillary nuclei (TMN HA) are important efferent pathways for Hcrt-induced wakefulness. The LC expresses Hcrt receptor 1 (HcrtR1), whereas HcrtR2 is found in the TMN. Although the dual Hcrt/orexin receptor antagonist almorexant (ALM) decreases wakefulness and increases NREM and REM sleep time, the neural circuitry that mediates these effects is currently unknown. To test the hypothesis that ALM induces sleep by selectively disfacilitating subcortical wake-promoting populations, we ablated LC NE neurons (LCx) or TMN HA neurons (TMNx) in rats using cell-type-specific saporin conjugates and evaluated sleep/wake following treatment with ALM and the GABAA receptor modulator zolpidem (ZOL). Both LCx and TMNx attenuated the promotion of REM sleep by ALM without affecting ALM-mediated increases in NREM sleep. Thus, eliminating either HcrtR1 signaling in the LC or HcrtR2 signaling in the TMN yields similar effects on ALM-induced REM sleep without affecting NREM sleep time. In contrast, neither lesion altered ZOL efficacy on any measure of sleep–wake regulation. These results contrast with those of a previous study in which ablation of basal forebrain cholinergic neurons attenuated ALM-induced increases in NREM sleep time without affecting REM sleep, indicating that Hcrt neurotransmission influences distinct aspects of NREM and REM sleep at different locations in the sleep–wake regulatory network.

Sleep-walking with Zolpidem: Need for Continued Postmarketing Surveillance

Sleep-walking with Zolpidem: Need for Continued Postmarketing Surveillance

Валидация методики количественного определения золпидема в цельной крови методом газовой хроматомасс-спектрометрии

Проведено количественное определение золпидема в крови методом ГХ/МС, в качестве внутреннего стандарта использовался имипрамина гидрохлорид. Коэффициент множественной регрессии r для полученной калибровочной прямой составил 0,999. Приведена метрологическая оценка методики по восьми статистическим параметрам. Определена эффективность экстракции золпидема из модельной крови на трех уровнях концентраций, при этом выход исследуемого вещества наблюдался в пределах 96 – 99 %. Проведена валидационная оценка методики по показателям: специфичность, предел обнаружения, предел количественного определения, линейность, аналитическая область методики, правильность, прецизионность (повторяемость и внутрилабораторная прецизионность). При статистической обработке полученные результаты находятся в пределах приемлемости. Предел обнаружения золпидема в крови составил 24 нг/мл; предел количественного определения — 72,7 нг/мл.

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems.

The dual hypocretin receptor (HcrtR) antagonist almorexant (ALM) may promote sleep through selective disfacilitation of wake-promoting systems, whereas benzodiazepine receptor agonists (BzRAs) such as zolpidem (ZOL) induce sleep through general inhibition of neural activity. Previous studies have indicated that HcrtR antagonists cause less-functional impairment than BzRAs. To gain insight into the mechanisms underlying these differential profiles, we compared the effects of ALM and ZOL on functional activation of wake-promoting systems at doses equipotent for sleep induction. Sprague-Dawley rats, implanted for EEG/EMG recording, were orally administered vehicle (VEH), 100 mg/kg ALM, or 100 mg/kg ZOL during their active phase and either left undisturbed or kept awake for 90 min after which their brains were collected. ZOL-treated rats required more stimulation to maintain wakefulness than VEH- or ALM-treated rats. We measured Fos co-expression with markers for wake-promoting cell groups in the lateral hypothalamus (Hcrt), tuberomammillary nuclei (histamine; HA), basal forebrain (acetylcholine; ACh), dorsal raphe (serotonin; 5HT), and singly labeled Fos(+) cells in the locus coeruleus (LC). Following SD, Fos co-expression in Hcrt, HA, and ACh neurons (but not in 5HT neurons) was consistently elevated in VEH- and ALM-treated rats, whereas Fos expression in these neuronal groups was unaffected by SD in ZOL-treated rats. Surprisingly, Fos expression in the LC was elevated in ZOL- but not in VEH- or ALM-treated SD animals. These results indicate that Hcrt signaling is unnecessary for the activation of Hcrt, HA, or ACh wake-active neurons, which may underlie the milder cognitive impairment produced by HcrtR antagonists compared to ZOL.

Low-Dose Atypical Antipsychotic Risperidone Improves the 5-Year Outcome in Alzheimer's Disease Patients with Sleep Disturbances

Sleep disturbances (SD) accelerate the progression of Alzheimer's disease (AD) and increase the stress of caregivers. However, the long-term outcome of disturbed nocturnal sleep/wake patterns in AD and on increased stress of spousal caregivers is unclear. This study assessed the 5-year effect of nocturnal SD on the long-term outcome in AD patients. A total of 156 donepezil-treated mild-moderate AD patients (93 AD + SD and 63 AD - SD as a control group) were recruited. The AD + SD patients were formed into 4 subgroups according to the preferences of spousal caregivers for treatment with atypical antipsychotics (0.5-1 mg risperidone, n = 22), non-benzodiazepine hypnotic (5-10 mg zolpidem tartrate, n = 33), melatonin (2.55 mg, n = 9), or no-drug treatment (n = 29). SD were evaluated by polysomnography, sleep scale, and cognitive scale examinations. Moreover, all spousal caregivers of AD patients were assessed using a series of scales, including sleep, anxiety, mood, and treatment attitude scales. Our data showed that nocturnal sleep/wake disturbances were significantly associated with lower 5-year outcomes for AD patients, earlier nursing home placement, and more negative emotions of spousal caregivers. Treatment with low-dose atypical antipsychotic risperidone improved the 5-year outcome in AD + SD patients. In conclusion, low-dose atypical antipsychotic risperidone improves the 5-year outcome in AD patients with SD. Moreover, improvement of nocturnal sleep problems in AD patients will also bring better emotional stability for AD caregivers.

Further evidence for the sleep-promoting effects of 5-HT 2A receptor antagonists and demonstration of synergistic effects with the hypnotic, zolpidem

Further evidence for the sleep-promoting effects of 5-HT 2A receptor antagonists and demonstration of synergistic effects with the hypnotic, zolpidem

Application of a method used to deconstruct a single dose pharmacokinetic profile from multiple dose data.

With traditional non-compartmental methods, it is challenging to deconstruct plasma concentration versus time curves to assess the influence of individual doses. This study describes the application of a mathematical approach used to deconstruct a single dose curve using data derived from the second, third, fourth or nth dosing interval. Using data from a prospective clinical trial it is demonstrated that this approach reliably estimates pharmacokinetic parameters measured following two doses of zolpidem tartrate. Additionally, the study demonstrates the application of this approach using previously published data from a single- and multiple-dose pharmacokinetic study of the antibiotic gatifloxacin. Copyright © 2015 John Wiley & Sons, Ltd.

Determination of zolpidem in human plasma by liquid chromatography-tandem mass spectrometry for clinical application.

Zolpidem (ZPD) is widely described for the short-term treatment of insomnia. We have developed and validated a simple and rapid liquid chromatography analytical method using tandem mass spectrometry (LC-MS/MS) for the quantification of ZPD in human plasma. Using dibucaine as an internal standard (IS), the analyte was extracted with methyl t-butyl ether (MTBE). Chromatographic separation of ZPD was performed on a reversed-phase Luna C18 column (50 mm × 2.0 mm i.d., 5 μm particles) with a mobile phase of 10mM ammonium formate buffer (pH 3.0)-methanol (15:85, v/v) at a flow rate of 250 μm/min. The total run-time was 2.5 min and the retention times of ZPD and IS were 0.66 and 0.74 min, respectively. The mass-to-charge transition monitored for quantification of ZPD and IS was 308.2→235.2 and 344.0→271.0, respectively. The lower limit of quantification (LLOQ) using 100 μL of human plasma was 0.05 ng/mL and the calibration curves were linear over a range of 0.05-200 ng/mL (r(2)>0.9964). The mean accuracy and precision for intra- and inter-run validation of ZPD were within acceptable limits. In the present LC-MS/MS method, we showed improved sensitivity for quantification of the ZPD in human plasma using lower volume of plasma compared with previously described analytical methods for ZPD. This validated method was successfully applied to a pharmacokinetic study in humans.

Surveillance of adverse psychiatric medication events.

RESULTS From 2009 through 2011, there were an estimated 89 094 (95% CI, 68 641-109 548) psychiatric medication ADE ED visits annually, with 19.3% (95% CI, 16.3%-22.2%) resulting in hospitalization and 49.4% (95% CI, 46.5%-52.4%) involving patients aged 19 to 44 years. Sedatives and anxiolytics, antidepressants, antipsychotics, lithium salts, and stimulants were implicated in an estimated 30 707 (95% CI, 23 406-38 008), 25 377 (95% CI, 19 051-31 704), 21 578 (95% CI, 16 599-26 557), 3620 (95% CI, 2311-4928), and 2779 (95% CI, 1764-3794) respective ADE ED visits annually. Antipsychotics and lithium salts were implicated in 11.7 (95% CI, 10.1-13.2) and 16.4 (95% CI, 13.0-19.9) ADE ED visits per 10 000 outpatient prescription visits, respectively, compared with 3.6 (95% CI, 3.2-4.1) for sedatives and anxiolytics, 2.9 (95% CI, 2.3-3.5) for stimulants, and 2.4 (95% CI, 2.1-2.7) for antidepressants. The commonly used sedative zolpidem tartrate was implicated in 11.5% (95% CI, 9.5%-13.4%) of all adult psychiatric medication ADE ED visits and in 21.0% (95% CI, 16.3%-25.7%) of visits involving adults 65 years or older, in both cases significantly more than any other psychiatric medication.

Impact of a US Food and Drug Administration Drug Safety Communication on Zolpidem Dosing: An Observational Retrospective Cohort.

Zolpidem is a sedative-hypnotic widely prescribed in the United States. Recently, the US Food and Drug Administration (FDA) issued a drug safety communication regarding its dosing in women. To compare compliance with FDA-approved dosing for zolpidem in women before and after a drug safety communication, and to evaluate compliance based on pharmacy location and prescriber type. This was a retrospective, observational cohort study. New prescriptions for Ambien, Ambien CR, Edluar, or Zolpimist or their respective generics dispensed from Kerr Drug pharmacies in North Carolina to women 18-64 years of age between April and September of 2012 ("before" cohort) or April and September of 2013 ("after" cohort) were included. χ(2) tests were conducted to assess overall compliance, as well as compliance based on location (urban or rural) and prescriber type (physician or midlevel), with FDA-approved dosing for zolpidem. Trends in total prescription volume and total zolpidem prescription volume for all Kerr Drug pharmacies over the study period were also described. A total of 14,156 prescriptions for zolpidem were included in the primary analysis. Sixteen percent of prescriptions dispensed were in compliance with FDA recommendations following the FDA alert. A statistically significant increase was observed in compliance with FDA-approved dosing for zolpidem (odds ratio = 1.49; 95% CI, 1.35-1.65; P < .0001) postdrug safety communication. Significant increases in compliance were also observed in the post-FDA communication subgroups based on location and prescriber type, though no subgroup was found to be significantly more compliant than another. The release of a drug safety communication by the FDA resulted in a statistically significant increase in proper dosing of zolpidem in women. Further research is needed in order to determine the impact of FDA alerts on prescribing patterns and the reasons for therapeutic substitution after such alerts.

Development of a Novel Oral Cavity Compartmental Absorption and Transit Model for Sublingual Administration: Illustration with Zolpidem.

Intraoral (IO) delivery is an alternative administration route to deliver a drug substance via the mouth that provides several advantages over conventional oral dosage forms. The purpose of this work was to develop and evaluate a novel, physiologically based oral cavity model for projection and mechanistic analysis of the clinical pharmacokinetics of intraoral formulations. The GastroPlus™ Oral Cavity Compartmental Absorption and Transit (OCCAT™) model was used to simulate the plasma concentration versus time profiles and the fraction and rate of intraoral drug transit/absorption for Intermezzo® sublingual tablets (zolpidem tartrate). The model was evaluated by the goodness-of-fit between simulated and observed concentrations and the deviation of key PK parameters (e.g., C max, T max, and AUC). In addition, a sensitivity analysis was conducted to demonstrate the interplay and impact of key modeling parameters on the fraction absorbed via oral mucosa (F a_IO). The OCCAT™ model captured the observed pharmacokinetics for Intermezzo® sublingual tablets (R (2) > 0.9). The predicted deviations (%) for C max, AUC0-inf, AUC0-20min, and T max were 5.7, 28.0, 11.8, and 28.6%, respectively, indicating good prediction accuracy. The model also estimated ~18% of total drug was absorbed via the IO route. Furthermore, the sensitivity analysis indicated that the F a_IO was not only associated with drug diffusivity and unbound fraction in epithelium tissue (f ut) but also depended on the physicochemical properties of compounds for IO delivery (e.g., solubility and logD pH = 7.4). The novel physiologically based IO absorption OCCAT™ model showed satisfactory performance and will be helpful to guide development of future intraoral formulations.

Simultaneous analysis of zolpidem and its metabolite in whole blood and oral fluid samples by SPE-LC/MS for clinical and forensic purposes

PurposeThe new analytical method of qualitative and quantitative determination of zolpidem and qualitative analysis of its main metabolite in blood and oral fluid samples was developed. Materials and methodsSample preparation was carried out using a polymeric ion-exchange sorbent in solid phase extraction (SPE). Analysis was realized using liquid chromatography with mass spectrometry detection (LC/MS). The method was validated in terms of few parameters. LOD, LOQ, linearity, precision, selectivity, ion suppression and stability were estimated. ResultsObtained method showed good linearity with determination coefficient (R2) of 0.9989 and 0.9998 for blood and oral fluid samples, respectively. LOD and LOQ of zolpidem were 0.2ng/mL and 1.0ng/mL, respectively, for both blood and oral fluid samples. SPE method recovery varies from 79.9±12.6 to 104.1±1.77 for blood sample and 80.2±0.48 to 103.8±1.51 for oral fluid sample. Samples collected from patients taking zolpidem with a prescription were analyzed. Detection of zolpidem was possible after 15h from ingestion of 10mg zolpidem tartrate in both types of samples. ConclusionThe developed method allows quantitation of zolpidem in therapeutic and subtherapeutic range as well as qualitative analysis of its main metabolite in blood and oral fluid samples. This method meets criteria required for bioanalytical applications and can be used for clinical and forensic purposes.

Pharmacokinetic effects of simultaneous administration of single-dose gabapentin 500 mg and zolpidem tartrate 10 mg in healthy volunteers: a randomized, open-label, crossover trial.

ObjectiveGabapentin is being investigated as a potential treatment for occasional disturbed sleep. This study assessed the pharmacokinetics and tolerability of gabapentin 500 mg and the commonly prescribed sedative/hypnotic zolpidem tartrate 10 mg, administered separately and in combination.MethodsForty healthy participants (19 male, 21 female) were randomized into this three-period crossover study [mean (range) age 34.1 (18–45) years, weight 68.3 (51.4–92.7) kg; 60 % white]. Participants were dosed with gabapentin alone (n = 39), zolpidem tartrate alone (n = 38), and the combination (gabapentin + zolpidem) (n = 38) over three treatment periods, which were separated by ≥7 days. Blood samples were collected pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, 24 and 36 h post-dose. Plasma concentrations of each drug were assayed using validated methods. Pharmacokinetic parameters were estimated from plasma concentration–time data using standard non-compartmental methods.ResultsFor gabapentin + zolpidem combination versus gabapentin alone, mean pharmacokinetic parameters were peak plasma concentration (C max) 4.61 versus 4.72 µg/mL, time to Cmax (t max) 4.63 versus 3.64 h and the area under plasma concentration–time curve extrapolated to infinity (AUC0–∞) 53.4 versus 51.0 µg h/mL. For the combination versus zolpidem alone, mean pharmacokinetic parameters were C max 154 versus 138 ng/mL, t max 1.45 versus 1.84 h and AUC0–∞ 912 versus 854 ng h/mL. The 90 % confidence intervals for C max (rate of absorption) and AUC0–∞ (extent of absorption) comparing the combination versus single drug administration fell within the 80–125 % range accepted for bioequivalence. All treatments were well tolerated.ConclusionThe pharmacokinetics of gabapentin 500 mg and zolpidem tartrate 10 mg are unaffected when both drugs are taken simultaneously, compared with each drug taken alone.

Single-hair analysis of zolpidem on the supposition of its single administration in drug-facilitated crimes

Little information is available on the amounts of hypnotics incorporated into hair after a single administration and about effective analytical procedures to document cases like drug-facilitated sexual assaults. To obtain basic information, single-hair specimens from a volunteer who took a single dose of 10-mg zolpidem (ZP) were analyzed by a newly established liquid chromatography–tandem mass spectrometry procedure, using a one-pot pulverization extraction method. The detection limit of ZP was 50 fg/2-cm single hair, and ZP in each segment was determined for the single black hair specimens (n = 15). ZP was detectable in 14 hairs (positive for all the proximal 0–2 cm segments, negative for all 2–4 cm segments), but was not detected in a single hair (probably in the telogen stage). The amounts of ZP detected in each positive 2-cm segment of single hair ranged from 27 to 63 pg (average 43 pg). The estimated total incorporation of ZP in the scalp hair (black hair ~110,000 strands) was about 4.7 μg, which corresponds to about 0.06 % of the single 10-mg dose (8.03 mg as free ZP). In addition, the direct detection of single-dose ZP incorporated in hair and its imaging were successfully achieved by matrix-assisted laser desorption ionization-mass spectrometry. It is suggested that a combination of these methodologies will provide the highest-level evidence to document such exposure to a hypnotic drug.