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Increased complications and costs of marketing of innovative drugs focused greater attention to the development of sustained release (SR) or controlled release (CR) drug delivery systems. Trazodone Hydrochloride (TRZ) is a well-known chemical compound that is used as an antidepressant that belongs to a selective serotonin reuptake inhibitor (SARI). The objective of present work was to develop and evaluated oral sustained release matrix tablet of TRZ. Pre-compression parameters were evaluated. The tablets were evaluated for post-compression parameters such as thickness, hardness, average weight, friability and In vitro release studies. No interactions were observed between TRZ and excipients from the Fourier transform infrared spectroscopy. The present research work was successful in improving the efficacy TRZ oral therapy as the drug release was extended for 12 hours thus reducing dosing frequency thereby improving patient compliance. The study also revealed the applicability of HPMC K-15, Gaur gum and PVP K30 as rate-controlling polymers in matrix tablets. The hydrophilic matrix of HPMC alone cannot control the release TRZ effective for 12 h while when combined with guar gum, may slow down the release of the drug and therefore, can be successfully employed for the formulation of matrix tablets SR. It may be concluded from the study that; the optimized formulation F-8 was shown maximum drug release 99.12 % in 12 h of dissolution. The release kinetic data of formulation F-8 shown first order release kinetics (R2 = 0.980).

This study evaluated the effect of 3 doses of a trazodone hydrochloride 6% oral drops solution on the QT interval of healthy volunteers. Subjects were randomly assigned to receive a single dose of trazodone 20 mg, 60 mg, and 140 mg, moxifloxacin 400 mg, and trazodone‐matched placebo in 5 periods separated by 7‐day washouts, according to a double‐blind, crossover study design. Subjects were monitored continuously, and triplicate ECGs were extracted from baseline (predose) until 24 hours postdose. Blood samples for trazodone and moxifloxacin analyses were collected at the same time points. The concentration‐QTc relationship assessed on placebo‐adjusted change from baseline for Fridericia‐corrected QT (ΔΔQTcF) was the primary end point. ΔΔQTcF values of 4.5, 12.3, and 19.8 ms for the 20‐, 60‐, and 140‐mg doses were observed at the corresponding trazodone peak plasma concentrations. The upper bound of the 90%CI exceeded 10 ms for the 60‐ and the 140‐mg doses. Time‐matched analysis results were in line with these findings. No significant trazodone effect on heart rate or PR or QRS intervals and no clinically significant new morphological changes were present. In this moxifloxacin‐validated ECG trial, trazodone had a modest, dose‐dependent effect on cardiac repolarization, with no QTc prolongation observed with the 20‐mg dose and an effect exceeding the values set in E14 guideline with the 60‐ and 140‐mg doses. The effect on cardiac repolarization is unlikely to represent a clinical risk for ventricular proarrhythmia, but caution should be used with concomitant use of other medications that prolong QT or increase trazodone exposure.

Companion dogs housed in animal shelters are subject to a great number of uncontrollable and unalterable stressors. To combat these stressors and the associated immunosuppression that can result in high rates of contagious disease in sheltered dogs, a large open admission municipal animal shelter in New York City introduced trazodone hydrochloride, a serotonin receptor antagonist and reuptake inhibitor, to help reduce their transitional stress. Dogs were given low doses of trazodone at intake (5 mg/kg), one to two doses within 48 hours of arrival. Prevalence of illness was calculated for two time periods at the Brooklyn and Manhattan Care Center locations (N = 1,766): November and December 2018, when trazodone was administered to the population, and a historical control in November and December 2017 and 2016, when no trazodone was administered. A statistically significant difference in the percentage of sick dogs was found when comparing the No Trazodone group (2016/2017) and Trazodone treatment group in 2018 (Chi2 [1, N = 1766] = 19.4, P

Trazodone hydrochloride (TRH) is a lipophilic drug which is used effectively as an antidepressant. Its poor solubility and short half-life represent an obstacle for its successful use. Nanocapsules with biodegradable polymeric shell are successful drug delivery systems for controlling the release of drugs. To enhance the entrapment of lipophilic drugs, oils can be added forming a lipophilic core in which the drug is more soluble. The aim of this study was to enhance the efficacy of TRH and prolong its action by formulating it into lipid core polymeric shell nanocapsules. Nanocapules were prepared using nanoprecipitation technique. All prepared formulations were in nano size range and negatively charged. The TRH entrapment efficiency (EE%) in lipid core nanocapsules was up to 74.8 ± 0.5% when using Labrafac lipophile as a lipid core compared to only 55.7 ± 0.9% in lipid free polymeric nanospheres. Controlled TRH release was achieved for all prepared formulations. Forced swim test results indicated the significant enhancement of antidepressant effect of the selected TRH loaded Labrafac lipophile core nanocapsules formulation compared to control and TRH dispersion in phosphate buffer. It is concluded that lipid core nanocapsules is a promising carrier for the enhancement of TRH efficacy.

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Nonsense-mediated mRNA decay (NMD) degrades transcripts with premature stop codons. Given the prevalence of nonsense single nucleotide polymorphisms (SNPs) in the general population, it is urgent to catalog the effects of clinically approved drugs on NMD activity: any interference could alter the expression of nonsense SNPs, inadvertently inducing adverse effects. This risk is higher for patients with disease-causing nonsense mutations or an illness linked to dysregulated nonsense transcripts. On the other hand, hundreds of disorders are affected by cellular NMD efficiency and may benefit from NMD-modulatory drugs. Here, we profiled individual FDA-approved drugs for their impact on cellular NMD efficiency using a sensitive method that directly probes multiple endogenous NMD targets for a robust readout of NMD modulation. We found most FDA-approved drugs cause unremarkable effects on NMD, while many elicit clear transcriptional responses. Besides several potential mild NMD modulators, the anticancer drug homoharringtonine (HHT or omacetaxine mepesuccinate) consistently upregulates various endogenous NMD substrates in a dose-dependent manner in multiple cell types. We further showed translation inhibition mediates HHT's NMD effect. In summary, many FDA drugs induce transcriptional changes, and a few impact global NMD, and direct measurement of endogenous NMD substrate expression is robust to monitor cellular NMD., Graphical abstract, Zheng and colleagues determined the effects of individual FDA-approved drugs on NMD activity by quantitatively assessing multiple endogenous NMD target isoforms. While many drugs induce transcriptional responses, some show the potentials of modulating NMD to varying degrees, including HHT, identified as a robust NMD inhibitor.

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Development of generic extended-release (ER) formulations is challenging. Especially under fed conditions, the risk of failure in bioequivalence trials is high because of long gastric residence times and susceptibility to food effects. We describe the development of a generic trazodone ER formulation that was aided with a biorelevant dissolution evaluation. Trazodone hydrochloride 300-mg monolithic matrix tablets were dissolved both in USP and EMA compliant conditions and in the StressTest device that simulated both physicochemical and mechanical conditions of the gastrointestinal passage. The final formulation was tested against the originator, Trittico XR 300 mg, in a randomized cross-over bioequivalence trial with 44 healthy volunteers, in agreement with EMA guidelines. Initially developed formulations dissolved trazodone similarly to the originator under standard conditions (f2 factor above 50), but their dissolution kinetics differed significantly in the biorelevant tests. The formulation was optimized by the addition of low-viscosity hypromellose and mannitol. The final formulation was approved for the bioequivalence trial. Calculated Cmax were 1.92 ± 0.77 and 1.92 ± 0.63 [μg/mL], AUC0-t were 27.46 ± 8.39 and 29.96 ± 9.09 [μg∙h/mL], and AUC0-∞ were 28.22 ± 8.91 and 30.82 ± 9.41 [μg∙h/mL] for the originator and test formulations, respectively. The 90% confidence intervals of all primary pharmacokinetic parameters fell within the 80–125% range. In summary, biorelevant dissolution tests supported successful development of a generic trazodone ER formulation pharmaceutically equivalent with the originator under fed conditions. Employment of biorelevant dissolution tests may decrease the risk of failure in bioequivalence trials of ER formulations. Electronic supplementary material The online version of this article (10.1208/s12249-020-01662-8) contains supplementary material, which is available to authorized users.

Objective: Conductometric determination of trazodone hydrochloride, with two precipitating reagents; Ammonium Reineckate and sodium tetraphenylborate has been investigated.Methods: The formed ion-associates were studied conductomterically for the determination of solubility products and other functions associated with the process of precipitating trazodone hydrochloride were determined. Moreover, two new maneuvers towards equivalence point detection were carried out. In this study, data processing was performed using numerical derivatization (second derivative) and Boltzmann algorithm. Results: Although, the described procedures allowed the determination of trazodone hydrochloride within the range of 2-14 mg using both reagents has less sensitivity other than reported method but has more advantages in simplicity, low cost , relatively short analysis time and direct analysis with good recoveries between 100.01% and 100.07% with relative standard deviation less than 2%. Conclusion: These methods were validated and successfully applied for the determination of trazodone hydrochloride in Trittico® tablets. The obtained results were statistically compared with those of the official method by applying t-test and F-value at 95% confidence level and no significant difference was observed regarding accuracy and precision.

Trazodone hydrochloride is an atypical antidepressant that has entered clinical use for dogs and cats for a variety of indications. These include management of anxiety disorders, facilitation of travel and veterinary examinations, and facilitation of calm behavior in hospitalized and postoperative patients. Despite the increasingly common use of trazodone in dogs, very little literature exists evaluating trazodone's efficacy against a placebo control. The aim of the study reported here was to evaluate trazodone in a randomized placebo-controlled clinical trial for use in facilitating calmness and ease of confinement in postoperative dogs. The study enrolled 29 dogs (14 in the trazodone group and 15 in the placebo group) and followed them during 4 postoperative weeks. Trazodone was well tolerated by dogs in the trazodone group. Although dogs in both groups were rated as improved on some behavioral measures, no difference was found between the trazodone and placebo groups in efficacy, with more than 70% of owners in both groups rating the test article (trazodone or placebo) as moderately or extremely helpful for facilitating both calming and crating of their dog. This observed lack of efficacy, over placebo, may be attributed to one or more of several factors that include features about the trial itself and the trial population, a caregiver or placebo-by-proxy effect, a lack of sensitive outcome measures for assessment, or a lack of true efficacy for the medication. It is concluded that future work will be needed to address these factors, and this report aims to provide not only results but lessons learned from the conduct of the described trial.

New pharmaceutically acceptable salts of trazodone for the treatment of central nervous system disorders are synthesized and described. Each salt (trazodone hydrogen bromide and trazodone 1-hydroxy-2-naphthoate) was obtained by two or three different methods leading to the same crystalline form. Although trazodone salts are poorly crystalline, single-crystal X-ray diffraction data for trazodone 1-hydroxy-2-naphthoate were collected and analyzed as well as compared to the previously described crystal structure of commercially available trazodone hydrochloride. The powder samples of all new salts were characterized by Fourier transform infrared spectroscopy and 13C solid-state nuclear magnetic resonance spectroscopy. Spectroscopic studies were supported by gauge including projector augmented wave (GIPAW) calculations of carbon chemical shielding constants. The main goal of our research was to find salts with better physicochemical properties and to make an attempt to associate them with both the anion structure and the most prominent interactions exhibited by the protonated trazodone cation. The dissolution profiles of trazodone from tablets prepared from various salts with lactose monohydrate were investigated. The studies revealed that salts with simple anions show a fast release of the drug while the presence of more complex anion, more strongly interacting with the cation, effects a slow-release profile of the active substance and can be used for the preparation of the tables with a delay or prolonged mode of action.

The aim of the present study was to appraise the mutagenic and recombinogenic potential of bupropion hydrochloride (BHc) and trazodone hydrochloride (THc). We used standard (ST) and the high bioactivation (HB) crossings from Drosophila melanogaster in the Somatic Mutation and Recombination Test. We treated third-instar larvae from both crossings with different concentrations of BHc and THc (0.9375 to 7.5 mg/mL). BHc significantly increased the frequency of mutant spots in both crossings, except for the lowest concentration in the ST crossing. ST had also the mostly recombinogenic result, and in the HB, BHc was highly mutagenic. On the other hand, THc significantly increased the frequency of mutant spots in both the ST and HB crossings at all concentrations. The three initial concentrations were recombinogenic and the highest concentration was mutagenic for the THc. BHc and THc at high concentrations were toxic, even though their mutagenicity was not dose-related. THc significantly increased the frequency of mutant spots when metabolized, probably as a result of the production of 1-(3′-chlorophenyl) piperazine. BHc was essentially recombinogenic and when metabolized, it became mutagenic. THc was recombinogenic in both crossings. Further studies are needed to clarify the action mechanisms from BHc and THc.

Summary Objectives Elderly people with dementia are commonly suffered from sleep disorders. So, the use of Donepezil hydrochloride as anti-Alzheimer drug and Trazodone hydrochloride as antidepressants with hypnotic action is very important in these cases. This study reports about novel and sensitive RP-HPLC method with fluorescence detection for simultaneous bioanalytical determination of Donepezil hydrochloride (DON) and co-administered, Trazodone hydrochloride (TRA) in their pure forms, spiked human plasma and tablets. Materials and methods Elution of both drugs was achieved with excellent resolution using a RP-C18 Hypersil Gold column and an isocratic mobile phase consisting of phosphate buffer (50 mm, pH 4.6): methanol: acetonitrile (60:35:5) with a flow rate of 1.5 mL/min and 20 μL as injection volume. A Fluorescence detector at 300 nm for excitation and 400 nm for emission was used. Results Retention times were 4.3 and 6.3 min for Donepezil hydrochloride and Trazodone hydrochloride, respectively. Linearity ranges of the assay were 25–1000 and 50–5000 ng/mL and the limits of detection (LOD) and quantitation (LOQ) were 8.52, 15.47 and 25.81, 46.89 ng/mL for Donepezil hydrochloride and Trazodone hydrochloride, respectively. Conclusion The high sensitivity of the proposed method enabled the successful determination of the cited drugs in spiked human plasma with mean percentage of recoveries of 91.58 ± 3.34 and 100.30 ± 5.11 for Donepezil hydrochloride and Trazodone hydrochloride, respectively.

Objective: The objective of the existing research was to develop an oral disintegrating dissolving system as one of the taste masking orodispersible forms together of trazodone hydrochloride tablets using direct compression technique through the use of superdisintegrants together with FlowLac, StarLac, and sodium starch glycolate. Methods: The tablets were formulated using the direct compression approach. The drugs prepared have been evaluated for diverse parameters which include hardness, friability, weight variation, drug content uniformity, water absorption ratio, in vitro drug release, and wetting time. Results: The hardness of all formulations from F1 to F7 proved that the tablet means thickness was nearly uniform in all formulations with the range of 0.520 mm–0.522 mm. Water absorption of prepared formulations was found to be 68.59%–73.21%. Bulk density, tapped density, and friability of the formulations were established within the limits, results of in vitro drug release study showed the drug released between 90.27% and 96.17% at 60 min. Conclusion: The overall study concluded that orodispersible tablets of trazodone hydrochloride have greater dissolution rate and will result in enhanced bioavailability. The taste masked systems are designed to provide better acceptability, improved bioavailability, for chronic patients. The study results revealed that the formulation F6 was contemplated as the top formulation.

In the present study, screen-printed electrodes unmodified and chemically modified with gold nanoparticles were used as sensitive electrochemical sensors for the determination of trazodone hydrochloride. The sensors were based on the use of a tetraphenylborate ion association complex as an electroactive material in screen-printed electrodes with dioctyl phthalate (DOP) as a solvent mediator modified with gold nanoparticles which improve the electrode conductivity and enhance the surface area. The sensors displayed a stable response for 5, 6 and 7 months with a reproducible potential and linear response over the concentration range 1 × 10−5–1 × 10−2 mol L−1 at 25 ± 1 °C with Nernstian slopes of 57.50 ± 0.66, 58.30 ± 0.45 and 59.05 ± 0.58 mV per decade and detection limits of 7.9 × 10−6, 7.6 × 10−6 and 6.8 × 10−6 mol L−1 for sensor 1, 2 and 3 respectively. The analytical performance of the screen printed electrodes in terms of selectivity coefficients for trazodone hydrochloride relative to the number of potentially interfering substances was investigated. The proposed method has been applied successfully for the analysis of the drug in its pure and dosage forms and there is no interference from any common pharmaceutical additives.

See Mercado and Hetz (doi:10.1093/brain/awx107) for a scientific commentary on this article. Signalling through the PERK/eIF2α-P branch of the Unfolded Protein Response is increased in many neurodegenerative diseases. Halliday et al. identify two safe compounds – one licensed – that act on this pathway and are neuroprotective in mice with neurodegeneration. These drugs can now be repurposed in clinical trials for the treatment of dementia., See Mercado and Hetz (doi:10.1093/brain/awx107) for a scientific commentary on this article. Signalling through the PERK/eIF2α-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is overactivated in brains of patients with Alzheimer’s disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions. Thus, in mouse models of neurodegenerative disease, prolonged overactivation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss. Re-establishing translation rates by inhibition of eIF2α-P activity, genetically or pharmacologically, restores memory and prevents neurodegeneration and extends survival. However, the experimental compounds used preclinically are unsuitable for use in humans, due to associated toxicity or poor pharmacokinetic properties. To discover compounds that have anti-eIF2α-P activity suitable for clinical use, we performed phenotypic screens on a NINDS small molecule library of 1040 drugs. We identified two compounds, trazodone hydrochloride and dibenzoylmethane, which reversed eIF2α-P-mediated translational attenuation invitro and invivo. Both drugs were markedly neuroprotective in two mouse models of neurodegeneration, using clinically relevant doses over a prolonged period of time, without systemic toxicity. Thus, in prion-diseased mice, both trazodone and dibenzoylmethane treatment restored memory deficits, abrogated development of neurological signs, prevented neurodegeneration and significantly prolonged survival. In tauopathy-frontotemporal dementia mice, both drugs were neuroprotective, rescued memory deficits and reduced hippocampal atrophy. Further, trazodone reduced p-tau burden. These compounds therefore represent potential new disease-modifying treatments for dementia. Trazodone in particular, a licensed drug, should now be tested in clinical trials in patients.

The interaction of antidepressant drug trazodone hydrochloride (TRZ) with dipalmitoyl phosphatidylcholine (DPPC) multilamellar liposomes (MLVs) in the presence and absence of cholesterol (CHO) was investigated as a function of temperature by using Electron Paramagnetic Resonance (EPR) spin labeling, Fourier Transform Infrared (FTIR) Spectroscopy and Differential Scanning Calorimetry (DSC) techniques. These interactions were also examined for dimyristoyl phosphatidylcholine (DMPC) multilamellar liposomes by using Electron Paramagnetic Resonance (EPR) spin labeling technique. In the EPR spin labeling studies, 5- and 16-doxyl stearic acid (5-DS and 16-DS) spin labels were used to monitor the head group and alkyl chain region of phospholipids respectively. The results indicated that TRZ incorporation causes changes in the physical properties of PC liposomes by decreasing the main phase transition temperature, abolishing the pre-transition, broadening the phase transition profile, and disordering the system around the head group region. The interaction of TRZ with unilamellar (LUV) DPPC liposomes was also examined. The most pronounced effect of TRZ on DPPC LUVs was observed as the further decrease of main phase transition temperature in comparison with DPPC MLVs. The mentioned changes in lipid structure and dynamics caused by TRZ may modulate the biophysical activity of membrane associated receptors and in turn the pharmacological action of TRZ. (C) 2014 Elsevier B.V. All rights reserved.

OBJECTIVE To compare the doses of propofol required to induce general anesthesia in dogs premedicated with acepromazine maleate or trazodone hydrochloride and compare the effects of these premedicants on cardiovascular variables in dogs anesthetized for orthopedic surgery. DESIGN Prospective, randomized study. ANIMALS 30 systemically healthy client-owned dogs. PROCEDURES 15 dogs received acepromazine (0.01 to 0.03 mg/kg [0.005 to 0.014 mg/lb], IM) 30 minutes before anesthetic induction and 15 received trazodone (5 mg/kg [2.27 mg/lb] for patients > 10 kg or 7 mg/kg [3.18 mg/lb] for patients ≤ 10 kg, PO) 2 hours before induction. Both groups received morphine sulfate (1 mg/kg [0.45 mg/lb], IM) 30 minutes before induction. Anesthesia was induced with propofol (4 to 6 mg/kg [1.82 to 2.73 mg/lb], IV, to effect) and maintained with isoflurane or sevoflurane in oxygen. Bupivacaine (0.5 mg/kg [0.227 mg/lb]) and morphine (0.1 mg/kg [0.045 mg/lb]) were administered epidurally. Dogs underwent tibial plateau leveling osteotomy (n = 22) or tibial tuberosity advancement (8) and were monitored throughout anesthesia. Propofol induction doses and cardiovascular variables (heart rate and systemic, mean, and diastolic arterial blood pressures) were compared between groups. RESULTS The mean dose of propofol required for anesthetic induction and all cardiovascular variables evaluated did not differ between groups. Intraoperative hypotension developed in 6 and 5 dogs of the acepromazine and trazodone groups, respectively; bradycardia requiring intervention developed in 3 dogs/group. One dog that received trazodone had priapism 24 hours later and was treated successfully. No other adverse effects were reported. CONCLUSIONS AND CLINICAL RELEVANCE At the described dosages, cardiovascular effects of trazodone were similar to those of acepromazine in healthy dogs undergoing anesthesia for orthopedic surgery.

OBJECTIVE To evaluate the efficacy of a single dose of trazodone for reducing anxiety in cats during transport to a veterinary hospital and facilitating handling during veterinary examination. DESIGN Double-blind, placebo-controlled, randomized crossover study. ANIMALS 10 healthy client-owned cats (2 to 12 years of age) with a history of anxiety during transport or veterinary examination. PROCEDURES Each cat was randomly assigned to first receive trazodone hydrochloride (50 mg) or a placebo PO. The assigned treatment was administered, and each cat was placed in a carrier and transported by car to a veterinary clinic, where it received a structured veterinary examination. Owners scored their cat's signs of anxiety before, during, and after transport and examination. The veterinarian also assessed signs of anxiety during examination. After a 1- to 3-week washout period, each cat received the opposite treatment and the protocol was repeated. RESULTS Compared with placebo, trazodone resulted in a significant improvement in the cats’ signs of anxiety during transport. Veterinarian and owner scores for ease of handling during veterinary examination also improved with trazodone versus the placebo. No significant differences were identified between treatments in heart rate or other physiologic variables. The most common adverse event related to trazodone administration was signs of sleepiness. CONCLUSIONS AND CLINICAL RELEVANCE Oral administration of a single dose of trazodone to cats prior to a veterinary visit resulted in fewer signs of transport- and examination-related anxiety than did a placebo and was generally well tolerated by most cats. Use of trazodone in this manner may promote veterinary visits and, consequently, enhance cat welfare.

The electrochemical response characteristics of poly(vinyl)chloride (PVC) based membrane electrodes for determination of trazodone hydrochloride (TZH) is described. The membranes of these electrodes consist of trazodone-phosphomolybdate (TZH-PMA) ion pair in a PVC matrix with di-butyl phosphate (DBP) or dioctyl pthalate (DOP) as a plasticizers. The influences of membranes composition, response time, pH of the test solution, and foreign ions on the electrodes performance were investigated. The electrodes exhibited mean slopes of calibration graphs of 56.25 and 58.55 mV per decade of trazodone concentration at 25.0 °C for the optimum electrode 6.0% with DBP (electrode I) and 10.0% with DOP (electrode II) plasticizers respectively. The electrodes were successfully applied to the determination of trazodone hydrochloride and its pharmaceutical preparation with good precision and accuracy.

Two simple, rapid and sensitive extractive spectrophotometric methods have been developed for the assay of trazodone hydrochloride (TRH) in pure and pharmaceutical formulations. These methods are based on the formation of chloroform soluble ion-association complexes of TRH with bromothymol blue (BTB) and with bromocresol purple (BCP) in KCl-HCl buffer of pH 2.0 (for BTB) and in NaOAc-AcOH buffer of pH of 3.6 (for BCP) with absorption maximum at 423 nm and at 408 nm for BTB and BCP, respectively. Reaction conditions were optimized to obtain the maximum color intensity. The absorbance was found to increase linearly with increase in concentration of TRH, which was corroborated by the calculated correlation coefficient values (0.9996, 0.9945). The systems obeyed Beer's law in the range of 0.2-14.5 and 0.2-14.1 microg/ml for BTB and BCP, respectively. Various analytical parameters have been evaluated and the results have been validated by statistical data. No interference was observed from common excipients present in pharmaceutical formulations. The proposed methods are simple, accurate and suitable for quality control applications.

Two sensitive methods, colorimetric and atomic absorption spectrometric (AAS) were developed for the determination of nefazodone HCl (I) and trazodone HCl (II). The methods are based on the formation of ternary complex between the cited drugs and molybdenum(V) thiocyanate in acid medium with the production of an orange red color followed by extraction with methylene chloride. The complex showed absorption maximum at 472 nm with apparent molar absorptivity 1.46 x 104 and 0.64 x 104 L mol-1 cm for I and II, respectively. Beer's law was obeyed in the range 2.5-32.5 and 2.5-30.0 µg ml-1 for I and II, respectively. The residue remained after evaporation of methylene chloride was dissolved in HCl and used for determination of molybdenum content by AAS as a direct method for the determination of the cited drugs. Results obtained by applying the proposed methods showed good recoveries of 99.9 ± 1.3% and 99.4 + 1.6% for colorimetric method, whereas using AAS the recoveries were 98.7 ±1.3% and 98.6 ± 1.8% for I and II, respectively. Results obtained by both methods showed good agreement with those of the official and reference methods. The developed methods were applied for determination of these drugs in their pharmaceutical formulations.

Objective—To investigate the safety and efficacy of oral administration of the serotonin antagonist and reuptake inhibitor trazodone hydrochloride to facilitate confinement and calming after orthopedic surgery in dogs. Design—Prospective open-label clinical trial. Animals—36 client-owned dogs that underwent orthopedic surgery. Procedures—Starting the day after surgery, dogs were administered trazodone (approx 3.5 mg/kg [1.6 mg/lb], PO, q 12 h) with tramadol (4 to 6 mg/kg [1.8 to 2.7 mg/lb], PO, q 8 to 12 h) for pain management. After 3 days, administration of tramadol was discontinued, and the trazodone dosage was increased (approx 7 mg/kg [3.2 mg/lb], PO, q 12 h) and maintained for at least 4 weeks. If needed, trazodone dosage was increased (7 to 10 mg/kg [3.2 to 4.5 mg/lb], PO, q 8 h). Owners completed electronic surveys rating their dogs’ confinement tolerance, calmness or hyperactivity level, and responses to specific provocative situations prior to surgery and 1, 2, 3, and 4 weeks after surgery and at the postsurgery evaluation (at 8 to 12 weeks). Results—Most (32/36 [89%]) of owners reported that their dogs, when given trazodone during the 8 to 12 weeks following orthopedic surgery, improved moderately or extremely with regard to confinement tolerance and calmness. Trazodone was well tolerated, even in combination with NSAIDs, antimicrobials, and other medications; no dogs were withdrawn from the study because of adverse reactions. Owner-reported median onset of action of trazodone was 31 to 45 minutes, and median duration of action was ≥ 4 hours. Conclusions and Clinical Relevance—Results suggested that oral administration of trazodone was safe and efficacious and may be used to facilitate confinement and enhance behavioral calmness of dogs during the critical recovery period following orthopedic surgery.

Polysomnography was performed on eight healthy men with trazodone hydrochloride, imipramine and placebo. Trazodone hydrochloride increased slow wave sleep significantly. Imipramine prolonged rapid eye movement (REM) latency and decreased the percentage of REM sleep significantly. Trazodone decreased stages 1 and 2 sleep, while imipramine increased it. These findings suggest that the antidepressive effect of trazodone might be different from that of imipramine with the suppression of REM sleep.

A simple, selective, and sensitive high performance liquid chromatography (HPLC) procedure has been developed for determination of trazodone in human plasma. Prazosin was employed as the internal standard (IS). Sample preparation involved liquid-liquid extraction by methyl tert-butyl ether after alkalinization with ammonia. The HPLC separation was performed on a CAPCELL PAK SCX column (250mm×4.6mm, 5.0μm, Shiseido, Japan) with a mobile phase of acetonitrile/80mmol/L ammonium phosphate (pH adjusted to 6.0) (60:40, v/v) at a flow rate of 1.2mL/min. The peaks were detected by using fluorescence detector (excitation wavelength 320nm and emission wavelength 440nm). The extraction recovery was 72.6-88.3% and the method was over the concentration range of 5.0-2486ng/mL with a lower limit of quantitation (LLOQ) of 5.0ng/mL using 300μL of plasma. The intra- and inter-day accuracy of the method at three concentrations ranged from 96.7% to 104.2% for trazodone with precision of 2.9-3.7%. This validated method was successfully applied to a pharmacokinetic study enrolling 12 Chinese volunteers administered a single oral trazodone hydrochloride extended-release tablet of 75mg.

OBJECTIVE To characterize the pharmacokinetics, safety, and tolerability of an extended-release formulation of trazodone hydrochloride (HCl), Trazodone Contramid® Once-a-Day (TzCOAD) developed as scored 150-mg and 300-mg caplets for oncedaily administration. METHODS Relative bioavailability studies compared the pharmacokinetics of TzCOAD and trazodone immediate-release (TzIR) tablets following single- and multiple-dose administration. In addition, the effect of food on the pharmacokinetics of TzCOAD was assessed. RESULTS After single-dose administration of 300 mg TzCOAD, trazodone AUC and C(max) were approximately 20% and 60% lower, respectively, than for TzIR 100-mg tablets administered as 3 doses, 8 h apart. After multipledose administration of 300 mg daily for 7 days, TzCOAD given once daily and TzIR given 3 times a day were equivalent with respect to AUC, while C(max) was 43% lower for TzCOAD. Trazodone AUC following single-dose administration of TzCOAD was similar to AUC at steady state, suggesting that steady-state exposure can be predicted from single-dose data. When TzCOAD was taken shortly after ingestion of a high-fat meal, C(max) increased 86% compared with fasting conditions. However, AUC and t(max) were not affected by food. CONCLUSION Administration of TzCOAD 300 mg once daily provides equivalent steady-state exposure to, with a lower C(max) than, TzIR 100 mg given 3 times a day. A high-fat meal results in an increase in C(max), but there is no substantial effect on AUC.