Alprazolam SR in the treatment of generalized anxiety: a multicentre controlled study with bromazepam

A multicentre, double‐blind, randomized trial compared the efficacy of a sustained‐release formulation of alprazolam with bromazepam in the treatment of generalized anxiety. One hundred and twenty‐one outpatients were randomly assigned to three weeks of active treatment with alprazolam SR (2 mg once daily) or bromazepam (3 mg three times daily), following a period of 3–7 days without medication. After treatment, doses were reduced by 50 per cent during a 1‐week dosage‐tapering period; patients were then followed for one additional week. There was no significant difference in the anxiolytic effects of alprazolam SR and bromazepam. The results in the two treatment groups were very similar and showed a rapid and statistically significant reduction in efficacy measures, including the total score on the Hamilton Anxiety Rating Scale and the Clinical Global Impression improvement and severity of illness scores. The mean changes from baseline scores were compared between treatments at each evaluation point and no statistically significant differences were observed. At week 3, more than 70 per cent of patients in the alprazolam SR and bromazepam groups were classified as responders. In conclusion, alprazolam SR, in a single daily dose, has a rapid onset of action and is effective in the treatment of generalized anxiety disorder. Its anxiolytic activity is similar to that of bromazepam taken in several daily doses and it has the advantage of enhancing patient compliance and reducing the potential for breakthrough anxiety. Copyright © 1999 John Wiley & Sons, Ltd.     

Controlled Comparison of Tianeptine,Alprazolam and Mianserin in the Treatment of Adjustment Disorders with Anxiety and Depression

A multicentre study compared tianeptine (37·5 mg/day), an original psychotropic compound characterized by both antidepressant and anxiolytic potentials, with a reference antidepressant, mianserin (60 mg/day) and a reference anxiolytic, alprazolam (1·5 mg/day), in the treatment of 152 patients fulfilling DSM-III-R criteria for adjustment disorder with mixed emotional features (anxiety and depression). The study used a double-blind parallel design over a 6-week period. Clinical assessments included the Clinical Global Impressions (CGI), the Montgomery and Asberg depression rating scale (MADRS), the Hamilton anxiety rating scale, a visual analogue scale, and the somatic scale of the system developed by the Association for the Methodology and Documentation in Psychiatry (AMDP). Results showed very similar improvement in the three treatment groups on all rating instruments. Moreover, the number of patients exhibiting adverse events did not differ among the three groups. Therefore, these results show similar antidepressant and anxiolytic activity for tianeptine, mianserin and alprazolam in patients suffering from adjustment disorder with mixed emotional features. These promising findings should however be confirmed in a placebo-controlled trial.     

Early clinical pharmacological studies with sercloremine—a novel antidepressant—utilizing pharmacokinetic,pharmaco-EEG,and psychometric analyses

Pharmacokinetic and pharmacodynamic properties of sercloremine (CGP 4718A), a novel, selective monoamine oxidase A and serotonin uptake inhibitor, were investigated in healthy volunteers in a double-blind, placebo-controlled, crossover study. The effect of single, oral doses of the drug (50, 100, 200 mg) were, in addition, compared to the effect of 75 mg amitriptyline, which was use as a reference compound. Pharmaco-EEG recordings and plasma level determinations as well as psychometric testings were performed intermittently from O hr up to 8 or 48 hr (pharmacokinetics), respectively. In addition, blood pressure, heart rate, and side effects were recorded. Pharmacokinetic analyses by means of gasliquid chromatography showed a rapid rise in plasma levels of sercloremine with peak concentrations 2 hr after administration. There was a rapid decline thereafter: the distribution and elimination half-lives were estimated to be 4–5 and 14 hr, respectively. Plasma concentrations as well as the area under the curve (AUC) showed clear-cut dose dependency. Computer-assisted spectral analyses of the EEG findings provided evidence of central effects of sercloremine, which were slight but characteristically reminiscent of effect provided by activating antidepressants (“desipramine-type”). Thus, sercloremine produced an increase in total power, alpha activity, and increase of relative and absolute power of dominant frequency, in particular 6 hr after administration. Entirely opposite and remarkably prominent changes were, by contrast, produced by amitriptyline. They were characterized by decrease of relative and absolute power of the dominant frequency and increase of delta and theta activity as well as of superimposed fast activity. Moreover, the centroid of the total activity was slowed down. These changes were previously described as typical for antiderpressants with sedative qualities. Psychometric testing largely confirmed the pharmaco-EEG findings. They indicated vigilance-improving properties of sercloremine which at all three tested doses significantly ameliorated the performance of the volunteers and increased the concentration, attention, cognitive, and mnestic functions. Also, at a dose of 100 mg, there was an improvement of wakefulness, mood, and extroversion as indicated by semantic differential polarity profile records. A vigilance-increasing effect of the drug was also suggested by parallel widening of the pupillary diameter. Consistent deterioration of all subjective and objective varibales tested was observed after administration of amitriptyline. Dose-efficacy calculations indicated that amitriptyline is the most effective centrally active compound, always clearly distinguished from placebo. By contrast, sercloremine was not at all times and in all measures significantly different from placebo. Time-efficacy calculations showed that the peak effect of amitriptyline was situated between 4 and 6 hr after administration, whereas sercloremine exerted maximal pharmacodynamic activity 6–8 hr after dosing. This time lag between the peak plasma concentrations and maximum pharmacodynamic action, described as a “hysteresis loop,” is discussed. Altogether, the results of this study suggest vigilance-increasing properties of sercloremine. The compound was also well tolerated; no cardiovascular or note worthy subjective side effects were recorded.     

阿普唑仑治疗社交恐怖症的双盲自身对照

阿普唑仑与安慰剂双盲自身对照治疗社交恐怖症16例(男性6,女性10;平均年龄23±5a),剂量为3.2mg/d,疗程4wk,以Marks的恐怖强迫量表为评定工具,按双向序贯t检验逐个观察。至第10例时便获得结论,阿普唑仑的疗效显著优于安慰剂,且未发现明显的副作用。     

Carnitine and acylcarnitines: pharmacokinetic, pharmacological and clinical aspects

L-Carnitine (levocarnitine) is a naturally occurring compound found in all mammalian species. The most important biological function of L-carnitine is in the transport of fatty acids into the mitochondria for subsequent β-oxidation, a process which results in the esterification of L-carnitine to form acylcarnitine derivatives. As such, the endogenous carnitine pool is comprised of L-carnitine and various short-, medium- and long-chain acylcarnitines. The physiological importance of L-carnitine and its obligatory role in the mitochondrial metabolism of fatty acids has been clearly established; however, more recently, additional functions of the carnitine system have been described, including the removal of excess acyl groups from the body and the modulation of intracellular coenzyme A (CoA) homeostasis. In light of this, acylcarnitines cannot simply be considered by-products of the enzymatic carnitine transfer system, but provide indirect evidence of altered mitochondrial metabolism. Consequently, examination of the contribution of L-carnitine and acylcarnitines to the endogenous carnitine pool (i.e. carnitine pool composition) is critical in order to adequately characterize metabolic status. The concentrations of L-carnitine and its esters are maintained within relatively narrow limits for normal biological functioning in their pivotal roles in fatty acid oxidation and maintenance of free CoA availability. The homeostasis of carnitine is multifaceted with concentrations achieved and maintained by a combination of oral absorption, de novo biosynthesis, carrier-mediated distribution into tissues and extensive, but saturable, renal tubular reabsorption. Various disorders of carnitine insufficiency have been described but ultimately all result in impaired entry of fatty acids into the mitochondria and consequently disturbed lipid oxidation. Given the sensitivity of acylcarnitine concentrations and the relative carnitine pool composition in reflecting the intramitochondrial acyl-CoA to free CoA ratio (and, hence, any disturbances in mitochondrial metabolism), the relative contribution of L-carnitine and acylcarnitines within the total carnitine pool is therefore considered critical in the identification of mitochondria dysfunction. Although there is considerable research in the literature focused on disorders of carnitine insufficiency, relatively few have examined relative carnitine pool composition in these conditions; consequently, the complexity of these disorders may not be fully understood. Similarly, although important studies have been conducted establishing the pharmacokinetics of exogenous carnitine and short-chain carnitine esters in healthy volunteers, few studies have examined carnitine pharmacokinetics in patient groups. Furthermore, the impact of L-carnitine administration on the kinetics of acylcarnitines has not been established. Given the importance of L-carnitine as well as acylcarnitines in maintaining normal mitochondrial function, this review seeks to examine previous research associated with the homeostasis and pharmacokinetics of L-carnitine and its esters, and highlight potential areas of future research.     

RP－HPLC法同时测定血浆中阿普唑仑和多虑平

本文首次采用反相ＨＰＬＣ法同时测定人血浆中阿普唑仑和多虑平。血浆样品在碱性条件下用乙酸乙酯提取，有机相在氮气下吹干，残渣用５０μｌ甲醇溶解，ＨＰＬＣ流动相为甲醇－０．０５ｍｏｌ／Ｌ醋酸铵缓冲液（内含１．０％三乙胺，ｐＨ５．０）（６０：４０），在２５４ｎｍ进行检测。阿普唑仑的线性范围为０～１００μｇ／Ｌ，ｒ＝０．９９８５，平均回收率为７７．３％，ＲＳＤ为３．２％～６．２％；多虑平的线性范围为０～５００μｇ／Ｌ，ｒ＝０．９９５７，平均回收率为９７．２％，ＲＳＤ为３．１％～６．２％。阿普唑仑和多虑平的最低检出限分别为１．２ｎｇ和４ｎｇ。本法简便、快速、灵敏、准确，适用于阿普唑仑和多虑平血药浓度的同时监测及临床药理学研究。     

Ibandronate: a clinical pharmacological and pharmacokinetic update

Ibandronate is a potent nitrogen-containing bisphosphonate. It has a strong affinity for bone mineral and potently inhibits osteoclast-mediated bone resorption. Ibandronate is effective for the treatment of hypercalcemia of malignancy, metastatic bone disease, postmenopausal osteoporosis, corticosteroid-induced osteoporosis, and Paget's disease. Oral ibandronate is rapidly absorbed (t(max) < 1 hour), with a low bioavailability (0.63%) that is further reduced (by up to 90%) in the presence of food. Ibandronate has a wide therapeutic index and is not metabolized and, therefore, has a low potential for drug interactions. Given its metabolic stability, ibandronate is eliminated from the blood by partitioning into bone (40%-50%) and through renal clearance (CL(R) approximately 60 mL/min). The CL(R) of ibandronate is linearly related to creatinine clearance. The sequestration of ibandronate in bone (V(D) > 90 L) results in a multiphasic elimination (t((1/2)) range approximately 10-60 hours), characterized by the slow release of ibandronate from the bone compartment. The potency of ibandronate and its sequestration into bone allow ibandronate to be developed as oral and intravenous injection formulations that can be administered with convenient extended between-dose intervals.     

Drug bioavailability and pharmacokinetic analysis from pharmacological data

Conclusions The objective of pharmacotherapy is to control drug effects rather than drug levels. Direct chemical assay data are always of secondary interest and are of value only in that plasma levels often correlate with pharmacological or toxic response.The use of methodologies of control theory, signal processing, and optimization, borrowed from engineering practice, allow the relations between drug inputs to be directly related to multiple, simultaneously occurring drug responses. These relations also permit time optimal drug inputs to be computed which optimize a multiple drug response behavior and represent a maximum therapeutic utility for the drug (8,9).In practice, such time optimal drug inputs may be achieved by programmed intravenous or other parenteral administration; such optimal response behavior may less precisely be realized through a predetermined dosage regimen with a drug product possessing the required dynamic drug bioavailability behavior. With the advent of increasingly more sophisticated biomedical recording and signal processing instrumentation and the increasing computerization of hospitals, it is not difficult to envisage that a maximum therapeutic utility of one or several drugs' actions may be automatically and continuously maintained using closed-loop feedback control. The process can be envisaged to involve monitoring of the patient's multiple drug responses and processing of the signals to compute an optimal pharmacotherapeutic control input signal, which in turn actuates servomechanistic drug-adminstering devices which deliver the drug(s) at the rate(s) required to maintain the patient's drug response behavior at optimal levels. In addition to the work now being pursued in the authors' laboratory, progress in approaching such ideals in pharmacotherapy is presently exemplified by the artificial beta cell developed by Whitaker Space Sciences which utilizes biofeedback controlled delivery of insulin in response to the patient's blood glucose levels.     

Alprazolam and lorazepam single and multiple-dose effects on psychomotor skills and sleep

Summary The effects of alprazolam 0.5 mg and lorazepam 2 mg on cognitive and psychomotor skills were assessed in twelve normal volunteer subjects in a randomised, double-blind, crossover design. Single and multiple dose effects were monitored using a battery of tests comprising critical flicker fusion threshold (CFFT), choice reaction time (CRT), simulated car tracking, and subjective ratings of perceived sedation (LARS) and of sleep behaviour (LSEQ). Compared with placebo baseline scores, treatment with lorazepam 2 mg (both single and multiple doses) resulted in a widespread impairment of CRT, tracking accuracy, and CFFT. Single doses of alprazolam 0.5 mg reduced CFFT with respect to the placebo baseline. Single and multiple dose treatment with both drugs resulted in subjective reports of sedation, a reduction of sleep onset latency, and improved sleep quality. Only lorazepam 2 mg significantly disrupted the integrity of behaviour on waking from sleep. These results suggest important pharmacodynamic differences between the two drugs in the doses used.     

用液相色谱-离子阱质谱联用法检测兔体液中阿普唑仑及其主要代谢产物

建立鉴别体液中阿普唑仑及其主要代谢物的高效液相色谱 电喷雾离子阱质谱联用(LC/MSn)法 .采用LC/MSn联用技术 ,检测家兔灌胃给药后血样和尿样中阿普唑仑原形药及其羟基化代谢物、葡萄糖苷酸型结合物 ,得到了它们的色谱、质谱以及特征碎片离子信息 .阿普唑仑的最低检测限小于 1ng .本法专属性强 ,可推广至其他生物检材的测定 ,尤其适用于需快速响应的临床和法医毒物分析     

Specific effects of benzodiazepines and tricyclic antidepressants in panic disorder: comparisons of clomipramine with alprazolam SR and adinazolam SR

In order to compare the efficacy and safety of tricyclic antidepressants and benzodiazepines in panic disorder, with or without agoraphobia, two studies were carried out comparing clomipramine with alprazolam sustained release (SR) or with adinazolam SR. Two hundred and fifty‐seven patients received alprazolam SR (2–6 mg/day given in two divided daily doses) or clomipramine (50–150 mg/day given in two divided daily doses) for 12 weeks in a single‐blind, randomised, multicentre study and 347 patients received adinazolam SR (30–90 mg/day given in two divided daily doses) or clomipramine (50–150 mg/day given in two divided daily doses) for 24 weeks in a double‐blind, randomised, multicentre study. Both benzodiazepines showed an earlier onset of therapeutic efficacy than clomipramine. At the end of the treatment periods, however, clomipramine was equally as effective as alprazolam SR and more effective than adinazolam SR. Withdrawal problems were also somewhat less common with clomipramine than with alprazolam SR and adinazolam SR. Both benzodiazepines were clearly better tolerated than clomipramine. The rate of premature withdrawal was also notably higher with clomipramine than with alprazolam SR. In conclusion, the benzodiazepines alprazolam and adinazolam SR are better tolerated than the tricyclic antidepressant clomipramine in the treatment of panic disorder, but have no advantages in terms of efficacy. Copyright © 1999 John Wiley & Sons, Ltd.     

Alprazolam: pharmacokinetics, clinical efficacy, and mechanism of action

Alprazolam, a triazolobenzodiazepine, is the first of this new class of benzodiazepine drugs to be marketed in the United States and Canada. It achieves peak serum levels in 0.7 to 2.1 hours and has a serum half-life of 12 to 15 hours. When given in the recommended daily dosage of 0.5 to 4.0 mg, it is as effective as diazepam and chlordiazepoxide as an anxiolytic agent. Its currently approved indication is for the treatment of anxiety disorders and symptoms of anxiety, including anxiety associated with depression. Although currently not approved for the treatment of depressive disorders, studies published to date have demonstrated that alprazolam compares favorably with standard tricyclic antidepressants. Also undergoing investigation is the potential role of alprazolam in the treatment of panic disorders. Alprazolam has been used in elderly patients with beneficial results and a low frequency of adverse reactions. Its primary side effect, drowsiness, is less than that produced by diazepam at comparable doses. Data on toxicity, tolerance, and withdrawal profile are limited, but alprazolam seems to be at least comparable to other benzodiazepines. Drug interaction data are also limited, and care should be exercised when prescribing alprazolam for patients taking other psychotropic drugs because of potential additive depressant effects.     

Rat Ultrasonic Vocalizations and Behavioral Neuropharmacology: From the Screening of Drugs to the Study of Disease

Several lines of evidence indicate that rats emit ultrasonic vocalizations (USVs) in response to a wide range of stimuli that are capable of producing either euphoric (positive) or dysphoric (negative) emotional states. On these bases, recordings of USVs are extensively used in preclinical studies of affect, motivation, and social behavior. Rat USVs are sensitive to the effects of certain classes of psychoactive drugs, suggesting that emission of rat USVs can have relevance not only to neurobiology, but also to neuropharmacology and psychopharmacology. This review summarizes three types of rat USVs, namely 40-kHz USVs emitted by pups, 22-kHz USVs and 50-kHz USVs emitted by young and adult animals, and relevance of these vocalizations to neuropharmacological studies. Attention will be focused on the issues of how rat USVs can be used to evaluate the pharmacological properties of different classes of drugs, and how rat USVs can be combined with other behavioral models used in neuropharmacology. The strengths and limitations of experimental paradigms based on the evaluation of rat USVs will also be discussed.     

Benzodiazepine receptor occupation and pharmacological effects of metaclazepam,a new benzodiazepine

The time course of benzodiazepine receptor occupation in mouse brain in vivo and the time courses of three pharmacological activities (anxiolytic/anticonvulsant, sedative, and muscle relaxant) were determined for metaclazepam and two of its putative minor metabolites, KC 3756 and KC 3757. Similar experiments were performed with diazepam as a reference compound. It was found that the in vivo receptor binding potency and the pharmacological activities of metaclazepam were three to four times less than those of diazepam, although the in vitro affinity of metaclazepam for the benzodiazepine receptor was only 1/100 that of diazepam. The in vivo benzodiazepine receptor binding potency and pharmacological activities of KC 3756 and KC 3757 were high (five to six times that of diazepam) and in good agreement with the in vitro affinity, K_i=0.93 and 1.4 nM, respectively. These findings suggest that the pharmacological activity of metaclazepam is partly regulated by the gradual formation of small quantities of highly active metabolites.     

Clomipramine/bentazepam combination in the treatment of major depressive disorders

Eighty-three patients were recruited in a multicentre study concerning the usefulness of benzodiazepines (BZ) in major depressive disorders, diagnosed according to the DSM-III-R criteria. After 1 week wash-out, patients were randomized to clomipramine (CLMP) or CLMP plus bentazepam (BTZ) treatments (47 and 36 patients respectively). It was necessary to add hypnotics, usually a BZ, in 11 patients in the CLMP group and in one patient in the CLMP + BTZ group. The clinical improvement was faster in the group treated with CLMP + BTZ and, at the end of 6 weeks of treatment, the mean score in Hamilton Anxiety Scale (HAS) was lower than the one found in the group treated with CLMP. There were no significant differences found in Hamilton Depression Scale (HDS) between the groups. The side-effects observed were those due to CLMP, and only drowsiness was more frequent in the CLMP+BTZ group. However, the CLMP+BTZ combination was equally or better tolerated by patients than by those treated with CLMP alone. Similar results were found in hospitalized as well as in outpatients. The tricyclic antidepressant (TCA)/BZ association showed better results than TCA alone, producing a symptomatic improvement extensive to the anxious components of depression.     

Boswellia serrata: an overall assessment of in vitro, preclinical, pharmacokinetic and clinical data

Non-steroidal anti-inflammatory drug (NSAID) intake is associated with high prevalence of gastrointestinal or cardiovascular adverse effects. All efforts to develop NSAIDs that spare the gastrointestinal tract and the cardiovasculature are still far from achieving a breakthrough. In the last two decades, preparations of the gum resin of Boswellia serrata (a traditional ayurvedic medicine) and of other Boswellia species have experienced increasing popularity in Western countries. Animal studies and pilot clinical trials support the potential of B. serrata gum resin extract (BSE) for the treatment of a variety of inflammatory diseases like inflammatory bowel disease, rheumatoid arthritis, osteoarthritis and asthma. Moreover, in 2002 the European Medicines Agency classified BSE as an 'orphan drug' for the treatment of peritumoral brain oedema. Compared to NSAIDs, it is expected that the administration of BSE is associated with better tolerability, which needs to be confirmed in further clinical trials. Until recently, the pharmacological effects of BSE were mainly attributed to suppression of leukotriene formation via inhibition of 5-lipoxygenase (5-LO) by two boswellic acids, 11-keto-β-boswellic acid (KBA) and acetyl-11-keto-β-boswellic acid (AKBA). These two boswellic acids have also been chosen in the monograph of Indian frankincense in European Pharmacopoiea 6.0 as markers to ensure the quality of the air-dried gum resin exudate of B. serrata. Furthermore, several dietary supplements advertise the enriched content of KBA and AKBA. However, boswellic acids failed to inhibit leukotriene formation in human whole blood, and pharmacokinetic data revealed very low concentrations of AKBA and KBA in plasma, being far below the effective concentrations for bioactivity in vitro. Moreover, permeability studies suggest poor absorption of AKBA following oral administration. In view of these results, the previously assumed mode of action - that is, 5-LO inhibition - is questionable. On the other hand, 100-fold higher plasma concentrations have been determined for β-boswellic acid, which inhibits microsomal prostaglandin E synthase-1 and the serine protease cathepsin G. Thus, these two enzymes might be reasonable molecular targets related to the anti-inflammatory properties of BSE. In view of the results of clinical trials and the experimental data from in vitro studies of BSE, and the available pharmacokinetic and metabolic data on boswellic acids, this review presents different perspectives and gives a differentiated insight into the possible mechanisms of action of BSE in humans. It underlines BSE as a promising alternative to NSAIDs, which warrants investigation in further pharmacological studies and clinical trials.     

Medifoxamine: Oral tolerance and pharmacokinetic study in healthy human volunteers

Summary Medifoxamine is a monoamine reuptake inhibiting antidepressant drug. We have investigated its pharmacokinetics in normal healthy volunteers. After an overnight fast, ascending doses of 200, 500, 750 and 1000 mg of medifoxamine were taken orally. Plasma samples were analysed using a specific HPLC method.Medifoxamine was well tolerated and exhibited a first order linear pharmacokinetic profile. It underwent rapid absorption and peak plasma concentrations were achieved about 1.0 h after administration. Thereafter the elimination profile was biphasic with a mean terminal half life less than 3 hours.We found a linear relationship (r=0.80) between administered dose and AUC values for the four doses. High values were obtained for the apparent volumes of distribution and the plasma clearance.     

Review of the pharmacological and clinical profile of rimcazole

Rimcazole is a carbazole derivative that acts in part as a sigma receptor antagonist. Wellcome Research Laboratories introduced this compound during the 1980s when it was hypothesized to be a novel antipsychotic with an improved side effect profile. However, subsequent clinical trials demonstrated that rimcazole lacked efficacy in schizophrenic patients and it is now primarily used as an experimental tool. In addition to its actions as a sigma receptor antagonist, rimcazole also has high affinity for dopamine transporters, and in recent years it has served as a lead compound for the development of novel dopamine transporter ligands. Although rimcazole cannot be considered a selective ligand for sigma receptors, the recent development of other selective agonists and antagonists for sigma receptors have aided in clarifying the involvement of these receptors in the actions of rimcazole. Many of the physiological and behavioral effects of rimcazole can in fact be ascribed to its action as a sigma receptor antagonist, although there are exceptions. Rimcazole is likely to have a continued role in elucidating sigma receptor function in either in vitro or in vivo systems where sigma receptor-mediated effects can be studied independently of the influence of dopamine and serotonin transporters.