Pharmacological and clinical profile of mitiglinide calcium hydrate (Glufast), a new insulinotropic agent with rapid onset

Mitiglinide calcium hydrate (mitiglinide, Glufast) is a new insulinotropic agent of the glinide class with rapid onset. Mitiglinide is thought to stimulate insulin secretion by closing the ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells, and its early insulin release and short duration of action would be effective in improving postprandial hyperglycemia. In studies of various cloned K(ATP) channels, mitiglinide shows a higher selectivity for the beta-cell type of SUR1/Kir6.2 than the cardiac and smooth muscle types of K(ATP) channels in comparison with glibenclamide and glimepiride. In vitro and in vivo studies demonstrated the insulinotropic effect of mitiglinide is more potent than that of nateglinide, and mitiglinide surpassed in controlling postprandial hyperglycemia in normal and diabetic animals. In clinical trials, treatment with mitiglinide provided lasting improvement of postprandial hyperglycemia in Type 2 diabetic patients and decreased the fasting plasma glucose levels and HbA(1C) values. The incidence of adverse events related to mitiglinide were nearly equivalent to placebo; in particular there was no difference with the frequency of hypoglycemia. The results from these studies indicated that mitiglinide could be expected to possess good therapeutic features of being effective in reducing postprandial glucose excursions in the early stage of Type 2 diabetes and less incidence of events suggestive of hypoglycemia.     

Pharmacological profile and clinical effects of montelukast sodium (Singulair chewable tablet), an antiasthmatic agent

Montelukast (Singulair) is an antiasthmatic agent that has the chemical structure of a quinoline. Montelukast has a high affinity for the CysLT1 receptor and a potency that is not influenced by human serum protein. Montelukast antagonizes contractions of guinea-pig trachea induced by LTD4 in a competitive manner. Intravenous montelukast inhibited bronchoconstriction induced by LTD4 in guinea pigs. Oral montelukast inhibited increased airway resistance induced by antigen in squirrel monkeys. Montelukast also inhibited both inflammatory and immunologic responses induced by either LTD4 or antigen in guinea pigs and rats. Plasma concentrations of montelukast after oral administration of 10 mg in humans were shown to be over the effective level for at least 24 h. These lines of evidence support the effectiveness of a regimen of 10 mg/day for asthmatic symptoms in humans. In a number of clinical experiments, montelukast not only improved asthmatic symptoms and respiratory indices, but also inhibited airway inflammation and exercise-induced bronchoconstriction. These effects persisted during extended treatment. Montelukast produced an additive effect to basic therapy with an inhaled steroid. There were no differences in the incidence and magnitude of adverse effects between montelukast and placebo groups in clinical experiments. Montelukast is expected to serve as a first line of asthmatic therapy because of its consistent efficacy and good safety profile and it is associated with good compliance in patients because of its simple regimen of one 10 mg tablet/day.     

Pharmacological and clinical profile of exemestane (Aromasin), a novel irreversible aromatase inhibitor

Aromatase is the rate-limiting enzyme playing a role at the final step of estrogen biosynthesis, which is attracting attention as the target enzyme of hormone therapy of postmenopausal breast cancer. Exemestane (Aromasin) is a novel steroidal irreversible aromatase inhibitor that was approved in Japan as a therapeutic drug for postmenopausal breast cancer. Exemestane selectively inhibits aromatase activity in vitro, in a time-dependent and irreversible manner, suggesting the mechanism of action that exemestane covalently binds to aromatase as a pseudo-substrate and inactivates the enzyme. In vivo studies show the inhibitory effect of exemestane on the ovarian aromatase activity and plasma estradiol level of PMSG-primed rats. In studies using DMBA-induced rat mammary tumor models, exemestane shows antitumor activity in both conventional (premenopausal) and ovariectomized, testosterone-treated postmenopausal models. Despite its steroidal structure, exemestane does not have hormonal or anti-hormonal activity, except for a slight androgenic activity. In the early and late phase II clinical trials conducted in Japan on postmenopausal breast cancer patients who received 25 mg/day of exemestane, the response rates were 31.4% and 24.2%, respectively. Blood estrogen levels were also markedly reduced. These results confirmed the clinical relevance of non-clinical study results, as well as the possibility of extrapolation to foreign trial data.     

Pharmacological and clinical profile of nifekalant (shinbit injection), a class III antiarrhythmic drug

Nifekalant (shinbit, MS-551) is a pure class III antiarrhythmic drug (Vaughan Williams' classification), which was approved in Japan in June 1999. This drug prolongs the action potential duration (APD) and the effective refractory period (ERP) in cardiac myocytes mainly by blocking the IKr (the rapid component of delayed rectifier K+ current). The antiarrhythmic efficacy depends on prolongation of ERP. The importance of this drug is to save patients from the life-threatening arrhythmias ventricular tachycardia (VT) and fibrillation (VF). Nifekalant was effective against reentrant arrhythmias such as VT and VF in postinfarction dogs. This drug does not have the negative inotropic effect that has been observed with other antiarrhythmic drugs. In clinical therapy, this drug was remarkably effective on patients who were unresponsive to therapy with other drugs or who were not able to receive other drugs due to decreased cardiac function. There has been no case of drug-induced worsening of the cardiac function. The significant adverse reaction is proarrhythmia such as ventricular tachycardia including TdP. Nifekalant is expected to be a useful drug for patients who could not be rescued from life-threatening arrhythmia by conventional therapies.     

Pharmacological,pharmacokinetic and clinical profile of eletriptan (Relpax), a new triptan for migraine

Eletriptan (Relpax) is a new anti-migraine medication commonly referred to as triptans. Eletriptan is considered to reduce neuronal transmission of pain by causing vasoconstriction of dilated cranial vessels and inhibiting the release of neuropeptides from trigeminal nerves via activation of the 5-HT(1B/1D) receptors. Eletriptan showed selectivity, high affinities, and potent agonistic activity to human 5-HT(1B/1D) receptors. It selectively constricted the cranial artery relative to the coronary artery of the anesthetized dog and the isolated human specimen. The affinity to the 5-HT(1B/1D) receptors and the selectivity for the cranial artery over the coronary artery of eletriptan are higher than those of sumatriptan. Eletriptan inhibited the trigeminal nerve mediated inflammation in the rat dura mater with equal potency and efficacy to sumatriptan. Orally taken eletriptan was rapidly absorbed with good bioavailability. In clinical trials, eletriptan improved the headache response rate with rapid onset, and reduced headache recurrence. The functional impairments as well as associated symptoms such as nausea, vomiting, and photophobia were also improved by eletriptan. Eletriptan showed stable efficacy in chronic use against multiple attacks with no increase in adverse events. Eletriptan was well tolerated in patients and most adverse events were mild-to-moderate in nature.     

Pharmacodynamic profile of Zaleplon,a new non-benzodiazepine hypnotic agent

The challenge in developing hypnotic agents for the treatment of insomnia is to balance the sedative effect needed at bedtime with the residual sedation on awakening. Zaleplon is a novel pyrazolopyrimidine hypnotic agent that acts as a selective agonist to the brain omega(1) receptor situated on the alpha(1) subunit of the GABA(A) receptor complex. Zaleplon was proven to be an effective hypnotic drug as it consistently and significantly reduced latency to persistent sleep in insomniac patients for doses of 10 mg and above in polysomnography studies. The pharmacodynamic profile of zaleplon on psychomotor performance, actual driving and cognitive function, including memory, was assessed in several randomized, double-blind, placebo-controlled studies in healthy young subjects as well as insomniac patients by using various positive controls (zolpidem, zopiclone, triazolam and flurazepam). The recommended hypnotic dose of zaleplon in young adults (10 mg) produced minimal or no impairment of psychomotor and memory performance even when administered during the night as little as 1 h before waking. No impairment of actual driving was observed when zaleplon 10 mg was administered either at bedtime or in the middle of the night as little as 4 h before waking. Zaleplon 20 mg, twice the recommended dose, generally produced significant impairment of performance and cognitive functions when these functions were measured at the time of peak plasma concentration, i.e. 1 h after dose administration, and no impairment of driving abilities was observed 4 h after a middle-of-the-night administration. In contrast, consistent detrimental residual effects on various aspects of psychomotor and cognitive functions were observed with the therapeutic doses of the various commonly prescribed hypnotic agents used as comparators, e.g. zolpidem 10 mg up to 5 h after dose administration, zopiclone 7.5 mg up to 10 h after, flurazepam 30 mg up to 14 h after and triazolam 0.25 mg up to 6 h after. Also, zolpidem 10 mg and zopiclone 7.5 mg were also shown to significantly impair driving ability the next morning when this was measured 4 h and up to 10 h after dose administration, respectively. The present review shows that zaleplon 10 mg has little or no residual effect when administered in the middle of the night, as late as 1 h before waking, and is devoid of impairment of driving abilities as assessed by actual driving 4 h after dose administration. The lack of clinically significant or minimally statistically significant residual effects of zaleplon even at its peak concentration may be explained by its unique pharmacokinetic (rapid elimination half-life) and pharmacodynamic (low affinity, and specific binding profile to various subunits of the GABA(A)receptor) profiles. These properties allow zaleplon to be used for treatment of symptoms only when they occur, either at bedtime or later in the night, without incurring significant risk of developing next-day impairment of psychomotor and cognitive functioning. Copyright 2001 John Wiley & Sons, Ltd.     

Pharmacological and clinical profile of the free radical scavenger edaravone as a neuroprotective agent

The involvement of oxygen radical species has been implicated in ischemic and post-ischemic brain cell damage. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one; M.W. 174.20, MCI-186, Radicut Injection) has an inhibitory effect on lipid peroxidation by scavenging free radicals and prevents vascular endothelial cell injury. In rat brain ischemic models, post-ischemic treatment with edaravone reduces .OH production and infarction of the ischemic penumbral area and suppresses delayed neuronal death. It also improves neurological deficits and diminishes deterioration of brain edema observed after ischemia. We investigated the efficacy and safety of edaravone in acute ischemic stroke patients. Edaravone improved the core neurological deficits, impaired activities of daily living, and disability, without serious safety problems. Edaravone was approved in Japan for the treatment of acute brain infarction within 24 h after onset in April, 2001. We hope that edaravone represents a promising neuroprotective agent that can contribute to the treatment of acute ischemic stroke.     

Encapsulation and release of the hypnotic agent zolpidem from biodegradable polymer microparticles containing hydroxypropyl-beta-cyclodextrin

The goal of this study was to design a prolonged release system of the hypnotic agent zolpidem (ZP) useful for the treatment of insomnia. In this work, ZP alone or in the presence of HP-beta-CD was encapsulated in microparticles constituted by poly(DL-lactide) (PDLLA) and poly(DL-lactide-co-glycolide) (PLGA) and the drug release from these systems was evaluated. ZP alone-loaded microparticles were prepared by the classical O/W emulsion-solvent evaporation method. Conversely, ZP/HP-beta-CD containing microparticles were prepared by the W/O/W emulsion-solvent evaporation method following two different procedures (i.e. A and B). Following procedure A, the previously produced ZP/HP-beta-CD solid complex was added to the water phase of primary emulsion. In the procedure B, HP-beta-CD was added to the aqueous phase and ZP to the organic phase. The resulting microparticles were characterized about morphology, size, encapsulation efficiency and release rates. FT-IR, X-ray, and DSC results suggest the drug is in an essentially amorphous state within the microparticles. The release profiles of ZP from microparticles were in general biphasic, being characterized by an initial burst effect and a subsequent slow ZP release. It resulted that co-encapsulating ZP with or without HP-beta-CD in PDLLA and PLGA the drug release from the corresponding microparticles was protracted. Moreover, in a preliminary pharmacological screening, the ataxic activity in rats was investigated and it was found that intragastric administration of the ZP/HP-beta-CD/PLGA microparticles prepared according to procedure B produced the same ataxic induction time as the one induced by the currently used formulation Stilnox. Interestingly moreover, there was a longer ataxic lasting and a lower intensity of ataxia produced by the ZP/HP-beta-CD/PLGA-B-formulation already after 60 min following the administration. However, a need for further pharmacokinetic and pharmacodynamic studies resulted to fully evaluate the utility of this last formulation for the sustained delivery of ZP.     

Pharmacological profiles of mycophenolate mofetil (CellCept), a new immunosuppressive agent

Mycophenolate mofetil (MMF, CellCept), a semisynthetic derivative of mycophenolic acid (MPA) produced by a fungus, is an inhibitor of the inosine monophosphate dehydrogenase (IMPDH) enzyme (IC50 = 25 nM) that catalyzes the synthesis of guanosine monophosphate (GMP) from inosine. GMP is an essential nucleoside for purine synthesis during cell division. As T and B-lymphocytes almost exclusively use the de novo pathway of purine synthesis, these cells are particularly sensitive to the inhibitory action of MMF. It has a mechanism of action distinct from cyclosporine and tacrolimus. Although MMF does not affect cytokine production, by inhibiting the rate-limiting enzyme IMPDH in the de novo synthesis of purines, it inhibits the proliferation of T and B-lymphocytes, the production of antibodies, and the generation of cytotoxic T lymphocytes. Reversal of acute allograft rejection and increased survival of kidney, heart and bone marrow cell allograft has been shown in several animal studies. Moreover, it was suggested that MMF combined with CsA prevented the acute rejection, and approximately half of the animals became long-term survivors. The Ministry of Health and Welfare approved MMF in 1999 for use for rejection treatment in renal transplantation based on several prospective, randomized and blind efficacy trials.     

Pharmacological profile of the imidazopyridine zolpidem at benzodiazepine receptors and electrocorticogram in rats

Summary Zolpidem is a novel non-benzodiazepine related hypnotic, which possesses an imidazopyridine structure. This drug has preferential affinity for the³H-diazepam binding site in the rat cerebellum, while it is only weakly active at inhibiting³H-Ro 5-4864 binding to the rat kidney. The potency of zolpidem at displacing³H-Ro 15-1788 binding to rat cerebral cortex membranes is enhanced in the presence of GABA. On the sleep pattern of the electrocorticogram in the curarised rat, zolpidem induces a physiological type of slow wave sleep with rapid onset of action. Zolpidem differs from classical benzodiazepine drugs, in possessing an atypical binding profile to³H-benzodiazepine receptors, and because it does not affect the sleep patterns.     

Assessment of a new hypnotic imidazo-pyridine (zolpidem) as oral premedication.

1 A new imidazo-pyridine hypnotic (zolpidem 10 mg and 20 mg) was compared with placebo as premedication before general anaesthesia in female patients undergoing minor gynaecological surgery. Efficacy and tolerance before and after anaesthesia were assessed. Psychomotor testing was used to study recovery from anaesthesia. 2 Both doses of zolpidem produced good sedation pre-operatively but only the higher dose was associated with anterograde amnesia. 3 Premorbid anxiety scores were low in the group of patients studied and were unaffected by either dose of zolpidem. 4 There were no significant effects on the course of anaesthesia. However, postoperatively there was a tendency for wake-up to be delayed in those patients who received either dose of zolpidem. 5 Postoperative recovery, as indicated by tests of psychomotor performance, was noticeably delayed with a dose of 20 mg compared with placebo whilst psychomotor performance had returned towards baseline levels 3 h after wake-up in those patients who had received placebo. The zolpidem 10 mg group was intermediate. 6 Zolpidem may be a suitable premedicant when hypnosis and amnesia only are required.     

Pharmacological profile of ramosetron,a novel therapeutic agent for IBS

Ramosetron is a potent and selective serotonin (5-HT)₃ receptor antagonist that has been shown to affect abnormal colonic function and abdominal pain in animals. Ramosetron (0.3 to 100 μg/kg, p.o.) has been found to significantly suppress abnormal defecation induced by conditioned-fear stress (CFS), restraint stress, corticotropin releasing factor (CRF) and 5-HT in rats and mice, and these effects were more potent than those of alosetron, cilansetron or loperamide. On the other hand, ramosetron (3,000 μg/kg, p. o., once daily for 7 days) did not inhibit normal defecation in dogs while tiquizium significantly inhibited it. Ramosetron (3 to 100 μg/kg, p. o.) also significantly prevented CFS-induced acceleration of colonic transit and CRF-induced abnormal water transport in rats, respectively. Moreover, ramosetron (0.3 to 3 μg/kg, p. o.) significantly suppressed restraint stress-induced decrease in colonic pain threshold, an effect not observed with loperamide. These results indicate that ramosetron produce beneficial clinical effects on IBS symptoms. Received 12 July 2006; accepted 21 August 2006     

Pharmacological profile of MDL 26,024GO: a novel antiasthmatic agent

MDL 26,024GO was shown to be an orally absorbed mediator release inhibitor in the rat PCA and PPA tests. In addition, the compound was shown to both elicit and inhibit elicitation of the Bezold-Jarisch reflex in the dog. MDL 26,024GO also significantly reduced Ascaris-induced changes in pulmonary mechanics in cynomolgus monkeys. The compound inhibited both early and late phase antigen induced-changes in Ascaris-sensitive sheep, as well as the increased airway hyperreactivity which normally follows antigen challenge. These results suggest the compound may have therapeutic potential in the treatment of asthma.