Topical metronidazole: a new therapy for rosacea

The chemistry, mechanism of action, pharmacokinetics, and adverse effects of topically applied metronidazole are reviewed, and the drug's use and efficacy in the treatment of rosacea and other conditions are discussed. Metronidazole is a synthetic, nitroimidazole-derivative antibacterial and antiprotozoal agent. For topical use, metronidazole is available in the United States as an aqueous gel. Polar reduction products of the drug appear to be responsible for its antimicrobial effects, which include disruption of DNA. The mechanism by which metronidazole ameliorates the lesions and erythema of rosacea may be related to anti-inflammatory or immunosuppressive actions of the drug rather than to suppression of skin bacteria. Metronidazole does not seem to be appreciably absorbed after topical application to the skin. Little is known about the distribution and elimination of topically applied metronidazole. Topical metronidazole has been designated an orphan drug by the FDA for the treatment of rosacea. In clinical studies metronidazole 0.75% topical gel or 1% cream resulted in improvement in inflammatory lesions in 68-96% of patients. Like other currently available therapies, metronidazole is only palliative; when the drug is withdrawn, symptoms commonly recur. Topical metronidazole has been used with some success in the treatment of decubitus and other ulcers and in certain dental conditions. The drug seems to have low toxicity and generally is well tolerated when applied topically. The principal adverse effects are local reactions, such as burning and stinging. Topical metronidazole provides another option for the treatment of rosacea.     

Topical metronidazole combination therapy in the clinical management of rosacea

Metronidazole was the first topical agent approved by the U.S. Food and Drug Administration for the treatment of rosacea. Several controlled studies have confirmed the efficacy and safety of topical metronidazole 0.75% gel, lotion and cream and 1% cream for rosacea. At present, little data exists regarding the use of combination topical therapy in rosacea management, although anecdotal evidence and preliminary studies suggest at least some additive benefit when topical metronidazole is used in combination with sulfacetamide 10% /sulfur 5%. In this paper, the results of observational experience evaluating topical metronidazole 0.75% gel used in combination with other topical rosacea therapies and/or subantimicrobial dose doxycycline are reported.     

Combination nicotine replacement therapy for smoking cessation: rationale, efficacy and tolerability

Currently available nicotine replacement therapy (NRT) medications provide effective treatment for tobacco dependence, typically doubling success rates compared with placebo. A strategy for further improving the efficacy of NRT is to combine one medication that allows for passive nicotine delivery (e.g. transdermal patch) with another medication that permits ad libitum nicotine delivery (e.g. gum, nasal spray, inhaler). The rationale for combining NRT medications is that smokers may need both a slow delivery system to achieve a constant concentration of nicotine to relieve cravings and tobacco withdrawal symptoms, as well as a faster acting preparation that can be administered on demand for immediate relief of breakthrough cravings and withdrawal symptoms. This article reviews 5 published studies that have examined the effectiveness of combination NRT compared with monotherapy in providing withdrawal relief and smoking cessation, and examines other factors relevant to the promotion of combination NRT for treating tobacco dependence. The data show that there are conditions under which combinations of NRT products provide greater efficacy in relieving withdrawal and enabling cessation than monotherapy, but the findings are not robust and additional research is warranted to better understand the magnitude and generality of the benefits of combination therapy. There are also regulatory and commercial obstacles that must be considered. Nonetheless, combination NRT has the potential to provide effective treatment of tobacco dependence in persons whose dependence is refractory to currently available treatments.     

Novel fluoropyrimidines: improving the efficacy and tolerability of cytotoxic therapy

The fluoropyrimidines were first synthesised nearly 50 years ago as rationally designed anti-cancer agents. Their target was pyrimidine and hence DNA synthesis. 5-Fluorouracil has been the most extensively used in a wide variety of malignancies. In more recent years a fuller understanding of the pharmacokinetics of these agents has lead to their utilisation as more effective and versatile anti-cancer drugs than might have been initially envisaged. This in part has occurred due to recognition of the schedule dependency of efficacy of 5-FU and modulation of its activity by leucovorin. However the development of novel fluropyrimidines such as capcetabine, UFT, and eniluracil which can be administered orally, has offered equal if not superior efficacy with improved tolerability and patient acceptance. It is now recognised that enzyme polymorphism's and heterogeneity of expression of key molecules are important determinants of the pharmacokinetic handling and pharmacodynamic effects of these drugs in individual patients. Further characterisation of such inter-individual and inter-tumoral variability, for example in enzymes such as DPD and thymidine phosphorylase is ongoing. This work offers the promise of improvements in efficacy and tolerability by the process of individualisation of chemotherapy (for both patient and tumour). In contrast to the advances made in the understanding of the pharmacokinetics, less progress has been made in Fluropyrimidine pharmacodynamics. The inhibition of thymidylate synthetase by dFUMP and thereby dTMP and DNA synthesis is thought to be the critical mechanism. The incorporation of FUTP and dFUTP into RNA and DNA are also postulated to be of importance. While these events have been well defined, exactly how they lead to cell death is less clearly understood. Similarly, the mechanism of selective cancer cell cytotoxicity is not well understood. Pharmacokinetics and cell cycle kinetics provide a partial explanation. There is some evidence to suggest that the most important factor in determining cytotoxicity is the cellular response to fluoropyrimidine induced biochemical abnormalities rather than the lesions themselves. In this hypothesis the difference in response between normal and cancer cells is of critical importance. Further improvements in efficacy and tolerability could be made by elucidation of the molecular mechanisms behind this process. This knowledge in combination with the advances already made (and ongoing) in pharmacokinetics may allow the full potential of fluoropyrimidines as anti-cancer agents to be realised in the future.     

Suppressive therapy versus episodic therapy with oral valacyclovir for recurrent herpes labialis: efficacy and tolerability in an open-label, crossover study

Oral valacyclovir's efficacy and tolerability as suppressive therapy versus episodic therapy were compared for recurrent herpes labialis (RHL). Subjects with a history of at least 3 RHL episodes in the past year were randomized to receive 6 months of oral valacyclovir episodic therapy at the first sign of prodrome (two 2-g doses separated by 12 hours) and 6 months of oral valacyclovir suppressive therapy (1 g once daily) for 6 months in open-label, crossover fashion. The mean +/- SE number of recurrences per 120 days of follow-up (primary endpoint) was lower with suppressive therapy (0.30 +/- 0.41) than episodic therapy (0.71 +/- 0.79) (P < .005). The probability of remaining recurrence free over 6 months was significantly higher with suppressive therapy than episodic therapy. The median time to first recurrence was 81 days with episodic therapy and was not calculable (> 180 days) for suppressive therapy (P = 0.021). Data for secondary efficacy endpoints (pain severity score, mean duration of recurrences, maximal total lesion area) showed approximately a 30% to 50% reduction in mean values with suppressive therapy compared with episodic therapy, but results were statistically significantly different between the regimens for pain severity only. The percentage of subjects with at least one adverse event over 6 months of treatment that was considered to be drug related was 3% with suppressive therapy and 6% with episodic therapy. Suppressive therapy with oral valacyclovir was more effective than episodic therapy with oral valacyclovir in reducing the frequency of recurrences of herpes labialis and prolonging the time to first recurrence and was also similarly well-tolerated.     

Upcoming agents for the treatment of schizophrenia: mechanism of action, efficacy and tolerability

Since the introduction of a group of atypical antipsychotics in the 1990s, there has been a decline in the rate of new antipsychotics being introduced into clinical practice. However, with increasing safety and efficacy concerns over currently available drugs and a dearth of options available for atypical depot formulations, there is a considerable need for the development of new formulations and agents. This review examines the profile of seven antipsychotic drugs currently in the premarketing stage of development and summarizes their mechanism of action, clinical potential and safety.Asenapine is an antipsychotic with activity for multiple receptors and has potential to improve negative and cognitive symptoms of schizophrenia. Bifeprunox is a partial dopamine D2 and serotonin 5-HT(1A) receptor agonist showing a less than convincing efficacy profile, but which may offer safety advantages over available agents by means of a reduced risk of metabolic complications. Iloperidone is a D2 and 5-HT(2A) receptor antagonist requiring further studies to establish its effectiveness. It has a high affinity for alpha(1)-adrenoceptors, which can lead to associated haemodynamic adverse effects. Nemonapride is essentially a typical antipsychotic drug, similar in structure to sulpiride, which has been available for some time in Japan. It has efficacy against positive symptoms and has shown some antidepressant and anxiolytic properties, although efficacy data for it are somewhat limited. Norclozapine (N-desmethylclozapine) is a major metabolite of clozapine formed by its demethylation. Its partial agonist activity at D2 receptors has raised interest in it as an antipsychotic in its own right. In addition, it appears to have muscarinic agonist activity, which is believed to be responsible for the observed positive effects it has on cognition. It was envisaged to be effective as an adjunct to other agents or at high doses in the treatment of refractory schizophrenia, although a recent randomized, controlled study showed that it was no more effective than placebo in patients with schizophrenia experiencing an acute psychotic episode. Olanzapine pamoate depot injection has shown comparable efficacy to oral olanzapine in several studies. However, it has provoked considerable safety concerns by its association with inadvertent intravascular injection events in numerous patients. This accidental intravascular administration of olanzapine pamoate leads to excessive sedation, confusion, dizziness and altered speech. Post-injection observation periods and postmarketing surveillance are planned following the introduction of the depot. Paliperidone palmitate is the palmitate ester of paliperidone, the major metabolite of risperidone, and is formulated as a long-acting injection for intramuscular use. Its pharmacology is comparable to risperidone, having D2 and 5-HT(2A) receptor antagonist activity. Efficacy studies have shown positive results, and because paliperidone has no antagonistic activity at cholinergic receptors, it has low potential for anticholinergic adverse effects, including cognitive dysfunction. However, with higher doses, the frequency of extrapyramidal side effects and orthostatic hypotension have been shown to be greater than with placebo.     

Optimizing antidepressant treatment: efficacy and tolerability

It has been suggested that dual-action antidepressants acting on both serotonin and noradrenaline pathways in the brain may offer superior therapeutic benefit over classical antidepressants, particularly in severe depression. Directly acting dual-action antidepressant drugs include venlafaxine and milnacipran. In addition, mirtazapine and nefazodone, may indirectly potentiate serotonergic and noradrenergic transmission, although evidence that they do indeed do so in vivo is limited. Meta-analysis of clinical trials suggests that venlafaxine has a more rapid onset of action than selective serotonin reuptake inhibitors (SSRIs), and the same may also be true for milnacipran and mirtazapine. Efficacy, both in terms of extent of antidepressant effect and in the proportion of patients responding, is probably superior to that of SSRIs, at least for venlafaxine and milnacipran. In terms of tolerability, all dual-action drugs clearly appear to be better tolerated than tricyclic antidepressants. Mirtazapine and nefazodone have specific side-effect profiles as a result of their antagonist action at biogenic amine and other receptors. Milnacipran, and to a lesser extent venlafaxine, are slightly better tolerated than SSRIs.     

Extended-release zolpidem: efficacy and tolerability profile

Zolpidem is currently the worldwide market leader in the hypnotic arena. It is characterized by a rapid onset of action as well as minimal residual and rebound effects. Its effects on sleep-maintenance parameters, however, have been rather inconsistent. In an attempt to improve this aspect, an extended-release zolpidem formulation has been developed, releasing 60% of the active ingredient immediately, with a slower release of the remainder through the latter part of the night. Volunteer studies have demonstrated that the extended-release formulation has a more prolonged pharmacodynamic effect than the immediate-release one, and is effective in patients on a robust measure of sleep-maintenance difficulty, wake time after sleep onset. A variety of secondary objective and subjective endpoints reflecting sleep initiation and maintenance have also been improved, and minimal residual and rebound effects have been demonstrated. These findings have been echoed in a six-month study using an intermittent dosing paradigm with subjective endpoints.     

An evaluation of rosuvastatin: pharmacokinetics, clinical efficacy and tolerability

BACKGROUND: The HMG Co-A reductase inhibitors (statins) are the most efficacious agents for lowering cholesterol. Statins reduce clinical cardiovascular events and are generally well tolerated. OBJECTIVE: To review the efficacy and safety of rosuvastatin, the newest and most potent of the approved statins. METHODS: A comprehensive (PubMed) search was performed to identify relevant publications up to May 2007. RESULTS/CONCLUSIONS: Rosuvastatin reduces LDL cholesterol (LDL-C) by up to 50%, and by 70% when combined with ezetimibe. Rosuvastatin also reduces plasma triglycerides and increases HDL-C, and slows atherosclerosis progression in coronary and carotid arteries in both low-risk and high-risk individuals. Tolerability is comparable with other statins. Clinical trials to evaluate cardiovascular outcomes have recently been published (CORONA) or are underway.     

Asenapine review,part II: clinical efficacy,safety and tolerability

Introduction: Asenapine is a second-generation (atypical) antipsychotic currently marketed for the treatment of schizophrenia and bipolar mania/mixed episodes.

Areas covered: The purpose of this review is to describe the clinical profile of asenapine.

Expert opinion: Asenapine's efficacy in the treatment of schizophrenia and in the acute management of bipolar manic or mixed episodes, within the recommended therapeutic dose range of 5 – 10 mg twice a day, is evidenced by a broad clinical development program. Asenapine's overall tolerability profile is notable for the potential for sedation (time-limited) and, to a lesser extent, extrapyramidal symptoms/akathisia, dizziness, and oral hypoesthesia. Asenapine's effects on weight and metabolic variables appear modest, as are its effects on the ECG QTc interval and on prolactin.     

Medicinal plants for insomnia: a review of their pharmacology, efficacy and tolerability

A number of medicinal plants are traditionally endowed with anxiolytic or sedative properties and, in the context of this revue, both indications are considered since the former may induce a mood conducive to the latter. For any sleep-inducing drug to be effective, a tranquil ambience needs to be established a priori. Thus, physical ailments (i.e. pain), factors interfering with sleep (i.e. noise), psychological conditions causing stress, psychiatric illnesses (i.e. depression) and other drugs that interfere with sleep (i.e. caffeine) need to be controlled, if possible. Kava-kava is a well-established hypnotic drug, with a rapid onset of effect, adequate duration of action and minimal morning after-effects. However, reports of serious hepatotoxicity with this preparation have led to it being banned in most countries worldwide. On the other hand, side-effects with valerian would appear to be bland indeed. However, it's slow onset of effect (2-3 weeks) renders it unsuitable for short-term use (i.e. 'jet-lag'), but it does have profound beneficial effects on sleep architecture (augments deep sleep) that may make it particularly suitable for long-term use and for the elderly. In a personal trial (not double-blind) in stress-induced insomnia, both kava and valerian improved sleep and the ill-effects of stress, and the combination of the two was even more effective for the control of insomnia. Aromatherapy (lavender, chamomile, Ylang-Ylang) would appear to improve sleep, but how practical a form of treatment this may be remains to be determined. The only other plant drug that may have some effect on sleep is melissa, but reports are too scanty to form any opinion about this. Based on animal experiments, passion flower (passiflora) may have a sedative action, but the sedative action of hops has not been investigated in any detail. In conclusion, there is a need for longer-term controlled studies with some of these compounds (particularly valerian). Aromatherapy constitutes a tantalising possibility. In the interpretation of this review, it should be borne in mind that the evidence on which it is based is often incomplete or missing, but that is all that is available. Consequently some conjecture on the part of the author is inevitable and should be appreciated as such.     

Ziprasidone: efficacy, tolerability, and emerging data on wide-ranging effectiveness

Ziprasidone is the fifth atypical antipsychotic to become available in the US market. This compound is a serotonin-dopamine-receptor antagonist, with greater affinity for the 5-HT(2A) receptor than the dopamine D2 receptor. Similar to aripiprazole, this compound also has agonist activity at the serotonin 5-HT(1A) receptor. This affinity has the potential to have particularly beneficial effects on cognitive and affective abnormalities in schizophrenia. Oral and short-acting intramuscular formulations are available. This compound has recently been approved for the treatment of acute mania as well as for schizophrenia. Ziprasidone is associated with low weight gain and a low potential to change lipid and glucose levels. Long-term tolerability data have indicated that initial concerns regarding QTc (corrected cardiac output) prolongation are not a major issue. Recent data have indicated that this compound has short-term antipsychotic efficacy that is equivalent to other members of the class, also with evidence of cognitive enhancement. Finally, longer term data has indicated that ziprasidone is successful in the prevention of relapse and has sustained cognitive benefits. Several issues remain to be addressed, including the efficacy of once-daily dosing, the need to take the medication with food, and the correct dosing strategy.     

Reboxetine: a review of efficacy and tolerability

Clinical data on the efficacy and tolerability of the novel selective noradrenergic reuptake inhibitor reboxetine are reviewed. Reboxetine appears to have almost no pharmacological activity other than potently blocking the reuptake of noradrenaline. Clinical studies show reboxetine to be highly effective for the treatment of major depression. Reboxetine is more effective than placebo and comparable in efficacy to tricyclic antidepressants and selective serotonin reuptake inhibitors. Some studies suggest that reboxetine may have slightly better efficacy than fluoxetine and imipramine. Reboxetine is effective in severely depressed patients as well as elderly depressed persons. Reboxetine is remarkably well tolerated, having very few side effects. Reboxetine appears to cause little sexual dysfunction. The most common side effects are dry mouth and constipation. The drug does not inhibit or induce hepatic cytochrome P450 enzymes and is safe in overdose. Reboxetine may prove to be as effective and better tolerated than any other antidepressant currently available.     

The mechanism,efficacy, and tolerability profile of agomelatine

Introduction: Agomelatine is a novel antidepressant that acts as a melatonin MT₁ and MT₂ receptor agonist and serotonin 5-HT_2C receptor antagonist, putatively reversing circadian rhythm disruption in major depressive disorder (MDD) and promoting dendritic neurogenesis in animal models of depression. It may be a preferable alternative to antidepressants currently in use due to its improved tolerability profile.

Areas covered: The PubMed database was searched for published randomized controlled trials (RCTs) evaluating the efficacy of agomelatine as well as its tolerability and safety in the treatment of MDD. The key search term used was agomelatine combined with major depressive disorder/depressive disorder/depression and antidepressant. Article selection was based upon sample size and overall methodological quality.

Expert opinion: Agomelatine is a multi-modal agent with novel mechanisms of action, having sound evidence supporting its overall statistical efficacy and adequate tolerability profile for MDD treatment. However, the clinical significance of agomelatine has been contested, calling for additional studies in evaluation of its effect size. Of further concern are reported transient elevations in transaminases and severe but rare liver reactions.     

Optimal management of papulopustular rosacea: rationale for combination therapy

The pathophysiology of papulopustular rosacea (PPR) is primarily characterized by inflammation associated with several factors such as abnormal innate immune response, neurovascular dysregulation, stratum corneum barrier dysfunction, and depletion of antioxidant reserve, with no definitive evidence supporting an underlying microbial etiology. Several molecular inflammatory pathways have now been identified that enable the development of therapeutic agents that target the signs and symptoms of disease by modifying specific pathophysiological mechanisms. Available evidence demonstrates that topical and oral agents commonly used to treat PPR appear to modify some of these pathophysiological mechanisms and may prove to be complimentary when used in combination potentially leading to better therapeutic outcomes. During the past two decades, six clinical studies have been published on the benefits of combining oral and topical therapies for PPR. Four studies suggest that doxycycline, including anti-inflammatory dose doxycycline (doxycycline 40 mg modified-release capsule once daily) can be combined with topical metronidazole or azelaic acid in patients with PPR to achieve more rapid control of a flare. At present, subantimicrobial dosing of a tetracycline agent that also maintains anti-inflammatory activity has only been established with doxycycline. Although antibiotic doses of tetracycline agents (such as doxycycline, minocycline, and tetracycline) are known to be effective for PPR, the use of subantimicrobial dosing of doxycycline avoids the risk of antibiotic resistance.     

The efficacy of compliance therapy in pharmacotherapy for alcohol dependence: a randomized controlled trial

OBJECTIVE: This study sought to evaluate the effectiveness of compliance therapy in increasing adherence to pharmacological treatment for alcohol dependence. METHOD: Forty subjects were randomly allocated to receive usual medical care (n = 20) or usual medical care plus compliance therapy (n = 20). All subjects were prescribed acamprosate (Campral) for 4 months. Subjects were volunteers treated at a hospital-based outpatient drug and alcohol treatment service, and were men and women who were 18-65 years old and with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of alcohol dependence. All subjects received usual medical care consisting of seven medical reviews (duration = 15 minutes) over 4 months. Compliance therapy consisted of four to six individual sessions (duration = 60 minutes) in which beliefs about medication side effects, ambivalence, the benefits of treatment, treatment maintenance and relapse prevention were addressed and explored with motivational interviewing and cognitive behavior therapy techniques. RESULTS: The outcome variables were number of days taking acamprosate, days to first drink, days to first relapse (more than five drinks) and days to first extended relapse (greater than 2 consecutive days of more than five drinks). Intention-to-treat analyses showed little difference between the two groups in the outcome drinking measures. Nevertheless, the per-protocol analyses revealed that participation in three or more sessions of compliance therapy significantly increased adherence to acamprosate and improved overall treatment outcomes. CONCLUSIONS: The present study highlights the need for psychological interventions to improve adherence to pharmacotherapy in the treatment of alcohol dependence and provides initial support for compliance therapy as an effective intervention.     

Safety, efficacy, and tolerability of nelfinavir-containing antiretroviral therapy for patients coinfected with HIV and hepatitis C undergoing methadone maintenance

The safety, efficacy, and tolerability of nelfinavir (NFV)-containing antiretroviral therapy were evaluated in patients coinfected with HIV and hepatitis C undergoing methadone maintenance at an urban outpatient opioid treatment program serving a minority adult population. Eligibility covered methadone-maintained patients coinfected with HIV and hepatitis C who had received or were currently receiving NFV. The yield was 51 case patients. Parameters examined looked into safety, efficacy, and tolerability. Nelfinavir was discontinued in 2 patients for liver function abnormalities but resumed in 1 patient. One patient developed laboratory abnormalities during NFV therapy that were not present before NFV therapy; in 12 case patients, pre-NFV therapy liver function abnormalities resolved completely during NFV therapy. There was a statistically significant increase in CD4 count during NFV therapy. Viral load decreased or was unchanged in 10 case patients and increased in 8, of whom 5 had a CD4 count increase during NFV therapy. Three patients had diarrhea and 4 patients had constipation. Nelfinavir was not discontinued—neither was dose adjusted—in any of these patients. Patients who had received NFV ≥36 months had a smaller increase in mean methadone dose as compared with patients who had received NFV <36 months. The results show that NFV is safe, efficacious, and well tolerated.