Vilazodone hydrochloride, a combined SSRI and 5-HT1A receptor agonist for major depressive disorder.

OBJECTIVE: Vilazodone (VIIBRYD, Trovis Pharmaceuticals; New Haven, Connecticut, also known as 659746, EMD68843, SB-659746-A) is a newly introduced antidepressant that has taken approximately a decade from its discovery to approval by the Food and Drug Administration. This paper will review the chemistry, pharmacodynamics, pharmacokinetics, clinical efficacy, tolerability, drug-drug interaction potential, dosing, and administration of this agent. DATA SOURCES: Medline/PubMed/IPA/EMBASE databases were searched using the terms "vilazodone," "659746," "EMD68843," and "SB-659746-A." All English-language papers from 1985 to April 2012 were reviewed for relevance. Bibliographies of all papers were reviewed to identify further papers. STUDY SELECTION: All English-language papers from 1985 to present appearing in these searches were reviewed for relevance to this paper. In addition, their bibliographies were reviewed to identify any papers not identified in the searches. Data are expressed as mean or mean ± standard deviation, unless otherwise noted. DATA SYNTHESIS: Vilazodone is the first combined selective serotonin reuptake inhibitor (SSRI)/5-HT1A receptor agonist antidepressant. Vilazodone must be administered with food to optimize bioavailability. The primary route of elimination is metabolism followed by excretion of metabolites. Advancing age and renal and hepatic impairment do not alter its disposition. Early phase II clinical trials were unable to demonstrate antidepressant efficacy. However, later phase III trials using 40 mg daily doses were able to demonstrate superior efficacy compared with placebo treatment. Adverse events, warnings, and precautions mirror those of other SSRIs. CONCLUSION: Although there are theoretical reasons why 5-HT1A agonism may be a desirable additional property in antidepressants, there is no evidence to date that vilazodone has any advantage over existing post-tricyclic antidepressants. It has a narrow therapeutic dosing range whose upper boundary is close to that producing intolerable gastrointestinal and central nervous system adverse events. Further research will clarify and refine the role of vilazodone in the management of psychiatric disorders.

Comment on the potential utility of the new atypical antipsychotic lurasidone in the geriatric population.

Lurasidone is the tenth atypical antipsychotic to be marketed in the United States. Like other atypical agents, lurasidone binds to a variety of central nervous system receptors, including dopamine (D2), norepinephrine (alpha 2A and 2C), and serotonin (1A, 2A, and 7) receptors. At these receptors, the drug acts as an antagonist except at serotonin 1A receptors, where it is a partial agonist. It behaves like an antipsychotic agent in animal models predictive of such activity. In addition, it behaves as a cognition enhancer in animal models of learning and memory impairment. In vivo in humans, lurasidone has been effective in significantly improving the positive and negative symptoms of schizophrenia in young adults as well as demonstrating preliminary positive effects on cognition in this population. The bioavailability of lurasidone is enhanced three-fold by administration with food. It is virtually completely metabolized, the major exo-hydroxy metabolite exhibiting the same pharmacology as the parent compound. Despite this, renal and hepatic impairment substantially affect the drug's pharmacokinetics, necessitating dose reduction or limitation. Several metabolic drug-drug interactions are clinically important (CYP450 isozyme 3A4-based). Lurasidone will be a difficult drug to use in the elder patient population because of the virtual absence of elder-specific information, limitations of existing formulations (40 and 80 mg nonscored tablets) in enabling precise dosage adjustment, and the substantial difference in bioavailability with food versus fasting, with attendant risks for over- and underdosing depending on when the drug is ingested. It would be prudent to avoid using this agent until relevant geriatric-specific data are published.

Dabigatran etexilate: a possible replacement for heparinoids and vitamin K antagonists?

Dabigatran etexilate is the first oral anticoagulant to be approved in the United States in decades. It works directly by inhibiting clot-bound and free factor IIa (ie, thrombin) and indirectly by inhibiting platelet aggregation induced by thrombin. It is approved in the United States for stroke prophylaxis in nonvalvular atrial fibrillation. There is evidence to suggest that it is also effective for the treatment of acute venous thromboembolism and venous thromboembolism prophylaxis after knee and hip replacement surgery. Dabigatran etexilate therapy does not require laboratory monitoring, an advantage over warfarin. Unlike the earlier direct thrombin inhibitor, ximelagatran, it has demonstrated no potential for serious hepatotoxicity. It is also subject to a much lower degree of interpatient variability in dose response, has no diet-drug interactions, and has fewer clinically significant drug-drug interactions compared with warfarin. Dabigatran etexilate appears to be a valuable addition to our anticoagulant armamentarium.

Oral hydromorphone extended-release.

OBJECTIVE: To review the chemistry, pharmacodynamics, pharmacokinetics, efficacy, tolerability, dosing, and role of the Osmotic-controlled Release Oral delivery System (OROS) hydromorphone extended-release (ER) tablets. DATA SOURCE: A MEDLINE/PUBMED search (1986-August 2010) was conducted to identify studies in the English language, with additional references being obtained from their bibliographies. STUDY SELECTION: All studies of hydromorphone ER were reviewed. DATA SYNTHESIS: This is the second long-acting hydromorphone formulation to receive approval by the Food and Drug Administration (a twice-daily formulation was approved in September 2004, but was subsequently withdrawn in July 2005). Hydromorphone is a semi-synthetic mu-opioid receptor agonist structurally similar to morphine, hydrocodone, and oxymorphone. OROS ER technology allows once-daily dosing. Clinical trials have focused on the convertibility of (an) other opioid(s) to hydromorphone ER in chronic malignant and nonmalignant pain. This product displays the expected opioid side effects, being comparable to oxycodone controlled-release. Coadministration with ethanol does not produce the degree of "dose-dumping" seen with the former hydromorphone twice-daily product or oxymorphone ER. Hydromorphone ER is indicated for the management of moderate-to-severe pain in opioidtolerant patients requiring continuous, around-the-clock opioid analgesia for an extended period of time. Dosage adjustment is recommended in patients with moderate hepatic impairment (Child-Pugh class B) and moderate renal impairment (creatinine clearance of 30-60 mL/min). CONCLUSION: Hydromorphone ER is the newest oral opioid to enter a crowded marketplace now totaling 15 different Schedule 2 opioids (including tapentadol), and tramadol, available in oral, parenteral, rectal, transdermal, transmucosal, and intranasal formulations. It does not appear to have any unique assets or liabilities and should be considered as one of many oral opioids available for the management of persistent pain of moderate-to-severe intensity.

Tetrabenazine, a monoamine-depleting drug used in the treatment of hyperkinetic movement disorders.

BACKGROUND: Few drugs are available for the management of hyperkinetic movement disorders such as the dystonias, choreas, dyskinesias, and tics. Those that are available (primarily neuroleptics) are associated with a wide range of potentially serious adverse effects, including induction of tardive movement disorders. Tetrabenazine (TBZ) is a monoamine-depleting agent initially studied in the 1950s and currently approved by the US Food and Drug Administration for the treatment of chorea in Huntington's disease. OBJECTIVE: This article reviews the chemistry, pharmacology, pharmacokinetics, therapeutic use, tolerability, drug-interaction potential, and dosing and administration of TBZ. METHODS: MEDLINE was searched (1950-February 2010) for English-language articles investigating any aspect of TBZ. Search terms included tetrabenazine, Ro 1-9569, Nitoman, benzoquinolizines, and reserpine. The reference lists of the identified articles were searched for other pertinent publications, particularly those that were not indexed in the 1950s and 1960s. RESULTS: In the search for a chemical compound that was simpler than reserpine while preserving reserpine-like psychotropic activity, TBZ was identified in the 1950s as one member of a large group of benzoquinolizine derivatives. TBZ acts by depletion of the monoamines serotonin, norepinephrine, and dopamine in the central nervous system (CNS). It does this by reversibly inhibiting vesicle monoamine transporter type 2 and thus preventing monoamine uptake into presynaptic neurons. Clinical studies suggest that TBZ may have therapeutic applications in a wide range of hyperkinetic movement disorders. TBZ has been associated with numerous adverse effects, some of them serious and potentially fatal; these include parkinsonism, other extrapyramidal symptoms (particularly akathisia), depression and suicidality, neuroleptic malignant syndrome, and sedation. TBZ is subject to important drug-drug interactions with inhibitors and inducers of cytochrome P450 (CYP) 2D6, reserpine, and lithium. It is one of very few drugs whose dosing is based, in part, on the results of genotyping (in its case, genotyping for CYP2D6 metabolizer status). CONCLUSIONS: TBZ is a complicated drug in terms of its mechanism of action and its activities against the 3 major monoamines in the CNS, making it difficult to predict its efficacy and tolerability in patients with hyperkinetic movement disorders. It is associated with numerous adverse effects and several important drug-drug interactions. Much work remains to be done to determine the therapeutic potential of TBZ in the treatment of hyperkinetic movement disorders.

Methylnaltrexone methobromide: the first peripherally active, centrally inactive opioid receptor-antagonist.

OBJECTIVE: To review the chemistry, pharmacodynamics, pharmacokinetics, clinical efficacy, tolerability, indications, and dosing and administration of methylnaltrexone methobromide, the first approved peripherally selective opioid receptor-antagonist. DATA SOURCE: MEDLINE/PUBMED and EMBASE searches (January 1966-February 2009) were conducted to identify pertinent English-language studies. STUDY SELECTION AND DATA EXTRACTION: All studies evaluating any aspect of methylnaltrexone methobromide. DATA SYNTHESIS: Subcutaneous methylnaltrexone methobromide is the first opioid receptor-antagonist to be approved for the treatment of opioid receptor-agonist-induced constipation (subset with advanced disease, receiving palliative care, with an inadequate response to laxative therapy). This agent lacks meaningful activity in the central nervous system and, hence, will not compromise centrally mediated analgesia or precipitate centrally mediated signs/symptoms of opioid receptor-agonist withdrawal. There are no published comparative trials with traditional pharmacologic/nonpharmacologic laxation regimens. CONCLUSION: Methylnaltrexone methobromide is administered into the upper arm, abdomen, or thigh once every other day, with the frequency of dosing being increased, if needed, to a maximum of once daily. Recommended doses are 8 mg, 12 mg, or 0.15 mg/kg, depending on patient weight. For creatinine clearances less than 30 mL/min, the dose should be reduced by 50%. The average wholesale price is $83.33 for a 12 mg single-use vial (Medispan, accessed December 4, 2008). Clearly, parenteral agents are not as useful as oral agents and results of ongoing studies with new oral formulations of this product are eagerly awaited.

Cranberry and urinary tract infections.

Urinary tract infection (UTI) refers to the presence of clinical signs and symptoms arising from the genitourinary tract plus the presence of one or more micro-organisms in the urine exceeding a threshold value for significance (ranges from 102 to 103 colony-forming units/mL). Infections are localized to the bladder (cystitis), renal parenchyma (pyelonephritis) or prostate (acute or chronic bacterial prostatitis). Single UTI episodes are very common, especially in adult women where there is a 50-fold predominance compared with adult men. In addition, recurrent UTIs are also common, occurring in up to one-third of women after first-episode UTIs. Recurrences requiring intervention are usually defined as two or more episodes over 6 months or three or more episodes over 1 year (this definition applies only to young women with acute uncomplicated UTIs). A cornerstone of prevention of UTI recurrence has been the use of low-dose once-daily or post-coital antimicrobials; however, much interest has surrounded non-antimicrobial-based approaches undergoing investigation such as use of probiotics, vaccines, oligosaccharide inhibitors of bacterial adherence and colonization, and bacterial interference with immunoreactive extracts of Escherichia coli. Local (intravaginal) estrogen therapy has had mixed results to date. Cranberry products in a variety of formulations have also undergone extensive evaluation over several decades in the management of UTIs. At present, there is no evidence that cranberry can be used to treat UTIs. Hence, the focus has been on its use as a preventative strategy. Cranberry has been effective in vitro and in vivo in animals for the prevention of UTI. Cranberry appears to work by inhibiting the adhesion of type I and P-fimbriated uropathogens (e.g. uropathogenic E. coli) to the uroepithelium, thus impairing colonization and subsequent infection. The isolation of the component(s) of cranberry with this activity has been a daunting task, considering the hundreds of compounds found in the fruit and its juice derivatives. Reasonable evidence suggests that the anthocyanidin/proanthocyanidin moieties are potent antiadhesion compounds. However, problems still exist with standardization of cranberry products, which makes it extremely difficult to compare products or extrapolate results. Unfortunately, most clinical trials have had design deficiencies and none have evaluated specific key cranberry-derived compounds considered likely to be active moieties (e.g. proanthocyanidins). In general, the preventive efficacy of cranberry has been variable and modest at best. Meta-analyses have established that recurrence rates over 1 year are reduced approximately 35% in young to middle-aged women. The efficacy of cranberry in other groups (i.e. elderly, paediatric patients, those with neurogenic bladder, those with chronic indwelling urinary catheters) is questionable. Withdrawal rates have been quite high (up to 55%), suggesting that these products may not be acceptable over long periods. Adverse events include gastrointestinal intolerance, weight gain (due to the excessive calorie load) and drug-cranberry interactions (due to the inhibitory effect of flavonoids on cytochrome P450-mediated drug metabolism). The findings of the Cochrane Collaboration support the potential use of cranberry products in the prophylaxis of recurrent UTIs in young and middle-aged women. However, in light of the heterogeneity of clinical study designs and the lack of consensus regarding the dosage regimen and formulation to use, cranberry products cannot be recommended for the prophylaxis of recurrent UTIs at this time.

Drug treatment of paraphilic and nonparaphilic sexual disorders.

BACKGROUND: Paraphilias are characterized by recurrent, intense, sexually arousing fantasies, urges, or behaviors, over a period of > or =6 months, generally involving nonhuman objects, suffering or humiliation of oneself or one's partner, or children or other nonconsenting persons. These fantasies, urges, and behaviors produce clinically significant distress or impairments in social, occupational, and other important areas of functioning. OBJECTIVE: The goal of this article was to provide an in-depth review of the clinical pharmacology of the main antiandrogens (cyproterone acetate, medroxyprogesterone acetate [MPA], and the luteinizing hormone-releasing hormone [LHRH] agonists) used in the treatment of the paraphilias, as well as a discussion of the relevant clinical case reports, case series, and controlled trials. Treatment recommendations are also provided. METHODS: Relevant publications were identified through a search of the English-language literature indexed on MEDLINE/PubMed (1966-September 2008) using the search terms paraphilia, sex offender, hypersexuality, sexual behaviors, fetish, transvestic fetishism, sexual addiction, sexual compulsivism, selective serotonin reuptake inhibitors, tricyclic antidepressants, antiandrogens, cyproterone acetate, medroxyprogesterone acetate, LHRH agonists, and estrogens. Additional publications were identified from the bibliographies of retrieved publications. RESULTS: In vitro and in vivo (animal) studies have revealed that serotonin and prolactin inhibit sexual arousal, while norepinephrine (via alpha(1)-adrenoceptor activation), dopamine, acetylcholine (via muscarinic receptor activation), enkephalins, oxytocin, gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, testosterone/dihydrotestosterone, and estrogen/progesterone stimulate it. Most of the currently used pharmacologic treatments of the paraphilias have serotonin and testosterone/dihydrotestosterone as their targets. Cognitive-behavioral psychotherapy should be initiated in all offenders. In those at the highest risk of reoffending, psychotherapy should be initiated at the same time as drug therapy because their combination is associated with better results compared with either as monotherapy (especially in pedophiles). In offenders committing non-"hands-on" or violent paraphilias and those at low risk of reoffending, serotoninergic monotherapies (selective serotonin reuptake inhibitors [SSRIs] or tricyclic antidepressants) are reasonable choices (SSRIs are preferred). In other offenders, initial dual combination therapy (serotoninergic plus antiandrogenic) is recommended. Progestogens should be used before LHRH agonists or estrogens. Cyproterone acetate and MPA are preferred as oral and IM progestogens, respectively. Failure of dual combination serotoninergic/ progestogen therapy should prompt a change in one or both of the components (eg, SSRI to tricyclic antidepressants or vice versa, or cyproterone acetate to MPA or vice versa) or the addition or substitution of an LHRH agonist (leuprolide or triptorelin) for the progestogen. Estrogens are second- or third-line agents. Rarely, triple combination therapy is necessary (serotoninergic plus LHRH agonist or progestogen plus estrogen). It appears that recidivism rates are reduced by the use of psychotherapy alone, drug therapy alone, and more so by their combination. CONCLUSIONS: Although some progress has been made in the therapy of paraphilic and nonparaphilic sexual disorders, much work remains to be done. The development of more specific, more effective, and better-tolerated medications for these disorders should be recognized as a program worthy of greater support from government and pharmaceutical industry sources. Clinical studies performed to date have largely been of poor design, making the recommendations provided in this review tentative at best.

Is tapentadol an advance on tramadol?

OBJECTIVE: To review the pharmacodynamics, pharmacokinetics, clinical efficacy, tolerability, dosing, and administration of tapentadol, a combination mu-opioid-receptor agonist and monoamine-reuptake inhibitor, and compare it with tramadol, the first drug in this class. DATA SOURCES: MEDLINE/PUBMED and EMBASE searches (1986 through March 2009) were conducted to identify pertinent English-language papers. In addition, meeting abstracts from multiple pain specialty organizations were searched (2000 through 2008). STUDY SELECTION AND DATA EXTRACTION: All papers/abstracts evaluating any aspect of tapentadol. DATA SYNTHESIS: Oral tapentadol hydrochloride (HCl) is the second combination mu-opioid-receptor agonist and monoamine-reuptake inhibitor to be approved by the Food and Drug Administration (approved for treatment of moderate-to-severe acute pain in adults). It was active in a wide variety of pain states in animals and humans. It behaved in a similar fashion to morphine and hydromorphone in animal and human models of physical/psychological dependence. Oral tapentadol HCI is administered in doses of 50 to 100 mg every four to six hours (dose and dosing interval being selected on the basis of pain intensity). No specific recommendations have been made for elders. CONCLUSION: Tapentadol overcomes some of the liabilities of tramadol. However, it still has some liabilities: its potential to contribute to/precipitate serotonin syndrome and anticholinergic/5-HT3 antagonist effects and to induce physical/psychological dependence (similar to schedule II opioids). There is also a dearth of information in terms of efficacy/tolerability in chronic pain states, clinical data in frail elders, and details of drug-drug interaction potential vis-à-vis glucuronidation and quantitation of the risk of serotonin syndrome.

Contemporary management of uncomplicated urinary tract infections.

Uncomplicated urinary tract infections (uUTIs) are common in adult women across the entire age spectrum, with mean annual incidences of approximately 15% and 10% in those aged 15-39 and 40-79 years, respectively. By definition, UTIs in males or pregnant females and those associated with risk factors known to increase the risk of infection or treatment failure (e.g. acquisition in a hospital setting, presence of an indwelling urinary catheter, urinary tract instrumentation/interventions, diabetes mellitus or immunosuppression) are not considered herein. The majority of uUTIs are caused by Escherichia coli (70-95%), with Proteus mirabilis, Klebsiella spp. and Staphylococcus saprophyticus accounting for 1-2%, 1-2% and 5-10% of infections, respectively. If clinical signs and symptoms consistent with uUTI are present (e.g. dysuria, frequency, back pain or costovertebral angle tenderness) and there is no vaginal discharge or irritation present, the likelihood of uUTI is >90-95%. Laboratory testing (i.e. urinary nitrites, leukocyte esterase, culture) is not necessary in this circumstance and empirical treatment can be initiated. The ever-increasing incidence of antimicrobial resistance of the common uropathogens in uUTI has been and is a continuing focus of intensive study. Resistance to cotrimoxazole (trimethoprim/sulfamethoxazole) has made the empirical use of this drug problematic in many geographical areas. If local uropathogen resistance rates to cotrimoxazole exceed 10-25%, empirical cotrimoxazole therapy should not be utilized (fluoroquinolones become the new first-line agents). In a few countries, uropathogen resistance rates to the fluoroquinolones now exceed 10-25%, rendering empirical use of fluoroquinolones problematic. With the exception of fosfomycin (a second-line therapy), single-dose therapy is not recommended because of suboptimal cure rates and high relapse rates. Cotrimoxazole and the fluoroquinolones can be administered in 3-day regimens. Nitrofurantoin, a second-line therapy, should be given for 7 days. beta-Lactams are not recommended because of suboptimal clinical and bacteriological results compared with those of non-beta-lactams. If a beta-lactam is chosen, it should be given for 7 days. Management of uUTIs can frequently be triaged to non-physician healthcare personnel without adverse clinical consequences, resulting in substantial cost savings. It can be anticipated that the optimal approach to the management of uUTIs will change substantially in the future as a consequence of antimicrobial resistance.

Inappropriate sexual behaviors in cognitively impaired older individuals.

BACKGROUND: Agitated and aggressive behaviors are common in older patients with dementia (33% of the community-dwelling and 80% of the institutionalized populations). Although inappropriate verbal and physical sexual behaviors are among the least common of these actions, they can be profoundly disruptive to caregivers (spouse, institutional staff, or both) and other individuals in the immediate surroundings. Substantial mental and physical harm can occur secondary to these behaviors. The common perception is that such behavior cannot be treated. OBJECTIVE: This review summarizes the epidemiology, etiology, and biology of abnormal sexual behaviors in cognitively impaired older individuals and highlights potentially useful drug therapies. METHODS: Primary research and review articles in the English language were identified through a search of MEDLINE/PubMed (1966-September 2008). Search terms included aged, hypersexuality, sexual disorders, paraphilia, sexual behaviors, tricyclic antidepressants, selective serotonin reuptake inhibitors, medroxyprogesterone acetate, cyproterone acetate, estrogens, LHRH agonists, leuprolide, and triptorelin. The bibliographies of all articles obtained were also reviewed for relevant citations. All articles involving abnormal sexual behaviors in older humans were reviewed. RESULTS: Use of pharmacotherapy in managing inappropriate sexual behaviors in cognitively impaired older individuals has been detailed in only 23 case reports and case series (N = 55 subjects). Additional supportive data from case reports and case series are available in nonsexual agitation/aggression in elderly patients with dementia (N = 16 subjects) and abnormal sexual behaviors in cognitively intact elderly (N = 2 subjects). One comparative trial in nonsexual agitation/aggression in elderly patients with dementia also exists (N = 27 subjects). There are no practice guidelines available for the treatment of abnormal sexual behaviors in the cognitively impaired elderly population. Recommendations must be individualized on the basis of clinical exigency and pragmatism; they should also be predicated on medical clearance to use estrogen or antiandrogen (progestogen, luteinizing hormone-releasing hormone [LHRH] agonist) therapies, if necessary. Very few data exist regarding the treatment of females of any age exhibiting abnormal sexual behaviors. For males, reasonable data support the use of serotoninergics (eg, tricyclic antidepressants [TCAs], selective serotonin reuptake inhibitors [SSRIs]), estrogens (oral, transdermal), antiandrogens (cyproterone acetate, medroxyprogesterone acetate), and the LHRH agonists (eg, leuprolide, triptorelin). Comparative trial data, both within and between these drug classes from the paraphilia literature, provide additional information that can be used to generate at least a provisional approach to drug treatment of abnormal sexual behaviors in older subjects with impaired cognition. CONCLUSIONS: In general, unless the patient is engaging in or threatening dangerous acts involving physical contact, serotoninergics (first choice, SSRIs; second choice, TCAs) are first-line agents followed by antiandrogens (cyproterone acetate or medroxyprogesterone acetate) as second-line agents. LHRH agonists (first choice) and estrogens (second choice) are considered third-line agents. Combination therapy is reasonable if the patient fails to respond to monotherapy.

Topical clindamycin in the management of acne vulgaris.

A small cadre of antimicrobials are commonly used and regarded as effective and safe, as systemic and topical treatments of acne vulgaris. These include oral tetracycline, doxycycline, minocycline and topical clindamycin and erythromycin. Topical antimicrobials work via both antimicrobial and non-antimicrobial mechanisms: the former due to suppression of the growth of propionibacterial species (especially Propionibacterium acnes and P. granulosum). Clindamycin appears to be superior in efficacy compared with erythromycin and tetracycline. However, the emergence and spread of resistance among propionibacteria to both erythromycin and clindamycin calls into question their long-term viability as topical anti-acne therapies. Only through judicious use of combination topical therapies (e.g., topical retinoid, benzoyl peroxide or azelaic acid plus clindamycin or erythromycin) and the practice of effective infection control (i.e., handwashing between seeing patients in the clinic) can both clindamycin's and erythromycin's widespread utility be preserved in this disorder.

Use of oral oxymorphone in the elderly.

OBJECTIVE: To review the pharmacodynamics, pharmacokinetics, efficacy, tolerability, dosing, and role of oral oxymorphone immediate-release (IR) and extended-release (ER). DATA SOURCE: A MEDLINE/PUBMED search (1970 to September 2006) of English language studies. Additional references were obtained from their bibliographies. STUDY SELECTION: All human studies of oxymorphone were reviewed. DATA SYNTHESIS: Oral oxymorphone IR/ER tablet formulations were approved in June 2006. Oxymorphone, a semi-synthetic -opioid receptor agonist structurally similar to hydromorphone, has an oral bioavailability of approximately 10%. Oxymorphone is extensively metabolized to oxymorphone-3-glucuronide and the active 6-hydroxyoxymorphone. Rapid clearance mandates every four- to six-hour dosing (IR) and every 12-hour dosing (ER). Hepatic impairment, renal impairment, and aging enhance systemic exposure. Oxymorphone IR was superior to placebo and oxycodone IR (acute pain studies). Oxymorphone ER was superior to placebo and equivalent to oxycodone CR and morphine CR (one acute and five chronic pain studies). Oxymorphone exhibits the expected opioid side effects, being comparable to oxycodone and morphine in clinical trials. Coadministration with ethanol causes "dose-dumping" (ER) and increases intersubject variability in drug absorption. Oxymorphone IR is indicated for the relief of moderate-to-severe pain, while oxymorphone ER is indicated for persistent pain. Initial doses (opioid-naïve) are 10 mg to 20 mg every 4 to 6 hours (IR) and 5 mg every 12 hours (ER). Dosage adjustment is recommended in mild hepatic impairment (Child-Pugh class A), renal impairment (creatinine clearance below 50 mL/min), and in the elderly. CONCLUSION: Oxymorphone is the newest oral opioid to enter a crowded marketplace now totaling 12 Schedule 2 opioids. It does not appear to have any unique assets or liabilities and should be considered as one of many oral opioids for the management of acute and persistent pain of moderate-to-severe intensity.

Newer antiepileptic drugs in the management of agitation/aggression in patients with dementia or developmental disability.

OBJECTIVE: To assess the potential role of newer antiepileptic drugs (AEDs) in the management of agitation/aggression in patients with dementia or developmental disability. DATA SOURCE: A MEDLINE/PUBMED search (1986-May 2007) was conducted to identify pertinent English language studies of six newer AEDs, as well as carbamazepine and valproate, in the management of agitation/aggression. STUDY SELECTION AND DATA EXTRACTION: All studies evaluating any aspect of management of agitation/aggression, emphasizing those associated with dementia or developmental disability. DATA SYNTHESIS: Pharmacotherapy of agitation/aggression in these two patient groups remains an underexplored area. Carbamazepine and valproate have a reasonable, readily available evidence base, and preliminary recommendations regarding their use in these two patient groups. The most published data with newer AEDs involve gabapentin, followed by topiramate. Even so, the literature regarding newer AEDs is modest in volume. CONCLUSION: Based on current data, gabapentin, oxcarbazepine, and topiramate are qualitatively similar in efficacy to carbamazepine/valproate in the management of agitation/aggression. However, studies-to-date in this field have had, in the main, numerous design flaws. In considering use of newer AEDs, the clinician needs to be aware of potential adverse events that are unique to these agents or infrequently seen with older AEDs (e.g., hyponatremia with oxcarbazepine, and acute myopia and angleclosure glaucoma, urinary tract stones, and cognition difficulties with topiramate). In addition, there is an extensive literature documenting that newer AEDs can precipitate new-onset or worsen existing behavioral disorders, including agitation/aggression.

Drug forecast - the peptide deformylase inhibitors as antibacterial agents.

The relatively rapid development of microbial resistance after the entry of every new antimicrobial into the marketplace necessitates a constant supply of new agents to maintain effective pharmacotherapy. Despite extensive efforts to identify novel lead compounds from molecular targets, only the peptide deformylase inhibitors (PDIs) have shown any real promise, with some advancing to phase I human trials. Bacterial peptide deformylase, which catalyzes the removal of the N-formyl group from N-terminal methionine following translation, is essential for bacterial protein synthesis, growth, and survival. The majority of PDIs are pseudopeptide hydroxamic acids and two of these (IV BB-83698 and oral NVP LBM-415) entered phase I human trials. However, agents to the present have suffered from major potential liabilities. Their in vitro activity has been limited to gram-positive aerobes and some anaerobes and has been quite modest against the majority of such species (MIC(90) values ranging from 1-8 mg/L). They have exerted bacteriostatic, not bacteriocidal, activity, thus reducing their potential usefulness in the management of serious infections in the immunocompromised. The relative ease with which microorganisms have been able to develop resistance and the multiple available mechanisms of resistance (mutations in fmt, defB, folD genes; AcrAB/TolC efflux pump; overexpression of peptide deformylase) are worrisome. These could portend a short timespan of efficacy after marketing. Despite these current liabilities, further pursuit of more potent and broader spectrum PDIs which are less susceptible to bacterial mechanisms of resistance is still warranted.

Ibandronate, an experimental intravenous bisphosphonate for osteoporosis, bone metastases, and hypercalcemia of malignancy.

Ibandronate is an experimental intravenous bisphosphonate under study for the prevention or treatment of osteoporosis and skeletal complications of bone metastases, as well as hypercalcemia of malignancy. To review the data on this drug, PubMed/MEDLINE was searched for pertinent studies in English; data from January 1986-October 2005 were reviewed. In preclinical studies, ibandronate was an extremely potent bisphosphonate compared with its predecessors and was active in all animal models of human postmenopausal and corticosteroid-associated osteoporosis. Similar to other bisphosphonates, ibandronate exhibits antitumor activity and prevents or reduces bone metastases. Forty to fifty percent of the dose is bound to bone; renal clearance of unchanged drug accounts for 70% of total body clearance. Early clinical trials demonstrated efficacy and tolerability of intravenous ibandronate in the prevention or treatment of postmenopausal and corticosteroid-associated osteoporosis when administered once every 3 months. Intravenous ibandronate also reduces skeletal complications of bone metastases, including pain, although the cumulative dose used is much higher than that used in osteoporosis, as the drug is administered every 3-4 weeks. Single doses of intravenous ibandronate are probably also effective in the treatment of hypercalcemia of malignancy. The major tolerability issue with intravenous bisphosphonates is renal safety, thus the drugs generally require infusion (e.g., 0.25 hr for zoledronic acid, 2-24 hrs for pamidronate). However, intravenous ibandronate can be administered by bolus injection over a few minutes without an elevated risk of nephrotoxicity. The experimental intravenous dosage is 2 mg every 3 months for treatment or prevention of osteoporosis, and 2-6 mg every 3-4 weeks or in a single dose for treatment of bone metastases or hypercalcemia of malignancy, respectively. Ibandronate can be used in the presence of severe renal impairment with proper dosage adjustment. The drug will be an interesting addition to the available drugs for osteoporosis, bone metastases, and hypercalcemia of malignancy. Studies of intravenous ibandronate as an adjunctive treatment for cancers that tend to metastasize to bone are under way. Whether intravenous ibandronate will be a therapeutic advance is best answered by randomized, controlled trials. These are ongoing and should provide data with which to make better-informed choices concerning intravenous bisphosphonates.

Rasagiline (TVP-1012): a new selective monoamine oxidase inhibitor for Parkinson's disease.

OBJECTIVE: This article reviews the chemistry, pharmacodynamics, pharmacokinetics, clinical efficacy, tolerability, drug-interaction potential, indications, dosing, and potential role of rasagiline mesylate, a new selective monoamine oxidase (MAO) type B (MAO-B) inhibitor, in the treatment of Parkinson's disease. METHODS: A MEDLINE/PUBMED search (1986 through September 2006) was conducted to identify studies involving rasagiline written in English. Additional references were obtained from the bibliographies of these studies. All studies evaluating any aspect of rasagiline, including in vitro, in vivo (animal), and human studies, were reviewed. RESULTS: Rasagiline mesylate was developed with the goal of producing a selective MAO-B inhibitor that is not metabolized to (presumed) toxic metabolites (eg, amphetamine and methamphetamine, which are byproducts of the metabolism of selegiline, another selective MAO-B inhibitor). In vitro and in vivo data have confirmed the drug's selectivity for MAO-B. Rasagiline is almost completely eliminated by oxidative metabolism (catalyzed by cytochrome P-450 [CYP] isozyme 1A2) followed by renal excretion of conjugated parent compound and metabolites. Drug clearance is sufficiently slow to allow once-daily dosing. Several studies have documented its efficacy as monotherapy for early-stage disease and as adjunctive therapy in L-dopa recipients with motor fluctuations. As monotherapy, rasagiline is well tolerated with an adverse-effect profile similar to that of placebo. As adjunctive therapy, it exhibits the expected adverse effects of dopamine excess, which can be ameliorated by reducing the L-dopa dosage. CYP1A2 inhibitors slow the elimination of rasagiline and mandate dosage reduction. Hepatic impairment has an analogous effect. The recommended dosage regimens for monotherapy and adjunctive therapy are 1 and 0.5 mg PO QD, respectively. CONCLUSIONS: Despite the well-documented selectivity of rasagiline, the manufacturer recommends virtually all of the dietary (vis-à-vis tyramine) and drug restrictions of the nonselective MAO inhibitors. Although useful, selective MAO-B inhibitors have a limited role in Parkinson's disease. Of greater interest is the potential neuroprotective effect of rasagiline and its major metabolite, 1(R)-aminoindan, which may have great utility in a wide variety of neurodegenerative disorders of aging. In addition, bifunctional molecules combining selective MAO-B inhibition (based on the active moiety of rasagiline) with acetylcholinesterase inhibition or iron chelation may eventually be useful in Alzheimer's disease.

Duloxetine for management of stress urinary incontinence.

OBJECTIVE: The aim of this article was to review data regarding the efficacy and tolerability of duloxetine, a selective serotonin (5-HT)-norepinephrine (NE) reuptake inhibitor that has received US Food and Drug Administration marketing approval for the treatment of major depressive disorder and painful diabetic neuropathy, and that has been investigated as a treatment for stress urinary incontinence. METHODS: A MEDLINE/PubMed search was conducted to identify English-language study reports. In addition, proceedings of meetings of the International Continence Society, European Association of Urology, American Urological Association, and American College of Obstetrics and Gynecology were reviewed for relevant abstracts (search terms included duloxetine, thiophenes, serotonin uptake inhibitors, adrenergic uptake inhibitors, and stress urinary incontinence). Additional references were obtained from the bibliographies of these sources. Data for the period from 1986 through January 2005 were reviewed. RESULTS: All in vitro and in vivo studies of duloxetine were included. Because both 5-HT and NE are involved in the maintenance of urinary continence, duloxetine may have a role in the treatment of urinary incontinence. Duloxetine is primarily eliminated via metabolism, with < 1% of the parent compound excreted via urine. Duloxetine QD or BID has been found to be significantly superior to placebo in reducing incontinence episode frequency (P < 0.001 to P < 0.05), increasing the interval between micturitions (P < 0.001 to P = 0.004), and improving the condition as measured by patient self-report (P < 0.001 to P = 0.028) and incontinence quality-of-life scores (P = 0.002 to P = 0.03). The most problematic adverse events are nausea, dry mouth, constipation, dizziness, and insomnia. CONCLUSIONS: Although statistically superior to placebo in efficacy trials, the clinical effects of duloxetine therapy on incontinence are small, suggesting that any benefits to the patient would be modest and must be weighed against the drug's adverse event profile. No comparative efficacy/tolerability data with alpha-receptor agonists (eg, pseudoephedrine) are available. On the basis of available data, duloxetine is a modest, but welcome, advance in the pharmacotherapeutic management of stress urinary incontinence.

Darifenacin: another antimuscarinic for overactive bladder.

OBJECTIVE: To review darifenacin, a new anticholinergic for overactive bladder, approved in December 2004 by the U.S. Food and Drug Administration. DATA SOURCE: A MEDLINE/PUBMED search was conducted to identify pertinent studies in the English language. In addition, proceedings of meetings of the International Continence Society, European Association of Urology, American Urological Association, and American College of Obstetrics and Gynecology were reviewed for relevant abstracts. Additional references were obtained from the bibliographies of these sources. Data over the time period of 1986 through September 2004 were reviewed. STUDY SELECTION: All studies evaluating any aspect of darifenacin in vitro or in vivo in animals or humans. DATA SYNTHESIS: Preclinical studies demonstrated that darifenacin was an antagonist at muscarinic cholinergic M1, M3, and M5 receptors. On the basis of preclinical data, darifenacin was felt to be a "uroselective" antimuscarinic. Darifenacin is extensively metabolized, with urinary excretion of parent compound being less than 10%. Darifenacin, dosed as 7.5 or 15 mg once daily, is significantly superior to placebo in reducing the numbers of micturitions, urges, incontinence episodes, and urge severity and increasing the warning time and volume per micturition. No active-controlled trial data are available. The most problematic adverse effects of darifenacin are the anticholinergic effects of dry mouth and constipation. CONCLUSION: Although promising in preclinical studies, the "uroselectivity" of the anticholinergic activity of darifenacin has not been confirmed in clinical trials. No comparative data with marketed (for overactive bladder) anticholinergics are available. On the basis of available data, darifenacin does not appear to be a substantial advance upon existing anticholinergics in the management of overactive bladder.