Pamidronate and Zoledronic Acid in the Treatment of Paget's Disease of Bone

Paget's disease of bone (PDB) is a condition characterized by excessive and abnormal bone remodelling. Due to a high rate of bone remodelling, bisphosphonates, and especially pamidronate and the newer zolendronate, are indicated in the treatment of PDB. The presence of asymptomatic, but active PDB represents an indication for treatment aimed at preventing later complications. An additional indication for treatment is the involvement of skeletal segments that may give rise to severe complications. Pamidronate has a long history in the treatment of PDB. The more utilised regimen is 3 to 6 i.v. infusion of 60 mg of pamidronate at an infusion rate of 1 mg/min within 3-21 days. Zolendronate (5 mg once yearly) is the most powerful amino-bisphosphonate currently used. This primacy recognizes both the ability to inhibit the farnesyl-pyrophosphate synthetase and the higher affinity to hydroxyapatite crystals as a cause. Both pamidronate and zolendronate are effective in PDB, with an evidence-based superiority of the latter.

Pharmacotherapy of Insomnia: Focus on Zolpidem Extended Release

The imidazopyridine drug zolpidem ( N,N,6-trimethyl-2[4-methyl-phenyl]imidazo[1,2-a]pyridine-3-acetamide) is a sedative/hypnotic with relative selectivity for α1 subunits of the GABAA receptor/chloride channel complex. Because of this selectivity and regional receptor distribution, zolpidem is less generalized in its CNS depressive actions than benzodiazepines and largely devoid of their major, undesired side- and after-effects, at recommended doses. Zolpidem is rapidly taken up and distributed, binds extensively to plasma proteins, and is readily inactivated by hepatic cytochrome P450 monooxygenases, especially CYP3A4. Zolpidem is thus a rapidly acting agent which provides effective facilitation of sleep onset. However, plasma levels of the immediate release (IR) formulation frequently decline too quickly for effective sleep maintenance. To address this problem zolpidem extended release (ER) has been developed. At age-specific dosages, it increases, in middle-aged and elderly patients, total sleep time and reduces the number of nocturnal awakenings. Both zolpidem IR and ER have favorable toxicological profiles. Adverse effects are moderate, frequently in the incidence range of placebos, and certainly less frequent and severe than those of benzodiazepines. Zolpidem IR and ER are practically devoid of next-day hangover effects and only infrequently cause rebound insomnia of usually short duration. Both variants of zolpidem have a limited potential for dependence and abuse.

Dexlansoprazole MR in the Management of Gastroesophageal Reflux Disease

Dexlansoprazole MR, an enantiomer of lansoprazole, is a unique proton pump inhibitor with a duel release mechanism. This release mechanism produces two distinct peak concentrations that result in a prolonged mean residence time with increased duration of plasma concentrations and a greater percent time the pH is maintained above 4. The prolonged residence time allows dexlansoprazole MR to be administered throughout the day without regards to meals or the timing before a meal. In two trials of patients with erosive esophagitis, dexlansoprazole MR 60 mg and 90 mg demonstrated comparable healing rates to lansoprazole 30 mg. In patients with healed EE, dexlansoprazole MR 30 mg (75%) and 60 mg (83%) were superior to placebo (27%; p < 0.0025) in maintenance of healing. Dexlansoprazole MR 30 mg and 60 mg had a greater pecentage of heartburn-free days (91%-96%) and heartburn-free nights (96%-99%) than placebo (29%-72%) over the 6-month maintenance trial. Dexlansorpazole MR appears to be well tolerated with the safety profile being similar to lansoprazole with gastrointestinal adverse events being the most common. Dexlansoprazole MR provides a new treatment option for gastroesophageal reflux disease due to the flexible dosing, the unique release mechanisms and prologned pharmacodynamic effect.

Triptans in the Treatment of Migraine

Migraine is a neurovascular disease, which pathogenesis is still unclear. It causes a severe headache and a substantial financial loss due to absenteeism, therefore, its effective treatment is particularly valuable. Triptans, selective 5HT1B and D receptor agonists, are effective treatment choices of acute migraine attacks. Migraine patients, who bear special conditions such as hypertension, hepatic or renal impairment, constitute a special subgroup of patients whose treatment with triptans has to be individually arranged. The review of Kalanuria and Peterlin, regarding the metabolism and efficacy of zolmitriptan in the abortive treatment of migraine, highlights many details of the use of zolmitriptan in migraine patients.

A Review of Enteric-coated Mycophenolate Sodium for Renal Transplant Immunosuppression

Mycophenolic acid inhibits an enzyme, inosine monophosphate dehydrogenase (IMPDH), blocking purine synthesis of lymphocytes and therefore functioning as an effective immunosuppressive agent in transplantation. Currently, there are two available forms of mycophenolic acid (MPA) available; mycophenolate mofetil (MMF) and enteric-coated, delayed-release mycophenolate sodium (EC-MPS). Both products are approved for prophylaxis of organ rejection in renal transplant recipients. The use of MPA may be associated with adverse gastrointestinal effects which can lead to a reduction of the dose or discontinuation of therapy. Enteric-coated MPS was developed to reduce the upper gastrointestinal side effects due to its delayed release in the small intestines. Similar systemic MPA exposure is provided by oral administration of MMF 1000 mg daily and EC-MPS 720 mg, which contain near equimolar MPA content. Clinical trials in renal transplant recipients have demonstrated that EC-MPS is therapeutically equivalent to MMF when used at the time of transplantation and when used for conversion for gastrointestinal complications. The available literature regarding the incidence and severity of gastrointestinal adverse effects and the impact on quality of life remains controversial. Prospective, randomized trials of the available MPA formulations are warranted to further explore the gastrointestinal adverse effect profiles.

A Review of the Pharmacokinetics, Pharmacodynamics and Efficacy of Zolmitriptan in the Acute Abortive Treatment of Migraine

Migraine is a common and often disabling neurovascular disorder. Changes in the metabolism and the central processing of serotonin, as well as abnormalities in the modulation of the central and peripheral trigeminal nociceptive pathways, have been shown to play significant roles in migraine pathophysiology. Recent evidence suggests that a low serotonin state facilitates activation of the trigeminal nociceptive pathways. In addition, several pharmacological agents that modulate serotonin are used in the treatment of migraine. Specifically there are seven FDA approved, 5-hydroxytryptamine (5-HT) 1B/1D receptor agonists, used for the acute abortive therapy of migraine. Zolmitriptan is one such triptan. Zolmitriptan is available as a tablet, orally disintegrating tablet and as a nasal spray. It is rapidly absorbed and detectable within the plasma, within 2 to 5 minutes for the nasal spray and within 15 minutes for the tablet. Zolmitriptan reaches peak plasma levels in 2-4 hours, with good levels maintained for up to 6 hours. Although the metabolism of zolmitriptan is predominantly hepatic, only 25% of zolmitriptan is bound to plasma proteins. Thus it is unlikely for drug interactions involving the displacement of highly protein-bound drugs. Zolmitriptan is very well tolerated with less than half of participants in clinical trials reporting adverse events, most of which were mild and transient. Although rare, serious cardiovascular events have been reported with all triptans. However, when patients are appropriately selected, zolmitriptan is both, a safe and effective acute migraine abortive agent. In this article, we will first briefly review the biological role of serotonin and the literature linking serotonin to migraine pathophysiology. This will be followed by a comprehensive review of the pharmacodynamics, pharmacokinetics and efficacy of zolmitriptan. Finally, the clinical application of the use of zolmitriptan in migraine therapy will be discussed.

Sitaxentan for the Oral Treatment of Pulmonary Arterial Hypertension: Benefits from Endothelin Receptor Subtype Selectivity?

Pulmonary arterial hypertension (PAH) is a deadly and underdiagnosed disease which causes right heart failure secondary to pressure overload resulting from the thickening of the pulmonary artery endothelium, associated with elevated levels of circulating endothelin-1. Sitaxentan was the first endothelin antagonist with high selectivity for receptor subtype A (over subtype ET-B) to gain regulatory approval for the treatment of PAH in major pharmaceutical markets. This review traces the development history of sitaxentan, summarizes the designs and results from its clinical studies, and relates the drug's profile to that of the two other broadly available endothelin receptor antagonists, bosentan and ambrisentan. All three drugs have comparable therapeutic efficacy in the 6-minute walk test–-a frequently employed standard–-during the first 3-4 months of therapy. Their performance might differ slightly in other clinically relevant outcome measures, especially in longer-term treatment where fully comparable data have not yet been reported. In clinical trials of up to one year duration the propensity of sitaxentan to induce elevation of liver transaminases and hepatic failure was significantly lower than that of bosentan. As a once-daily oral drug with good tolerability sitaxentan has become a crucial element in the treatment of PAH.

Ibandronate in the Management of Postmenopausal Osteoporosis

Oral daily and weekly bisphosphonates were considered, for several years, as the mainstay for the treatment of postmenopausal osteoporosis. However, the inconvenience of frequent dosing is known to negatively affect adherence to therapy in the long-term, hence outcomes. This has prompted the development of convenient oral bisphosphonate regimens that feature simple, less frequent dosing schedules. Ibandronate is a potent, nitrogen-containing bisphosphonate which, uniquely, can be administered either orally, monthly, or as an intravenous injection, every 3 months. A positive impact for adherence has been observed with a reduction in the bisphosphonate dosing frequency. Anti-fracture efficacy of the various currently available regimens of ibandronate is documented in randomized controlled clinical trials, non-inferiority studies, meta-analyses and real-life settings studies. The present paper summarizes the pharmacology, efficacy and tolerability of oral and intravenous ibandronate, when administered with extended dosing intervals, in postmenopausal osteoporosis.

Current Approaches to the Treatment of Gastrointestinal Infections: Focus on Nitazoxanide

Nitazoxanide is a broad-spectrum agent active against several protozoa, helminths, and bacteria, including C. difficile and H. pylori. It is available as an oral tablet and suspension, both with adequate bioavailability. Nitazoxanide is associated with minimal side effects, has an acceptable safety profile, and has been classified as a pregnancy category B agent. It is 99% protein bound, which could result in drug interactions. It is the preferred agent for the treatment of Cryptospordiosis and Giardiasis in immunocompetent patients and has shown promise for the treatment of rotavirus, mild to moderate initial C. difficile infection, refractory C. difficile infection, Amoebiasis, Blastocystosis, and Taenia saginata.