Clinical Drug Investigation 

About: Clinical Drug Investigation is an academic journal published by Adis, Springer Healthcare. The journal publishes majorly in the area(s): Tolerability & Medicine. It has an ISSN identifier of 1173-2563. Over the lifetime, 3007 publications have been published receiving 43065 citations. The journal is also known as: Drug investigation.

Pharmacology of Silymarin

Abstract: The flavonoid silymarin and one of its structural components, silibinin, are substances with documented hepatoprotective properties. Their mechanisms of action are still poorly understood. However, the data in the literature indicate that silymarin and silibinin act in four different ways: (i) as antioxidants, scavengers and regulators of the intracellular content of glutathione; (ii) as cell membrane stabilisers and permeability regulators that prevent hepatotoxic agents from entering hepatocytes; (iii) as promoters of ribosomal RNA synthesis, stimulating liver regeneration; and (iv) as inhibitors of the transformation of stellate hepatocytes into myofibroblasts, the process responsible for the deposition of collagen fibres leading to cirrhosis. The key mechanism that ensures hepatoprotection appears to be free radical scavenging. Anti-inflammatory and anticarcinogenic properties have also been documented. Silymarin is able to neutralise the hepatotoxicity of several agents, including Amanita phalloides, ethanol, paracetamol (acetaminophen) and carbon tetrachloride in animal models. The protection against A. phalloides is inversely proportional to the time that has elapsed since administration of the toxin. Silymarin protects against its toxic principle α-amanitin by preventing its uptake through hepatocyte membranes and inhibiting the effects of tumour necrosis factor-α, which exacerbates lipid peroxidation. Clinical trials have shown that silymarin exerts hepatoprotective effects in acute viral hepatitis, poisoning by A. phalloides, toxic hepatitis produced by psychotropic agents and alcohol-related liver disease, including cirrhosis, at daily doses ranging from 280 to 800mg, equivalent to 400 to 1140mg of standardised extract. Hepatoprotection has been documented by improvement in liver function tests; moreover, treatment with silymarin was associated with an increase in survival in a placebo-controlled clinical trial in alcoholic liver disease. Pharmacokinetic studies have shown that silymarin is absorbed by the oral route and that it distributes into the alimentary tract (liver, stomach, intestine, pancreas). It is mainly excreted as metabolites in the bile, and is subject to enterohepatic circulation. Toxicity is very low, the oral 50% lethal dose being 10 000 mg/kg in rats and the maximum tolerated dose being 300 mg/kg in dogs. Moreover, silymarin is devoid of embryotoxic potential. In conclusion, silymarin is a well tolerated and effective antidote for use in hepatotoxicity produced by a number of toxins, including A. phalloides, ethanol and psychotropic drugs. Numerous experimental studies suggest that it acts as a free radical scavenger, with other liver-specific properties that make it a unique hepatoprotective agent.

The Safety of Melatonin in Humans

Abstract: Exogenous melatonin has been investigated as treatment for a number of medical and surgical diseases, demonstrating encouraging results. The aim of this review was to present and evaluate the literature concerning the possible adverse effects and safety of exogenous melatonin in humans. Furthermore, we provide recommendations concerning the possible risks of melatonin use in specific patient groups. In general, animal and human studies documented that short-term use of melatonin is safe, even in extreme doses. Only mild adverse effects, such as dizziness, headache, nausea and sleepiness have been reported. No studies have indicated that exogenous melatonin should induce any serious adverse effects. Similarly, randomized clinical studies indicate that long-term melatonin treatment causes only mild adverse effects comparable to placebo. Long-term safety of melatonin in children and adolescents, however, requires further investigation. Due to a lack of human studies, pregnant and breast-feeding women should not take exogenous melatonin at this moment.

Efficacy and safety of Tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee: a randomized, double-blind, placebo- and active-controlled phase III study.

Abstract: Background: Tapentadol is a novel, centrally acting analgesic with μ-opioid receptor agonist and norepinephrine reuptake inhibitor activity. Objective: To evaluate the efficacy and safety of tapentadol extended release (ER) compared with oxycodone controlled release (CR) for management of moderate to severe chronic osteoarthritis-related knee pain. Methods: This was a randomized, double-blind, active- and placebo-controlled, parallel-arm, multicentre, phase III study during which patients received tapentadol ER, oxycodone CR or placebo for a 3-week titration period followed by a 12-week maintenance period. The study was carried out at sites in Australia, Canada, New Zealand and the US. A total of 1030 patients with chronic osteoarthritis-related knee pain were randomized to receive tapentadol ER 100–250 mg twice daily, oxycodone HCl CR 20–50 mg twice daily or placebo. Primary endpoints (as determined prior to initiation of the study) were the changes from baseline in average daily pain intensity (rated by patients on an 11-point numerical rating scale) over the last week of maintenance and over the entire 12-week maintenance period; last observation carried forward was used to impute missing values after early treatment discontinuation. Results: Efficacy and safety were evaluated for 1023 patients. Tapentadol ER significantly reduced average pain intensity from baseline to week 12 of the maintenance period versus placebo (least squares mean [LSM] difference [95% CI], −0.7 [−1.04, −0.33]), and throughout the maintenance period (−0.7 [−1.00, −0.33]). Oxycodone CR significantly reduced average pain intensity from baseline throughout the maintenance period versus placebo (LSM difference [95% CI], −0.3 [−0.67, −0.00]) but not at week 12 (−0.3 [−0.68, 0.02]). A significantly higher percentage of patients achieved ≥50% improvement in pain intensity in the tapentadol ER group (32.0% [110/344]) compared with the placebo group (24.3% [82/337]; p = 0.027), indicating a clinically significant improvement in pain intensity, while a significantly lower percentage of patients achieved ≥50% improvement in pain intensity in the oxycodone CR group (17.3% [59/342]; p = 0.023 vs placebo). In the placebo, tapentadol ER and oxycodone CR groups, respectively, 61.1% (206/337), 75.9% (261/344) and 87.4% (299/342) of patients reported at least one treatment-emergent adverse event (TEAE); incidences of gastrointestinal-related TEAEs were 26.1% (88/337), 43.0% (148/344) and 67.3% (230/342). Conclusion: Treatment with tapentadol ER 100–250 mg twice daily or oxycodone HCl CR 20–50 mg twice daily was effective for the management of moderate to severe chronic osteoarthritis-related knee pain, with substantially lower incidences of gastrointestinal-related TEAEs associated with treatment with tapentadol ER than with oxycodone CR. [Trial registration number: NCT00421928 (ClinicalTrials.gov Identifier)]

Impact of adherence to interferons in the treatment of multiple sclerosis: a non-experimental, retrospective, cohort study.

Abstract: Background: Relapsing-remitting multiple sclerosis (RRMS) is a chronic disease affecting about 400 000 people in the US characterized by increasing patient disability and burden on society. While there is no cure for multiple sclerosis (MS), pharmaceutical treatments exist that can limit the number of relapses a patient experiences, and slow disease progression. One such class of agents used to treat RRMS are the interferons: interferon-β-1a (Rebif® and Avonex®) and interferon-β-1b (Betaseron® and Extavia®). Patients must take these injectable medications regularly to achieve the optimal outcomes. However, patient issues and potential adverse effects of the medication may prevent the patient from taking the medication as directed and lower adherence. To date, limited evidence exists regarding the effect of patient adherence to interferon-β therapies on clinical and economic outcomes.

Postoperative Pain Clinical Evidence with Piroxicam-β-Cyclodextrin

Abstract: Although the analgesic properties of piroxicam in the postoperative setting have been well documented, the relatively slow onset of action of this nonsteroidal anti-inflammatory drug (NSAID) has somewhat limited its usefulness in this setting. To counter this disadvantage, piroxicam has been complexed with the cyclic oligosaccharide β-cyclodextrin, to form piroxicam-β-cyclodextrin. This new compound enhances the aqueous solubility of piroxicam, increases its rate of absorption, and results in more rapid achievement of therapeutic levels than occurs with standard piroxicam. Furthermore, clinical studies have shown that theonset,intensityanddurationofanalgesiaprovidedbyoralpiroxicam-β-cyclodextrin in postoperative settings are equivalent, and in some cases superior, to those achieved following injection of NSAIDs such as standard piroxicam, tenoxicam and ketorolac tromethamine. Oral piroxicam-β-cyclodextrin therapy, which is also well tolerated, more convenient for patients, and less costly to administer, thus appears to have clear advantages in the postoperative setting.