Pharmacology of drugs used to treat osteoarthritis in veterinary practice

As in humans, pain in animals may be associated with a wide range of conditions and circumstances, ranging from acute trauma to joint diseases. Joint diseases are common in companion animal medicine (horse, dog, cat) and at least 80% of cases are classified as osteoarthritis (OA). Several drug classes are available for OA therapy, including corticosteroids, non-steroidal antiinflammatory drugs (NSAIDs), agents with potential disease modifying properties and nutraceuticals. For long-term maintenance OA treatment, particularly in the horse and dog, NSAIDs are routinely and extensively used. This review outlines the pharmacokinetics (PK) and pharmacodynamics (PD) of NSAIDs in companion and farm animal species. NSAID PK and PD have been studied in models of acute inflammation, which enable use of PK-PD modeling to facilitate (a) studies of mechanism of action at the molecular level and (b) prediction of dosages for clinical use. The PK-PD approach is a powerful but underutilized tool which also facilitates inter-species comparisons.     

Place of OTC analgesics and NSAIDs in osteoarthritis

The risk related to the use of non-steroid anti-inflammatory drugs (NSAIDs) depends on the dose and duration of their use, in addition to the nature of the drug, and patient characteristics. The measures of risk and recent promotion of safer drugs have been mostly based on the results of clinical trials using continuous full-dose use of NSAIDs for periods up to 12 months which may not reflect real-life use and risks of the drugs. To assess this we did two studies of the utilisation of NSAIDs, one in a claims database to measure the amount of drugs dispensed to OA patients over 9 months, which showed that only a small fraction of patients actually bought enough analgesics or NSAIDs to cover the whole study period. On average, patients bought enough NSAIDs to cover 60 of 270 days. The second study was a survey of General Practitioners and rheumatologists to assess the number of users of NSAIDs seen over 2 days' consultations, the indications for and patterns of NSAIDs use. 11% of GP patients and 26% of rheumatologists' patients used NSAIDs, one-third for osteoarthritis (OA), about 8-10% for rheumatoid arthritis (RA) and the rest for various painful conditions. In OA and other conditions patients, more than 70% of patients had been taking their NSAIDs for less than 15 days at the time of consultation, whereas 42% of RA patients had been taking them for more than 6 months.     

Clinical pharmacokinetics of drugs used to treat urge incontinence

Urge incontinence (also known as overactive bladder) is a common form of urinary incontinence, occurring alone or as a component of mixed urinary incontinence, frequently together with stress incontinence. Because of the pathophysiology of urge incontinence, anticholinergic/antispasmodic agents form the cornerstone of therapy. Unfortunately, the pharmacological activity of these agents is not limited to the urinary tract, leading to systemic adverse effects that often promote nonadherence. Although the pharmacokinetics of flavoxate, propantheline, scopolamine, imipramine/desipramine, trospium chloride and propiverine are also reviewed here, only for oxybutynin and tolterodine are there adequate efficacy/tolerability data to support their use in urge incontinence. Oxybutynin is poorly absorbed orally (2-11% for the immediate-release tablet formulation). Controlled-release oral formulations significantly prolong the time to peak plasma concentration and reduce the degree of fluctuation around the average concentration. Significant absorption occurs after intravesical (bladder) and transdermal administration, although concentrations of the active N-desethyl metabolite are lower after transdermal compared with oral administration, possibly improving tolerability. Food has been found to significantly affect the absorption of one of the controlled-release formulations of oxybutynin, enhancing the rate of drug release. Oxybutynin is extensively metabolised, principally via N-demethylation mediated by the cytochrome P450 (CYP) 3A isozyme. The pharmacokinetics of tolterodine are dependent in large part on the pharmacogenomics of the CYP2D6 and 3A4 isozymes. In an unselected population, oral bioavailability of tolterodine ranges from 10% to 74% (mean 33%) whereas in CYP2D6 extensive metabolisers and poor metabolisers mean bioavailabilities are 26% and 91%, respectively. Tolterodine is metabolised via CYP2D6 to the active metabolite 5-hydroxymethyl-tolterodine and via CYP3A to N-dealkylated metabolites. Urinary excretion of parent compound plays a minor role in drug disposition. Drug effect is based upon the unbound concentration of the so-called 'active moiety' (sum of tolterodine + 5-hydroxymethyl-tolterodine). Terminal disposition half-lives of tolterodine and 5-hydroxymethyl-tolterodine (in CYP2D6 extensive metabolisers) are 2-3 and 3-4 hours, respectively. Coadministration of antacid essentially converts the extended-release formulation into an immediate-release formulation. Knowledge of the pharmacokinetics of these agents may improve the treatment of urge incontinence by allowing the identification of individuals at high risk for toxicity with 'usual' dosages. In addition, the use of alternative formulations (controlled-release oral, transdermal) may also facilitate adherence, not only by reducing the frequency of drug administration but also by enhancing tolerability by altering the proportions of parent compound and active metabolite in the blood.     

The use of NSAIDs in rheumatic disorders 2005: a global perspective

Population studies and World Health Organisation (WHO) statistics indicate that 10-50% of individuals suffer from musculoskeletal disorders. Up to 3% will be classified as disabled due to their bone and joint condition, and the majority will suffer from pain. Almost all will require non-steroidal anti-inflammatory drugs (NSAIDs) and other analgesics for their management. The large majority of this population is elderly and, hence, at greater risk of adverse effects to the NSAIDs. The NSAIDs are a necessary choice in pain management because of the integrated role of the cyclo-oxygenase (COX) pathway in the generation of inflammation and in the biochemical recognition of pain. For over 80 years the management of musculoskeletal pain was hampered by NSAID toxicity problems related to the traditional NSAIDs. In the early 1990s, paracetamol was recommended as the first-choice analgesic for osteoarthritis, but subsequent studies have shown that paracetamol has a significant gastrointestinal (GI) toxicity profile. In addition, it has lower analgesic efficacy than NSAIDs and is, thus, not an effective alternative to NSAIDs in any of the inflammatory arthritides. The identification of cyclo-oxygenase 2 (COX-2) and the subsequent introduction of the COX-2-selective inhibitor NSAID drugs was thought to be a major breakthrough with the expectation of a significant reduction in G/I side-effects. This has not been the case for celecoxib, and indeed for all COX-2-selective inhibitors when given with ASA. The COX-2-selective inhibitors also inhibit renal COX-2 with the potential for problems of fluid retention, oedema, hypertension and congestive heart failure. The major controversy with respect to the COX-2-selective inhibitors as a class has been the increase in myocardial infarction and other cardiovascular events observed in some studies. Thus, the initial expected global benefits of the COX-2-selective inhibitors may be outweighed by their potential for toxicity. Recent studies have shown that the use of a proton-pump inhibitor drug with traditional NSAIDs and with COX-2-selective inhibitors has been shown to significantly reduce GI symptoms and peptic ulceration. Thus, the traditional NSAIDs have been re-established as the preferred choice in the management of arthritis and musculoskeletal disorders.     

The safety of novel drugs used to treat irritable bowel syndrome

Introduction: Irritable bowel syndrome (IBS) is a chronic gastrointestinal (GI) disorder with a high prevalence. Besides efficacy, the safety of each drugs used to treat GI disorders is an important issue in the drug development process.

Areas covered: This article reviews all Phase I to IV clinical trials or case reports with results related to the safety of novel GI drugs. The drugs are currently approved or under evaluation for approval.

Expert opinion: Most of the reported adverse events were related to the GI tract with mild-to-moderate severity. Diarrhea was significantly higher versus placebo following use of linaclotide and renzapride, similar to that of constipation with ramosetron. Lubiprostone, linaclotide and rifaximin with low systemic bioavailability have less adverse events and exert more advantageous results. Asimadoline acts peripherally on κ-opioid receptors and is not associated with CNS side effects. As lubiprostone and linaclotide cause dose-dependent adverse events, starting the treatment with the lowest effective doses is advised. Ramosetron is under evaluation for diarrhea-predominant IBS due to its acceptable safety and tolerability, besides its efficacy. Rifaximin, asimadoline and renzapride are still in need of more long-term studies regarding their safety.     

Efficacy and adverse effects of drugs used to treat adult cystic fibrosis

Introduction: Cystic fibrosis (CF) is an autosomal recessive disease and is the most commonly seen monogenetic disease in Caucasians. The disease has various manifestations resulting from the abnormal thick secretions, most common being chronic lung infection and airway obstruction. Many new promising drugs have appeared on the horizon over the years. This review here is an attempt to bring together the various treatments being used to prolong and enhance the quality of life of CF patients.

Areas covered: A literature review of published as well as ongoing clinical trials, meta-analysis and systematic reviews regarding the drugs used in CF management was carried out using PubMed and Ovid databases.

Expert opinion: New concepts have been formed and some positive results in this direction have already led to the approval of cystic fibrosis transmembrane conductance regulator potentiator drug. Gene therapy and stem cell therapy are under development. The current therapies such as dornase alfa and pancreatic enzymes targeting the symptoms continue to evolve as they play an important complementary role. Development of new simple and cost-effective markers, which help assess the efficacy and safety of these constantly emerging new drugs, is also being investigated.     

A profile of the rat gastrointestinal toxicity of drugs used to treat inflammatory diseases

The gastrointestinal (GI) toxicity of some immunologic agents (IA) and some nonsteroidal anti-inflammatory agents (NAA) was studied in two rat models. The first model was designed to detect the potential of drugs for producing gastric lesions. Drugs were administered orally to fasted rats and the stomachs were examined 0.5, 1, 2, 4, 8, 16, and 32 hr after dosing. The second model was designed to evaluate the toxic effects on the small intestine. Drugs were administered daily by the oral route for 4 days. Groups of rats were killed at 24-hr intervals and the stomach and small intestine were examined. The results show that the drugs evaluated can be divided into three categories. One category consists of IA, which cause only gastric mucosal bleeding. The second category consisting of acetaminophen, aspirin, and oxaprozin, causes gastric mucosal bleeding and gastric submucosal lesions. The third category, composed of NAA, causes gastric mucosal and submucosal lesions and perforations and/or adhesions of the small bowel.     

Number needed to treat analyses of drugs used for maintenance treatment of bipolar disorder

Rationale  

Due to the episodic and chronic nature of bipolar disorder (BD), maintenance therapy represents a critical part of treatment; however, there is a paucity of studies comparing effectiveness of available long-term treatments.     

Toxic side effects of drugs used to treat Chagas' disease (American trypanosomiasis)

Chagas' disease (American trypanosomiasis) is an endemic parasitic disease in some areas of Latin America. About 16-18 million persons are infected with the aetiological agent of the disease, Trypanosoma cruzi, and more than 100 million are living at risk of infection. There are different modes of infection: (1) via blood sucking vector insects infected with T. cruzi, accounting for 80-90% of transmission of the disease; (2) via blood transfusion or congenital transmission, accounting for 0.5-8% of transmission; (3) other less common forms of infection, eg, from infected food or drinks or via infected organs used in transplants. The acute phase of the disease can last from weeks to months and typically is asymptomatic or associated with fever and other mild nonspecific manifestations. However, life-threatening myocarditis or meningoencephalitis can occur during the acute phase. The death rate for persons in this phase is about 10%. Approximately 10-50% of the survivors develop chronic Chagas' disease, which is characterized by potentially lethal cardiopathy and megacolon or megaoesophagus. There are two drugs available for the aetiological treatment of Chagas' disease: nifurtimox (Nfx) and benznidazole (Bz). Nfx is a nitrofurane and Bz is a nitroimidazole compound. The use of these drugs to treat the acute phase of the disease is widely accepted. However, their use in the treatment of the chronic phase is controversial. The undesirable side effects of both drugs are a major drawback in their use, frequently forcing the physician to stop treatment. The most frequent adverse effects observed in the use of Nfx are: anorexia, loss of weight, psychic alterations, excitability, sleepiness, digestive manifestations such as nausea or vomiting, and occasionally intestinal colic and diarrhoea. In the case of Bz, skin manifestations are the most notorious (e.g., hypersensitivity, dermatitis with cutaneous eruptions, generalized oedema, fever, lymphoadenopathy, articular and muscular pain), with depression of bone marrow, thrombocytopenic purpura and agranulocytosis being the more severe manifestations. Experimental toxicity studies with Nfx evidenced neurotoxicity, testicular damage, ovarian toxicity, and deleterious effects in adrenal, colon, oesophageal and mammary tissue. In the case of Bz, deleterious effects were observed in adrenals, colon and oesophagus. Bz also inhibits the metabolism of several xenobiotics biotransformed by the cytochrome P450 system and its reactive metabolites react with fetal components in vivo. Both drugs exhibited significant mutagenic effects and were shown to be tumorigenic or carcinogenic in some studies. The toxic side effects of both nitroheterocyclic derivatives require enzymatic reduction of their nitro group. Those processes are fundamentally mediated by cytochrome P450 reductase and cytochrome P450. Other enzymes such as xanthine oxidoreductase or aldehyde oxidase may also be involved.     

Changes in bone turnover, bone mineral and fracture risk induced by drugs used to treat epilepsy

Antiepileptic drugs (AEDs) have traditionally been associated with osteoporosis. However, recent studies have only shown a very limited increase in the risk of fractures with the use of some but not all AEDs. Patients with epilepsy have an increased risk of fractures, but this increase is mainly linked to fractures sustained during seizures. Patients with epilepsy may also have a decreased bone mineral density but this decrease is far too small to explain the increase in fracture risk. The decrease in bone mineral density is seen mainly in children with complicating diseases and developmental disorders that lead to vitamin D deficiency. Much of the increase in fracture risk may be due to the underlying disorder and the severity of seizures rather than to the drugs used to treat epilepsy. The prevention of seizures seems to be of greater importance than any potential detrimental effects of the AEDs on the skeleton, provided that vitamin D status is kept at an optimal level. From a fracture point of view most AEDs seem to be relatively safe.     

Pharmacokinetics and safety of recently approved drugs used to treat methicillin-resistant Staphylococcus aureus infections in infants,children and adults

Methicillin-resistant Staphylococcus aureus (MRSA) remains a significant cause of morbidity in hospitalized infants. Over the past 15 years, several drugs have been approved for the treatment of S. aureus infections in adults (linezolid, quinupristin/dalfopristin, daptomycin, telavancin, tigecycline and ceftaroline). The use of the majority of these drugs has extended into the treatment of MRSA infections in infants, frequently with minimal safety or dosing information. Only linezolid is approved for use in infants, and pharmacokinetic data in infants are limited to linezolid and daptomycin. Pediatric trials are underway for ceftaroline, telavancin, and daptomycin; however, none of these studies includes infants. Here, we review current pharmacokinetic, safety and efficacy data of these drugs with a specific focus in infants.     

Newly developed drugs invented to treat tuberculosis in clinical trial

Tuberculosis (TB) is a leading cause of morbidity and mortality in more than one-third of the world population. Its impact on global health is a result of decades of neglect for such an important infectious disease, lack of resources for national TB control programs, poor case detection, and inadequate/inappropriate therapy in high-burden countries. The worldwide dissemination of multidrug (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis poses a serious threat to human health due to inadequacy of long and cumbersome tuberculosis (TB) therapy. Treatment regimens consist of at least four drugs with different mechanisms of action. Several new molecules in clinical development hasencouraged the scientific community to discover new drug targets and new drug candidates. Therefore, new drugs are urgently needed to shorten and improve the treatment course in drug resistant TB, and to minimize the occurrence of new infections and death. Nowadays, various new investigational drugs, such as bedaquine (TMC207), nitroimidazoles (PA-824, OPC-67683), diamines (SQ109), oxazolidinones (Linezolid, PNU-100480 (Sutezolid), ADZ5847), pyrroles (LL3858) and fluoroquinolones (moxifloxacin and gatifloxacin), have entered clinical trials and are in progress to be developed for the treatment of MDR-TB. In this perspectivearticle, an overview of the new anti-TB drugs with different structures that are either being clinically used or in advanced stages clinical stages as well as of preclinical development are presented. This review provides snapshots of the efforts that are being made in the development of new drugs as lead anti-TB agents. Finally, it is crucial to improve the connection between research and development institutes, industries, drug control authorities, and international policy-making bodies to deliver efficacious therapies for patients who are suffering from TB.     

Acute toxicity to freshwater organisms of antiparasitic drugs for veterinary use

The acute toxicity of five antiparasitic drugs used in the veterinary field-amprolium hydrochloride (APH), bithionol (BT), levamisole hydrochloride (LVH), pyrimethamine (PYM) and trichlorfon (TRC)-to the aquatic organisms Oryzias latipes, Daphnia magna, and Brachionus calyciflorus was examined. The toxicity test with O. latipes was conducted in accordance with the OECD Guidelines for the Testing of Chemicals (1993) to determine the 24-, 48-, 72-, and 96-h LC(50) values. In addition, 24- and 48-h EC(50) values for D. magna and a 24-h EC(50) for B. calyciflorus were determined with the DAPHTOXKIT F(trade mark) magna (Creasel, Belgium) and the ROTOXKIT F(trade mark) (Creasel, Belgium), respectively. High-performance liquid chromatographic analysis revealed that APH, LVH, and PYM were stable in water, but BT was unstable, decreasing by 84% on average at 24 h. TRC rapidly decomposed, with only 0.7% of the initial concentration remaining after 96 h, forming dichlorvos. The toxicity of TRC to O. latipes was determined in two ways: exposure to the same medicated water for 96 h (static test) and exposure to medicated water replaced every 24 h (semistatic test). AMP, LVM, and PYM were tested in the static condition, and BT was tested in the semistatic condition. BT was most toxic to O. latipes, with a 96-h LC(50) of 0.24 mg L(-1), followed by PYM, with a 96-h LC(50) of 5.6 mg L(-1). The 24-, 48-, 72-, and 96-h LC(50) values of TRC in the static test were 92.0, 45.2, 29.5, and 17.6 mg L(-1), respectively, which tended to be lower than those in the semistatic test, especially late in the observation period. D. magna was the most susceptible to TRC, with a 48-h EC(50) as low as 0.00026 mg L(-1). The 48-h EC(50) values of BT, PYM, and LVH for D. magna were 0.3, 5.2, and 64.0 mg L(-1), respectively. B. calyciflorus was the most susceptible to BT, with an EC(50) of 0.063 mg L(-1), followed by PYM, with an EC(50) of 15.0 mg L(-1). Among the test compounds, APH was the least toxic to all the freshwater organisms tested, with a 96-h LC(50) of >600 mg L(-1) for O. latipes, a 48-h EC(50) of 227 mg L(-1) for D. magna, and an EC(50) of 403 mg L(-1) for B. calyciflorus.