Drugs

Ponti, Fabrizio; Tonini, Marcello

doi: 10.2165/00003495-200161030-00001pmid: 11293643

Although the past few years have seen an exponential growth of compounds of potential interest for the treatment of functional gastrointestinal (GI) tract disorders, the gap that still exists between basic and clinical research is easily noticed if one considers the relative paucity of drugs that have received marketing authorisation for the treatment of irritable bowel syndrome (IBS). Traditional efficacy outcomes in drug development for IBS include the ability of the compound to affect GI tract motility (i.e. to exert a prokinetic or an antispasmodic effect), which is thought to be of importance if a motor disorder is the underlying pathophysiological mechanism. More recently, altered visceral sensitivity to a distending stimulus has been suggested to be a key pathophysiological feature, at least in some patients, and has become a target for therapeutic interventions. However, there is now growing consensus that the primary outcome measure in the treatment of functional disorders are those that reflect overall control of the patient’s symptoms (pain, diarrhoea, constipation) in everyday situations such as the clinical global improvement scales. Although, in general, guidelines on the design of treatment trials for functional GI tract disorders advise against subcategorisation of patients according to the main symptom (because of symptom instability), subcategorisation indeed makes sense especially in IBS (constipation- or diarrhoea-predominant). Compounds with a specific indication for each subpopulation of patients are now emerging.

Mather, Laurence; Chang, Dennis

doi: 10.2165/00003495-200161030-00002pmid: 11293644

The recognition that long-acting local anaesthetics, particularly bupivacaine the de facto standard long-acting local anaesthetic, were disproportionately more cardiotoxic than their shorter-acting counterparts stimulated the development of the bupivacaine congeners, ropivacaine and levobupivacaine. These agents, like all local anaesthetics, can produce cardiotoxic sequelae by direct and indirect mechanisms that derive from their mode of local anaesthetic actions, i.e. inhibition of voltage-gated ion channels. While all local anaesthetics can cause direct negative inotropic effects, ropivacaine and levobupivacaine are less cardiotoxic than bupivacaine judging by the larger doses tolerated in laboratory animal preparations before the onset of serious cardiotoxicity (particularly electro-mechanical dissociation or malignant ventricular arrhythmias). Additionally, they are less toxic to the CNS than bupivacaine judging by the larger doses tolerated before the onset of seizures. This may be clinically important because CNS effects may be involved in the production of serious cardiotoxicity. Preclinical studies in humans are a ‘blunt instrument’ in their ability to distinguish significant differences between these drugs because of the relatively small doses that can be used. Nevertheless, available evidence from human studies corroborates the preclinical laboratory animal studies. Because clinically significant differences between these drugs are more quantitative than qualitative, i.e. toleration of a larger dose before manifestation of toxicity, we have concluded that these newer agents have a lower risk of causing serious cardiotoxicity than bupivacaine. Thus, compared with bupivacaine, the newer agents may be seen as ‘safer’, but they must not be regarded as ‘safe’.

Toivanen, Auli

doi: 10.2165/00003495-200161030-00003pmid: 11293645

Reactive arthritis (ReA) is definitely caused by an infection. Several observations suggest that the triggering microbe may persist in the tissues of the patient for a prolonged time. The obvious conclusion is to consider antibacterial treatment. In two instances antibacterial agents are of definite value: in the primary and secondary prevention of rheumatic fever and for early eradication of Borrelia burgdorferi in order to prevent development of the arthritis associated with Lyme disease. Altogether, clinical and experimental data exist to indicate that if antibacterial treatment of ReA can be started very early during the pathogenetic process, the disease can be prevented or the prognosis improved. In fully developed ReA, the value of antibacterial agents is less certain. All available evidence indicates that short term antibacterial treatment has no effect on the prognosis and final outcome of ReA, and the results with long term administration of anti-bacterials are also overall poor. In some instances sulfasalazine appears useful, rather as a result of its antirheumatic effect or influence on an underlying inflammatory bowel disease than its action as an antibacterial agent. Tetracyclines have also been found to have an effect on ReA, but again, this is probably due to their anti-inflammatory action rather than any antibacterial effect.

Guay, David

doi: 10.2165/00003495-200161030-00004pmid: 11293646

There have been few recent reviews of the nitrofurans in the literature, and none include recently available data on the use of nitrofurazone (nitrofural) in the prevention of catheter-associated urinary tract infection (CAUTI). Nitrofurazone and nitrofurantoin are the only nitrofurans that have become established in clinical use in the 20th century. These 2 nitrofurans have remained clinically useful against a wide spectrum of Gram-positive and Gram-negative bacteria, including many strains of common urinary tract pathogens. Today, the primary use of nitrofurantoin is as an oral antibacterial treatment for genitourinary infections. Nitrofurazone is primarily used as a topical antibacterial agent in burns and skin grafts and recently was approved for the prophylaxis of CAUTI. The recent development of a nitrofurazone-impregnated catheter as a novel modality in the prevention of CAUTI reflects a renewed interest in the effectiveness of nitrofurans. In an era when concern about bacterial resistance to many anti-infective agents is growing, the nitrofurans have continued to be active against organisms that have developed resistance to antibacterials. The presence of multiple mechanisms of action for the nitrofurans might be expected to reduce the ability of bacteria to develop resistance. Considering that an emergence of resistance to the nitrofurans has not appreciably occurred after several decades of clinical use, the nitrofurans may be unique among common antibacterial agents in this regard.

Yang, Xi

doi: 10.2165/00003495-200161030-00005pmid: 11293647

Allergy in patients with atopy is caused by clinical adverse reactions to environmental antigen, which is often associated with allergen-specific immunoglobulin (Ig)E production. Since allergy reflects an inappropriate immunological reaction, a therapeutic approach related to immunology is likely to actively alter the natural course of allergic disorders. Allergen immunotherapy, known at various times as desensitisation or hyposensitisation, is very recently defined by the World Health Organization as therapeutic vaccines for allergic diseases.

Karmazyn, Morris; Sostaric, John; Gan, Xiaohong

doi: 10.2165/00003495-200161030-00006pmid: 11293648

The myocardial Na+/H+ exchange (NHE) represents a major mechanism for pH regulation during normal physiological processes but especially during ischaemia and early reperfusion. However, there is now very compelling evidence that its activation contributes to paradoxical induction of cell injury. The mechanism for this most probably reflects the fact that activation of the exchanger is closely coupled to Na+ influx and therefore to elevation in intracellular Ca2+ concentrations through the Na+/Ca2+exchange. The NHE is exquisitely sensitive to intracellular acidosis; however, other factors can also exhibit stimulatory effects viaphosphorylation-dependent processes. These generally represent various autocrine and paracrine as well as hormonal factors such as endothelin-1, angiotensin II and α1-adrenoceptor agonists, which probably act through receptor-signal transduction processes.

Holimon, Teresa; Chafin, Carol; Self, Timothy

doi: 10.2165/00003495-200161030-00007pmid: 11293649

Asthma is an inflammatory disease of the airways that is frequently characterised by marked circadian rhythm. Nocturnal and early morning symptoms are quite common among patients with asthma. Increased mortality and decreased quality of life are associated with nocturnal asthma. Although numerous mechanisms contribute to the pathophysiology of nocturnal asthma, increasing evidence suggests the most important mechanisms relate to airway inflammation. According to international guidelines, patients with persistent asthma should receive long term daily anti-inflammatory therapy. A therapeutic trial with anti-inflammatory therapy alone (without a long-acting bronchodilator) should be assessed to determine if this therapy will eliminate nocturnal and early morning symptoms. If environmental control and low to moderate doses of inhaled corticosteroids do not eliminate nocturnal symptoms, the addition of a long-acting bronchodilator is warranted.

Leighton, Carol

doi: 10.2165/00003495-200161030-00008pmid: 11293650

Scleroderma or systemic sclerosis is a rare condition with many clinical manifestations including Raynaud’s phenomenon. As with many other rarely encountered diseases, drug therapy for scleroderma is often empirical with little evidence in the form of randomised controlled trials to aid drug choice.