Topical NSAIDs for musculoskeletal conditions. A review of the literature

In recent years a growing number of topical nonsteroidal anti-inflammatory drugs (NSAIDs) have become available. This has been prompted in large part by the high incidence of serious gastrointestinal adverse events associated with the use of systemic NSAIDs, and the premise that minimisation of plasma concentrations of active drug may result in fewer systemic adverse effects. Evidence in humans and animals with topical NSAIDs demonstrates lower plasma concentrations than with systemically administered drugs, while those in soft tissues are still of a magnitude considered consistent with exerting an anti-inflammatory effect. In joints, however, the evidence is less strong, and there is still dispute whether in this case the drug reaches the joint predominantly via the transcutaneous or systemic route. There has been a sufficient number of studies of soft tissue conditions to demonstrate the superiority of topical NSAIDs over placebo and to suggest equivalent efficacy in comparison with some oral NSAIDs. For arthropathies, however, the literature is more sparse. Although several studies claim a benefit for topical NSAIDs against placebo, the results are less conclusive and further study is required. Trials of topical agents against intra-articular corticosteroids and rubefacients are either lacking or inconclusive. The adverse event profile of topical agents is reasonable: minor cutaneous effects occur in up to 2% of patients but tend to be self-limiting. Gastrointestinal events appear from the existing literature to be infrequent and minor, although long term studies are required. Bronchospasm and renal impairment have been reported and may be more frequent in patients who have experienced these effects with oral agents. The initial costs of topical agents tend to be higher than those of oral agents but a cost-effectiveness analysis suggests an overall benefit: this issue requires further clarification.     

Infantile spasms associated with proximal duplication of chromosome 15q

Trabeculectomy has a reported success rate of between 67-94%. Many studies have been performed on operative variables which may influence surgical outcome. Youth, pigmented race and anterior segment inflammation have been shown to be associated with trabeculectomy failure. Little is known of the surgical outcome of trabeculectomy in one eye in relation to its partner, when surgery is standardized and the above known adverse conditions to trabeculectomy success are absent. We therefore carried out a prospective study on 62 patients who underwent bilateral trabeculectomies. There was a significant failure rate amongst pairs of eyes (postoperative intraocular pressure > or = 21 mmHg), with the majority of failures occurring within 6 months of surgery. Failure appeared to be associated with a longer period from diagnosis of glaucoma to surgery, and the use of a wider variety and number of topical medications. All other trabeculectomy complications occurred more commonly in any single eye, than in any pairs of eyes.     

Adjuvant post-operative therapy

About 90% of patients with Crohn's disease require surgery at some time in their lives but the clinical recurrence rate after surgery is about 50% within 5 years, with 50% requiring further surgery within 10 years. Endoscopic evidence of relapse can be found in 75% within 12 weeks of resection. There is therefore a major problem to be solved. The solution is less clear. Retrospective studies suggest that smoking is a major factor determining a poor prognosis after surgery and it is most important that patients are encouraged to stop. There is strong evidence linking diet with Crohn's disease but the mechanism and nature of this link remains unclear. A low total fat intake, possibly supplemented with eudragitcoated n-3 fatty acid (fish oil) looks reasonable on current evidence but not proven. Mesalazine and metronidazole are the drugs for which most supportive evidence is available. The individual trials of mesalazine have generally proved inconclusive and meta-analyses have been needed to demonstrate a significant beneficial effect (approximately halving the relapse rate at 1 year). More recent large controlled studies performed after the meta-analyses however have again proved negative and the benefit is probably more modest than the meta-analyses suggested. Metronidazole, 20 mg/day for the first 3 months after surgery, has been shown to reduce relapse by just over one-third with a beneficial effect that was surprisingly sustained throughout a 3 year follow-up period. Peripheral neuropathy is a problem and further studies are needed at lower dosage. Azathioprine, 1.5-2 mg/kg/day is effective as maintenance therapy but there is insufficient evidence to recommend its routine post-operative use, moreover it takes up to 3 months to have an effect. Although budesonide has been shown to delay the time to relapse in non-operated patients it, like other corticosteroids, has been shown to be no better than placebo when maintenance is assessed according to the proportion of patients who remain relapse-free after 1 year. Patients undergoing operation for Crohn's disease should therefore be strongly advised to stop smoking. A 3 month course of oral metronidazole plus continued maintenance with oral mesalazine can be justified on current evidence but further studies are needed.     

Perioperative assessment and management of risk from coronary artery disease

PURPOSE: To summarize available evidence on preoperative cardiac risk stratification so that the internist may 1) use clinical and electrocardiographic findings to stratify a patient's perioperative risk for myocardial infarction and death; 2) decide which tests provide useful additional risk-related information; and 3) understand the benefits, risks, and evidence surrounding the decision to undertake coronary revascularization before elective noncardiac surgery. DATA SOURCES: A MEDLINE search and review of the reference lists of identified articles. Sensitivities, specificities, and likelihood ratios for diagnostic tests were calculated, and a quality rating for study methods was applied. DATA EXTRACTION: Myocardial infarction and mortality were the major outcomes considered, and a quality rating for study methods was applied. DATA SYNTHESIS: Clinical and electrocardiographic findings, organized by multivariate prediction indices, accurately identify patients as having low, intermediate, or high risk for myocardial infarction or death. Pharmacologic stress imaging with thallium or echocardiography probably improves risk stratification for intermediate-risk patients having vascular surgery. These tests have not been shown to be effective prognostic indicators for patients having nonvascular surgery. No studies of angiography for risk prediction have been reported. Decision analyses and retrospective series suggest that the risks incurred by doing coronary angiography and revascularization before elective surgery outweigh the benefits. Prospective, controlled studies of coronary revascularization are lacking. Evidence from a randomized, controlled trial has shown a survival benefit with the perioperative use of beta-blockers in patients at risk for coronary artery disease. CONCLUSIONS: Evaluation of all surgical patients by use of clinical indices is recommended. Low-risk patients need no further evaluation before surgery. High-risk patients need optimal management of their high-risk problems, including (if appropriate) beta-blocker use, and may need to have their elective procedures canceled. Intermediate-risk patients probably benefit from further noninvasive stress testing, especially if they are having vascular surgery. Further clinical trials are needed for most areas of concern.     

Therapeutic potential of peptides in allergic disease

Immunotherapy with crude allergens prevents allergic symptoms in many patients, but its effects are temporary and variable. This type of intervention provokes a transient increase in IgE antibody synthesis that may produce untoward side effects. Recent research has suggested that such immunotherapy downregulates T-cell activity, indicating that regulation of proinflammatory T cells may be a critical mechanism of the therapeutic response. Animal studies have shown that T cells can be rendered anergic by the administration of nonimmunogenic, T-cell-active peptides. Peptides prepared by urea denaturation of purified allergens and by pepsin digestion of crude allergens have been evaluated in humans. Although evidence of specific immunosuppression was noted, allergic reactions occurred as well. Subsequently, researchers synthesized peptides representing short sequences from the protein chains of principal allergens, such as Amb a I of ragweed and Fel d I of cat. Assays of proliferation of T-cell lines from ragweed- and cat-sensitive patients have shown that relatively short sequences from these proteins are responsible for a major portion of the activity of the whole protein. One such cat peptide has shown no reactivity with human IgE. The characteristics of these peptides suggest they should be evaluated further in clinical trials of allergic patients. The anticipated outcome would be prolonged T-cell downregulation, which might result in suppression of late-phase allergic inflammation and IgE antibody synthesis. The question whether such changes will reduce clinical reactivity sufficiently to be clinically useful remains to be answered in future studies.     

Current options for the topical treatment of acne vulgaris

The etiopathogenesis of acne vulgaris, a common disorder of youth and adolescence, includes four primary processes: hyperkeratinization (plugging) of the pilosebacous follicles, increased testosterone levels, bacterial colonization with Propionibacterium acnes, and inflammation. No single agent has yet been developed that addresses all of these factors. Combination regimens, therefore, which usually include an antibiotic and an agent to reduce follicular plugging, have become the mainstay of treatment. Despite a relative dearth of new treatments for almost a decade, recent research has produced a number of new significant oral and topical agents. Azelaic acid, a naturally occurring dicarboxylic acid analogue, has shown promise, and a group of retinoids that include adapalene, tazarotene, and reformulations of tretinoin represent new and forthcoming agents for topical treatment of acne vulgaris. Some studies indicate that several of these agents are associated with less skin irritation than previous formulations while they retain potent comedolytic activity. Adapalene also possesses significant anti-inflammatory activity.     

A reader's guide to the evaluation of causation

In this article, we review the criteria used to establish a causal association. A literature search strategy will be outlined. We present a clinical scenario that was formulated to examine the evidence for nonsteroidal anti-inflammatory drugs as a possible cause of gastrointestinal ulceration and bleeding. Several of the studies identified in the literature search were critically appraised and the criteria needed to confirm a causal link were then applied. These guidelines may be employed to not only demonstrate the aetiology of a disease but have wider applicability in terms of determining whether a medication may be causing certain adverse events.     

Efficacy of silicone punctal plugs as adjuncts to topical pharmacotherapy of glaucoma--a pilot study. Punctal Plugs in Glaucoma Study Group

BACKGROUND: The concept of enhancing the ocular hypotensive effects of topical antiglaucoma medications by impeding lacrimal drainage of medication has been insufficiently studied. This investigation sought to evaluate the effect of bilateral inferior punctal occlusion using silicone punctal plugs on the ocular hypotensive effect of topically applied timolol. METHODS: A randomized, double-masked, cross-over clinical trial was conducted, comparing the ocular hypotensive effect of timolol maleate 0.25 percent, both with and without occlusion of the inferior punctum with the Freeman silicone punctal plug. Following a 2-week washout of topical medication, 17 subjects with early primary open-angle glaucoma or ocular hypertension received one drop of timolol 0.25 percent in each eye with or without punctal plugs in place. Blood pressure, resting pulse rate, and intraocular pressure were measured both before timolol instillation and at intervals of 1, 2, 4, 8, and 12 hours following drop instillation. Following a 2-week washout period, the subjects were evaluated with the alternative treatment. RESULTS: There was no statistically significant difference (p = 0.648) in IOP levels between treatment groups. CONCLUSIONS: This pilot suggests that need for a longer-term study with larger numbers of subjects to evaluate the potential role of silicone punctal plugs to enhance the ocular bioavailability of topically applied antiglaucoma medications.     

Intraarterial calcium stimulation test for detection of insulinomas

The choice of drugs to reduce pain and excessive inflammatory reactions after surgery or accidental trauma is reviewed and discussed, with particular reference to a series of Norwegian studies based on bilateral oral surgery. In this model, paracetamol has proved capable of reducing post-operative swelling by about 30%, while acetylsalicylic acid (in common analgesic doses) failed to reduce or even tended to increase swelling. Paracetamol is a recommendable alternative for reducing acute post-traumatic pain and swelling, while acetylsalicylic acid should be avoided. Non-steroidal anti-inflammatory drugs which efficiently reduce rheumatoid swelling may provide good pain relief, but the effect on an acute post-operative swelling is less impressive. In the oral surgical model, glucocorticoids reduced post-traumatic swelling by about 50% and provided better or at least as good pain relief as any tested non-steroidal anti-inflammatory drug, including paracetamol. Single dose or short-term administration of a glucocorticoid is recommended as an efficient and valuable means of reducing both pain and excessive inflammation in surgery and traumatology. Of practical implication in traumatology is the finding that, for both paracetamol and glucocorticoids, almost the same reductions were recorded in swelling and pain whether the drug was administered prior to surgery or 2-3 hours afterwards.     

Comparative analgesic efficacy of nimesulide and diclofenac gels after topical application on the skin

Nimesulide is a newer non-steroidal anti-inflammatory drug (NSAID) with selective cyclo-oxygenase (COX)-2 blocking property and has demonstrated a potent analgesic and anti-inflammatory activity on oral and rectal administration. However, the Cmax through both these routes is reached only after 3 h of administration. Dose-dependent gastrointestinal side effects also limit the concentration of drug that can be achieved at the site of inflammation when administered through these routes. The present study was conducted to evaluate the antinociception induced by a new gel formulation of nimesulide when applied on the skin. Efficacy of topical nimesulide gel 1% (w/w) was studied on mice in the acetic-acid-induced writhing, tail flick latency (TFL) test and formalin-induced pain models. The antinociceptive effect of nimesulide was compared to diclofenac gel (1% w/w). Both the drugs induced dose-dependent analgesia with peak effect seen between 90 and 120 min after treatment. Greater antinociceptive effect (expressed as percent maximum possible effect) was seen in the writhing test than in the TFL test, indicating the peripheral action of both drugs. Nimesulide evidenced significant protection in the first phase of formalin-induced pain indicating modulation of peripheral nociceptors unlike other conventional NSAIDs. This suggests that COX-2 may be a primary contributor to afferent evoked increase in prostanoid-mediated changes in pain processing. Antinociception seen following drug application on the skin was lower than that seen on intraperitoneal administration, indicating localised action following topical application. The findings of the present study suggest that the transgel formulation of nimesulide provides significant analgesic activity when applied topically.     

Pharmacokinetics of glibenclamide and its metabolites in diabetic patients with impaired renal function

P-glycoprotein, a membrane-associated transport protein, has recently been recognised as an important element of the intestinal epithelium. This paper summarises the in vivo data on the pharmacological role of intestinal P-glycoprotein. These data show that P-glycoprotein contributes to the elimination of many drugs by mediating their direct secretion from the blood into the intestinal lumen. In addition, there is also evidence that this protein can limit oral drug absorption. Hence, inhibition of intestinal P-glycoprotein, e.g. by a reversal agent like cyclosporin A, may be a promising strategy for improving the oral bioavailability of P-glycoprotein substrate drugs. Indeed, several preclinical and clinical studies have shown that coadministration of drugs with a reversal agent can substantially increase oral drug absorption.     

Treatment of Herpes simplex virus infections with topical antiviral agents

Clinical studies of topical therapy against Herpes simplex virus (HSV) infections have been reviewed. Idoxuridine (IDU) 15% in dimethyl sulfoxide (DMSO), interferons, and penciclovir result in significant clinical benefit against this virus. IDU reduced pain duration and decreased time to loss of crust in a study of 301 patients. Alpha-interferon has shown synergism with other anti-HSV drugs such as caffeine, trifluorothymidine (TFT), DMSO, and nonoxynol-9. Finally, in a study of over 2,000 patients, application of penciclovir cream, both early and late in the course of HSV infection, decreased the duration of lesions, pain, and viral shedding. Acyclovir (ACV)-resistant strains of HSV are susceptible to (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine (HPMPC), and ascorbic acid shows promising effects against HSV. Using a vehicle that enhances skin penetration of a drug or possibly further exploring combination therapy may result in efficacious treatment of HSV. The possibility of topical vaccination or topical gene therapy may also prove beneficial in the future.     

Is gene therapy in cystic fibrosis a realistic expectation?

To date there are 11 human protocols either ongoing or approved for gene therapy for cystic fibrosis (CF) in the United States. There are also two protocols in the United Kingdom and one in France. Of these, results have been published in four. The protocols vary in the cells targeted, the vectors used, and the frequency of administration, but despite these differences all have contributed toward answering the key questions that will determine the future of gene therapy for CF: the questions of efficacy and safety. These studies have demonstrated that it is feasible to transfer the normal human CF transmembrane conductance regulator complementary DNA to the respiratory epithelium and that this will lead to production of normal CF transmembrane conductance regulator protein and in some cases to a physiologic response. The most frequently used vector is the adenovirus. Obstacles to be overcome with this system include the need for improved and prolonged expression, efficacy on repeat administration, and decreased inflammation. Recent work on the immune response to adenoviral vectors may help achieve these goals. The cationic lipid method of gene delivery is less likely than adenovirus to cause inflammation, at least in the nose, but improved efficacy of gene transfer is necessary as well as improved complex stability. Furthermore, this system has yet to be tested in the lungs of individuals with CF. Finally, the adeno-associated virus, the other vector approved for human gene therapy studies in CF, has shown some promise in preclinical studies but remains to be tested in humans. The results of these studies give some cause for guarded optimism, but point out a number of problems that must be overcome before gene therapy for CF delivers on the promise of a safe effective treatment for this condition.     

Antimicrobial photosensitive reactions

Photosensitivity reactions are recognized as unwanted adverse effects of an array of commonly administered topical or systemic medications, including nonsteroidal antiinflammatory agents, antifungals, and antimicrobials. When a drug induces photosensitivity, exogenous molecules in the skin absorb normally harmless doses of visible and UV light, leading to an acute inflammatory response. In phototoxic reactions, the damage to tissues is direct; in photoallergic reactions, it is immunologically mediated. In vitro and in vivo assay systems can assist in predicting or confirming drug photosensitivity. The incidence of photosensitivity reactions may be too low to be detected in clinical studies and may become recognized only in the postmarketing stage of drug development. Some drugs have been withdrawn because of photosensitivity effects that appeared after general release. Photosensitivity reactions have been studied for a number of topical antimicrobials and for the sulfonamides, griseofulvin, the tetracyclines, and the quinolones. Incidence and intensity of drug phototoxicity can vary widely among the different compounds of a given class of antimicrobials. When phototoxic effects are relatively low in incidence, mild, reversible, and clinically manageable, the benefits of an antimicrobial drug may well outweigh the potential for adverse photosensitivity effects.     

Chronic non-allergic rhinitis. Etiology, diagnosis and treatment

Chronic rhinitis can be defined as an inflammation of the nasal mucosa lasting for more than three months. The condition may be due to allergy or infection, or to a number of non-allergic and non-infectious causes, such as trauma, hormonal imbalance, toxic influence or locally applied drugs. The etiology, diagnostic procedures and treatment of non-allergic chronic rhinitis are discussed.     

The prospects for gene therapy in cystic fibrosis

Gene therapy provides the best prospect of a fundamental new treatment for cystic fibrosis. The lungs are the most important target, because this organ is the most severely affected by the disease and is also accessible for topical treatment. Advances in this field have been very rapid, and the prospects remain good although a number of problems need to be overcome. The two main approaches to gene transfer, namely adenoviruses and liposomes, are efficient in vitro, but early clinical trials have shown that they work less well in vivo. A number of proof of concept studies have shown that gene transfer is possible, but full functional correction of the cystic fibrosis defect has not yet been achieved. Adenoviruses have provoked an inflammatory response, and new viral vectors are being developed to overcome this. Existing lipids are relatively inefficient, but new liposomes are being developed to enhance gene transfer. Much work needs to be done to improve safety and efficacy of gene transfer before materials are ready for large scale clinical trials. However, progress is very rapid, and there is a real prospect of developing an effective gene therapy for cystic fibrosis within the next decade.     

A randomized clinical trial of the nonsteroidal eyedrop diclofenac after strabismus surgery

OBJECTIVE: This study aimed to compare the anti-inflammatory and analgesic effects of topical diclofenac sodium 0.1% (Voltaren) with prednisolone sodium phosphate 1% ophthalmic solution after strabismus surgery. DESIGN: A prospective, double-masked, randomized, two-center clinical trial. PARTICIPANTS: Eighty eyes of 52 patients undergoing strabismus surgery were examined. INTERVENTION: For 1 week after surgery, the eye that was operated on received one drop of either diclofenac or prednisolone four times a day. MAIN OUTCOME MEASURES: The diclofenac- and prednisolone-treated eyes were compared on postoperative days 3 and 7 with respect to signs of inflammation (e.g., erythema, edema, discharge), patient comfort, and conjunctival incisional healing. RESULTS: On postoperative day 7, in eyes that received prednisolone, the conjunctival defects were larger (P = 0.004) and more frequent (P = 0.02). For all subjects, despite adequate statistical power, there was no statistically significant difference in inflammatory scores between eyes that received diclofenac or prednisolone. In cases of bilateral surgery, however, there was less postoperative erythema and edema in the diclofenac-treated eyes. CONCLUSIONS: In the first week after strabismus surgery, topical diclofenac proved at least as effective as prednisolone in controlling inflammation and discomfort with less delay in incisional wound healing. Topical diclofenac, a nonsteroidal anti-inflammatory agent, may be considered for use after strabismus surgery in place of corticosteroids.     

Possible dangers of anaesthesia in patients receiving fenfluramine. Results of animal studies following a case of human cardiac arrest

Following the report of the death of a patient concurrently taking fenfluramine, following routine general anaesthesia, a series of anaesthetised rabbits received injections of adrenaline or fenfluramine. There were abnormal electrocardiographic changes and phonocardiographic evidence of altered heart activity in both groups, but the changes seen with fenfluramine were greater in number and less readily reversed with beta blockers and resuscitative drugs. This evidence may support an interaction between halothane and fenfluramine in man, and it is suggested that the latter drug be discontinued for a week prior to anaesthesia for elective surgery.