Conventional Pharmacotherapy Research Articles

Cell and Gene Therapies for Refractory Epilepsy

Despite recent advances in the development of antiepileptic drugs, refractory epilepsy remains a major clinical problem affecting up to 35% of patients with partial epilepsy. Currently, there are few therapies that affect the underlying disease process. Therefore, novel therapeutic concepts are urgently needed. The recent development of experimental cell and gene therapies may offer several advantages compared to conventional systemic pharmacotherapy: (i) Specificity to underlying pathogenetic mechanisms by rational design; (ii) specificity to epileptogenic networks by focal delivery; and (iii) avoidance of side effects. A number of naturally occurring brain substances, such as GABA, adenosine, and the neuropeptides galanin and neuropeptide Y, may function as endogenous anticonvulsants and, in addition, may interact with the process of epileptogenesis. Unfortunately, the systemic application of these compounds is compromised by limited bioavailability, poor penetration of the blood-brain barrier, or the widespread systemic distribution of their respective receptors. Therefore, in recent years a new field of cell and gene-based neuropharmacology has emerged, aimed at either delivering endogenous anticonvulsant compounds by focal intracerebral transplantation of bioengineered cells (ex vivo gene therapy), or by inducing epileptogenic brain areas to produce these compounds in situ (in vivo gene therapy). In this review, recent efforts to develop GABA-, adenosine-, galanin-, and neuropeptide Y- based cell and gene therapies are discussed. The neurochemical rationales for using these compounds are discussed, the advantages of focal applications are highlighted and preclinical cell transplantation and gene therapy studies are critically evaluated. Although many promising data have been generated recently, potential problems, such as long-term therapeutic efficacy, long-term safety, and efficacy in clinically relevant animal models, need to be addressed before clinical applications can be contemplated.

Review article: the role of antibiotics vs. conventional pharmacotherapy in treating symptoms of irritable bowel syndrome

The concept of augmenting the management of irritable bowel syndrome with antibiotics is evolving, and many questions remain regarding this therapy relative to known and hypothesized irritable bowel syndrome pathophysiology. The clinical evidence of small intestinal bacterial overgrowth as an important aetiology of irritable bowel syndrome continues to accumulate. Clinical symptoms of bacterial overgrowth and irritable bowel syndrome are similar; however, a definitive cause-and-effect relationship remains unproven. It is unclear whether motility dysfunction causes bacterial overgrowth or gas products of enteric bacteria affect intestinal motility in irritable bowel syndrome. To discusses the efficacy and tolerability of current symptom-directed pharmacotherapies and of antibiotics in the treatment of irritable bowel syndrome. A computerized search of PubMed was performed with search terms "IBS", "pharmacotherapy" and "antibiotics". Relevant articles were selected, and the reference list of selected articles was reviewed to identify additional references. Antibiotic treatment benefits a subset of irritable bowel syndrome patients. The non-absorbed antibiotic rifaximin has a favourable safety and tolerability profile compared with systemic antibiotics and demonstrates a therapeutic efficacy comparable with symptom-based irritable bowel syndrome pharmacotherapies. Rifaximin is the only antibiotic with demonstrated sustained benefit beyond therapy cessation in irritable bowel syndrome patients in a placebo-controlled trial. Whether antibiotics can improve quality of life in patients with irritable bowel syndrome warrants further research.

MTP inhibition as a treatment for dyslipidaemias: time to deliver or empty promises?

The development of cholesterol-lowering drugs, including a statins, bile acid sequestrants and cholesterol absorption inhibitors has expanded the options for cardiovascular prevention. Recent treatment guidelines emphasise that individuals at substantial risk for atherosclerotic coronary heart disease should meet defined lipid targets. Combination therapy with drugs that have different and complementary mechanisms of action is often needed to achieve these goals. Existing approaches to the treatment of hypercholesterolaemia are still ineffective in halting the progression of coronary artery disease in some patients despite combination therapies. Other patients are resistant to, or intolerant of, conventional pharmacotherapy and remain at high-risk of atherosclerotic cardiovascular disease, so that alternative approaches are needed. New agents, including inhibitors of microsomal triglyceride transfer protein (MTP), may play a future role, either alone or in combination, in the treatment of hyperlipidaemias. This review focuses on novel approaches to treat dyslipidaemias via the inhibition of MTP. Patients most suitable for use of MTP inhibitors include those with hepatic hypersecretion of apoB, including the metabolic syndrome, Type 2 diabetes mellitus and familial combined hyperlipidaemia, as well as homozygous and heterozygous familial hypercholesterolaemia. However, certain safety issues with these agents need resolving, particularly fatty liver disease.

Immunoadsorption Plasmapheresis Using a Phenylalanine Column as an Effective Treatment for Lupus Nephritis

Immunoadsorption plasmapheresis (IAPP) is effective for eliminating pathogenic molecules such as anti-DNA antibody (anti-DNA Ab) and immune complexes from the serum of patients with systemic autoimmune diseases. The purpose of this study was to assess patients with lupus nephritis (LN) treated by IAPP using a phenylalanine column and determine its efficacy with respect to conventional therapies. Six patients (M = 1, F = 5) with histologically proven LN associated with proteinuria and abnormal sedimentation on urinalysis were the subjects for this study. All were treated with oral corticosteroid (prednisolone 1 mg/kg/day) and IAPP (Immusorba PH - 350; 2 L of plasma twice weekly for 2 weeks). Serum anti-DNA Ab and complement, urinary protein, and creatinine clearance were measured over 6 weeks (pretreatment, before and after each of 2 IAPP sessions, and 1 and 4 weeks after the second IAPP session). Clinical efficacy of IAPP was compared with conventional pharmacotherapy regimes by conducting a retrospective review of 23 LN patients treated at our hospital using corticosteroid pulse therapy (CSPT, N = 7, intravenous methylprednisolone 500 mg/day for 3 days), intravenous cyclophosphamide pulse therapy (IVCY, N = 7), or corticosteroid monotherapy (CSMT, N = 9, oral prednisone 1 mg/kg body weight daily, for 4 weeks). Immunosuppressants and anticoagulants were not used. With IAPP, mean urinary protein excretion decreased from 2.2 +/- 1.7 g/day pretreatment to 0.4 +/- 0.6 g/day post-treatment (P < 0.001). Mean serum anti-DNA Ab also decreased from 84.0 +/- 88.1 U/mL pretreatment to 5.8 +/- 5.5 U/mL post-treatment (P < 0.05). In combination with corticosteroid therapy, IAPP would appear to be an effective and safe treatment for LN.

Recent Progress in Pharmacological and Non-Pharmacological Treatment Options of Major Depression

In spite of recent progress in the pharmacotherapy of depression major issues are still unresolved. These include the non-response rate of approximately 30% to conventional antidepressant pharmacotherapy, side effects of available antidepressants and the latency of several weeks until clinical improvement. The only non-pharmacological biological treatment options available so far which exert more rapid antidepressant efficacy are electroconvulsive therapy and, as an augmentation strategy, sleep deprivation. Current pharmacological treatments aim to enhance serotonergic and/or noradrenergic neurotransmission. In spite of emerging knowledge, the crucial mechanisms underlying both non-pharmacological treatments, which are responsible for antidepressant efficacy, are not yet clear so far. In the meantime several new pharmacological principles are under investigation with regard to their putative antidepressant potency. These include 5-HT1A receptor agonists, tachykinin receptor antagonists and various interventions within the hypothalamic-pituitary-adrenal system. While there is evidence for antidepressant properties of these new treatments in animal studies, in case series, in open studies and to some degree also in placebo controlled studies, no definite proof for the antidepressant efficacy of these new pharmacological strategies according to the requirements for evaluation of antidepressant drugs has been furnished so far. In contrast, for the established non-pharmacological treatment strategies including bright light therapy the clinical efficacy has been proven at least in subgroups of depression, but more knowledge of the main mechanisms underlying their antidepressant efficacy is still necessary. In addition new non-pharmacological treatments like repetitive transcranial magnetic stimulation, magnetic seizure therapy and Vagus nerve stimulation are currently under development. Nevertheless, a follow-up of both the new pharmacological strategies and non-pharmacological treatment options is of major importance to provide even better strategies for the clinical management of depression, which also is of great socio-economic impact.

Emotional processing in schizophrenia

Introduction. Persons with schizophrenia have impaired emotional processing, involving experience, expression, and recognition of emotions. Methods. This article reviews the historical descriptions and more recent work on emotion processing in schizophrenia. Results. Although abilities of emotional processing relate directly to interpersonal communication and psychosocial functioning, methodological issues exist in the current body of studies and resultant knowledge, which limit translation to novel treatment options. Conclusions. Further improvement in emotion processing in persons with stable schizophrenia are unlikely to result from conventional pharmacotherapy of psychosis. New treatment modalities and behavioural interventions offer possible improvements in quality of life and psychosocial functioning.

New biological treatment approaches to obsessive compulsive disorder (OCD)

OCD is a prevalent and disabling lifespan disorder with a life time prevalence of between 2 and 3%. First line pharmacotherapy are selective serotonine reuptake inhibitors (SSRIs) or clomipramine in comparatively high dosages which have been shown to the effective in acute and long-term studies (1). However, a part of the patients do not respond to conventional pharmacotherapy and also in responders, the effect is limited to a mean reduction of symptoms of between 20 and 40% and remission rarely occurs. A couple of studies performed in the last years demonstrated that about 50% of therapy refractory patients with OCD improve with lower doses of atypical antipsychotics added to SSRIs. A further and highly interesting treatment approach is deep brain stimulation (DBS) which has been tested in several case series of patients with severe and treatment refractory OCD (2). Despite single reports on dra-matic effects results are still inconclusive. The implications of the studies with atypical antipsychotics and with DBS on the understanding of the pathophysiology of OCD will be ad-dressed.

The Role of Extracorporeal Membrane Oxygenation in the Management of Infants with Congenital Diaphragmatic Hernia

Many infants with CDH can be managed with conventional mechanical ventilation and pharmacotherapy. However, some infants will require levels of ventilator support that are not compatible with survival. In these circumstances, extracorporeal membrane oxygenation (ECMO) has been used with varying results. The indication, type, and timing of ECMO in relation to surgery continue to evolve in an attempt to improve the outcome. At the same time, there is growing body of literature showing adverse outcomes among infants with CDH treated with ECMO, raising questions about the usefulness of ECMO in CDH. This paper reviews some of the controversies associated with the use of ECMO in CDH.

Is there an association between ephedra and heart failure? a case series

Background Ephedra is a sympathomimetic commonly used for the purposes of athletic performance enhancement and weight loss. It is known to be associated with gastrointestinal and psychiatric manifestations. We report here on 6 cases of dilated cardiomyopathy associated with ephedra use. Methods and results Over a period of 18 months, 6 patients attending our outpatient department with new onset heart failure were noted to have exposure to ephedra. The case record was reviewed and detailed clinical and echocardiographic data were extracted. All 6 patients (4 males) had left ventricular dysfunction at presentation (mean ejection fraction 20 ± 5%) and were treated with conventional heart failure pharmacotherapy. All patients discontinued ephedra use as advised. New York Heart Association class improved from class III in 5 patients (class II in 1 patient) to class I, within a median of 6 months (range 3–96). Ejection fraction improved to a mean of 47 ± 6%. Conclusions Ephedra may be associated with left ventricular systolic dysfunction. Withdrawal of this agent, in conjunction with proven pharmacotherapy, results in a significant improvement in functional status and left ventricular ejection fraction. We recommend specific enquiry into the use of over-the-counter supplements, particularly ephedra and its derivatives, when being evaluated with heart failure symptoms. These cases illustrate the potential risk of ephedra and provide additional support for the recent decision to ban this supplement.

Herb–drug interactions: an overview of the clinical evidence

Herbal medicines are mixtures of more than one active ingredient. The multitude of pharmacologically active compounds obviously increases the likelihood of interactions taking place. Hence, the likelihood of herb-drug interactions is theoretically higher than drug-drug interactions, if only because synthetic drugs usually contain single chemical entities. Case reports and clinical studies have highlighted the existence of a number of clinically important interactions, although cause-and-effect relationships have not always been established. Herbs and drugs may interact either pharmacokinetically or pharmacodynamically. Through induction of cytochrome P450 enzymes and/or P-glycoprotein, some herbal products (e.g. St John's wort) have been shown to lower the plasma concentration (and/or the pharmacological effect) of a number of conventional drugs, including cyclosporine, indinavir, irinotecan, nevirapine, oral contraceptives and digoxin. The majority of such interactions involves medicines that require regular monitoring of blood levels. To date there is less evidence relating to the pharmacodynamic interaction. However, for many of the interactions discussed here, the understanding of the mechanisms involved is incomplete. Taking herbal agents may represent a potential risk to patients under conventional pharmacotherapy.

TREATMENT OF ALZHEIMER’S DISEASE WITH A COMBINATION OF LASER, MAGNETIC FIELD AND CHROMO LIGHT (COLOUR) THERAPIES: A DOUBLE-BLIND CONTROLLED TRIAL BASED ON A REVIEW AND OVERVIEW OF THE ETIOLOGICAL PATHOPHYSIOLOGY OF ALZHEIMER’S DISEASE

Alzheimer’s disease presents a major problem as far as successful treatment is concerned, which is exacerbated by the ageing of the world’s population, and the increasing number of elderly in the ‘at risk’ age groups. Low reactive-level laser therapy (LLLT) has been reported as having beneficial effects on the blood vascular and neurological systems, including the regeneration of degenerated axons. The present study with 154 AD patients examined LLLT used as a monotherapy (intravenous HeNe laser irradiation) as well as magnetic field therapy (MFT), light chromotherapy (LCT) and conventional AD pharmacotherapy all as monotherapies, compared with a placebo control group. A further group received a combination of LLLT, MFT and LCT (the LMLCT group). Patients were assessed using the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) before treatment and at the end of the 18-month treatment regimen. LLLT and MFT significantly slowed down AD-related deterioration compared with controls (p‹0.05), but theLMLCTgroup was even more significantly effective (p‹0.001). Of all the monotherapies, LLLT was the most effective compared with the others, but the differences were not statistically significant. This may have been a factor of the low statistical power of the study due to small group numbers. Pharmacotherapy was the second most efficacious approach, but is associated with severe side effects particularly in elderly patients, and is often contraindicated. The results of the sudy suggest that combined LLLT, MFT and LCT is a safe, effective, easy-to-deliver, well-tolerated and side effect free therapeutic approach for slowing down the deterioration associated with AD.

24-H MONITORING OF ARTERIAL PRESSURE IN HYPERTENSIVE PATIENTS TREATED WITH PULSE LOW-FREQUENCY ALTERNATING ELECTRIC FIELD

The effect of pulse low-frequency alternating electric field (HIVAMAT-200 unit) on 24-h profile of arterial pressure was studied in 30 hypertensive patients. The evidence obtained at 24-h blood pressure monitoring showed that the above physiotherapy increased a nocturnal surge of arterial pressure and normalized its 24-h profile more effectively than conventional pharmacotherapy.

Role of thiopentone infusion for management of intractable status epilepicus in pediatric patients

Intractable status epilepticus not responding to conventional pharmacotherapy is a medical emergency. Deeper suppression of cortical activity, documented electrocerebral silence and titrable length of time during which such electrocerebral silence can be maintained all make thiopentone the ideal drug for initial management of status epilepticus [1,2]. A long-lasting anti-epileptic drug regimen can be established during thiopentone-induced burst suppression, which can then be tapered and discontinued with minimal chances of recurrence.

Expanded PTFE bladder neck slings for incontinence in children: the long-term outcome.

To assess the long-term outcome of circumferential expanded PTFE (Gore-tex, WL Gore Associates, Scotland) bladder neck slings for achieving urethral continence in children with a neuropathic bladder. The records were reviewed of 19 children undergoing bladder reconstruction (most with a neuropathic bladder) who had a Gore-tex sling placed circumferentially at the bladder neck, over a 5-year period. Of these, seven had spina bifida; two each spinal dysraphism, surgery for anorectal anomalies and an idiopathic neuropathic bladder; five who developed a neuropathic bladder from other causes, and one born with bladder exstrophy. All children had an uncompliant bladder with a low urethral leak-point pressure on preoperative urodynamics. In all children conventional clean intermittent catheterization and pharmacotherapy had failed. Four had had previous augmentation surgery while 15 had concomitant bladder augmentation and formation of a Mitrofanoff stoma. The main outcome measure was achieving dryness. The original intention of the procedure was also to maintain urethral catheterization. Full details of the follow-up were available in 17 patients. Despite initial good short-term results, at a median follow up of 7 years, in 14 patients the sling had to be removed because of erosion, often with transient urethral leakage before the bladder neck subsequently closed. A bladder calculus was associated with each case of erosion except one. Although in the short term this technique had favourable results, it was not a useful technique in the long term.

Neurotrophic factors for the investigation and treatment of movement disorders.

Neurotrophic factors (NFs) are proteins that enhance neuronal survival, differentiation, neurotransmitter function and resistance to neurotoxins and lesions. For these reasons the NFs are considered as a new potential therapeutic tool for the treatment of neurodegenerative disorders, a group of diseases that produce the most important cause for disability in the Western world. Some NFs prevent or even reverse the behavioral, biochemical, pharmacological and histological abnormalities observed in several in vitro and in vivo models of neurodegenerative disorders, namely Parkinson's disease. Several NFs have been investigated in primate models of neurological disorders and some of them have been used for patients with these diseases. The results so far obtained in humans have been disappointing for several reasons, including technical problems for delivery, unbearable side effects or lack of efficacy. Future approaches for the use of NFs in humans should include the following: (1) Investigation of the putative compounds in animal models more related to the pathophysiology of each disease, such as in genetic models of neurodegenerative diseases; (2) New methods of delivery including genetic engineering by viral vectors and administration through implantable devices; (3) More precise methods of continuous response evaluation, including the novel neuroimaging techniques; (4) Investigation of the effects of behavioral stimulation and conventional pharmacotherapy on the metabolism of NFs.

Tumor implantation in mouse humerus evokes movement-related hyperalgesia exceeding that evoked by intramuscular carrageenan

In this paper we compare two innovative models of movement-related pain: tumor-induced nociception following implantation of fibrosarcoma cells into bone and muscle inflammation-induced nociception following injection of the irritant carrageenan into muscle. Importantly, using the grip force test, an assay of movement-related hyperalgesia, both non-malignant and malignant pain are examined in parallel. Movement-related hyperalgesia, known clinically as a specific type of ‘breakthrough pain’, is a common feature of bone cancer and is thought to be a predictor of poor response to conventional analgesic pharmacotherapy ( Bruera et al., 1995, J. Pain Symptom. Manage. 10 (1995) 348; Mercadaute et al., 1992, Pain 50 (1992) 151; Pain 81 (1999) 129). Implantation of NCTC 2472 sarcoma cells in both humeri or injection of carrageenan (4%) in both triceps of C3H/He mice produced apparent forelimb hyperalgesia that was not associated with mechanical hyperalgesia in the forepaw, whereas carrageenan at 6 and 8% did evoke significant cutaneous hyperalgesia of the forepaw as well. Control groups receiving implants of vehicle or no treatment at all did not manifest this forelimb hyperalgesia. B6C3/F1 mice implanted with non-lysis-inducing G3.26 melanoma cells or vehicle did not manifest significant hyperalgesia when compared to B6C3/F1 mice receiving fibrosarcoma cells, indicating a dependence on bone involvement for induction of hyperalgesia in this model. Histological examination at days 3, 7, and 10 post-implantation showed a clear correlation of tumor growth-induced bone destruction with behavioral hyperalgesia. Morphine was more potent in decreasing the maximal hyperalgesia induced by carrageenan than that induced by tumor implantation. Acutely administered morphine (3–100 mg/kg, i.p.) attenuated peak hyperalgesia of carrageenan-injected mice (ED 50 6.9 mg/kg) and tumor-bearing mice (ED 50 23.9 mg/kg) in a dose-related manner with a difference in potency of 3.5. Tumor-implanted mice with a level of hyperalgesia comparable to that induced by carrageenan required almost three times more morphine (ED 50 18.5 mg/kg) for equivalent attenuation of forelimb hyperalgesia. These animal models of movement-related hyperalgesia may aid in discerning the peripheral and central mechanisms underlying pain that accompanies bone metastases and distinguishing it from the pain associated with muscular inflammation. Importantly, they may also aid in predicting differences in analgesic efficacy in different types of musculoskeletal pain.

Pathological peptide folding in Alzheimer's disease and other conformational disorders.

Main neuropathological hallmarks of Alzheimer's disease (AD) and other neurodegenerative disorders are the deposition of neurofibrillary tangles consisting of abnormally phosphorylated protein tau and of senile plaques largely containing insoluble beta-amyloid peptides (A beta), containing up to 43 amino acid residues derived from the beta-amyloid precursor protein. Such A beta-sheets become visible by using suitable histochemical methods. Molecular simulation showed that the central, alpha-helical, lipophilic, antigenic folding domain of the A beta-peptide loop is a promising molecular target of beta-sheet breakers that thus prevent the polymerization of A beta into aggregates. It seems that di- and tetramers of A beta-peptides have a beta-barrel- like structure. In the present review, an optimized neural network analysis was applied to recognize possible structure-activity relationships of peptidomimetic beta-sheet breakers. The anti-aggregatory potency of beta-sheet breakers largely depends upon their total, electrostatic, and hydration energy as derived from their geometry-optimized conformations using the hybrid Gasteiger-molecular mechanics approach. Moreover, we also summarize peptide misfolding in several disorders with distinct clinical symptoms, including prion diseases and a broad variety of systemic amyloidoses, as the common pathogenic step driving these disorders. In particular, conversion of nontoxic alpha-helix/random-coils to beta-sheet conformation was recognized as being critical in producing highly pathogenic peptide assemblies. Whereas conventional pharmacotherapy of AD is mainly focused on restoring cholinergic activity and diminishing inflammatory responses as a consequence of amyloid accumulation, we here survey potential approaches aimed at preventing or reserving the transition of neurotoxic peptide species from alpha-helical/random coil to beta-sheet conformation and thus abrogating their effects in a broad variety of disorders.

Healing through social and spiritual affiliation.

Two very different approaches can be employed to promote recovery from psychiatric disorders. One approach is grounded in an understanding of individual psychopathology, and it is clearly central to contemporary care. The second approach to recovery, which is based on group psychology and the support derived from participation in a group, can also be valuable in promoting recovery. In examining this second approach, I consider Alcoholics Anonymous (AA) and other movements that operate through social and ideologically grounded support. The term “spiritual recovery movement” (1) can be applied to them. On the basis of studies that I and my colleagues have conducted, I describe a psychological model to clarify the operation of such groups. Charismatic groups Social and spiritual recovery can be considered from the perspective of naturally occurring, highly cohesive, and religiously oriented cultic groups, two of which I have studied. One was the Divine Light Mission, headed by a guru who began preaching at the age of six in his native India. Members’ responses to a research questionnaire indicated a reduction in their symptoms of psychological distress after they joined the group, and the extent of the reduction was significantly correlated with the intensity of the social cohesiveness a member felt toward the group (2). Further clarification of the psychology of cultic groups emerged from our studies of the Unification Church, the “Moonies.” Using two scales I found that the stronger an individual’s affiliative feelings toward the group, the greater his or her psychological wellbeing (3). A study of long-term members who were matched to their future spouses by the Reverend Moon

Anti-T-cell strategies in the treatment of allergic disease.

Specific allergen immunotherapy (SIT) has been shown to be effective in modulating allergic responses in diseases such as rhinitis and asthma. However, the ability of whole allergen to cross link mast cell bound IgE, resulting in release of mediators such as histamine, has limited the application of this therapy to carefully selected patients who have failed conventional pharmacotherapy. The use of peptide sequences corresponding to T cell epitopes of the allergen has been postulated as an alternative to SIT in which high molar doses of T cell epitope can be delivered over a shorter time period and with improved safety. Using peptides from the sequence of the major cat allergen, Fel d 1, we have demonstrated the ability to induce transient T cell activation, resulting in isolated late asthmatic reactions, which are followed by prolonged periods of allergen-specific hyporesponsiveness, both to peptide re-challenge and to cutaneous challenge with whole allergen. Thus, peptide therapy may prove safe and efficacious in the treatment of allergic diseases.

Inhibition of human T-cell responses by allergen peptides.

Of the many significant advances in the field of immunology that have occurred in the last 30 years arguably the most important, at least from a T-cell biologists point of view, has been the definition of major histocompatibility complex (MHC) restriction1 and the crystal structure of human leucocyte antigen (HLA) molecules.2–4 These demonstrations have enabled detailed study of the way in which T cells recognize antigen and also how this process differs from that in B cells. With a few notable exceptions, production of specific immunoglobulin by B cells is T-cell dependent. Furthermore, recruitment of non-lymphoid effector cells into areas of inflammation is a process largely marshalled by the T lymphocyte. It follows therefore that inhibition of T-cell function may have beneficial outcomes in situations in which detrimental immune responses occur and give rise to pathology. Suppression of T-cell function has been achieved with the use of pharmacological agents, such as glucocorticosteroids and cyclosporin, and more recently with biological agents, such as monoclonal antibodies directed against CD3 and CD4. Whilst achieving the desired aim of immunosuppression, these approaches suffer from serious weaknesses, the most obvious of which is a lack of specificity for the antigen(s) which drive the inflammatory process. The same may be said to be true of other therapeutic approaches currently being developed which aim to neutralize the effects of individual mediators in the inflammatory cascade. Here, a notable success has been the use of monoclonal antibodies to tumour necrosis factor (TNF) to treat patients with rheumatoid arthritis.5 However, the long-term consequences of removing individual mediators remain to be seen. Of concern is the recent report of subjects receiving anti-TNF therapy developing a lupus-like syndrome thought to be a direct result of the therapy itself.6 The challenge of introducing specificity into strategies aimed at modulating T-cell responses is one that has been met with considerable success in animal models by the use of peptide epitopes from the antigen in question. Peptide-induced tolerance has been demonstrated in models of experimental autoimmune encephalomyelitis (EAE),7,8 collagen-induced arthritis9 and, more recently, in models of allergic disease. Briner and colleagues sensitized mice to the cat allergen Fel d I and subsequently demonstrated the ability of allergen-derived peptides to inhibit T-cell cytokine and antibody production.10 Hoyne and colleagues demonstrated the ability of peptides from the house dust mite allergen Der p II to down-regulate T-cell and antibody responses to challenge with intact protein and also to prevent sensitization by prior administration.11,12 Bauer administered a dominant T-cell epitope of Bet v I to CBA/J mice either prior to or following sensitization with the whole allergen. No change in antibody isotype was observed but T-cell proliferative responses were inhibited by both treatments.13 More recently, mice sensitized to bee venom allergen phospholipase A2 (PLA2), were treated by intranasal administration of a mixture of three long peptides spanning the entire molecule. A marked reduction in specific immunoglobulin E (IgE) was observed coupled with a decreased interleukin-4 (IL-4) to interferon-γ (IFN-γ) ratio. Pre-administration of peptide resulted in a failure to develop IgE sensitization to subsequent immunization with the whole molecule.14 In addition to animal models, the ability of high-dose peptides to modulate human T-cell responses has also been demonstrated. In vitro studies with human T cells were performed by Lamb and colleagues, who demonstrated the induction of antigen-specific non-responsiveness following the incubation of T-cell clones with supraoptimal doses of specific ligand in the absence of professional antigen-presenting cells.15 Collectively, these studies provided a logical basis for the translation of a peptide-based therapeutic approach in man.