Pharmacotherapy of corneal transplantation

Introduction: Corneal transplantation is a surgical procedure in which damaged or diseased cornea is replaced by cadaveric corneal tissue. It is the most common form of solid-tissue transplantation in humans but its pharmacotherapy (in relation to graft rejection) has changed little for several decades. The mainstay of treatment of corneal graft rejection remains corticosteroids but these are variably effective and are associated with potentially serious adverse effects. Newer immunosuppressive drugs are increasingly being employed to manage high-risk grafts. However, these drugs are also not without side-effects, some of which can be severe and life-threatening.

Areas covered: This review outlines the corneal transplant procedure and the treatment options available in the management of transplant rejection.

Expert opinion: The surgical technique of corneal lamellar grafting has allowed for transplantation of smaller quantities of donor tissue to the recipient, thereby reducing the antigen load as a means of preventing a rejection episode. With greater understanding of the underlying molecular mechanisms involved in corneal transplant rejection pathology, potentially newer medications that will target specific cytokines or cells involved in rejection, whilst minimizing the potential side effects to the graft recipient, will be made available.     

Outcome of corneal transplantation

Corneal transplantation is a sight restoring surgery done for corneal blindness. The purpose of this retrospective preliminary study is to analyze the outcome of 54 corneal transplantations (for 32 females and 22 males) done in the Department of Ophthalmology between September 1998 and June 2002. The mean follow-up period was 13 months. Hundred percent (6/6) of the keratoconus (KC) and 85.4% of the nonkeratoconus grafts survived at a mean duration of 7.1 months and 16 months respectively. Seven of the 54 grafts (13%) have failed. The causes of graft failure were graft rejction in 4 and bacterial keratitis in 3 cases. Fifty of the 54 cases (92.6%) had a preoperative visual acuity of < 3/60. As a result of the transplantation, the percentage of blind eyes dropped from 92.6% to 21%. The data in this study confirms that corneal transplantation is a reasonably successful procedure in restoring sight for seleted cases of corneal blindness in Ethiopia.     

The impact of HLA-A matching in corneal transplantation

Previously, we have reported the results of our retrospective study on the effect of HLA class II allele matching on the outcome of corneal transplant. Here, we demonstrate our findings of the study for HLA class I allele matching in the same study subjects. Eighty transplant recipients were typed for HLA-A, and 79 transplant recipients were typed for HLA-B alleles, by PCR-SSOP. The association between HLA class I allele matching and 1-year rejection-free graft survival was evaluated. When a total of 79 transplant recipients were subdivided into groups with matching (one to four alleles matched) and without matching (no allele matched) for HLA class I (HLA-A and -B), a significantly higher rate of 1-year rejection-free graft survival was detected in transplant recipients with matching, compared with those without matching (p=0.0258). We have found that matching for at least one HLA class I allele was more beneficial especially in high-risk transplant recipients (p=0.0076). Also, an analysis of matching for each locus separately, detected that, HLA-A matching was significantly associated with a higher rate of 1-year rejection-free graft survival. Transplant recipients with HLA-A matching (one or two-alleles matched) had significantly higher rejection-free graft survival compared with those without matching (no allele matched), when high- and low-risk groups were analyzed together (p=0.0099). Furthermore, matching for HLA-A allele was significantly beneficial compared with no matching in high-risk transplant recipients (p=0.0154). Nevertheless, no significant effect of HLA-B matching was detected. We conclude that HLA class I, especially HLA-A matching has a beneficial effect for corneal transplant outcome.     

新鲜羊膜移植术治疗角膜溃疡

目的探讨新鲜羊膜移植术治疗角膜溃疡的临床疗效。方法采用新鲜羊膜移植治疗角膜溃疡共14只眼，其中细菌性角膜溃疡8只眼(其中穿孔2只眼)，病毒性角膜溃疡4只眼，真菌性角膜溃疡2只跟。结果术后1周内炎症控制，2～3周溃疡愈合。所有病例视力较术前均有提高，遗留有不同程度的角膜斑翳。2例溃疡穿孔瘢痕愈合，前房恢复。结论新鲜羊膜移植是治疗角膜溃疡的一种有效手段。     

自体角膜缘干细胞移植联合丝裂霉素C治疗翼状胬肉疗效观察

目的：探讨自体角膜缘干细胞移植联合丝裂霉素C治疗翼状胬肉的临床疗效。方法：45例（48眼）胬肉切除后自体角膜缘干细胞移植术中应用丝裂霉素C,术后随访12～18个月。结果：随访期间有1眼（2．08％）复发。结论：角膜缘干细胞移植联合丝裂霉素C治疗翼状胬肉是一种有效的方法。     

强迫障碍的药物治疗

在过去的20年中，治疗强迫障碍的药物研究和临床应用有了重大的进展，而且随着精神生物学和临床精神药理学的研究进展，会有越来越多的抗强迫障碍的药物被研制、发现和用于临床。以下介绍目前临床应用的抗强迫障碍药物。     

Pharmacotherapy of onychomycosis

Fungal infections of the nails are frequent in some segments of the population. Dermatophytes, yeasts and moulds are potential pathogens. A series of antifungal treatments are available to the clinician, differing by both their mechanistic nature and mode of administration. The pharmacodynamic and pharmacokinetic properties of each antifungal agent are distinct. This review focuses on the characteristics of amorolfine, bifonazole, ciclopirox, fluconazole, griseofulvin, itraconazole, ketoconazole, ravuconazole, R126638 and terbinafine. Single drug treatments and combined therapies are presented. None of the current drug regimens have demonstrated reliable efficacy against all cases of onychomycosis. Treatment failures, relapses and reinfections remain stubborn problems in the management of onychomycosis.     

Pharmacotherapy of Obesity

In many industrialized nations, obesity is now considered an epidemic, resulting in accelerated morbidity and mortality. Obesity is associated with an increased risk of coronary artery disease as well as the metabolic syndrome comprising abdominal obesity, increased fasting blood glucose levels, dyslipidemia and hypertension, which are all recognized cardiovascular risk factors. Diet, exercise, and lifestyle changes constitute important recommendations for treatment. Unfortunately, although effective in some individuals, these recommendations have proven to be ineffective in adequately addressing the broad, enlarging scope of this public health problem. Drug treatment is often indicated but is somewhat limited by the minimal number of well tolerated drugs that have proven to have long-term efficacy in maintaining bodyweight loss. For example, phentermine may result in modest bodyweight loss through suppression of appetite, but potential cardiovascular adverse effects exist and the efficacy is mainly short-term. Sibutramine, an inhibitor of serotonin and norepinephrine (noradrenaline) reuptake, may increase satiety and result in modest bodyweight loss. However, cardiovascular adverse effects may occur in susceptible patients. Nonetheless, sibutramine is one of the few drugs that has been approved by the US Food and Drug Administration (FDA) for bodyweight loss. Orlistat, a lipase inhibitor, is also approved by the FDA for bodyweight loss but may have bothersome gastrointestinal adverse effects, especially among patients who do not adhere to the recommended low-fat diet. Ongoing studies continue to evaluate other drug treatments that may result in bodyweight reduction through a number of different mechanisms. It is anticipated that the development of effective and well tolerated antiobesity drugs will elevate the pharmacologic treatment of obesity to the status of other cardiovascular risk factors and metabolic disorders. This may be especially important given that dyslipidemia, hypertension and type 2 diabetes mellitus are often secondary to, or exacerbated by, obesity.     

Pharmacotherapy of anxiety

The pharmacological treatment of anxiety has a long and chequered history, and recent years have seen a rich development in the options available to prescribers. Most of the currently used anxiolytic agents act via monoaminergic (chiefly serotonin) or amino acid (GABA or glutamate) neurotransmitters, and this chapter describes the pharmacology of the major drug groups. Clinical applications are discussed with respect to the five major anxiety disorders, as well as simple phobia and depression with concomitant anxiety. Prospective future developments in the field are considered.     

Pharmacotherapy of onychomycosis

Fungal infections of the nails are frequent in some segments of the population. Dermatophytes, yeasts and moulds are potential pathogens. A series of antifungal treatments are available to the clinician, differing by both their mechanistic nature and mode of administration. The pharmacodynamic and pharmacokinetic properties of each antifungal agent are distinct. This review focuses on the characteristics of amorolfine, bifonazole, ciclopirox, fluconazole, griseofulvin, itraconazole, ketoconazole, ravuconazole, R126638 and terbinafine. Single drug treatments and combined therapies are presented. None of the current drug regimens have demonstrated reliable efficacy against all cases of onycho-mycosis. Treatment failures, relapses and reinf-ections remain stubborn pro-blems in the management of onychomycosis.     

Pharmacotherapy of insomnia

INTRODUCTION: Insomnia is one of the most prevalent sleep disorders in developed countries, being surpassed only by chronic sleep deprivation. Patients with insomnia tend to have an altered quality of life, impaired daytime functioning and an increased risk of work accidents and motor vehicle crashes. Insomnia is commonly associated with chronic medical conditions, metabolic illnesses and mental disorders (such as depression and anxiety), with which there is a dual, reciprocal relationship. AREAS COVERED: This paper focuses on current pharmacotherapy options for the treatment of insomnia, particularly benzodiazepine receptor agonists, which nowadays represent the mainstay of hypnotic therapy. The melatonin receptor antagonist, ramelteon, is reviewed (an alternative for some patients with only sleep-onset difficulty), as are sedating antidepressants, which are commonly used 'off-label' to treat insomnia, despite limited efficacy data and potential significant safety concerns. Orexin (OX) antagonists are also discussed, especially those that block OX2 or both OX1 and OX2 receptors, as these are the most promising new agents for the treatment of insomnia, with encouraging results in preliminary clinical trials. EXPERT OPINION: Research to evaluate and formulate treatments for insomnia is often complicated by the fact that insomnia is usually of multifactorial etiology. Understanding the molecular and receptor mechanisms involved in promoting sleep in varied disorders could provide future approaches in new drug development. In the long term, more randomized controlled trials are needed to assess both short-term and long-term effects of these medications and their efficacy in comorbid diseases that affect sleep quality or quantity.     

Pharmacotherapy of uveitis

Importance of the field: The term ‘uveitis’ covers a broad spectrum of ocular inflammation affecting the iris, ciliary body, and/or the choroid, all of which comprise the uveal tract. Severe cases of uveitis need be treated aggressively to prevent damage caused by chronic inflammation. Untreated or poorly managed cases can lead to ciliary body dysfunction, inadequate aqueous production, chorioretinal damage, and possibly blindness.

Areas covered in this review: There are many medications that can be used to treat uveitis. Corticosteroids are available in several formulations: topical drops, regional injections, oral and intravenous. Immunomodulatory agents that can be used for uveitis are antimetabolites, T-cell inhibitors, alkylating agents, and biologic response modifiers. These medications, their appropriate uses, and side effect monitoring will be detailed.

What the reader will gain: There is a stepladder approach to treatment of ocular inflammation. Corticosteroids are the treatment of choice for treating acute flares. Steroid free remission is the goal of therapy and can be achieved with the use of chemotherapeutic agents. Which medications are appropriate and how to escalate therapy will be reviewed.

Take home message: Chronic systemic corticosteroid therapy is not an acceptable long treatment plan for uveitis, unless all other medications have failed. Steroid sparing immunosuppressive therapy should be pursued as soon as acute flares of uveitis have been controlled.     

Pharmacotherapy of sarcoma

Background: Comprising < 1% of adult malignancies and approximately 12% of pediatric malignancies, sarcomas are derived from a variety of connective tissues and exhibit highly variable responsiveness to therapy. The clinical and biologic heterogeneity of the > 50 histologic subtypes of sarcomas often require different therapeutic approaches. Objective: This review describes the use of therapeutic agents in the management of bone and soft-tissue sarcomas. Methods: Relevant literature is identified and presented from major conference proceedings, as well as using the PubMed search engine. Results/conclusions: Chemotherapy has improved outcomes over the past few decade, particularly in patients with certain bone sarcomas and gastrointestinal stromal tumors; while in the majority of patients, additional strategies are necessary.     

Pharmacotherapy of neuroblastoma

Importance of the field: Neuroblastoma, a tumor of the sympathetic nervous system, is the most common extracranial solid tumor of early life. High risk disease in older children remains a therapeutic challenge, despite high-intensity therapy with correspondingly significant short- and long-term toxicities.

Areas covered in this review: We have reviewed therapy for neuroblastoma over the last three decades. This includes cytotoxic chemotherapy, immunotherapy, radionuclides, antiangiogenic compounds, and molecularly targeted agents. We provide a perspective on the incorporation of these drugs into therapy for neuroblastoma.

What the reader will gain: The reader will gain a better understanding of these novel agents and their targets in neuroblastoma. The reader will also gain insight into the need to define through sequential, carefully designed clinical trials, the roles and toxicities of these therapies, especially if the combination of targeted and conventional cytotoxic agents is used.

Take home message: Advanced-stage neuroblastoma in older infants and children remains a disease that is difficult to cure. New, targeted agents may improve both the therapeutic index and the outcome, but are, for the most part, in early development and present a challenge for clinical trial design given both the rarity of this disease and its responsiveness (albeit incomplete) to currently used cytotoxic agents.     

Pharmacotherapy of osteoporosis

Osteoporosis with increased risk of bone fracture is a disabling syndrome that naturally occurs as long as one ages and moves on two legs. Recent progress in bone cell biology has shed light on the mechanisms underlying the anti-osteoporotic properties of drugs that have been in use for a long time, providing a fresh stage for novel pharmacotherapies. In addition, large scale clinical trials developed in the past decade appear not only to rationalize the clinical utilities of these drugs but also to provide new concepts for the development of new therapeutic modalities. Progress in the fields of basic and clinical research field is briefly reviewed herein.     

Pharmacotherapy of gastroparesis

The evaluation and management of gastric motor dysfunction continues to represent a significant clinical challenge. The very definition of what constitutes a clinically relevant disturbance of gastric motility remains unclear. The spectrum of gastroparesis extends from those with classical symptoms and severe delay of gastric emptying to those with dyspepsia and a mild delay in emptying rate. Indeed, for many patients with dyspepsia, the role of gastric emptying delay in the pathogenesis of symptoms, remains unclear. Any assessment of the efficacy of any therapeutic class in gastroparesis must be mindful, therefore, of these variations in definition. For those individuals with severe established gastroparesis, therapeutic success often remains elusive and i.v. erythromycin and oral dopamine antagonists, or substituted benzamides, remain the best options for acute severe exacerbations and chronic maintenance therapy, respectively. Alternatives, currently under investigation, include a number of 5-HT4 agonists, macrolides devoid of antibiotic activity, CCK antagonists and gastric electrical stimulation. Other novel approaches include strategies to address some of the regional abnormalities in gastric motor function that have been identified in some patients with dyspepsia.     

Pharmacotherapy of insomnia

Insomnia is the most common sleep disorder in the industrialized world. A variety of precipitating events have been identified, but when it becomes a persistent problem, maladaptive patterns become established, thereby, perpetuating the sleep disturbance. Individuals with insomnia have impaired next-day functioning, which impacts their quality of life and places them at increased risk of motor vehicle accidents. Insomnia is commonly associated with chronic medical conditions, as well as an increased incidence of mental disorders. Despite considerable scientific advances in both the understanding and treatment, insomnia continues to be inadequately identified and treated, with < 15% of those with severe insomnia receiving appropriate treatment. The mainstay of treatment for insomnia is cognitive-behavioral therapy, along with judicious use of hypnotic agents.     

Pharmacotherapy of gastroparesis

The evaluation and management of gastric motor dysfunction continues to represent a significant clinical challenge. The very definition of what constitutes a clinically relevant disturbance of gastric motility remains unclear. The spectrum of gastroparesis extends from those with classical symptoms and severe delay of gastric emptying to those with dyspepsia and a mild delay in emptying rate. Indeed, for many patients with dyspepsia, the role of gastric emptying delay in the pathogenesis of symptoms, remains unclear. Any assessment of the efficacy of any therapeutic class in gastroparesis must be mindful, therefore, of these variations in definition. For those individuals with severe established gastroparesis, therapeutic success often remains elusive and iv. erythromycin and oral dopamine antagonists, or substituted benzamides, remain the best options for acute severe exacerbations and chronic maintenance therapy, respectively. Alternatives, currently under investigation, include a number of 5-HT₄ agonists, macrolides devoid of antibiotic activity, CCK antagonists and gastric electrical stimulation. Other novel approaches include strategies to address some of the regional abnormalities in gastric motor function that have been identified in some patients with dyspepsia.