Investigational drug therapies of treatment of multiple sclerosis

The licensing of interferon beta-1b dramatically changed the treatment of multiple sclerosis (MS) in the United States. Although it was the first therapeutic agent shown to affect the natural course of the disease, interferon beta-1b is not appropriate for all patients and is far from being a cure. Several other promising therapies now under study include immunosuppressive and immunomodulatory drugs to limit inflammation; oral administration of myelin to induce tolerance; monoclonal antibodies designed to deliver targeted immunotherapy; potassium channel blockers to facilitate conduction along demyelinated axons; and glial growth factors to promote remyelination. Clinical trials of potential therapeutic agents have proliferated in the past decade in conjunction with rapid advances in our understanding of the immunologic basis of MS. Some investigational therapies are associated with problematic toxicities, others benefit only a minority of patients, and many are still in the early stages of development. Nevertheless, because current therapeutic options are limited, and because the history of MS therapy is one of disappointment and frustration, it is essential that legitimate, scientifically based advances be widely disseminated to the neurologic community. This article reviews some of the most promising current and investigational therapies for MS.     

Antifungals: use in high-risk patients

1. Panic disorder, which encompasses both biological and psychological dimensions, is a common anxiety-related problem that can result in significant disability. 2. Cognitive-behavioral approaches to panic disorder are effective in 70% to 80% of patients treated, and generally involve a combination of patient education, relaxation training, exposure, and cognitive restructuring. 3. Mental health nurses can benefit their panic disorder patients by becoming aware of cognitive-behavioral treatment options, and should consider adding these methods to their repertoire of therapeutic skills.     

Endoluminal treatment of vascular occlusive disease

The logical desire to avoid major cutaneous incisions and surgical dissection in the treatment of vascular occlusive disease has, in recent years, led to a surge of new therapeutic options whereby access to the diseased blood vessel is obtained via a distant site and treatment is effected from within the vessel. Such endoluminal treatment modalities include thrombolysis, balloon angioplasty, atherectomy, stenting, and stent grafting. For the purpose of this surgically oriented article, the latter two techniques are discussed.     

Travelers' diarrhea. Epidemiology, prevention, and self-treatment

Risk factors for travelers' diarrhea include adventurous behavior, consumption of unclean water or food, and special hosts like those taking long acting H2 blockers. Approaches to prevention include education about risk factors, which often fails to lead to modification of risky behavior, and chemoprophylaxis with bismuth subsalicylate-containing compounds or antimicrobial agents. Chemoprophylaxis is generally discouraged except in special circumstances and in high-risk hosts. Self-treatment of travelers' diarrhea is successful in limiting the course of diarrhea and minimizing losses of vacation and business time. Current therapeutic options, in order of increasing effectiveness, include attapulgite, BSS-containing compounds, loperamide, antimicrobial agents such as the fluoroquinolones, and the combination of loperamide and an antimicrobial agent. Under study are a nonabsorbed antimicrobial agent, rifaximin, and a novel calmodulin inhibitor, zaldaride. Development and evaluation of vaccines against enterotoxigenic Escherichia coli and Shigella are proceeding apace but are not yet available for routine use.     

Potassium currents in freshly dissociated uterine myocytes from nonpregnant and late-pregnant rats

In freshly dissociated uterine myocytes, the outward current is carried by K+ through channels highly selective for K+. Typically, nonpregnant myocytes have rather noisy K+ currents; half of them also have a fast-inactivating transient outward current (ITO). In contrast, the current records are not noisy in late pregnant myocytes, and ITO densities are low. The whole-cell IK of nonpregnant myocytes respond strongly to changes in [Ca2+]o or changes in [Ca2+]i caused by photolysis of caged Ca2+ compounds, nitr 5 or DM-nitrophene, but that of late-pregnant myocytes respond weakly or not at all. The Ca2+ insensitivity of the latter is present before any exposure to dissociating enzymes. By holding at -80, -40, or 0 mV and digital subtractions, the whole-cell IK of each type of myocyte can be separated into one noninactivating and two inactivating components with half-inactivation at approximately -61 and -22 mV. The noninactivating components, which consist mainly of iberiotoxin-susceptible large-conductance Ca2+-activated K+ currents, are half-activated at 39 mV in nonpregnant myocytes, but at 63 mV in late-pregnant myocytes. In detached membrane patches from the latter, identified 139 pS, Ca2+-sensitive K+ channels also have a half-open probability at 68 mV, and are less sensitive to Ca2+ than similar channels in taenia coli myocytes. Ca2+-activated K+ currents, susceptible to tetraethylammonium, charybdotoxin, and iberiotoxin contribute 30-35% of the total IK in nonpregnant myocytes, but <20% in late-pregnant myocytes. Dendrotoxin-susceptible, small-conductance delayed rectifier currents are not seen in nonpregnant myocytes, but contribute approximately 20% of total IK in late-pregnant myocytes. Thus, in late-pregnancy, myometrial excitability is increased by changes in K+ currents that include a suppression of the ITO, a redistribution of IK expression from large-conductance Ca2+-activated channels to smaller-conductance delayed rectifier channels, a lowered Ca2+ sensitivity, and a positive shift of the activation of some large-conductance Ca2+-activated channels.     

On becoming a team: a view from the field

Early intervention services have expanded the concept of team participation for speech-language pathologists. Unlike traditional teams that grew out of the individual, direct service model of treatment, early intervention teams include the child's family along with professionals. Family members are invited to participate in assessing and treating their child, and the child is seen from a slightly different perspective by each team participant. Different viewpoints must be integrated and used to the benefit of the child. In this way, treatment options are expanded. Further, professionals may release their roles to other team members as well as learn new skills from other team members. The process of team development is illustrated through the experiences of one family-centered early intervention team.     

Treatment response of depressed outpatients unresponsive to both a tricyclic and a monoamine oxidase inhibitor antidepressant

BACKGROUND: Data regarding effective treatment options for the minority of patients refractory to initial antidepressant trials are essential to guide therapeutic choices and to sustain the hope of patients and perseverance of clinicians. Few such data are available concerning the treatment of patients refractory to treatment with both a tricyclic antidepressant and a monoamine oxidase inhibitor given singly. METHOD: In a study of mood reactive depressed patients, most of whom met Columbia criteria for atypical depression, 20 patients refractory to vigorous 6-week double-blind trials of both imipramine and phenelzine given singly were given clinician's choice open treatment. A chart review of course in open treatment was conducted. RESULTS: Eleven patients (55%) had a full response to subsequent treatments, principally continued phenelzine and the combination of phenelzine with amitriptyline. Another 6 (30%) had at least moderate benefit from a variety of other treatments. CONCLUSION: These data suggest that even among patients who have failed to respond to two vigorous trials of different antidepressants, at least half appear to benefit from other pharmacologic regimens.     

Management of impotence. Diagnostic considerations and therapeutic options

Impotence affects an estimated 10 million American men. The cause is usually organic in men over age 50; psychogenic impotence is more common in younger men. Vascular disease is the most common cause of impotence. Evaluation in patients with impotence includes thorough history taking and diagnostic testing. Once the cause of impotence is determined, appropriate management can be chosen. Current therapeutic options include vacuum tumescence devices, self-injection, oral therapy, psychotherapy, and penile prostheses.     

Pressure ulcer management in the geriatric patient

OBJECTIVE: To increase the understanding of pharmacists and other health-system clinicians regarding pharmaceutical applications of pressure ulcer prevention and treatment in geriatric patients. DATA SOURCES: An extensive MEDLINE retrieval was conducted which encompassed the years 1967-1998; the search terms used included pressure sore, pressure ulcer, decubitus ulcer, and geriatrics. DATA SUMMARY: Pressure ulcers affect populations with limited mobility, reduced cognition, and less-independent activities of daily living, such as the elderly. Identification of the high-risk patient is required for successful prevention outcomes. For existing lesions, a variety of treatment modalities exist, not all of which have demonstrated therapeutic benefit. Given these options, clinicians are faced with treatment selection challenges that should be based on the clinical setting, available scientific evidence, and individualized patient care needs. CONCLUSIONS: Prevention of pressure ulcerations is imperative to reduce patient morbidity, mortality, and overall healthcare costs. Given the number of treatment options available, pharmacists can assist in the treatment selection process. Education of the patient and family regarding pressure ulcer prevention and treatment requires early and ongoing involvement by the interdisciplinary team.     

Modern dilemmas in the treatment of breast carcinoma

By means of a detailed analysis of literature data and our own results when available, the paper presents different therapeutic options in the treatment of breast cancer patients that are applied in our country today and the that might be applied in relation to modern knowledge and discoveries in experimental oncology, early detection and diagnostics of breast cancer. It is stressed that the use of this knowledge may result in slightly better rate of survival but the main emphasis is on the quality of life of treated patients and more rational delivery of available therapeutic options.     

Abuse against women in rural Minnesota

Several botanicals, including Crataegus oxycantha, Terminalia arjuna, Inula racemosa, and Astragalus membranaceus, have been found to have therapeutic benefit for the treatment of cardiovascular disease. Crataegus oxycantha has been used traditionally as a cardiac tonic and current uses include treatment for angina, hypertension, arrhythmias, and congestive heart failure. Animal studies have also indicated that Crataegus extracts may also have potential use as anti-ischemic and lipid-lowering agents. The bark of the Terminalia arjuna tree has a long history of use as a cardiac tonic as well, and has been indicated in the treatment of coronary artery disease, heart failure, hypercholesterolemia and for relief of anginal pain. Additionally, it has been found to have antibacterial and antimutagenic properties. Inula racemosa, also known as Pushkarmoola, is another traditional Ayurvedic botanical that has potential cardioprotective benefit. In human trials, a combination of Inula racemosa and Commiphora mukul was shown to be superior to nitroglycerin in reducing the chest pain and dyspnea associated with angina. Astragalus membranaceus, a Chinese herb, is often used as a "Qi tonifier" and has been studied for its therapeutic benefit in treatment of ischemic heart disease, myocardial infarction, heart failure, and relief of anginal pain. Clinical studies have indicated that its in vitro antioxidant activity is the mechanism by which it affords its cardioprotective benefit.     

Age-related macular degeneration

Macular degeneration is now responsible for approximately 95% of blindness and partial sighted registrations in the UK. This review has been written specifically to make the general medical community of the UK aware of the prevalence and clinical manifestations of aged-related macular degeneration. The review encompasses the risk factors, the disabilities and problems experienced by suffers of the condition and current therapeutic options. Age related macular degeneration increases in prevalence in our community from 0% among people under 55 years old to 18.5% among those 85 years or older. There is a marked female preponderance. The exudative form of the disorder is commoner. Treatment remains supportive for most patients with macular degeneration although a minority will benefit from macular laser photocoagulation.     

A recombinant adenovirus expressing wild type p53 induces apoptosis in drug-resistant human breast cancer cells: a gene therapy approach for drug-resistant cancers

The different therapeutic options available for the treatment of chronic leukemias and myelofibrosis are discussed. In reference to chronic myeloid leukemia (CML), the choice of the most appropriate treatment must take into account not only the clinical condition but also the age of the patient. While subjects under 50 might benefit from the options offered by alpha-interferon, bone marrow and peripheral stem cell transplant, in older age groups treatment of the chronic phase must still rely on standard treatment. Chronic lymphocytic leukemia (CLL) and its variants is a disease of mostly middle and late life, with a variable clinical course. Patients show wide differences in morbidity and mortality. Many features have been shown to influence the prognosis, and the most important ones are incorporated into the staging systems currently in use. The results obtained from the study of large trials support the concept that treatment of patients with stable stage A CLL should be postponed until progression of disease. Treatment relies principally on alkylating agents, corticosteroids and radiation therapy; the new nucleoside analogues, such as fludarabine and 2-chlorodeoxyadenosine, have recently acquired established value in improving overall survival. With regard to myelofibrosis, the histological and biological features that influence the natural course of the disease are described, as well as the choice of the most appropriate treatment, which ranges from the use of alkylating agents and androgens, to splenectomy and splenic irradiation.     

Menopause: when hormone replacement therapy is not an option. Part I

Although the perimenopausal period is often experienced as a positive life transition, it is frequently accompanied by a variety of distressing physical and emotional sequelae. Hormone replacement therapy (HRT) has been hailed as the first-line treatment for many of these symptoms. A significant number of women, however, are unable to take exogenous hormones because of absolute or relative contraindications to therapy. Other women are unwilling to use this treatment for a variety of reasons, including reluctance to use unnatural exogenous hormones and fear of unknown risks of HRT. This two-part review discusses the physiology of menopause and its related symptoms, as well as the risks and benefits of both oral and non-oral routes of hormone administration. Self-help measures and alternative therapeutic options are recommended for the treatment of menopausal symptoms, which include vasomotor instability, urogenital atrophy, psychologic disturbances, and risk of osteoporosis and cardiovascular disease.     

Refractory ascites: definition, pathogenesis and treatment

Refractory ascites, that is ascites which cannot be mobilized by low sodium diet and maximal doses of diuretics (up to 400 mg spironolactone or potassium canrenoate and 160 mg furosemide per day), occurs in 5% of cirrhotic patients with ascites. The development of refractory ascites is mainly related to the progression of arterial vasodilation-mediated vascular underfilling and to the imbalance between reduced synthesis of renal vasodilating factors (especially renal prostaglandins) and extreme activation of vasoconstricting systems. Further features include increased sodium reabsorption in the proximal tubule and altered pharmacokinetics and pharmacodynamics of diuretics. In patients with impaired renal function (as is the case for most patients with refractory ascites), the marked reduction of renal perfusion and glomerular filtration rate, with the consequent decrease of filtered sodium load, becomes the main pathogenetic factor. The principal therapeutic options for refractory ascites include repeated paracentesis and implantation of the LeVeen shunt. Paracentesis is a rapid and safe procedure to remove ascites, but it does not correct sodium retention. Ascites recurrence, therefore, may occur after a brief interval. The LeVeen shunt allows for better long-term control of ascites, but severe complications may supervene, and shunt occlusion is common. Neither therapeutic procedure improves survival. Different experimental therapeutic procedures have been proposed. Administration of ornipressin corrects hyperdynamic circulation and improves renal function. Thromboxane synthase inhibitors, by reducing renal synthesis of thromboxane A2, potentiate the diuretic and natriuretic response to furosemide. More invasive procedures, including portosystemic shunt and transjugular intrahepatic stent, are rarely used in the treatment of refractory ascites.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intermediate filament-mediated stretch-induced changes in chromatin: a hypothesis for growth initiation in cardiac myocytes

Excessive stretching of the myocardium leads to hypertrophy, but how the stretch message is communicated to hypertrophy-initiating genes is unknown. Candidates hypothesized as couplers of physical stretch to growth initiation include neural and hormonal factors, stretch-activated and stretch-inactivated ion channels, microtubules, microfilaments, and contractile activity. Upon investigation, however, all were ruled out. We provide evidence here that it is the intermediate filaments in the mechanically stressed myocyte that transmit the stretch message to the chromatin. Using rat myocytes and an immunogold desmin-lamin-labeling technique, we found that when cardiac myocytes are stretched there are changes in the spatial arrangement of both the desmin-lamin intermediate filament network and the nuclear-envelope-associated chromatin. We hypothesize that (a) by physically linking the sarcomere to chromatin, the desmin-lamin intermediate filament network couples sarcomere length to chromatin distribution, and (b) stretch-induced changes in chromatin (mediated by the intermediate filament network) activate hypertrophy-associated genes. Further investigation is needed to test this hypothesis.     

Outward K+ current densities and Kv1.5 expression are reduced in chronic human atrial fibrillation

Chronic atrial fibrillation is associated with a shortening of the atrial action potential duration and atrial refractory period. To test the hypothesis that these changes are mediated by changes in the density of specific atrial K+ currents, we compared the density of K+ currents in left and right atrial myocytes and the density of delayed rectifier K+ channel alpha-subunit proteins (Kv1.5 and Kv2.1) in left and right atrial appendages from patients (n = 28) in normal sinus rhythm with those from patients (n = 15) in chronic atrial fibrillation (AF). Contrary to our expectations, nystatin-perforated patch recordings of whole-cell K+ currents revealed significant reductions in both the inactivating (ITO) and sustained (IKsus) outward K+ current densities in left and right atrial myocytes isolated from patients in chronic AF, relative to the ITO and IKsus densities in myocytes isolated from patients in normal sinus rhythm. Quantitative Western blot analysis revealed that although there was no change in the expression of the Kv2.1 protein, the expression of Kv1.5 protein was reduced by > 50% in both the left and the right atrial appendages of AF patients. The finding that Kv1.5 expression is reduced in parallel with the reduction in delayed rectifier K+ current density is consistent with recent suggestions that Kv1.5 underlies the major component of the delayed rectifier K+ current in human atrial myocytes, the ultrarapid delayed rectifier K+ current, IKur. The unexpected finding of reduced voltage-gated outward K+ current densities in atrial myocytes from AF patients demonstrates the need to further examine the details of the electrophysiological remodeling that occurs during AF to enable more effective and safer therapeutic strategies to be developed.