Endothelial cell analysis of corneas from donor eyes with an intraocular lens: a comparative study

OBJECTIVES: To examine the relationship between patient-reported depression and adherence to therapy with interferon beta-1b (IFN beta-1b) and to test the hypothesis that treatment of depression is associated with improved adherence. DESIGN: Patients with multiple sclerosis were followed up 6 months after initiating therapy with IFN beta-1b. SETTING: A university outpatient multiple sclerosis center, an academic group practice, and a health maintenance organization. PATIENTS: Eighty-five patients with clinically evident multiple sclerosis taking IFN beta-1b. MAIN OUTCOME MEASURE: Follow-up questionnaire. RESULTS: Thirty-five (41%) of the 85 patients reported new or increased depression within 6 months of initiating therapy with IFN beta-1b. Patients experiencing symptoms of depression were more likely to discontinue therapy. Among the patients reporting new or increased depression, 86% who received psychotherapy or antidepressant medication and 38% of the patients who received no therapy for depression continued the IFN beta-1b therapy (P = .003). Although psychotherapy was used as a treatment option more frequently in university and academic group practice-based multiple sclerosis clinics than in the health maintenance organization (P = .02), the treatment adherence patterns were similar across sites. CONCLUSIONS: These findings support previous findings that patients report increased depression after initiating therapy with IFN beta-1b. Although the source of this depression is unclear, these findings suggest that treating patient-reported depression increases adherence to treatment.     

Interferon beta for multiple sclerosis

OBJECTIVE: To introduce readers to the use of a new agent, interferon beta-1b (IFN beta ser), in the treatment of relapsing-remitting multiple sclerosis (RRMS). Therapeutic and economic issues surrounding IFN beta ser are discussed, as are its pharmacology, clinical efficacy, adverse effects, and dosage guidelines. DATA SOURCES: A MEDLINE search was used to identify pertinent literature, including clinical trials and reviews. STUDY SELECTIONS: All available trials were reviewed. DATA EXTRACTION: Since trials evaluating subcutaneously administered interferon beta are sparse, clinical trials evaluating intrathecal IFN beta ser were included, as was toxicology information from the oncology population. DATA SYNTHESIS: IFN beta ser has recently been approved by the Food and Drug Administration for the treatment of RRMS. Its exact mechanism of action is unknown, but it may downregulate interferon gamma (IFN gamma) production and the IFN gamma-stimulated major histocompatibility complex antigen expression, and/or augment T-suppressor cell function. Primary adverse effects include flu-like symptoms, fever, chills, myalgia, sweating, and injection-site reactions. Clinical efficacy has been investigated in 372 ambulatory patients with RRMS. IFN beta ser treatment resulted in a reduction in the annual exacerbation rate and a greater proportion of exacerbation-free patients. Burden of central nervous system disease was also significantly reduced in treated patients. However, no reductions were detected on the Scripps Neurologic Rating Scale or with confirmed endpoint scores on the Kurtzke Expanded Disability Status Scale. Although many questions remain concerning IFN beta ser's long-term efficacy, its benefits in patients with other types of multiple sclerosis (MS), and its effect on progression of disease and ultimate disability, IFN beta ser is the first treatment modality that has substantially altered the natural course of MS in a controlled clinical trial. CONCLUSIONS: IFN beta ser is not a cure for MS, but it is well tolerated and patients with RRMS have shown significant improvements in exacerbation rates and burden of central nervous system disease. IFN beta ser should be considered a definite improvement in RRMS treatment, although many therapeutic issues remain unanswered. Additional clinical trials are needed.     

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.     

Measurements of directional hearing aid function

We conducted a comprehensive review of selected adverse event reports that were submitted to the Food and Drug Administration (FDA) for interferon beta-1b during the first 30 months following licensure. The adverse events reviewed were injection site reactions, injection site necroses, and non-injection site necroses. These adverse events were selected because of the relative frequency of injection site reactions and because of the severity and sequelae of certain injection site and non-injection site necroses. Our review enabled us to characterize the clinical presentation and the treatment received, which were not described in the package insert or by the IFN beta (interferon beta-1b) Multiple Sclerosis Study Group publication. The time of onset of the adverse events ranged from 1-29 months after initiation of interferon beta-1b treatment, with a mean of 1 month. In general, the more clinically significant adverse events (i.e., injection site necrosis and non-injection site necrosis) developed more slowly than the injection site reactions. Greater than 85% of the adverse events presented with one or two signs/symptoms, although the number of signs/ symptoms ranged from 1-8. No predominance of treatments for the adverse events was observed. The most striking finding was that the overall sex ratio, which could be due to reporting artifacts, was 8.1:1 female:male.     

Profile of efficacy and safety in the treatment of remittent-recurrent multiple sclerosis with interferon beta-1b

BACKGROUND: Interferon beta 1b (IFN beta-1b) has showed a reduction of exacerbation rate and a decrease in multiple sclerosis activity as evidenced by MRI. After the approval of IFN beta-1b in our country more than 1,000 patients are under treatment, however the experience is limited. The purpose of this study is to describe the clinical results and the tolerance of IFN beta-1b during the postmarketing period in our country. MATERIAL AND METHODS: We studied 95 patients treated with IFN beta-1b. An exhaustive follow-up has been performed in order to assess the tolerance and the efficacy of the drug. We registered the haematological and biochemical abnormalities, secondary effects, relapses, clinical evolution and drop-outs. RESULTS: Mean age was 32.5 +/- 9 years, and the mean follow-up was 13.2 months. Seventy patients (74%) have been followed for more than one year. Haematological abnormalities are frequent, lymphopenia being the most common finding (37%). Flulike symptoms appear in 90% of the patients and skin reaction in the 70%. We have observed a drop-out rate of 7%. One patient developed depressive symptoms and the treatment was temporally discontinued. We have observed a significant decrease in relapses of the disease, however disability has not changed in the first year after treatment. CONCLUSIONS: IFN beta-1b has been well tolerated in the postmarketing period. The profile of secondary effects is similar, although not identical to that reported. The patient awareness of secondary effects and the realistic expectations of the drug are important in order to decrease the drop-out rate.     

Activity and tolerance of a continuous subcutaneous infusion of interferon-alpha2b in patients with chronic hepatitis C

We administered interferon-alpha2b (IFN-alpha2b) by continuous subcutaneous infusion (60,000 IU/h, or 10 million IU/week) over 3 months to 7 patients with chronic hepatitis C. All had previously responded, as assessed by normalization of transaminases to the same dose of IFN administered by intermittent injection over 6 months, but had relapsed after cessation of therapy. The continuous infusion was tolerated well at the site of infusion, and the systemic side effects were similar in type but were lesser in intensity than with intermittent dosage. Four of 7 subjects had normalization of transaminase at the end of week 12 of therapy. Serum HCV RNA and HCV by PCR decreased with treatment, and there was a prompt and sustained increase in serum beta2-microglobulin and of 2', 5' OAS activity. The level of the latter appeared to correlate with response of the transaminase. Serum IFN concentrations were low but detectable throughout therapy. After stopping IFN administration, the transaminases in responders increased again to pretreatment levels.     

Effect of transforming growth factor beta-1 on the intracellular calcium in cardiac fibroblasts

We attempted to determine the effects of transforming growth factor beta-1 on intracellular Ca2+ concentration changes in the presence of isoproterenol in cardiac fibroblasts. Transforming growth factor beta-1 inhibited the increase of intracellular Ca2+ concentration in the presence of isoproterenol in fibroblasts. It also inhibited the production of cyclic-AMP in fibroblasts in the presence of isoproterenol. Islet-activating protein did not block these reactions of transforming growth factor beta-1. Forskolin did not affect the intracellular calcium concentration change resulting from treatment with transforming growth factor beta-1. Binding of [3H]CGP-12177 was decreased to 47% of control preincubated for 24 hours with transforming growth factor beta-1 in fibroblasts. Scatchard plots suggested a decrease in beta-adrenergic receptor number without specific change in receptor affinity. These results suggested that transforming growth factor beta-1 modulates the signal transduction through beta-adrenergic receptor and intracellular Ca2+ concentration by regulating the number of receptors in fibroblasts.     

Acute reductions in serum testosterone levels by narcotics in the male rat: stereospecificity, blockade by naloxone and tolerance

The effects of a single injection of morphine (20 mg/kg) on serum testosterone levels were examined in the male rat. Within 2 hours after the morphine injection, testosterone levels were significantly lower than control levels. The decline in testosterone levels reached a maximum 4 hours after the administration of morphine, at which time testosterone levels were reduced by more than 85% with respect to controls. The ability of a large number of narcotics to depress serum testosterone levels, 4 hours after their administration, was also examined. All narcotics depressed testosterone levels significantly and their potency relative to morphine was comparable to that observed in several other preparations, such as the guinea-pig ileum and mouse vas deferens. The testosterone-depleting effects of the narcotics appear to represent specific narcotic effects since the (-)-isomers of the narcotics were considerably more potent than the (+)-isomers, naloxone competitively inhibited the effects of morphine on testosterone levels and tolerance developed to the testosterone-depleting effects of these drugs. Acute treatment with morphine also lowered serum luteinizing hormone levels, and this reduction preceded the fall in testosterone levels by 1 to 2 hours.     

Side effects of alpha-interferon therapy and impact on health-related quality of life in children with chronic viral hepatitis

BACKGROUND: Interferon (IFN) is standard therapy for chronic viral hepatitis in children. The aim of this study was to evaluate the side effects of alpha-interferon (IFN) in 94 consecutive children (58 males; age range, 3 to 14 years) affected by chronic viral hepatitis treated with different schedules ranging from 3 to 10 MU and from 3 to 12 months, and the impact of this therapy on health-related quality of life. METHODS: Side effects were evaluated with clinical and laboratory examinations and were recorded on a diary card. The health-related quality of life was evaluated with a modified version of the Sickness Impact Profile. RESULTS: All patients experienced at least one adverse reaction to IFN treatment; 80% had more than five side effects. There were no life-threatening reactions. Three children experienced severe reactions (febrile seizure, severe hypertransaminasemia and relapsing episodes of epistaxis, respectively) that required permanent IFN withdrawal. Another child had a febrile seizure requiring temporary IFN withdrawal. In seven children the neutrophil count fell below 1000/mm3 and promptly increased when IFN was temporarily discontinued. The remaining children had mild or moderate clinical and/or laboratory adverse reactions. Age, sex, viral etiology of chronic hepatitis and response to therapy were not significantly associated with the appearance of side effects. The pre-IFN health-related quality of life was good in all children; it deteriorated significantly during IFN therapy and returned to basal standards within 3 months after IFN withdrawal. No patient required suspension of IFN therapy because of worsening of health-related quality of life. CONCLUSION: Children have a low risk of developing severe IFN-induced side effects. Adverse reactions and worsening of health-related quality of life were tolerable and did not seem to be a limiting factor for IFN therapy in young candidates.     

Hereditary angioedema. Complex symptoms can make diagnosis difficult

Although rare, hereditary angioedema is a potentially life-threatening disorder that can be difficult to diagnose. It is characterized by a deficiency in C1 esterase inhibitor (C1 INH). Manifestations include gastrointestinal, subcutaneous, and respiratory edema. Factors that trigger episodes vary. Symptoms typically last 48 to 72 hours, but they can last 4 hours to 1 week. Treatment includes prophylactic therapy with attenuated androgens or antifibrinolytic agents. Acute episodes can be medical emergencies, and airway management is a major concern. The treatment of choice in an acute episode is administration of plasma concentrate of C1 INH.     

Occurrence of thyroid autoimmunity and dysfunction throughout a nine-month follow-up in patients undergoing interferon-beta therapy for multiple sclerosis

Thyroid autoimmunity and dysfunction are a well known side effect of IFN alpha therapy for viral hepatitis and tumors, while the IFN beta effects on the thyroid gland in neurological patients have not been studied. The aim of this longitudinal study was to look for the appearance of thyroid autoimmunity as well as for the occurrence of overt thyroid disease in the patients affected by multiple sclerosis (MS) treated with IFN beta 1b. Eight patients (4 males, 4 females) undergoing r-IFN beta 1b treatment (8 M.U. every other day for 9 months) for relapsing remitting multiple sclerosis entered the study. We have analyzed thyroid function parameters and auto antibody levels before and after 1, 2, 3, 6 and 9 months of therapy. None of them referred to familiar thyroid pathology or presented clinically overt thyroid disease except for one patient (case 4) who showed TPO-Ab pretreatment positivity and another (case 8) who was in therapy with Levothyroxine 100 microg/die for multinodular goiter. The number of patients with appearance of thyroid antibodies has slowly increased, until the third month of therapy with 3 patients out of 7 positive for TPO-Ab. The only case of overt thyroid dysfunction reported by us appeared after nine months of therapy and consisted of a hypothyroidism. Our data suggest that short-term interferon beta treatment is able to induce thyroid autoimmunity (42.8%) and dysfunction (12.5%).     

Immunotherapy of metastatic kidney cancer

Interleukin 2 (IL2), like Interferon alpha (IFN), is active in metastatic renal cancer, considered to be a chemoresistant cancer. 20 to 30% of objective responses, including 5 to 10% of complete remissions are reported with various protocols of IL2 administration. The considerable toxicity is now well controlled, allowing treatments to be administered in standard wards or even on an outpatient basis by subcutaneous injection. IFN, generally given as long-term treatment, achieved average response rates of between 15 and 20%. Although IL2 and IFN have been granted Product Marketing Authorization in France, the modalities of optimal administration, the place of the combination of IL2-Interferon alpha and the factors predictive of response to treatment still remain unclear.     

Incidence of exacerbations in the first 90 days of treatment with recombinant human interferon beta-1b in patients with relapsing-remitting multiple sclerosis

Interferon beta-1b (IFNbeta-1b) is effective in reducing the frequency of exacerbations in patients with relapsing-remitting multiple sclerosis (RRMS). Recently, a study suggested that treatment with IFNbeta-1b may place MS patients at risk of exacerbations by increasing interferon-gamma (IFNgamma)-secreting cells in the blood early after onset of treatment. We conducted a retrospective study in 192 RRMS patients treated with IFNbeta-1b. We did not observe an increase in the frequency of exacerbations early after the onset of treatment and suggest that the IFNgamma-secreting cell surge linked to the onset of treatment with IFNbeta-1b may not be clinically significant.     

Acute dystonic reaction with low-dose pimozide

It is essential to recognize individual susceptibility to neuroleptic-induced side effects for treatment guidelines. This paper reports on a 6.9-year-old autistic male who developed repeated episodes of acute dystonic reactions associated with pimozide administration at the doses of 0.096 mg/kg/day and 0.032 mg/kg/day and 32 hours following pimozide withdrawal, as well as during subsequent thioridazine administration. It draws the clinician's attention to unusual susceptibility to extrapyramidal side effects and suggests that if a child shows this type of susceptibility to one neuroleptic, he/she may react similarly to other neuroleptics as well.     

Metabolism of oral contraceptive drugs. The formation and disappearance of metabolites of norethindrone and mestranol after intravenous and oral administration

Previous studies from this laboratory reported that 3H-labeled metabolites with half-lives of more than 24 hours may remain in the plasmaa of women receiving an intravenous injection of 3H norethindrone or 3H mestranol. To confirm the presence of these metabolites, blood samples were collected for five days after injection of 3H norethindrone or 3H mestranol; 3H representing metabolites of norethindrone disappeared with half-life values of 42 to 84 hours (mean 67 hours), while 3H representing metabolites of mestranol declined with an average half-life of 45 hours (range 37 to 65 hours). When the 3H-labeled drugs were administered orally, metabolites of similar half-life were formed. Because these compounds exist for several days after a single administration and since oral contraceptive drugs are normally taken daily, the possiblity of the accumulation of 3H in the plasm of women receiving several consecutive doses of 3H norethindrone was investigated. The results of this study show a stepwise accumulation of the 3H metabolites when 3H norethindrone was administered in six daily oral doses. However, the 3H levels declined from the peak on the sixth and last day of the treatment at a rate equivalent to those previously measured after intravenous or oral administration.     

Analysis of small peripheral lung cancer diagnosed by open lung or thoracoscopic biopsy

Interferons are cytokines produced by cells in response to stimulation by certain antigens and infectious agents. In recent years, recombinant interferons have been developed, which have antiviral, antiproliferative, and immunomodulatory functions. Several cutaneous reactions have been reported, including cutaneous ulceration at injection sites. We now report three cases of cutaneous ulceration caused by interferon beta-1b injections. In addition, we review all of the previously reported cases of cutaneous ulceration caused by recombinant interferons and discuss the different mechanisms by which these substances may produce this effect.     

Compatibility of parenteral nutrient solutions with selected drugs during simulated Y-site administration

The compatibility of 102 drugs with parenteral nutrient (PN) solutions during simulated Y-site administration was studied. Five milliliters of each of four representative PN solutions was combined in duplicate in a 1:1 ratio with 5-mL samples of solutions of 102 drugs in 5% dextrose injection or 0.9% sodium chloride injection. Visual examinations were performed in fluorescent laboratory light and under high-intensity monodirectional light, and turbidity was measured. Particle sizing and counting were performed for selected solutions. All evaluations were performed at intervals up to four hours; storage was at 23 degrees C. Most of the drugs tested were compatible with the PN solutions. However, 20 drugs exhibited various incompatibilities with one or more of the PN solutions. During simulated Y-site administration, four PN solutions were compatible with 82 of 102 drugs for four hours at 23 degrees C. Twenty drugs were incompatible with one or more of the PN solutions.     

Interferon alpha 2b as maintenance therapy in low grade malignant lymphoma improves duration of remission and survival

We assessed the efficacy and toxicity of interferon alpha 2b (IFN) as maintenance therapy in patients with low grade malignant lymphoma. Between March 1986 and December 1989, 98 patients with low-grade malignant lymphoma in complete remission after conventional chemotherapy were randomly assigned to received IFN, 5.0 MU three times a week for one year, as maintenance therapy (n = 48), or to receive no treatment (control group, n = 50). In March 1994, the median duration of response had not yet been reached in the patients treated with IFN compared to 46 months in the control group. At 9-years 62% of the patients in the IFN arm remain in first complete remission compared to only 25% in the control group (p <.001). In addition, the median duration of survival has not yet been reached in either the IFN arm compared to 74 months in the control group (p <.001). Quality of life was excellent in both groups and severe side effects secondary to IFN treatment were not observed. All patients completed the planned dose of IFN. We conclude that IFN as maintenance therapy in low-grade malignant lymphoma is an excellent therapeutic option because it improves the duration of remission and survival without producing severe side effects or reducing the quality of life.     

Transforming growth factor beta-1 modulates the number of beta-adrenergic receptors in cardiac fibroblasts

The effects of transforming growth factor beta-1 on concentration of intracellular Ca2+ changes in the presence of isoproterenol were studied in cardiac fibroblasts. Transforming growth factor beta-1 effect on cyclic-AMP production and ligand assay of beta-adrenergic receptors were also examined. Production of cyclic-AMP in fibroblasts preincubated with transforming growth factor beta-1 decreased compared with non-transforming growth factor beta-1-treated fibroblasts in the presence of isoproterenol. An increase of intracellular Ca2+ concentration in the presence of isoproterenol was also inhibited in transforming growth factor beta-1-treated fibroblasts. Islet-activating protein did not restore these reactions of transforming growth factor beta-1. Concentration change of intracellular calcium under the treatment of transforming growth factor beta-1 was unaffected by forskolin addition. Binding of [3H]CGP-12177 was decreased to 47% of control preincubated for 24 h with transforming growth factor beta-1 in fibroblasts. Scatchard plots suggested a decrease in beta-adrenergic receptor number without specific change in receptor affinity. These results suggested that transforming growth factor beta-1 modulates the signal transduction through beta-adrenergic receptor and intracellular Ca2+ concentration by regulating the number of receptor in fibroblasts.