Objective. To assess the efficacy and safety of R788 (fostamatinib disodium), an inhibitor of spleen tyrosine kinase (Syk), in patients with active rheumatoid arthritis (RA) that did not respond to biologic therapies.Methods. A total of 219 patients with active RA in whom treatment with biologic agents had failed were enrolled in a 3-month multicenter, randomized, doubleblind, placebo-controlled trial of R788. The primary end point was the percentage of patients who met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at month 3. Secondary end points included changes in inflammation and damage, as assessed by magnetic resonance imaging (MRI), and changes in the Disease Activity Score.Results. The ACR20 response in the R788 100 mg twice daily group was 38%, versus 37% in the placebo group, at month 3. No significant differences were achieved in the ACR20, ACR50, or ACR70 response levels at 3 months. There were differences between the groups from baseline to month 3 in the secondary end points C-reactive protein (CRP) level and synovitis score on MRI. There were baseline differences in steroid use, prior biologic use, and synovitis score on MRI between the R788 group and the placebo group that may have affected the outcomes. A high placebo response rate was seen in this trial, and exploratory analysis suggested that this may in part have been driven by patients who entered the trial with an elevated erythrocyte sedimentation rate but normal CRP level.Conclusion. Our findings indicate that there were no differences in the primary end point between the R788 and placebo groups. Differences were observed between the R788 and placebo groups in secondary end points, particularly in those patients who entered the study with an elevated CRP level.The treatment of rheumatoid arthritis (RA) has traditionally been based on the use of conventional disease-modifying antirheumatic drugs (DMARDs) and, since the late 1990s, on newer, biologically based therapies that inhibit cytokine activity, block T cell-mediated ClinicalTrials.gov identifier: NCT00665926.

The course of spinal muscular atrophy (SMA) is not well established except for those patients whose age of onset is before 6 months and who achieve only "sit with support" as their maximum function (Werdnig-Hoffmann disease or SMA I). This study shows that there is another group of SMA patients whose age of onset and maximum function achieved can be used as prognostic guides. Fifty percent of SMA patients who could walk without assistance and whose onset was prior to age 2 years lost the ability to walk independently by age 12. Fifty percent of SMA patients who walked and whose onset was between 2 and 6 years of age lost walking ability by age 44 years. Fifty percent of SMA patients who could walk with assistance as their best function ever achieved lost this ability by age 7 years, unrelated to age of onset; none could walk with assistance after age 14 years. Seventy-five percent of SMA patients who developed the ability to sit independently as their best function were still sitting after age 7 years independent of age of onset; 50% of this group could sit independently after age 14 years. Eighty-five percent of SMA patients who could walk could not negotiate stairs without holding onto a rail. They could raise their hands above the head; however, as they lost walking ability, they lost this function as well. Only one SMA patient whose maximum function was sitting independently could get to the sitting position on his own. Only two of these patients could hold their hands above their heads. All patients with SMA lose function over time. This function loss occurs slowly and is related primarily to maximum function achieved; knowledge of age of onset provides helpful information, especially for predicting the loss of independent walking.

Over a 7-year period, we analyzed 261 dose regimens of antimicrobial drugs in the treatment and prevention of Pneumocystis carinii pneumonia in an immunosuppressed rat model. These compounds ranged from drugs in clinical use to newly synthesized agents. Drug efficacy was expressed as the magnitude of the reduction in median P. carinii cyst or nucleus counts on a scale ranging from inactive (<5-fold) to very markedly active (.1,000-fold). The classification system was reproducible and allowed drugs studied at different times to be compared with each other. The system demonstrated a hierarchy of anti-P. carinii activity not only among classes of compounds but also among individual members of a drug class. Sulfonamides, sulfones, and diamidines were the most active agents; some purine nucleosides and nitrofurans also showed promising activity; and most antiparasitic, antifungal, antibacterial, and antiviral drugs were inactive. We conclude that this classification system represents a simple, quantitative method of comparing the activities of antimicrobial drugs against P. carinii. Information gained from this system should be helpful in developing new anti-P. carinii compounds and establishing standard procedures for their evaluation.Over the past decade, there has been a major rise in the number of cases of Pneumocystis carinii pneumonia associated with AIDS. The well-publicized limitations of currently available anti-P. carinii drugs in AIDS patients have emphasized the need for new therapeutic approaches (37). Most drug testing has been performed in an immunosuppressed rat model of pneumocystosis, which accurately predicts activity against human P. carinii. Compounds which have exhibited anti-P. carinii activity in the rat model include antifolate drugs (alone or in combination) such as dihydrofolate reductase (DHFR) inhibitors, sulfonamides, sulfones, and sulfonylureas (7, 9, 12, 14, 16-20, 23, 24, 27, 35, 39, 42, 43); sulfonamides in combination with other drugs (e.g., macrolides) (13); diamidines and related cationic compounds (8,11,21,34,40); 8-aminoquinolones, alone or in combination with other agents (1, 28); purine nucleosides (la, 32, 36); polyamine inhibitors (3, 4); nitrofurans (38); 3-glucan inhibitors (26, 29, 30); hydroxynaphthoquinones (14); fluoroquinolones (2); iron chelators (4); and immunological agents (antibodies, cytokines) (10,31).Although the rat model has been very valuable, evaluation of anti-P. carinii drugs is time-consuming, expensive, and labor intensive; only a few compounds can be tested in a given experiment. Treatment studies have been performed by different experimental protocols and methods of evaluating drug efficacy; this lack of standardization has prevented the results of one investigator from being compared directly with those of another. Little attention has also been devoted to quantitating the reduction in organism burden which can be achieved with different doses of anti-P. carinii drugs. In addition, there have been few published sources of information of the compound...

The efficacy of antifolate, antiviral, and other drugs was compared in an experimental model of pneumocystosis. Sulfamethoxazole (SMX) administered alone in doses of .60 mg/kg/day was highly effective in treatment and prophylaxis. Low (c15 mg/kg/day) doses of SMX showed limited, dose-related antiPneumocystis carinii activity in therapy but were more effective in prophylaxis. The dihydrofolate reductase (DHFR) inhibitors trimethoprim (TMP), pyrimethamine, and trimetrexate exhibited little anti-P. carinii activity when administered alone and did not enhance the efficacy of SMX; the effects of the DHFR inhibitors could not be related to the dose or the concentration in serum. These data suggested that the rat model is an excellent system for studying the anti-P. carinii activity of sulfonamides but is of limited value in studying DHFR inhibitors. The antiviral drugs azidothymidine, dideoxyinosine, inosine pranobex (Isoprinosine), amantadine, and acyclovir displayed little or no activity against P. carinii; however, azidothymidine did not impair the efficacy of SMX or TMP-SMX. These results supported the clinical practice of giving antiviral agents together with antifolate drugs to patients infected with human immunodeficiency virus and suggested that the beneficial effects of antiviral agents on the occurrence of pneumocystosis are due mainly to their effects on the virus or the host immune response. In contrast to the antiviral drugs, 9-deazainosine, a nucleoside analog with antiprotozoal properties, deinonstrated marked activity against P. carinii which was related to dose and route of administration. These data raised the possibility that anti-P. carinii activity is a general property of purine nucleosides Experimental studies of anti-P. carinii drugs have usually been performed in an immunosuppressed rat model of pneumocystosis, which is a reliable predictor of activity against the human form of the disease (10,13,20). In a previous study of antifolate drugs in this model (34), we found that anti-P. carinii activity was a general property of sulfonamides; these compounds were so effective that a doseresponse curve could not be established at the doses used. By contrast, DHFR inhibitors exhibited little anti-P. carinii activity and did not improve the efficacy of the sulfonamides * Corresponding author.or the sulfone dapsone. This lack of synergism differed from the results of previous workers (10,14,15) and raised questions about the value of using the rat model to screen antifolate drugs.In the present study, we have extended these observations by exploring the effect of lower doses of the sulfonamide sulfamethoxazole (SMX) in the therapy of experimental pneumocystosis. We

Spinal muscular atrophy is a genetic disorder of the motor neurons that causes profound hypotonia, severe weakness, and often fatal restrictive lung disease. Patients with spinal muscular atrophy present a spectrum of disease from the most severe infantile-onset type, called Werdnig-Hoffmann disease (type 1), associated with a mortality rate of up to 90%, to a late-onset mild form (type 3), wherein patients remain independently ambulatory throughout adult life. Although many clinicians agree that patients with spinal muscular atrophy lose motor abilities with age, it is unknown whether progressive weakness occurs in all patients with spinal muscular atrophy. We present here results of the first prospective study of muscle strength in patients with spinal muscular atrophy. There was no loss in muscle strength as determined by a quantitative muscle test during the observation period. However, motor function diminished dramatically in some patients with spinal muscular atrophy. Explanations for this loss of function could not be determined from our data. Decrease in motor function could be caused by factors other than loss of strength. Therefore, it is not clear from our results whether spinal muscular atrophy is a neurodegenerative disease. We conclude that treatment trials in spinal muscular atrophy should be designed with consideration of the natural history of strength and motor function in this disorder.