Short-course subcutaneous treatment with PQ Grass strongly improves symptom and medication scores in grass allergy.

BACKGROUND: A modified grass allergen subcutaneous immunotherapy (SCIT) product with MicroCrystalline Tyrosine and monophosphoryl lipid-A as an adjuvant system (Grass MATA MPL [PQ Grass]) is being developed as short-course treatment of grass-pollen allergic rhinitis (SAR) and/or rhinoconjunctivitis. We sought to evaluate the combined symptom and medication score (CSMS) of the optimized cumulative dose of 27,600 standardized units (SU) PQ Grass in a field setting prior to embarking on a pivotal Phase III trial. METHODS: In this exploratory, randomized, double-blind, placebo-controlled trial subjects were enrolled across 14 sites (Germany and the United States of America). Six pre-seasonal subcutaneous injections of PQ Grass (using conventional or extended regimens) or placebo were administered to 119 subjects (aged 18-65 years) with moderate-to-severe SAR with or without asthma that was well-controlled. The primary efficacy endpoint was CSMS during peak grass pollen season (GPS). Secondary endpoints included Rhinoconjunctivitis Quality of Life Questionnaire standardized (RQLQ-S) and allergen-specific IgG4 response. RESULTS: The mean CSMS compared to placebo was 33.1% (p = .0325) and 39.5% (p = .0112) for the conventional and extended regimens, respectively. An increase in IgG4 was shown for both regimens (p < .01) as well as an improvement in total RQLQ-S for the extended regimen (mean change -0.72, p = .02). Both regimens were well-tolerated. CONCLUSIONS: This trial demonstrated a clinically relevant and statistically significant efficacy response to PQ Grass. Unprecedented effect sizes were reached for grass allergy of up to ≈40% compared to placebo for CSMS after only six PQ Grass injections. Both PQ Grass regimens were considered equally safe and well-tolerated. Based on enhanced efficacy profile extended regime will be progressed to the pivotal Phase III trial.

Electrogastrography as a diagnostic tool for delayed gastric emptying in functional dyspepsia and irritable bowel syndrome.

Several pathophysiological mechanisms have been proposed in functional gastrointestinal (GI) disorders, e.g. altered GI motility and sensitivity. The aim of this study was to investigate gastric electrical activity (GEA) in patients with functional dyspepsia (FD) or irritable bowel syndrome (IBS) compared with healthy controls (HC), and to assess if abdominal symptoms and delayed gastric emptying are associated with alterations in GEA, as determined by electrogastrography (EGG). Forty patients with FD, IBS or both were compared with 22 HC. EGG was performed before and after a standard meal. Frequencies and amplitudes pre- and post-prandially were analysed. Furthermore, gastric emptying and symptom scores were assessed. Eight of 40 patients (20%; three FD, three IBS, two FD and IBS) had delayed gastric emptying. Disturbed gastric emptying and lack of a postprandial increase in the EGG amplitude were significantly correlated (r = 0.8; P < 0.005). No differences between controls and patients were observed in the distribution of EGG frequencies. Treatment with the prokinetically active macrolide erythromycin improved gastric emptying, GEA and symptoms (n = 4). The data suggest that EGG could be useful as a diagnostic tool in patients with FD and IBS to identify a subgroup of patients with delayed gastric emptying.

Retroviruses and their play-pals.

A 28-year-old man with a previous history of Neissena infection presented with diminished vision, disc swelling, and panuveitis. Serologic tests revealed positive titers for both HIV and syphilis. Current epidemiology and treatment of such cases are discussed.

Cluster headache. Local anesthetic abortive agents.

Cocainization of the sphenopalatine fossa region has been shown to abort acute cluster headaches rapidly. Whether this response occurs by sympathomimetic action or via local anesthetic effect has been unknown. In this study, lidocaine hydrochloride was given as a therapeutic abortive agent to patients with cluster headache to elucidate cocaine's mechanism of action in relieving symptoms and to search for a safe, nonaddicting agent for self-administration. Using a 4% lidocaine solution applied to the sphenopalatine fossa, four of five patients obtained rapid relief of nitrate-induced cluster headaches and associated signs. Lidocaine was also effective in relieving spontaneous attacks. These results indicated that anesthetic rather than sympathomimetic effects are responsible for cocaine-medicated abortion of cluster headache, that transmission of pain in cluster headache likely occurs via the sphenopalatine fossa, and that topical lidocaine is effective in rapidly aborting acute cluster headache.

Transient monocular visual loss from narrow-angle glaucoma.

Three patients had transient monocular visual loss from subacute attacks of narrow-angle glaucoma. In all three cases the visual loss had been previously diagnosed as being due to other neurologic causes.

Specificities of antibodies to acetylcholine receptors in sera from myasthenia gravis patients measured by monoclonal antibodies.

The pattern of antibody specificities in sera from patients with myasthenia gravis (MG) was determined by the ability of monoclonal antibodies against defined determinants on the acetylcholine receptor molecule to inhibit binding of the serum antibodies to receptor from human muscle. We found that MG patients produce fundamentally the same pattern of specificities as that produced by animals immunized with receptor purified from fish electric organs or mammalian muscle. Most of the antibodies are directed at the "main immunogenic region' which is located on the extracellular surface of the alpha subunit and is distinct from the acetylcholine binding site. Regions on the beta and gamma subunits near the main immunogenic region are also significantly immunogenic. In one patient the proportions of antibodies to various regions are constant over time despite changes in total antibody amount and clinical state. Between patients there is no obvious correlation between antibody specificities and clinical state. These data suggest that the autoimmune response in MG is stimulated by human receptor rather than a crossreacting (e.g., viral) antigen and that in both MG and experimental autoimmune MG the pattern of specificities produced is determined by the inherently immunogenic structural features of the receptor molecule. They also suggest that the wide differences in clinical state sometimes observed between patients with the same total concentration of antireceptor antibody are due primarily to differences in endogenous factors which affect the safety factor for neuromuscular transmission rather than to the presence of especially pathogenic antireceptor specificities.

Immunopathology of acetylcholine receptors in myasthenia gravis.

It is now clear that the muscular weakness and fatigability seen in MG result from an antibody-mediated immune response to AChR. The mechanisms by which antibodies impair transmission are moderately well understood and detection of antibodies in patient's sera is a reliable diagnostic test for the disease. The spectrum of antibody specificities produced in MG is also beginning to be understood, largely through the use of antibodies produced in the experimental model EAMG. Treatment for MG continues to rely heavily on the symptomatic relief afforded by acetylcholinesterase inhibitors. However, the recent recognition of the autoimmune nature of MG has led to increased emphasis on immunosuppression and antibody removal with some beneficial effects. Despite all that has been learned, the level of ignorance has just been pushed back one step--from the neuromuscular junction to the immune system. What initiates the immune response to AChR in MG and how to specifically suppress this aberrant response remain completely unknown.

Use of arginine compounds to examine the role of an essential arginine in the mechanism of glycogen phosphorylase.

The possible role of arginine in the mechanism of muscle glycogen phosphorylase qas studied by examining the effect of arginine compounds. Guanidino compounds with an aromatic group inhibit native phosphorylase b, reduced phosphorylase b, phosphorylase b', and phosphorylase a. The inhibition was found to be uncompetitive with respect to glucose 1-phosphate and noncompetitive toward glycogen for phosphorylase b. This is consistent with a kinetic mechanism where the inhibitor binds after the substrate, glucose 1-phosphate. In the presence of citrate and l-cysteine, N-alpha-tosylarginine methyl ester, a good inhibitor, promotes the removal of tightly bound pyridoxal phosphate. Potato phosphorylase has many similarities to the muscle enzyme, but it lacks the regulatory sites and does not have a polysaccharide storage site [Shimomura, S., & Fukui, T. (1980) Biochemistry 19, 2287]. N-alpha-Tosylarginine methyl ester inhibited the potato enzyme, was uncompetitive with glucose 1 -phosphate, and was competitive with starch; therefore, it seems likely that TAME is binding near the active site of both the potato and muscle enzyme. The different inhibitory patterns with respect of polysaccharide for potato and muscle phosphorylase can be explained by the absence of the polysaccharide storage site on the potato enzyme. Inhibition by arginine compounds is related to the pKa of the guanidino fuction, i.e., the lower pKa value, the greater the inhibition. On the basis of these studies and those of Dreyfus et al. [Dreyfus, M., Vandenbunder, B., & Buc, H. (1980) Biochemistry 19, 3834], who found that Arg-568 was essential for activity, we suggest that arginyl compounds inhibit when an unprotonated guanidino group competes for the "binding site" of Arg-568.

Antiacetylcholine receptor antibody and its relationship to HLA type in asymptomatic siblings of a patient with myasthenia gravis.

Antibodies to acetylcholine receptors (AChR-ab) were detected in a patient with myasthenia gravis (MG) and at much lower levels in her asymptomatic fraternal twin and one other asymptomatic sibling. These three carried the HLA-B8 allele, as did four other family members. In a previous study, we observed no AChR-ab in 175 non-MG patients. The occurrence of AChR-ab in 3 of 12 siblings suggests that all were affected by an unidentified pathologic factor acting on a favorable genetic background.