Rituximab is an effective treatment in patients with pemphigus vulgaris and demonstrates a steroid-sparing effect.

BACKGROUND: Corticosteroids (CS) with or without adjuvant immunosuppressant agents are standard treatment for pemphigus vulgaris (PV). The efficacy of adjuvant therapies in minimizing steroid-related adverse events (AEs) is unproven. OBJECTIVES: To utilize data collected in a French investigator-initiated, phase III, open-label, randomized controlled trial to demonstrate the efficacy and safety of rituximab and seek approval for its use in PV. METHODS: This was an independently conducted post hoc analysis of the moderate-to-severe PV subset enrolled in the Ritux 3 study. Patients were randomized to rituximab plus 0·5 or 1·0 mg kg-1 per day prednisone tapered over 3 or 6 months, or 1·0 or 1·5 mg kg-1 per day prednisone alone tapered over 12 or 18 months, respectively (according to disease severity). The primary end point was complete remission at month 24 without CS (CRoff) for ≥ 2 months, and 24-month efficacy and safety results were also reported. RESULTS: At month 24, 34 of 38 patients (90%) on rituximab plus prednisone achieved CRoff ≥ 2 months vs. 10 of 36 patients (28%) on prednisone alone. Median total cumulative prednisone dose was 5800 mg in the rituximab plus prednisone arm vs. 20 520 mg for prednisone alone. Eight of 36 patients (22%) who received prednisone alone withdrew from treatment owing to AEs; one rituximab-plus-prednisone patient withdrew due to pregnancy. Overall, 24 of 36 patients (67%) on prednisone alone experienced a grade 3/4 CS-related AE vs. 13 of 38 patients (34%) on rituximab plus prednisone. CONCLUSIONS: In patients with moderate-to-severe PV, rituximab plus short-term prednisone was more effective than prednisone alone. Patients treated with rituximab had less CS exposure and were less likely to experience severe or life-threatening CS-related AEs. What's already known about this topic? Pemphigus vulgaris (PV) is the most common type of pemphigus. Corticosteroids, a standard first-line treatment for PV, have significant side-effects. Although their effects are unproven, adjuvant corticosteroid-sparing agents are routinely used to minimize steroid exposure and corticosteroid-related side-effects. There is evidence that the anti-CD20 antibody rituximab is effective in the treatment of patients with severe recalcitrant pemphigus and in patients with newly diagnosed pemphigus. What does this study add? This study provides a more detailed analysis of patients with PV enrolled in an investigator-initiated trial. Rituximab plus prednisone had a steroid-sparing effect and more patients achieved complete remission off prednisone. Fewer patients experienced grade 3 or grade 4 steroid-related adverse events than those on prednisone alone. This collaboration between academia and industry, utilizing independent post hoc analyses, led to regulatory authority approvals of rituximab in moderate-to-severe PV.

[Orbita - anatomy, development and deformities]. / Orbita - Anatomie, Entwicklung und Fehlbildungen.

The development of the structures of the human orbita is very complex, but understanding the development makes it easier to understand normal anatomy and dysplasia. The following article first discusses the embryonic development of the eye structures and then presents the "normal" radiological anatomy using different investigation techniques and the most common deformities.

[CNS infections in immunocompromised patients]. / ZNS-Infektionen bei immunsupprimierten Patienten.

CNS infections caused by infective agents are rare in immunocompetent hosts, but more frequent in immunocompromised patients. In addition, the spectrum of causative agents is completely different. There are no pathognomonic alterations in radiologic imaging, even in clinically severely ill patients imaging is often non-specific or inconspicious. This article gives a review of the most frequent infective agents and image alterations. Modern radiology is not yet able to replace the gold standard of pathogen detection.

Understanding conscious sedation in the operating room.

Conscious sedation is an appropriate choice for patients who do not require a general anesthetic, but rather need sedation to alleviate anxiety, minimize the discomfort of less invasive surgical procedures, or even to tolerate a regional or local anesthetic. New pharmaceutical agents, with their short half lives, provide amnesia, analgesia, and sedation quite safely. This concept, combined with standardized and controlled safety monitoring, offers an anesthetic alternative quite acceptable to many patients and health care providers. Standards and guidelines have been extensively developed by the American Society of Anesthesiologists, and the American Association of Nurse Anesthetists, to set forth a practice for all providers that will promote patient safety and provider vigilance (AANA, 1998). The purpose of this article is to review the process of conscious sedation.

Planarity of nitro-substituted phenothiazines.

The structures of three nitro-substituted phenothiazines [1,3,4-trifluoro-2-nitrophenothiazine, 10-(4-chlorobutyl)-1,3,4-trifluoro-2-nitrophenothiazine and 10-(4-chlorobutyl)-3-nitrophenothiazine] have been determined. The first of these red compounds forms infinite stacks in the solid state, in which donor and acceptor regions of the approximately planar molecules alternate. The molecules of the other two compounds, which have folded, or 'butterfly', conformations in the solid state, do not form stacks, presumably because the bulky chlorobutyl substituents cannot be accommodated. The very dark color of solid 3-nitrophenothiazine suggests the presence of extended molecular stacks, but crystals suitable for a structure determination could not be obtained.

Synthesis, binding affinity, and cross-linking of monodentate photoactive phenothiazines to calmodulin.

Various photoactive phenothiazines were synthesized that possessed a 2-azido, 3-azido, 2-benzoyl, or 1,3,4-trifluoro-2-azido functionality in combination with various modifications of the N-alkyl side chain. These phenothiazines were evaluated for their ability to inhibit the calmodulin-mediated activation of phosphodiesterase (PDE). All were active in inhibiting the action of calmodulin (CaM), but those possessing either a 3-azido and a 4-(4-methyl-1-piperazinyl)butyl side chain or a 2-benzoyl group and 3-(dimethylamino)propyl side chain proved to be most active (I50 = 14 +/- 3 microM and 7 +/- 1 microM, respectively) when compared to the known inhibitor, chlorpromazine (CPZ, I50 = 30 microM). Calmodulin was photolabeled with ca. 35% efficiency in a light- and calcium-dependent fashion using a radiolabeled analog, 3-azido-10-(4-(4-[14C]methyl-1-piperazinyl)butyl)phenothiazine, of one of these compounds. Competition studies using this radiolabeled analog and CPZ were consistent with binding to one or both of the hydrophobic binding pockets of CaM.

Synthesis and use of a biotinylated 3-azidophenothiazine to photolabel both amino- and carboxyl-terminal sites in calmodulin.

The biotinylated probe, 3-azido-10-(4-(4-biotinyl-1-piperazinyl)butyl)phenothiazine, was used to examine the phenothiazine binding domains in calmodulin (CaM) by photolabeling. This phenothiazine, synthesized from 3-azido-10-(4-(1-piperazinyl)butyl)phenothiazine and d-biotinyl tosylate, inhibited the CaM-mediated activation of phosphodiesterase (PDE) with an I50 of 12.5 (+/- 2.8) microM. Photolabeling of CaM produced covalent adducts in excellent yield (32%) in a light- and Ca2+-dependent manner. Studies performed over a range of drug concentrations suggested a 2:1 stoichiometry for the binding of the phenothiazine probe to CaM. Limited trypsin digestion and purification of the resulting fragments by either SDS-PAGE or HPLC provided two principal phenothiazine-containing peptides. Amino acid composition and sequence analyses performed on these two peptides established that both the N- and C-terminal domains in CaM, particularly the regions amino terminal to Ca2+-binding loops 1 and 3, were modified by the photoactivated phenothiazine derivative. These data, particularly for the C-terminal domain, are in excellent agreement with the X-ray structure analysis of a 1:1 CaM-trifluoperazine complex.

Synthesis and binding affinity of bidentate phenothiazines with two different photoactive groups.

The development of targeted, bidentate photoaffinity reagents for mapping the interacting domains of calmodulin (CaM) with the enzymes that it regulates required the synthesis and evaluation of the binding affinity of various phenothiazines. These photoaffinity reagents would possess a photoactive 3-azidophenothiazine group for cross-linking the hydrophobic binding domain of CaM, a second photoactive benzophenone group that would be activated at a different wavelength than the 3-azidophenothiazine group, and a suitable radiolabel. Difficulties were encountered in identifying those structural features that would be compatible with the introduction of a benzophenone group, with the solubility of these benzophenone-substituted phenothiazines, and with the ability of these phenothiazines to inhibit the calmodulin-mediated activation of phosphodiesterase. Solutions to this problem involved the preparation of phenothiazines possessing a quaternary ammonium salt, a zwitterionic amino acid, or a carbohydrate moiety. The phenothiazines that possessed photoactive 3-azido and benzophenone groups and in which one of the piperazine nitrogens in the side chain was converted to a quaternary, N-methylammonium iodide inhibited the calmodulin-mediated activation of phosphodiesterase at a level comparable to that of chlorpromazine.

Preemptive analgesia.

Preemptive analgesia describes a situation where the administration of a pharmacological agent administered before the onset of a painful stimulus causes a decrease in the intensity of pain felt, and subsequently there is a decrease in the total amount of analgesic required compared with the administration of an agent after a painful stimulus. It is best understood if it is thought of as a block to afferent impulses that are trying to reach the central nervous system before a tissue injury. Preemptive analgesia, administered in the form of narcotics, nonsteroidal antiinflammatory agents, or local anesthetics, is thought to alter peripheral and central sensitization to nociceptive impulses.

Malignant hyperthermia: a review.

Malignant hyperthermia (MH) was first identified as an anesthetic-related patient syndrome with familial tendencies in 1960. It is defined as a chain reaction of abnormalities triggered in susceptible individuals by commonly used anesthetic agents, and is classified as a hypermetabolic disorder of skeletal muscle. It is believed that susceptible patients possess a genetic predisposition for the development of the disease. In an acute episode of MH, the anesthetic triggering agent appears to interfere with the calcium ion reentry into the sarcoplasmic reticulum after muscle contraction. This process involving the calcium ion is the basis for all the clinical symptoms observed.

Prostaglandin photoaffinity probes: synthesis and binding affinity of C-18 substituted PGF2 alpha prostanoids bearing a perfluorinated aryl azide.

C-18 Phenoxy analogs of prostaglandin F2 alpha (PGF2 alpha) that possessed a perfluorinated aryl azide and an aryl iodide substituent were synthesized and evaluated as potential photoaffinity probes for PGF2 alpha. Prior studies indicated that only hydrophobic modifications in the omega-side chain of PGF2 alpha were compatible with high binding affinity, and this finding excluded the use of a hydroxyl-substituted C-18 phenoxy group as an activated aryl ring capable of radioiodination. Consequently, an alternate means of introducing the iodine substituent using an ipsosubstitution of a trimethylsilyl arene was developed. Although this strategy was successful from a synthetic perspective, the potential PGF2 alpha photoaffinity probe, (15S)-18-[3'-((4''-azido-2'',3'',5'',6''-tetrafluorophenyl)- methoxy) methyl-5'-iodophenoxy]-19,20-bisnorprostaglandin F2 alpha, exhibited only marginal competitive binding with [3H]-PGF2 alpha to ovine luteal cells and to plasma membranes of bovine corpora lutea. The hydrophobic but bulky C-18 substituent was presumably incompatible with effective receptor binding.

Prostaglandin photoaffinity probes: synthesis and binding affinity of aryl azide-substituted C-1 esters of prostaglandin F2 alpha.

In seeking prostaglandin F2 alpha (PGF2 alpha) photoaffinity probes possessing both an efficient, photoactive cross-linking substituent and a radiolabel of high specific activity, the synthesis and binding affinity of PGF2 alpha C-1 esters in which the alcohol component possessed either an aryl azide or a perfluorinated aryl azide was investigated. These derivatives showed great promise due to their ability to compete for the binding of [3H]-PGF2 alpha in both a luteal membrane binding assay and in a whole luteal cell binding assay. Identification of the C-1 site in PGF2 alpha as a site for modification of the PGF2 alpha molecule with photoactive alcohol derivatives represented a logical step toward the goal of developing a useful PGF2 alpha photoaffinity probe.