Immunomodulation of autoimmune and inflammatory diseases with intravenous immunoglobulin

Abstract Intravenous immunoglobulin (IVIg) has been used in the treatment of primary and secondary antibody deficiencies for over two decades. Since the early 1980s, the therapeutic efficacy of IVIg has been established in idiopathic thrombocytopenic purpura, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, dermatomyositis and Kawasaki syndrome, and the prevention of graft versus host disease in recipients of allogeneic bone marrow transplants. Its use has also been reported in a large number of other autoimmune and systemic inflammatory conditions. In this review, we discuss the mechanisms by which IVIg exerts immunomodulatory effects in immune pathologies.     

Role of ventricular assist devices in the German heart allocation system

The Eurotransplant (ET) allocation algorithm, newly implemented in 2000, gives priority for heart transplantation (HTx) to patients with high urgency (HU) status, but now this status is rescinded upon ventricular assist device (VAD) implantation and only regained if severe complications occur during mechanical circulatory support (MCS). We studied the effects of this change on the patients in our institute who were waiting for HTx with MCS. The median duration of MCS until HTx in adult patients gradually increased from 3.1 months in 1994, reaching a peak of 16.7 months in 2000, and then gradually decreased to 6.0 months in 2003. Among the patients with VAD implantation as a bridge to HTx, two patients were on MCS for more than 1 year (the longest duration of MCS being 1.6 years) at the end of 1999, and this figure increased to nine patients and a maximum MCS duration of 3.7 years at the end of 2003. These data imply that the patients in whom a complication occurred in the early phase of MCS and who had overcome this complication underwent HTx early with HU status, and those who were stable during MCS waited a long time for HTx. Furthermore, the number of patients in the latter group is increasing. The new allocation algorithm imposes on patients with MCS waiting for HTx who are relatively young and free from complications and serious coexisting disease, very long-term MCS without an end to VAD bridging, which is almost equivalent to destination therapy. Part of this paper was presented at the 42nd JSAO Conference (Tokyo, October 5–7, 2004)     

Suppression of charge movement by calcium antagonists is not related to calcium channel block

The calcium channel-inhibiting drugs nitrendipine and diltiazem represent two important classes of organic calcium antagonists. In the present study, the effect of these drugs on calcium currents and charge displacement currents in bullfrog semitendinosus muscle fibers was examined using a vaseline gap voltage clamp. Nitrendipine (10 M) reduced the quantity of charge that moved both during the ON phase (Q_ON) and the OFF phase (Q_OFF) of charge movement. This action appeared to be most selective for Q_ON. However, at this same concentration, nitrendipine had no blocking action on inward calcium currents. In contrast to these findings, diltiazem blocked calcium currents in a concentration-dependent manner, while slightly increasing the quantity of charge moved during Q_ON and Q_OFF. The enhancement of charge movement by diltiazem resulted from two actions. First, diltiazem shifted the voltage-dependence of charge movement to more negative potentials. Second, diltiazem increased the maximum amount of charge moved. (Supported by NIH NS 03178 and HL 07382.)     

DIFFERENTIAL SENSITIVITY OF TWO PALMAR SWEAT MEASURES

Two techniques for measuring palmar sweating were tested for their sensitivity to a standard anticholinergic agent. The finger sweat-print and palmar sweatweight methods were compared in a double-blind, crossover study by determining their relative sensitivity in detecting the antisweating effects of 0.5 mg of atropine sulfate. The sweat-print method was significantly superior in detecting drug-induced sweat reduction and hypothesized sex differences.     

Eye Movements and Visually Active Dreams

There are a number of reports suggesting an association between profusion of eye movements and active dreaming. It has however been suggested that this relationship might only be evident in comparisons across the night and would not be evident in comparisons within one REM period. Data from 20 subjects taking placebo, amylobarbitone, and nitrazepam were used to test this. Dream reports were collected from REM awakenings and rated blind as visually active or passive. Eye movement profusion (number of 2 sec epochs) was assessed for each REM period. Correlation between dream content and eye movement was low but significant in comparisons including the whole night, and including data from drug, withdrawal, and placebo conditions. A significant correlation was not consistently obtained, however, when data from each REMP were considered separately. Correlations based on data from non-drug nights only were also small and could have been due to chance effects alone. The low correlations were not explicable solely by poor reliability of content ratings. It is concluded that the relationship between visually active dreaming and eye movement is slight, and may not hold when time of night is adequately controlled.     

Delayed pressure urticaria

Delayed pressure urticaria (DPU) is a poorly understood syndrome. We describe 17 patients with DPU. Chronic urticaria was present in 94%. All had negative challenges for immediate demographism and cold urticaria. DPU was induced with a pressure challenge on the shoulder of 15 pounds for 15 min. Average onset of pressure lesions after challenge was 6.5. Lesions were painful, not pruritic, peaked at 9 hr, and disappeared by 24 to 48 hr. Fever, chills, and/or arthralgias occurred in 78%. Positive laboratory abnormalities included leukocytosis in 20% and elevated erythrocyte sedimentation rate in 37.5%. Skin biopsies of lesions showed perivascular round cell infiltrates and negative immunofluorescence. Urticaria responded to antihistamines, but not aspirin, in 100% of patients, while pressure lesions improved with nonsteroidal anti-inflammatory drugs (NSAID), but not antihistamines, in 80% of patients. Both urticaria and DPU were controlled with prednisone, which was necessary in 87.5% of patients. A severe nonremitting course was noted in 7%, 40% had a moderate remitting course requiring intermittent prednisone, and 53% had a mild remitting disease requiring no medication or antihistamines and/or NSAID only. We conclude that DPU is more common than previously appreciated and likely involves mediators other than histamine, possibly the prostaglandin system.     

Ro 11-2465 (cyan-imipramine), citalopram and their N-desmethyl metabolites: Effects on the uptake of 5-hydroxytryptamine and noradrenaline in vivo and related pharmacological activities

Ro 11-2465 (cianopramine, cyan-imipramine) and citalopram (CIT), putative antidepressant drugs, are very potent and selective 5-hydroxytryptamine (5-HT) uptake inhibitors in vitro. This study investigated the effects of these drugs and their desmethyl metabolites, Ro 12-5419 (desmethylcianopramine, cyan-desipramine) and desmethylcitalopram (DCIT), respectively, on the uptake of 5-HT and noradrenaline (NA) in vivo [protection against H 77/77 (4, alpha-dimethyl-metatyramine)-induced displacement of 5-HT and NA] and on related pharmacological activities. All the investigated drugs antagonized H 77/77-induced displacement of 5-HT in the rat brain, though the effects of the metabolites were considerably weaker than those of the parent compounds. The H 77/77-induced displacement of brain NA in rats and mice was antagonized only by Ro 12-5419 and Ro 11-2465. All the drugs potentiated the pressor response to 5-HT in pithed rats; however, Ro 12-5419 and particularly Ro 11-2465 could also block the response when used in higher doses (0.1 mg/kg). Only Ro 12-5419 and Ro 11-2465 were able to potentiate the pressor response to NA. Ro 12-5419 also potentiated thyrotropin releasing hormone (TRH) hyperthermia and antagonized reserpine hypothermia in mice; Ro 11-2465 potentiated the TRH hyperthermia only. CIT and DCIT were inactive in both these tests. Of all the four drugs only CIT and Ro 12-5419 considerably stimulated the hind limb flexor reflex in spinal rats. However, whereas the stimulatory effect of CIT was inhibited by the 5-HT antagonists metergoline and cyproheptadine, that of Ro 12-5419 was counteracted by the NA antagonist phenoxybenzamine only. Ro 11-2465, when used in low doses (ca. 1 mg/kg), slightly potentiated the flexor reflex, whereas in higher doses (4–16 mg/kg) it had no effect itself but antagonized the stimulatory action of the 5-HT agonists fenfluramine, quipazine and LSD. The results obtained indicate that Ro 11-2465 and CIT, as well as their desmethyl metabolites, are also potent 5-HT uptake inhibitors in vivo. However, only CIT and DCIT are concurrently devoid of effect on uptake of NA. In contrast, Ro 11-2465 and particularly Ro 12-5419 appear to also inhibit the uptake of NA. Moreover, Ro 11-2465 appears to block central and peripheral 5-HT receptors.The results were presented at the 14th CINP Congress, Florence, June 19–23, 1984