Trimetrexate for the treatment of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome

Preclinical studies have demonstrated that trimetrexate is a potent inhibitor of dihydrofolate reductase from Pneumocystis carinii. On the basis of this evidence, this lipid-soluble antifolate was used as an antipneumocystis agent in 49 patients with the acquired immunodeficiency syndrome (AIDS) and pneumocystis pneumonia. Simultaneous treatment with the reduced folate leucovorin was used as a specific antidote to protect host tissues from the toxic effects of the antifolate without affecting the antipneumocystis action of trimetrexate. Patients were assigned to three groups and treated for 21 days: in Group I, trimetrexate with leucovorin was used as salvage therapy in patients in whom standard treatments (both pentamidine isethionate and trimethoprim-sulfamethoxazole) could not be tolerated or had failed (16 patients); in Group II, trimetrexate with leucovorin was used as initial therapy in patients with a history of sulfonamide inefficacy or intolerance (16 patients); and in Group III, trimetrexate with leucovorin plus sulfadiazine was used as initial therapy (17 patients). The response and survival rates were, respectively, 69 percent and 69 percent in Group I; 63 percent and 88 percent in Group II; and 71 percent and 77 percent in Group III. Trimetrexate therapy had minimal toxicity; transient neutropenia or thrombocytopenia occurred in 12 patients and mild elevation of serum aminotransferases in 4. We conclude that the combination of trimetrexate and leucovorin is safe and effective for the initial treatment of pneumocystis pneumonia in patients with AIDS and for the treatment of patients with intolerance or lack of response to standard therapies.     

Platelet activating factor and tracheobronchial respiratory glycoconjugate release in feline and human explants: Involvement of the lipoxygenase pathway

It has been suggested that platelet activating factor (PAF) may participate in many aspects of bronchial asthma, including stimulation of mucus secretion. Feline tracheal and human bronchial explant production of respiratory glycoconjugates (RGC) in response to platelet activating factor (PAF) was investigatet, in order to differentiate the actions of this putative mediator on mucus secretion. PAF caused a dose-dependent increase in RGC release in concentrations ranging from 100–0.5 M during a 1–2 hours incubation with either feline or human explants, and the effect was inhibited by the PAF receptor antagonists Ro 19-3704. Several lines of evidence suggest that PAF enhances RGC release indirectly through stimulation of the production of lipoxygenase metabolites of arachidonic acid. 1) Incubation of 10 M PAF together with arachidonic acid (100 g/ml) enhances PAF's stimulatory effect on RGC release in cats. 2) The cyclooxygenase inhibitor ibuprofen (65 and 420 M) either failed to effect or slightly enhanced PAF induced RGC release in both species. 3) The combined cyclooxygenase and lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) as well as the putatively specific 5-lipoxygenase inhibitor L-651, 392 (both at 50 M) inhibited the response to PAF in both species. 4) The putative LTD₄ receptor antagonists (L-660, 711, 100 M) slightly reduced the PAF secretory response in human bronchi. We conclude that PAF causes specific receptor mediated RGC release. This response is indirectly mediated through the generation of lipoxygenase metabolite formation including 5-lipoxygenase pathway metabolites.Parts of this report has previously been published as abstract in: Clin. Res., 36(3), A257 (1988); J. Allergy Clin. Immunol., 83, 274 (1989); and FASEB J., 3(3), A609 (1989).     

Dexamethasone inhibits respiratory glycoconjugate secretion from feline airways in vitro by the induction of lipocortin (lipomodulin) synthesis

The effect of glucocorticoids on respiratory glycoconjugate (RGC) secretion was studied in a cat tracheal organ culture system. Dexamethasone (10(-5) to 10(-9) M) added to culture medium for 24 h caused a dose-related reversible inhibition of RCG of as much as 40% with a peak effect at 24 to 60 h after initiation of dexamethasone treatment. A monoclonal antilipocortin antibody added to the cultures blocked the inhibitory effect of dexamethasone on RGC secretion and accelerated the reversal of the dexamethasone effect after discontinuation of dexamethasone treatment. A control antibody without antilipocortin activity had no effect on RGC secretion or dexamethasone-induced inhibition of RGC secretion. Measurement of the concentration of lipocortin in airways revealed a 220% increase after treatment with dexamethasone for 24 h. We conclude that dexamethasone inhibits RGC secretion through the induction of lipocortin synthesis.     

Disorders of ciliary motility

Clearance of mucus and other debris from the airways is achieved by 3 main mechanisms: mucociliary activity, coughing, and alveolar clearance. Disorders of ciliary structure or function results in impaired clearance, and result in chronic sinopulmonary disease manifested as chronic sinusitis, otitis media, nasal polyposis, and ultimately bronchiectasis. In addition, situs inversus, dextrocardia, and infertility can be associated with dysfunctional ciliary activity. The term primary ciliary dyskinesia has been proposed for the spectrum of these diseases. The term Kartagener syndrome applies to this syndrome when accompanied by infertility and dextrocardia or situs inversus. The more common types of ciliary dysmotility syndromes are characterized by missing dynein arms, central microtubule pairs, inner sheath, radial spokes, or nexin links. In addition to structural defects within the cilia, disordered ciliary beating and disordered ciliary arrays on epithelial cell surfaces have been described in this syndrome. Treatment includes rigorous lung physiotherapy, prophylactic and organism-specific antibiotics, and immunization against common pulmonary pathogens. Late stages of the disease may require surgical intervention for bronchiectasis or lung transplant for end-stage lung disease.     

Prognostic factors and life expectancy of patients with acquired immunodeficiency syndrome and Pneumocystis carinii pneumonia

To assess determinants of prognosis for 43 patients with the acquired immunodeficiency syndrome (AIDS) and Pneumocystis carinii pneumonia, objective clinical and histopathologic characteristics were analyzed for acute and long-term prognostic significance. Severe abnormalities on initial chest radiographs and alveolar-arterial oxygen differences (AaPO2) greater than 30 mm Hg were associated with higher mortality during the period of treatment for the acute episode (p less than 0.05). Decreased long-term survival after the diagnosis of Pneumocystis pneumonia correlated with the severity of interstitial edema (a component of diffuse alveolar damage) on initial transbronchial biopsy and elevation of AaPO2 at the time of diagnosis (Cox proportional hazards analysis, p less than 0.05). The persistence of Pneumocystis cysts after 3 wk of therapy was associated with significantly decreased long-term survival (p less than 0.05) when follow-up biopsy was performed in 27 of the patients. Patients with a diagnosis of Pneumocystis pneumonia before July 1985 had more advanced disease at the time of diagnosis and a worse prognosis than did those in whom the diagnosis was made after July 1985 (p less than 0.05). This study demonstrates that important prognostic information can be derived from information obtained at initial presentation and follow-up bronchoscopic evaluation in patients with AIDS and Pneumocystis carinii pneumonia, and suggests that early detection and initiation of therapy may improve chances for survival.     

Behavioral analysis of predictive saccade tracking as studied by countermanding

The ability to make predictive saccadic eye movements is dependent on neural signals that anticipate the onset of a visual target. We used a novel paradigm—based on the saccade-countermanding task—as a tool to investigate rhythm saccade pacing and to provide information on the mechanisms of predictive timing. In particular, we examined the ability of normal subjects to stop a sequence of periodically paced eye movements when cued by a stop signal that was presented at different times with respect to the last target of the sequence (stop signal delay, SSD). The timing of the stop signal affected the ability to stop the saccadic sequence (make a saccade to a central target rather than to the peripheral alternating targets) in different ways, depending on the preceding tracking behavior. For the same SSD, subjects cancelled fewer trials during predictive tracking (promoted by tracking targets alternating at a fast pacing rate, 1.0 Hz) than during reactive tracking (tracking alternating targets at a low pacing rate, 0.2 Hz). In addition, on non-canceled trials, there was an increase in the delay of the corrective saccade to the central target with increasing SSD for pacing at 0.2 Hz, but the timing of the corrective saccade remained near constant for 1.0 Hz pacing. In examining the timing between movements, we estimate that the repetitive GO process that drives the saccades during predictive tracking begins earlier and has a shorter duration than the repetitive GO process during reactive tracking. These behavioral results provide further insight into the initiation process of predictive responses. In particular, the reduced reaction time and the corresponding short duration of the predictive process may result from a faster accumulation of neuronal discharge to a relatively fixed threshold.     

Sensory versus motor information in the control of predictive saccade timing

Humans readily make predictive saccades to periodic alternating targets. This predictive behavior depends on internal monitoring of timing error of past saccades in order to determine the time of initiation of future saccades; our earlier studies have confirmed this by finding correlations between latencies of consecutive predictive saccades. It is natural to consider that timing error is determined by visual detection of the difference between the time the target appears and the time the eyes arrive at the target; this in turn implies that saccades must actually be produced in order for their timing errors to be determined and predictive saccade timing to be established. We tested this hypothesis by having subjects view alternating visual targets while fixating a central target in order to eliminate saccade production. After six alternating target presentations, subjects began tracking the alternating targets. Tracking performance was assessed with an error measure that compared saccade latency and inter-saccade interval with desired values (zero and inter-stimulus interval, respectively). Errors in this Prior Viewing paradigm were compared to those from a conventional De Novo paradigm in which saccades began as soon as the alternating targets were presented. Saccades under Prior Viewing reached a low-error steady predictive state more rapidly than under De Novo tracking. The initial saccade under Prior Viewing had a higher latency than the others, suggesting that this saccade was reactive even though the paradigm is predictable; other reasons for this higher latency include time to disengage from the fixation target and time required to pre-program the initial set of saccades. The results show that visual detection of timing error from an actual motor act (saccades) is not necessary to establish predictive saccadic pacing: sensory-only information from viewing the moving targets can help to establish this predictive state.     

Acquisition of context-specific adaptation is enhanced with rest intervals between changes in context state, suggesting a new form of motor consolidation

We previously showed that the saccadic system could be adapted in a context-specific manner: two different adapted gains could be associated with two different context cues, with the gain state switched when the context state was switched. This was accomplished by alternating context/adaptation states several times over the course of an adaptation session, and assessing saccade gain in each context state before and after adaptation. One context cue we studied was vertical eye position; an adaptive gain increase was induced with the eyes up 10 degrees, and an adaptive gain decrease with the eyes down 10 degrees. This context cue was only partially effective: there was considerable undesired transfer of adaptation from the eyes-down condition (gain-decrease) to the eyes-up condition (gain-increase), with the result that there was little or no gain-increase adaptation. One explanation for this is that the two context/adaptation states, presented one after the other, interfered with each other. In the present study, we tested this hypothesis by interposing one-minute rest intervals between each alternation in context/adaptation state. The resulting context-specific adaptation is greatly improved (relative to the case when there are no rest intervals): both gain-increase and gain-decrease adaptations are stronger and occur more rapidly. This effect resembles that found in studies on the consolidation of motor learning, although such consolidation is believed to occur over much longer time spans (hours rather than minutes).