Roblee Allen - Academia.edu (original) (raw)

Papers by Roblee Allen

C52. USE YOUR ILLUSION II: CLINICAL RESEARCH IN PAH, 2019

The Lancet Respiratory Medicine, 2021

BACKGROUND Riociguat and phosphodiesterase-5 inhibitors (PDE5i), approved for the treatment of pu... more BACKGROUND Riociguat and phosphodiesterase-5 inhibitors (PDE5i), approved for the treatment of pulmonary arterial hypertension (PAH), act on the same pathway via different mechanisms. Riociguat might be an alternative option for patients with PAH who do not respond sufficiently to treatment with PDE5i, but comparisons of the potential benefits of riociguat and PDE5i in these patients are needed. The aim of this trial was to assess the effects of switching to riociguat from PDE5i therapy versus continued PDE5i therapy in patients with PAH at intermediate risk of 1-year mortality. METHODS Riociguat rEplacing PDE5i therapy evaLuated Against Continued PDE5i thErapy (REPLACE) was an open-label, randomised controlled trial in 81 hospital-based pulmonary hypertension centres in 22 countries. The study enrolled patients aged 18-75 years with symptomatic PAH at intermediate risk of 1-year mortality (based on the European Society for Cardiology-European Respiratory Society guideline thresholds for WHO functional class and 6-min walk distance [6MWD]) who were receiving treatment with a PDE5i with or without an endothelin receptor antagonist for at least 6 weeks before randomisation. Patients were excluded if they had been previously treated with riociguat, had used prostacyclin analogues or prostacyclin receptor agonists within 30 days before randomisation, had clinically significant restrictive or obstructive parenchymal lung disease, or had left heart disease. Patients were randomly assigned (1:1) to remain on PDE5i treatment (oral sildenafil [≥60 mg per day] or oral tadalafil [20-40 mg per day]; the PDE5i group) or to switch to oral riociguat (up to 2·5 mg three times per day; the riociguat group), using an interactive voice and web response system, stratified by cause of PAH. The primary endpoint was clinical improvement by week 24, defined as an absence of clinical worsening and prespecified improvements in at least two of three variables (6MWD, WHO functional class, and N-terminal prohormone of brain natriuretic peptide), analysed using last observation carried forward in all randomly assigned patients with observed values at baseline and week 24 who received at least one dose of study medication (the full analysis set). Secondary endpoints included clinical worsening events. The trial has been completed and is registered with ClinicalTrials.gov, NCT02891850. FINDINGS Between Jan 11, 2017, and July 31, 2019, 293 patients were screened, of which 226 patients were randomly assigned to the riociguat group (n=111) or to the PDE5i group (n=115). 211 patients completed the study and 14 patients discontinued (seven in each group). One patient assigned to the PDE5i group did not receive treatment, so 225 patients were included in the safety analysis, and one further patient in the PDE5i group had missing components of the composite primary endpoint at baseline, so 224 patients were included in the full analysis set. The primary endpoint was met by 45 (41%) of 111 patients in the riociguat group and 23 (20%) of 113 patients in the PDE5i group; odds ratio [OR] 2·78 (95% CI 1·53-5·06; p=0·0007). Clinical worsening events occurred in one (1%) of 111 patients in the riociguat group (hospitalisation due to worsening PAH) and 10 (9%) of 114 patients in the PDE5i group (hospitalisation due to worsening PAH [n=9]; disease progression [n=1]; OR 0·10 [0·01-0·73]; p=0·0047). The most frequently occurring adverse events were hypotension (15 [14%]), headache (14 [13%]), and dyspepsia (10 [9%]) in the riociguat group, and headache (eight [7%]), cough (seven [6%]), and upper respiratory tract infection (seven [6%]) in the PDE5i group. Serious adverse events were reported in eight (7%) of 111 patients in the riociguat group and 19 (17%) of 114 patients in the PDE5i group. During the study, four patients died in the PDE5i group, one of them during the safety follow-up period. INTERPRETATION Switching to riociguat from PDE5i treatment, both of which act via the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway, could be a strategic option for treatment escalation in patients with PAH at intermediate risk of 1-year mortality. FUNDING Bayer AG, Merck Sharp & Dohme.

Systemic sclerosis (SSc) is a very rare rheumatologic disorder with systemic involvement includin... more Systemic sclerosis (SSc) is a very rare rheumatologic disorder with systemic involvement including pulmonary, gastrointestinal, renal and musculoskeletal complications. Pulmonary hypertension is an important manifestation of SSc with multiple etiologies, including pulmonary arterial hypertension (PAH), left heart dysfunction, interstitial lung disease and chronic thromboembolic disease. PAH is present in 7-12% of SSc patients and is a leading cause of death in this population with a 2-year mortality of >60%. Routine screening for pulmonary hypertension is warranted in this group and results in earlier detection and initiation of therapy, which may result in improved outcomes. PAH treatment includes use of prostanoids, endothelin receptor antagonists, and/or phosphodiesterase-5 inhibitors/guanylate cyclase stimulators as monotherapy or in combination. This review will consider the multiple etiologies of pulmonary hypertension in SSc and address the epidemiology, clinical manifestations, screening guidelines, diagnostic considerations, current treatment and prognosis of SSc-associated PAH. Kavita B Khaira1*, Mark V Avdalovic2, Charles K Whitcomb3, Roblee Allen2 and Ezra A Amsterdam3 1Department of Internal Medicine, UC Davis Medical Center, USA 2Department of Pulmonary and Critical Care Medicine, UC Davis Medical Center, USA 3Department of Cardiovascular Medicine, UC Davis Medical Center, USA Kavita B Khaira, et al. Journal of Respiratory Medicine and Lung Disease Remedy Publications LLC. 2016 | Volume 1 | Issue 1 | Article 1003 2 Risk Factors For The Development of PAH in Ssc Patients Include: older age, post menopausal status, longer disease duration, diffusing capacity of carbon monoxide (DLCO) <50% predicted, limited cutaneous/CREST syndrome variant, telangiectasias, digital ulcers, positive anti-centromere, anti-U1-ribonucleoprotein and antiphospholipid antibodies and negative anti-Scl-70 antibody [1618]. However, it is important to recognize that PAH can also affect patients with diffuse cutaneous involvement and can occur early in the disease course [16]. Hemodynamic findings associated with progression to PAH include: exercise-induced PAH, an annual increase in right ventricular systolic pressures by >3 mmHg per year, a mean pulmonary artery pressure (mPAP) between 21-24 mmHg and a transpulmonary gradient >11mmHg [16]. Clinical Manifestations Many SSc patients with PAH remain asymptomatic for a prolonged period until they have reached the advanced stages of disease with right heart failure. Symptoms are nearly indistinguishable from patients with idiopathic PAH (IPAH) and initially include dyspnea on exertion, lethargy, fatigue and later progress to chest pain, presyncope/syncope, edema, and rest symptoms as right heart failure develops [19,20]. Clinical signs include elevated jugular venous pressure, hepatomegaly, peripheral edema, ascites, cool extremities, pronounced pulmonary component of the second heart sound, pansystolic murmur of tricuspid regurgitation, diastolic murmur from pulmonary insufficiency and/or right ventricular fourth heart sound [21]. These patients may also have signs and symptoms related to other organ involvement in SSc including characteristic dermatologic changes, gastrointestinal reflux, dysphagia, diarrhea, arthritis, muscle weakness, acute renal injury, severe hypertension and calcinosis [1,7].

PubMed, Sep 1, 1999

The successful use of a laryngeal mask airway over a 48-hour period is reported in a patient with... more The successful use of a laryngeal mask airway over a 48-hour period is reported in a patient with partial upper airway obstruction who required continuous positive airway pressure.

PubMed, Mar 1, 1977

The cytotoxic potential of heterologous rabbit antibody directed against mouse serum albumin (MSA... more The cytotoxic potential of heterologous rabbit antibody directed against mouse serum albumin (MSA) and alpha-fetoprotein (AFP) was investigated in vitro with a cell line (Hepa) derived from the mouse hepatoma BW7756. Anti-AFP in the presence of complement could kill Hepa cells at concentrations of anti-MSA that were virtually nontoxic. The specificity of the anti-AFP was defined by demonstrating that Hepa cell toxicity was dependent upon and paralleled the secretion of AFP in synchronized cultures. Furthermore, neither antiserum could be shown to be significantly toxic to mouse neuroblastoma cells (Neuro-2A). Immunoglobulin purified from pools of antisera was also highly effective in producing cytotoxicity even in a complement-free system. This reaction proceeded more slowly, requiring nearly 48 hr to reach maximum effect in comparison to the 12 hr for complement-mediated toxicity. MSA and AFP are secreted during different phases of the cell cycle. In cultures arrested by isoleucine starvation, labeled AFP appears in the medium 10 hr after release of the blockade in association with S phase. The appearance of labeled MSA is delayed until the first mitosis. Cytotoxic effects of anti-AFP parallel the secretion of AFP in synchronous cultures. Both antisera could be inhibitory to the secretion and synthesis of the proteins of their antigenic specificity. MSA synthesis was more susceptible to this inhibition than was AFP synthesis. The significance of this phenomenon and its association with the differential cytotoxicity of the antiserum are discussed.

Current Opinion in Pulmonary Medicine, Mar 1, 2004

Purpose of review Bronchiolitis obliterans (BO) occurs in both post-lung transplant and nontransp... more Purpose of review Bronchiolitis obliterans (BO) occurs in both post-lung transplant and nontransplant-related individuals, and is characterized by mainly irreversible airflow obstruction that is often ultimately progressive. Recent findings While post-lung transplant BO is a major cause of lung allograft dysfunction, and hence is better characterized than nontransplant-related BO, it is likely that many similarities in pathogenesis and treatment apply to both categories. Summary Optimal management for BO remains to be established, and the role of retransplantation in this disease requires further consensus. Minimization of risk factors for BO and earlier detection in the form of methacholine challenge testing and HRCT scans of the chest amongst other forms of detection, may help in the stabilization and possible resolution of early BO.

Biochimica Et Biophysica Acta - Proteins And Proteomics, Mar 1, 1977

ABSTRACT

Clinical Immunology and Immunopathology, Nov 1, 1978

ABSTRACT

Chest, Sep 1, 2007

We determined the relative efficacy of subcutaneous (SC) treprostinil in stable World Health Orga... more We determined the relative efficacy of subcutaneous (SC) treprostinil in stable World Health Organization class II and III patients transitioned from IV epoprostenol. This was an 8-week, multicenter, randomized study in which patients were transitioned from IV epoprostenol to SC treprostinil or placebo over a period of up to 14 days and monitored carefully during and after the transition period for signs of deterioration. Patients with clinical deterioration were returned promptly to epoprostenol. Placebo or SC treprostinil doses were titrated in response to symptoms. Time to adjudicated clinical deterioration was compared between treatment groups, and exercise capacity, symptoms of disease, and safety were assessed throughout the study. Twenty-two patients were enrolled and completed the study. Seven of 8 patients (88%) [corrected] withdrawn to placebo had clinical deterioration, while only 1 of 14 patients (7%) [corrected] withdrawn to SC treprostinil had clinical deterioration (p = 0.00023 based on a treatment comparison of time to deterioration). Analyses of exercise capacity and symptoms strongly supported the efficacy of SC treprostinil in epoprostenol-treated patients. Adverse events consisted of painful infusion site reactions and anticipated prostacyclin side effects. SC treprostinil is effective in pulmonary arterial hypertension and prevents clinical deterioration and maintains functional status in patients transitioned from epoprostenol.

Chest, Aug 1, 1991

I read with keen interest the article on airway hyperreactivity in bopical pulmonary eosinophilia... more I read with keen interest the article on airway hyperreactivity in bopical pulmonary eosinophilia by Drs Chhabra and Gaur, which appeared in the May 1988 issue of Chest,• as well as the comments on that article by Drs Chitkara and Donath, which appeared in the January 1990 issue of Chest.• It was rightly pointed out in the latter communication that the presence of measurable hyperresponsiveness in tropical pulmonary eosinophilia (TPE) might indeed be useful in elucidating the pathogenesis. In addition to my findings in an article" quoted in the letter by Drs Chitkara and Donath, we subsequently documented improvement in lung capacity in acute TPE within eight weeks following successful treatment with diethylcarbamazine.• ~also studied the bronchial response to inhaled isoprenaline in TPE and found that patients during the first episode ofTPE of recent onset were on the whole unresponsive whereas those experiencing a relapse of the disease _showed a significant response.• The pathologic picture of TPE in the first few weeks is one of outpouring of histiocytes, soon followed by eosinophils in alveolar, interstitial, peribronchial, and perivascular spaces and eosinophilic infiltration of the bronchioles with edema of the walls and blocking of the lumen with shedding of mucous membrane and clumps of esoinophils. • ~ thought that these earliest changes in TPE may have acted as a mechanical hindrance to satisfactory bronchial response in our patients with primary TPE. It would be interesting to know whether either or both patients ofDrs Chhabra and Gaur had any previous eosinophilic episode. If these two hyperreactive patients with acute illness were indeed studied during the first episode of TPE, then the more likely explanation fur our finding would be that the bronchospasticity due to intense major basic protein activity and excessive release of leukotrienes 7 is so severe in the patients with an acute attack of primary TPE that they, unlike those in relapse, may not show significant bronchial response to the 10 mg of aerosol isoprenaline commonly administered.

Critical Care Clinics, Jul 1, 1991

We have reviewed the actions, indications, and toxicity of steroids and several important biologi... more We have reviewed the actions, indications, and toxicity of steroids and several important biologic pharmaceutical agents used in critical care medicine. This is a rapidly expanding area of therapeutics. Space limitations prevent an exhaustive review of all biologic pharmaceuticals, such as tissue plasminogen activating substance, hormones (e.g., thyroid, insulin, growth hormone, erythropoietin), clotting factors, and blood products. The future of biologic pharmaceuticals appears to be bright in the face of new biotechnology, and the critical care physician can anticipate new and exciting treatments to evolve from current basic and clinical research into biologic agents.

The Journal of Immunology

Blood monocytes are important cellular sources of a vast array of bioactive substances, including... more Blood monocytes are important cellular sources of a vast array of bioactive substances, including regulatory and chemotactic cytokines. The regulation of these cytokines is of critical importance to the expression of acute and chronic inflammatory responses. IL-7, a T and B cell-activating cytokine, has recently been shown to have stimulatory effects on the expression of several monocyte-derived proinflammatory cytokines. We now describe the induction of IL-8 mRNA and extracellular protein from human blood monocytes by IL-7. The up-regulation of IL-8 mRNA by IL-7 was not altered by concomitant treatment with cycloheximide, suggesting that the direct stimulatory effects of IL-7 were not dependent upon de novo protein synthesis. In addition, IL-7 significantly potentiated the production of IL-8 from LPS-, TNF-, and IL-1-treated peripheral blood monocytes. Our findings suggest that IL-7 may play a critical role in the modulation of macrophage-derived cytokine expression and may functio...

C52. USE YOUR ILLUSION II: CLINICAL RESEARCH IN PAH, 2019

The Lancet Respiratory Medicine, 2021

BACKGROUND Riociguat and phosphodiesterase-5 inhibitors (PDE5i), approved for the treatment of pu... more BACKGROUND Riociguat and phosphodiesterase-5 inhibitors (PDE5i), approved for the treatment of pulmonary arterial hypertension (PAH), act on the same pathway via different mechanisms. Riociguat might be an alternative option for patients with PAH who do not respond sufficiently to treatment with PDE5i, but comparisons of the potential benefits of riociguat and PDE5i in these patients are needed. The aim of this trial was to assess the effects of switching to riociguat from PDE5i therapy versus continued PDE5i therapy in patients with PAH at intermediate risk of 1-year mortality. METHODS Riociguat rEplacing PDE5i therapy evaLuated Against Continued PDE5i thErapy (REPLACE) was an open-label, randomised controlled trial in 81 hospital-based pulmonary hypertension centres in 22 countries. The study enrolled patients aged 18-75 years with symptomatic PAH at intermediate risk of 1-year mortality (based on the European Society for Cardiology-European Respiratory Society guideline thresholds for WHO functional class and 6-min walk distance [6MWD]) who were receiving treatment with a PDE5i with or without an endothelin receptor antagonist for at least 6 weeks before randomisation. Patients were excluded if they had been previously treated with riociguat, had used prostacyclin analogues or prostacyclin receptor agonists within 30 days before randomisation, had clinically significant restrictive or obstructive parenchymal lung disease, or had left heart disease. Patients were randomly assigned (1:1) to remain on PDE5i treatment (oral sildenafil [≥60 mg per day] or oral tadalafil [20-40 mg per day]; the PDE5i group) or to switch to oral riociguat (up to 2·5 mg three times per day; the riociguat group), using an interactive voice and web response system, stratified by cause of PAH. The primary endpoint was clinical improvement by week 24, defined as an absence of clinical worsening and prespecified improvements in at least two of three variables (6MWD, WHO functional class, and N-terminal prohormone of brain natriuretic peptide), analysed using last observation carried forward in all randomly assigned patients with observed values at baseline and week 24 who received at least one dose of study medication (the full analysis set). Secondary endpoints included clinical worsening events. The trial has been completed and is registered with ClinicalTrials.gov, NCT02891850. FINDINGS Between Jan 11, 2017, and July 31, 2019, 293 patients were screened, of which 226 patients were randomly assigned to the riociguat group (n=111) or to the PDE5i group (n=115). 211 patients completed the study and 14 patients discontinued (seven in each group). One patient assigned to the PDE5i group did not receive treatment, so 225 patients were included in the safety analysis, and one further patient in the PDE5i group had missing components of the composite primary endpoint at baseline, so 224 patients were included in the full analysis set. The primary endpoint was met by 45 (41%) of 111 patients in the riociguat group and 23 (20%) of 113 patients in the PDE5i group; odds ratio [OR] 2·78 (95% CI 1·53-5·06; p=0·0007). Clinical worsening events occurred in one (1%) of 111 patients in the riociguat group (hospitalisation due to worsening PAH) and 10 (9%) of 114 patients in the PDE5i group (hospitalisation due to worsening PAH [n=9]; disease progression [n=1]; OR 0·10 [0·01-0·73]; p=0·0047). The most frequently occurring adverse events were hypotension (15 [14%]), headache (14 [13%]), and dyspepsia (10 [9%]) in the riociguat group, and headache (eight [7%]), cough (seven [6%]), and upper respiratory tract infection (seven [6%]) in the PDE5i group. Serious adverse events were reported in eight (7%) of 111 patients in the riociguat group and 19 (17%) of 114 patients in the PDE5i group. During the study, four patients died in the PDE5i group, one of them during the safety follow-up period. INTERPRETATION Switching to riociguat from PDE5i treatment, both of which act via the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway, could be a strategic option for treatment escalation in patients with PAH at intermediate risk of 1-year mortality. FUNDING Bayer AG, Merck Sharp & Dohme.

Systemic sclerosis (SSc) is a very rare rheumatologic disorder with systemic involvement includin... more Systemic sclerosis (SSc) is a very rare rheumatologic disorder with systemic involvement including pulmonary, gastrointestinal, renal and musculoskeletal complications. Pulmonary hypertension is an important manifestation of SSc with multiple etiologies, including pulmonary arterial hypertension (PAH), left heart dysfunction, interstitial lung disease and chronic thromboembolic disease. PAH is present in 7-12% of SSc patients and is a leading cause of death in this population with a 2-year mortality of >60%. Routine screening for pulmonary hypertension is warranted in this group and results in earlier detection and initiation of therapy, which may result in improved outcomes. PAH treatment includes use of prostanoids, endothelin receptor antagonists, and/or phosphodiesterase-5 inhibitors/guanylate cyclase stimulators as monotherapy or in combination. This review will consider the multiple etiologies of pulmonary hypertension in SSc and address the epidemiology, clinical manifestations, screening guidelines, diagnostic considerations, current treatment and prognosis of SSc-associated PAH. Kavita B Khaira1*, Mark V Avdalovic2, Charles K Whitcomb3, Roblee Allen2 and Ezra A Amsterdam3 1Department of Internal Medicine, UC Davis Medical Center, USA 2Department of Pulmonary and Critical Care Medicine, UC Davis Medical Center, USA 3Department of Cardiovascular Medicine, UC Davis Medical Center, USA Kavita B Khaira, et al. Journal of Respiratory Medicine and Lung Disease Remedy Publications LLC. 2016 | Volume 1 | Issue 1 | Article 1003 2 Risk Factors For The Development of PAH in Ssc Patients Include: older age, post menopausal status, longer disease duration, diffusing capacity of carbon monoxide (DLCO) <50% predicted, limited cutaneous/CREST syndrome variant, telangiectasias, digital ulcers, positive anti-centromere, anti-U1-ribonucleoprotein and antiphospholipid antibodies and negative anti-Scl-70 antibody [1618]. However, it is important to recognize that PAH can also affect patients with diffuse cutaneous involvement and can occur early in the disease course [16]. Hemodynamic findings associated with progression to PAH include: exercise-induced PAH, an annual increase in right ventricular systolic pressures by >3 mmHg per year, a mean pulmonary artery pressure (mPAP) between 21-24 mmHg and a transpulmonary gradient >11mmHg [16]. Clinical Manifestations Many SSc patients with PAH remain asymptomatic for a prolonged period until they have reached the advanced stages of disease with right heart failure. Symptoms are nearly indistinguishable from patients with idiopathic PAH (IPAH) and initially include dyspnea on exertion, lethargy, fatigue and later progress to chest pain, presyncope/syncope, edema, and rest symptoms as right heart failure develops [19,20]. Clinical signs include elevated jugular venous pressure, hepatomegaly, peripheral edema, ascites, cool extremities, pronounced pulmonary component of the second heart sound, pansystolic murmur of tricuspid regurgitation, diastolic murmur from pulmonary insufficiency and/or right ventricular fourth heart sound [21]. These patients may also have signs and symptoms related to other organ involvement in SSc including characteristic dermatologic changes, gastrointestinal reflux, dysphagia, diarrhea, arthritis, muscle weakness, acute renal injury, severe hypertension and calcinosis [1,7].

PubMed, Sep 1, 1999

The successful use of a laryngeal mask airway over a 48-hour period is reported in a patient with... more The successful use of a laryngeal mask airway over a 48-hour period is reported in a patient with partial upper airway obstruction who required continuous positive airway pressure.

PubMed, Mar 1, 1977

The cytotoxic potential of heterologous rabbit antibody directed against mouse serum albumin (MSA... more The cytotoxic potential of heterologous rabbit antibody directed against mouse serum albumin (MSA) and alpha-fetoprotein (AFP) was investigated in vitro with a cell line (Hepa) derived from the mouse hepatoma BW7756. Anti-AFP in the presence of complement could kill Hepa cells at concentrations of anti-MSA that were virtually nontoxic. The specificity of the anti-AFP was defined by demonstrating that Hepa cell toxicity was dependent upon and paralleled the secretion of AFP in synchronized cultures. Furthermore, neither antiserum could be shown to be significantly toxic to mouse neuroblastoma cells (Neuro-2A). Immunoglobulin purified from pools of antisera was also highly effective in producing cytotoxicity even in a complement-free system. This reaction proceeded more slowly, requiring nearly 48 hr to reach maximum effect in comparison to the 12 hr for complement-mediated toxicity. MSA and AFP are secreted during different phases of the cell cycle. In cultures arrested by isoleucine starvation, labeled AFP appears in the medium 10 hr after release of the blockade in association with S phase. The appearance of labeled MSA is delayed until the first mitosis. Cytotoxic effects of anti-AFP parallel the secretion of AFP in synchronous cultures. Both antisera could be inhibitory to the secretion and synthesis of the proteins of their antigenic specificity. MSA synthesis was more susceptible to this inhibition than was AFP synthesis. The significance of this phenomenon and its association with the differential cytotoxicity of the antiserum are discussed.

Current Opinion in Pulmonary Medicine, Mar 1, 2004

Purpose of review Bronchiolitis obliterans (BO) occurs in both post-lung transplant and nontransp... more Purpose of review Bronchiolitis obliterans (BO) occurs in both post-lung transplant and nontransplant-related individuals, and is characterized by mainly irreversible airflow obstruction that is often ultimately progressive. Recent findings While post-lung transplant BO is a major cause of lung allograft dysfunction, and hence is better characterized than nontransplant-related BO, it is likely that many similarities in pathogenesis and treatment apply to both categories. Summary Optimal management for BO remains to be established, and the role of retransplantation in this disease requires further consensus. Minimization of risk factors for BO and earlier detection in the form of methacholine challenge testing and HRCT scans of the chest amongst other forms of detection, may help in the stabilization and possible resolution of early BO.

Biochimica Et Biophysica Acta - Proteins And Proteomics, Mar 1, 1977

ABSTRACT

Clinical Immunology and Immunopathology, Nov 1, 1978

ABSTRACT

Chest, Sep 1, 2007

We determined the relative efficacy of subcutaneous (SC) treprostinil in stable World Health Orga... more We determined the relative efficacy of subcutaneous (SC) treprostinil in stable World Health Organization class II and III patients transitioned from IV epoprostenol. This was an 8-week, multicenter, randomized study in which patients were transitioned from IV epoprostenol to SC treprostinil or placebo over a period of up to 14 days and monitored carefully during and after the transition period for signs of deterioration. Patients with clinical deterioration were returned promptly to epoprostenol. Placebo or SC treprostinil doses were titrated in response to symptoms. Time to adjudicated clinical deterioration was compared between treatment groups, and exercise capacity, symptoms of disease, and safety were assessed throughout the study. Twenty-two patients were enrolled and completed the study. Seven of 8 patients (88%) [corrected] withdrawn to placebo had clinical deterioration, while only 1 of 14 patients (7%) [corrected] withdrawn to SC treprostinil had clinical deterioration (p = 0.00023 based on a treatment comparison of time to deterioration). Analyses of exercise capacity and symptoms strongly supported the efficacy of SC treprostinil in epoprostenol-treated patients. Adverse events consisted of painful infusion site reactions and anticipated prostacyclin side effects. SC treprostinil is effective in pulmonary arterial hypertension and prevents clinical deterioration and maintains functional status in patients transitioned from epoprostenol.

Chest, Aug 1, 1991

I read with keen interest the article on airway hyperreactivity in bopical pulmonary eosinophilia... more I read with keen interest the article on airway hyperreactivity in bopical pulmonary eosinophilia by Drs Chhabra and Gaur, which appeared in the May 1988 issue of Chest,• as well as the comments on that article by Drs Chitkara and Donath, which appeared in the January 1990 issue of Chest.• It was rightly pointed out in the latter communication that the presence of measurable hyperresponsiveness in tropical pulmonary eosinophilia (TPE) might indeed be useful in elucidating the pathogenesis. In addition to my findings in an article" quoted in the letter by Drs Chitkara and Donath, we subsequently documented improvement in lung capacity in acute TPE within eight weeks following successful treatment with diethylcarbamazine.• ~also studied the bronchial response to inhaled isoprenaline in TPE and found that patients during the first episode ofTPE of recent onset were on the whole unresponsive whereas those experiencing a relapse of the disease _showed a significant response.• The pathologic picture of TPE in the first few weeks is one of outpouring of histiocytes, soon followed by eosinophils in alveolar, interstitial, peribronchial, and perivascular spaces and eosinophilic infiltration of the bronchioles with edema of the walls and blocking of the lumen with shedding of mucous membrane and clumps of esoinophils. • ~ thought that these earliest changes in TPE may have acted as a mechanical hindrance to satisfactory bronchial response in our patients with primary TPE. It would be interesting to know whether either or both patients ofDrs Chhabra and Gaur had any previous eosinophilic episode. If these two hyperreactive patients with acute illness were indeed studied during the first episode of TPE, then the more likely explanation fur our finding would be that the bronchospasticity due to intense major basic protein activity and excessive release of leukotrienes 7 is so severe in the patients with an acute attack of primary TPE that they, unlike those in relapse, may not show significant bronchial response to the 10 mg of aerosol isoprenaline commonly administered.

Critical Care Clinics, Jul 1, 1991

We have reviewed the actions, indications, and toxicity of steroids and several important biologi... more We have reviewed the actions, indications, and toxicity of steroids and several important biologic pharmaceutical agents used in critical care medicine. This is a rapidly expanding area of therapeutics. Space limitations prevent an exhaustive review of all biologic pharmaceuticals, such as tissue plasminogen activating substance, hormones (e.g., thyroid, insulin, growth hormone, erythropoietin), clotting factors, and blood products. The future of biologic pharmaceuticals appears to be bright in the face of new biotechnology, and the critical care physician can anticipate new and exciting treatments to evolve from current basic and clinical research into biologic agents.

The Journal of Immunology

Blood monocytes are important cellular sources of a vast array of bioactive substances, including... more Blood monocytes are important cellular sources of a vast array of bioactive substances, including regulatory and chemotactic cytokines. The regulation of these cytokines is of critical importance to the expression of acute and chronic inflammatory responses. IL-7, a T and B cell-activating cytokine, has recently been shown to have stimulatory effects on the expression of several monocyte-derived proinflammatory cytokines. We now describe the induction of IL-8 mRNA and extracellular protein from human blood monocytes by IL-7. The up-regulation of IL-8 mRNA by IL-7 was not altered by concomitant treatment with cycloheximide, suggesting that the direct stimulatory effects of IL-7 were not dependent upon de novo protein synthesis. In addition, IL-7 significantly potentiated the production of IL-8 from LPS-, TNF-, and IL-1-treated peripheral blood monocytes. Our findings suggest that IL-7 may play a critical role in the modulation of macrophage-derived cytokine expression and may functio...