Prevalence of primary aldosteronism without hypertension in the general population: Results in Shika study.

OBJECTIVE: Recent studies have reported a high prevalence of primary aldosteronism (PA) among hypertensive patients. However, few data exist regarding the prevalence of PA in the general population. Therefore, we examined the prevalence of PA in the general population including normotensive subjects. METHODS: Plasma renin activity (ng/mL/hr), plasma aldosterone concentration (pg/mL) and aldosterone renin ratio (ARR) were determined in 309 subjects aged >40 years in Horimatsu and Higashi-Matsuho district, Shika-machi, Ishikawa, Japan. RESULTS: Among them, 195 subjects (78 males, mean age: 62 ± 11 years) did not take antihypertensive agents: 113 normotensive subjects and 82 hypertensive subjects. Under these conditions, 68 subjects (13 males, age 62 ± 10 years) had an ARR >200. In 14 subjects who underwent captopril suppression test, PA was documented in 5 subjects, yielding a minimum prevalence of 2.6% in total subjects (1.8% in normotensive subjects and 3.7% in hypertensive subjects). Interestingly, females subjects demonstrated significant differences in ARR between subjects with age <50 (172 ± 105) and those with age 51-60 (388 ± 531), although there were no differences in male subjects. CONCLUSIONS: These results demonstrate that PA including normotensive subjects exists more commonly than that expected in the general population. We suggest further investigation about the cause and progression of PA associated with sex and aging.

Angiotensin II receptor blocker combined with eplerenone or hydrochlorothiazide for hypertensive patients with diabetes mellitus.

Experimental models recently suggested an interaction between aldosterone and adipose tissue, but clinical investigation has been limited. We studied the effects of eplerenone compared to hydrochlorothiazide (HCTZ) on blood pressure (BP), glucose, and lipid levels in 50 patients with essential hypertension (EHT) and type 2 diabetes mellitus whose BP failed to reach target levels with 8 mg of candesartan alone. BP improved similarly in both groups over the 12-month study period, but BMI, waist circumference, and LDL-cholesterol were decreased in the eplerenone group, while glycohemoglobin was elevated in the HCTZ group.

Multi-drug Treatment for COVID-19-induced Acute Respiratory Distress Syndrome

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), broke out in late 2019 to become a serious global threat to human health. In the absence of specific treatments for COVID-19, treatment options are being examined. Recently, the anti-SARS-CoV-2 activities of tetracyclines, macrolide antibiotics, and ivermectin (IVM), have attracted considerable attention for their potential as a single or multi-drug treatment regimen. Moreover, tetracyclines, macrolide antibiotics, and IVM possess anti-inflammatory and immunomodulatory effects to reduce the production of cytokines. COVID-19 is characterized by early exponential viral replication, cytokine storm-associated organ damage, including acute respiratory distress syndrome (ARDS) and thrombosis. Considering anti-inflammatory and immunomodulatory effects of the aforementioned drugs and corticosteroids, early treatment with doxycycline, azithromycin, IVM, and corticosteroids is thought to be the most promising option for combating COVID-19-induced ARDS.

Tetracycline plus macrolide: A potential therapeutic regimen for COVID-19?

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that struck in late 2019 and early 2020 is a serious threat to human health. Since there are no approved drugs that satisfactorily treat this condition, all efforts at drug design and/or clinical trials are warranted and reasonable. Drug repurposing is a well-known strategy that seeks to deploy existing licensed drugs for newer indications and that provides the quickest possible transition from the bench to the bedside to meet therapeutic needs. At present, several existing licensed drugs such as chloroquine, hydroxychloroquine, methylprednisolone, dexamethasone, and remdesivir have been used because of their potential efficacy in inhibiting COVID-19. Recently, antibiotics such as tetracyclines and macrolides have been reported to be effective against COVID-19. A combination of tetracyclines and macrolides may be a potential treatment for COVID-19 because there are some differences in the mechanism of action of tetracyclines and macrolides.

Multidrug treatment for COVID-19.

An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which began in Wuhan, China in December 2019, has rapidly spread all over the world. The World Health Organization characterized the disease caused by SARS-CoV-2 (COVID-19) as a pandemic in March 2020. In the absence of specific treatments for the virus, treatment options are being examined. Drug repurposing is a process of identifying new therapeutic uses for approved drugs. It is an effective strategy to discover drug molecules with new therapeutic indications. This strategy is time-saving, low-cost, and has a minimal risk of failure. Several existing approved drugs such as chloroquine, hydroxychloroquine, doxycycline, azithromycin, and ivermectin are currently in use because of their efficacy in inhibiting COVID-19. Multidrug therapy, such as a combination of hydroxychloroquine and azithromycin, a combination of doxycycline and ivermectin, or a combination of ivermectin, doxycycline, and azithromycin, has been successfully administered. Multidrug therapy is efficacious because the mechanisms of action of these drugs differ. Moreover, multidrug therapy may prevent the emergence of drug-resistant SARS-CoV-2.

[Successful treatment with clarithromycin for Mixed phenotype acute leukemia, T/myeloid, NOS].

A 79-year-old woman was admitted with submandibular lymphadenopathy and was diagnosed as having bacterial and fungal lymphadenitis by lymph nodal biopsy. Laboratory examination demonstrated leukopenia with 7% blasts. The bone marrow was infiltrated with about 90% blasts and surface antigen analysis of these blasts demonstrated expression of cyCD3, TdT and MPO. The diagnosis was Mixed phenotype acute leukemia, T/myeloid, NOS. The patient was treated with prednisone (10 mg/day) for fever and subsequently CAM (800 mg/day) for pneumonia. Three months later, leukemic cells had disappeared on both bone marrow aspiration and peripheral blood smear. This clinical course suggests CAM is effective for this leukemia.

[The detection of biphasic reactivity of the airway by astograph].

Dose-related curves of the airway responses to Methacholine by Astograph are frequently biphasic. That is, respiratory resistance (Rrs) increases slowly at first and rapidly after that. We proposed (-dGrs/dt)/Grs obtained by using Astograph as an index of dynamic property of the airway, which we suggested was related to a coefficient of the contraction or dilatation of the airway. Grs represents respiratory conductance. By calculating (-dGrs/dt)/Grs, we found that biphasic dose-related curves were composed of the slow and subsequently rapid contraction of the airways. And by mathematical analysis, we found that all segments of the airway contracted simultaneously at a uniform velocity. The combination of slow and rapid contraction explains three types of the airway responses, that is, the monophasic reactivity of the airway with slow contraction, the monophasic reactivity of the airway with rapid contraction and the biphasic reactivity of the airway with slow and subsequently rapid contraction. We found that the frequency of the monophasic reactivity of the airway with slow contraction was significantly higher in patients with COPD than in healthy subjects or in patients with mild asthma. But there was no significant difference in (-dGrs/dt)/Grs values among healthy subjects, patients with mild asthma and patients with COPD.

Macrolide treatment for COVID-19: Will this be the way forward?

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic that has developed in late 2019 and 2020 is a serious threat to human health. With no vaccines or drugs approved for prevention and treatment until now, all efforts at drug design and/or clinical trials of already approved drugs are worthy and creditable. Using structure-based drug selection for identification of SARS-CoV-2 protease inhibitors, old drugs such as macrolides (MAC) were predicted to be effective for COVID-19. Lately, the anti-viral effects of macrolides have attracted considerable attention. Very recently, hydroxychloroquine in combination with azithromycin treatment was reported to be effective for COVID-19. We believe that treatments with macrolides alone or in combination with other drugs are promising and open the possibility of an international strategy to fight this emerging viral infection.

Successful additional clarithromycin and tacrolimus treatment for hypereosinophilia associated with eosinophilic granulomatosis with polyangiitis.

A 41-year-old man suffering from eosinophilic granulomatosis with polyangiitis (EPGA), diagnosed at another clinic on the basis of American College of Rheumatology Criteria, with a history of bronchial asthma, eosinophilia, mononeuritis multiplex, and non-fixed pulmonary infiltrates, was admitted to our department for further treatment. The patient complained of chest pain that started recently. An echocardiogram identified myocardial thickening and decreased wall motion, based on which the patient was diagnosed as having EPGA with myocarditis. The patient was successfully treated using glucocorticoids, such as methyl prednisolone (PSL) and PSL in combination with cyclophosphamide (CPM). However, CPM administration was discontinued afterwards because of the risk of bone marrow toxicity, the increased eosinophilic count (EOC) that we considered as an index of disease activity. Subsequently, the patient received additional clarithromycin (CAM) and tacrolimus (TAC) treatment considering their immunomodulatory effects. As a result, the EOC decreased and the PSL dosage could be reduced. This case shows that additional CAM and TAC treatment may be beneficial in some cases of EPGA.

Successful treatment of primary immune thrombocytopenia accompanied by diabetes mellitus treated using clarithromycin followed by prednisolone.

Macrolides have immunomodulatory effects including anti-inflammatory effects as well as antibacterial activity. In consideration of these immunomodulatory effects, we report a patient with primary immune thrombocytopenia (ITP) treated using clarithromycin (CAM), a macrolide, followed by prednisolone (PSL). A 78-year-old man with thrombocytopenia was admitted to our hospital for further examination. Initial laboratory data showed reduced platelet counts (1.7 × 104/µL). Finally, we diagnosed the patient as having primary ITP. Because the patient was suffering from diabetes mellitus (DM), he was treated with CAM as an alternative to PSL. The platelet count increased to 6.1 × 104/µL. The CAM treatment was terminated owing to gradual nausea and palpitation. During the CAM treatment, the DM was under control. We reinitiated treatment for ITP. The patient was successfully treated using PSL without severe hyperglycemia. This case shows that CAM treatment may represent a useful option for ITP patients who cannot receive PSL due to DM.

Successful treatment with clarithromycin and/or tacrolimus for two patients with polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease in the elderly. Glucocorticoids (GCs) remain the mainstay of treatment. GC therapy usually dramatically improves the clinical picture, but approximately one-third of patients experience disease recurrence when the dose is reduced. Moreover, long-term use of GCs causes adverse reactions. Macrolide antibiotics have anti-inflammatory action. Several recent studies have reported the successful treatment of rheumatoid arthritis (RA) and PMR treated using clarithromycin (CAM), a macrolide, because of its anti-inflammatory action. Tacrolimus (TAC) has been indicated as a treatment for RA in patients who failed to respond to methotrexate. Recently, a case of RA was successfully treated using CAM and TAC according to one report. Reported here are two cases of PMR treated using CAM and/or TAC. Case 1: A 73-year-old man suffering from PMR was successfully treated with prednisolone (PSL) and CAM. Because his muscle pain disappeared, CAM was discontinued. However, the pain returned after that discontinuation, so CAM was successfully administered again. Case 2: An 83-year-old man suffering from PMR was successfully treated with PSL and CAM. Because muscle pain disappeared, the CAM dosage was halved. The pain returned after the dosage was reduced, so the CAM dosage was successfully resumed and the PSL dosage was reduced. When the PSL dosage was reduced, muscle pain recurred. Because the PSL and CAM dosages were not successfully increased, TAC was also administered and was found to be effective at treating muscle pain. These two cases suggest that CAM and/or TAC are effective at treating PMR.

Multiple cavities with halo sign in a case of invasive pulmonary aspergillosis during therapy for drug-induced hypersensitivity syndrome.

A 67-year-old female with rheumatoid arthritis and asthma-chronic obstructive pulmonary disease overlap syndrome was admitted for drug-induced hypersensitivity syndrome (DIHS) caused by salazosulfapyridine. Human herpes virus 6 (HHV-6) variant B was strongly positive on peripheral blood. Multiple cavities with ground grass opacities rapidly emerged predominantly in the upper and middle lobes. She was diagnosed with invasive pulmonary aspergillosis (IPA), and was treated successfully with antifungal agents. Therapeutic systemic corticosteroids, emphysematous change in the lungs, and the worsening of the patient's general condition due to DIHS were considered major contributing factor leading to IPA. HHV-6 reactivation could have an effect on clinical course of IPA. Cavities with halo sign would provide an early clue to IPA in non-neutropenic and immunosuppressive patients.

A case of Waldenström's macroglobulinemia treated using clarithromycin and prednisolone.

We report a case of Waldenström's macroglobulinemia (WM) treated using clarithromycin (CAM) and prednisolone (PSL). An 84-year-old woman was admitted to our hospital for bleeding after a tooth extraction and hematuria. Computed tomography showed multiple ill-defined nodules in the omentum (omental cake). Although the cause of the omental cake remained unclear, the patient was diagnosed with WM, based on the detection of M-protein of immunoglobulin (Ig) M in serum and lymphoplasmacytes in bone marrow. The bleeding tendency in the patient may have been due to acquired hemophilia and/or hyper IgM-induced platelet dysfunction. The patient was treated using CAM (800 mg/day) and PSL (10 mg/day). As a result, IgM levels gradually decreased. Because the omental cake contracted along with improvement in IgM, it was thought to be lymphoplasmacytic lymphoma-like lymphoma. This case shows that treatment using CAM and PSL may be effective in some cases of WM.

Successful treatment of three patients with organizing pneumonia associated with rheumatoid arthritis using clarithromycin and prednisolone.

Macrolides have anti-inflammatory effects and have been used to treat diffuse panbronchiolitis, bronchiectasis, and cystic fibrosis. Lately, several cases of cryptogenic organizing pneumonia (COP) and radiotherapy-related organizing pneumonia (OP) that were successfully treated with macrolides considering their anti-inflammatory effects were reported. We report three cases of OP associated with rheumatoid arthritis (RA) successfully treated with clarithromycin (CAM) and prednisolone (PSL). Case 1: A 70-year-old woman suffering from RA was admitted with cough and severe dyspnea. She was diagnosed with OP associated with RA on the basis of computed tomography (CT) findings and transbronchial lung biopsy results. She was successfully treated with PSL and cyclosporine A. At the exacerbation of OP, she was successfully treated with CAM and PSL. Case 2: A 74-year-old man suffering from COP visited our department with arthralgia and articular swellings. He was diagnosed with RA, which was thought to be associated with OP. He was successfully treated with CAM and PSL. Case 3: A 54-year-old man suffering from RA presented with an exacerbation of arthralgia and articular swellings and cough. He was diagnosed with OP associated with RA on the basis of CT findings. He was successfully treated with CAM and PSL. The present cases suggest that CAM and PSL treatment may be effective in some cases of OP associated with RA.

[The proposal of an index of dynamic property of the airway].

We propose (-deltaG(rs)/deltat)/G(rs) obtained from Astograph as an index of dynamic property of the airway. G(rs) represents respiratory conductance. Fluid mechanics suggests that (- deltaG(aw)/deltat)/G(aw) is related to a coefficient of airway contraction or dilatation. G(aw) represents airway conductance. R(rs) (=1/G(rs)) is approximately equal to R(aw) (=1/G(aw)) + Constant. R(rs) and R(aw) represent respiratory and airway resistance, respectively. As R(rs) is thought to be closely correlated to R(aw), G(rs) should be correlated to G(aw). Thus, if G(rs) is used as a substitute for G(aw), (-deltaG(rs)/deltat)/G(rs) should also be related to a coefficient of airway contraction or dilatation. We found that asthmatics had significantly higher (-deltaG(rs)/deltat)/G(rs) than normal subjects. That is, the airway smooth muscles of the asthmatics are more contractive than those of normal subjects.

Comparison of eplerenone and spironolactone for the treatment of primary aldosteronism.

The mineralocorticoid receptor (MR) is expressed in the kidneys and in adipose tissue, and primary aldosteronism (PA) is associated with metabolic syndrome. This study assessed the effects of MR blockade by eplerenone (EPL) and spironolactone (SPL) on blood pressure (BP) and metabolic factors in patients with PA. Fifty-four patients with PA were treated with one of two MRAs, EPL (25-100 mg daily, n=27) or SPL (12.5-100 mg daily, n=27) for 12 months. Visceral (VAT) and subcutaneous adipose tissue were quantified using CT and FatScan imaging analysis software. Body mass index, homeostasis model assessment-insulin resistance (HOMA-IR), serum creatinine, potassium and lipids, urinary albumin excretion (UAE) and plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were measured before and after treatment. EPL and SPL decreased BP and increased serum potassium levels to similar degrees. PAC and PRA did not differ between the two groups. Although treatment with the MRAs did not change HOMA-IR or serum lipids, they significantly decreased UAE and VAT (P<0.05). These results suggest that EPL and SPL are effective and safe for the treatment of PA. The long-term metabolic and renal effects of these MRAs should be further investigated.

A Case of Adult-Onset Still's Disease Treated with Monitoring of Serum Tacrolimus Levels.

Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology. The mainstays of treatment are glucocorticoids (GCs) and non-steroidal anti-inflammatory drugs, although most cases are refractory to these conventional therapies. Immunosuppressants,such as methotrexate (MTX), cyclosporine A, tumor necrosis factor-α blockers, an interleukin (IL)-1 blocker, and an IL-6, receptor blocker, have been suggested in previous reports for the treatment of steroid-resistant AOSD. We report herein the case of an AOSD patient who was successfully treated with tacrolimus, another immunosuppressant, in combination with GC and MTX. Blood concentrations of tacrolimus were monitored because of the narrow therapeutic window.

[Three cases of idiopathic thrombocytopenic purpura showing an increase in the platelet count following clarithromycin treatment].

Macrolides have immuno-modulatory effects as well as anti-bacterial effects. We successfully treated three idiopathic thrombocytopenic purpura (ITP) patients with clarithromycin (CAM). Case 1: A 69-year-old male ITP patient was treated with CAM at a dose of 400 mg/day. His platelet count increased from 5.6 x 10(4)/microliter to 10.1 x 10(4)/microliter. Case 2: A 72-year-old male ITP patient was treated with CAM at the same dose. The platelet count increased from 1.3 x 10(4)/microliter to 12.3 x 10(4)/microliter. Case 3: A 68-year-old female ITP patient was treated with CAM at the same dose. The platelet count increased from 2.3 x 10(4)/microliter to 13 x 10(4)/microliter. These facts suggest that CAM is useful in the treatment of ITP.