Levofloxacin-azithromycin combined triple therapy for Helicobacter pylori eradication]

BACKGROUND/AIMS: Antibiotic resistance and poor compliance are the main causes of Helicobacter pylori (H. pylori) eradication failure. This study evaluated the eradication rate, tolerability, and compliance of levofloxacin- azithromycin combined triple therapy for H. pylori eradication. METHODS: 1) First-line eradication: A total of 78 H. pylori-positive patients were enrolled. Seventeen military men in Armed Forces Capital Hospital were treated with 7 days of levofloxacin-azithromycin combined triple therapy (omeprazole 20 mg bid, levofloxacin 500 mg od, and azithromycin 500 mg od), and 61 patients in Kangbuk Samsung Hospital were treated with standard PPI-based triple therapy (omeprazole 20 mg bid, amoxicillin 1.0 g bid, and clarithromycin 500 mg bid) for 7 days. 2) Second-line eradication: A consecutive series of 59 patients who failed H. pylori eradication with standard PPI-based triple therapy in Kangbuk Samsung Hospital were randomized to two groups. Thirty patients were retreated with 7 days of bismuth-based quadruple therapy (omeprazole 20 mg bid, bismuth 120 mg qid, metronidazole 500 mg tid, and tetracycline 500 mg qid), and remaining 29 patients were retreated with levofloxacin-azithromycin combined triple therapy. Patient's compliance and tolerability were evaluated at the end of treatment. The status of H. pylori infection was assessed 8 weeks later then. The successful eradication of H. pylori was defined as negative results from histology and CLO test, or 13C-urea breath test. RESULTS: First-line eradication rate of levofloxacin-azithromycin triple therapy was lower than that of standard PPI-based triple therapy, but there was no statistically significant difference (70.6% vs. 80.3%, p=0.390). Second-line eradication rate of levofloxacin-azithromycin combined triple therapy was significantly lower than that of bismuth-based quadruple therapy (ITT/PP 65.5%/73.1% vs. 90%/90%, p<0.0001). The compliances of all patients were more than 85%. Two of patients with levofloxacin-azithromycin combined triple therapy complained self-limiting side effects (mild dizziness; mild insomnia with general weakness). CONCLUSIONS: Levofloxacin-azithromycin combined triple therapy should not be recommended as the first-line or second-line H. pylori eradication regimen in Korea.     

A case of primary small cell carcinoma arising from the common bile duct]

Small cell carcinoma is usually seen in the lung, but rarely involves the gastrointestinal tract including biliary tract. A 65 year-old man was admitted because of obstructive jaundice. A smooth-surfaced round intraluminal mass with proximal bile duct dilatation was seen in the proximal common bile duct on endoscopic retrograde cholangiogram. Under the diagnosis of bile duct cancer, pylorus-preserving pancreatoduodenectomy was done. Pathology revealed a 2 cm sized small cell carcinoma in the proximal common bile duct and distal common hepatic duct. On immunohistochemical stain, the tumor cells were positive for neuroendocrine markers CD56 and synaptophysin. After surgery, the patient received 5 cycles of adjuvant chemotherapy with VIP (etoposide, ifosfamide, and cisplatin) regimen. However, the patient died of liver metastasis 12 months after the diagnosis. We report a case of extrapulmonary small cell carcinoma arising from the common bile duct.     

Decreased expression of phospholipase C-beta 2 isozyme in human platelets with impaired function

Platelets from a patient with a mild inherited bleeding disorder and abnormal platelet aggregation and secretion show reduced generation of inositol 1,4,5-trisphosphate, mobilization of intracellular Ca2+, and phosphorylation of pleckstrin in response to several G protein mediated agonists, suggesting a possible defect at the level of phospholipase C (PLC) activation (see accompanying report). A procedure was developed that allows quantitation of platelet PLC isozymes. After fractionation of platelet extracts by high-performance liquid chromatography, 7 out of 10 known PLC isoforms were detected by immunoblot analysis. The amount of these isoforms in normal platelets decreased in the order PLC- gamma 2 > PLC-beta 2 > PLC-beta 3 > PLC-beta 1 > PLC-gamma 1 > PLC- delta 1 > PLC-beta 4. Compared with normal platelets, platelets from the patient contained approximately one-third the amount of PLC-beta 2, whereas PLC-beta 4 was increased threefold. These results suggest that the impaired platelet function in the patient in response to multiple G protein mediated agonists is attributable to a deficiency of PLC-beta 2. They document for the first time a specific PLC isozyme deficiency in human platelets and provide an unique opportunity to understand the role of different PLC isozymes in normal platelet function.     

Switch from oral pramipexole or ropinirole to rotigotine transdermal system in advanced Parkinson’s disease: an open-label study

Objective: Investigate safety, feasibility and efficacy of switching therapy in patients with advanced-stage Parkinson’s disease (PD) inadequately controlled with pramipexole (≤ 3.5 mg/day) or ropinirole (≤ 14 mg/day) to rotigotine transdermal system (≤ 14 mg/24 h; dose adjustments ≤ 16 mg/24 h permitted).

Methods: PD0009 (ClinicalTrials.gov: NCT01711866) was an open-label study in patients with advanced-stage PD receiving levodopa, and experiencing sleep disturbance or early-morning motor impairment. Pramipexole/ropinirole was switched to equivalent dose rotigotine overnight or in two stages. During the 4-week treatment period rotigotine dose adjustments were permitted (up to 16 mg/24 h). Primary variable: Clinical Global Impressions (CGI) item 4: side effects (assessing safety) at end of treatment.

Results: 79/87 (91%) patients completed the study; 2 (2%) withdrew due to adverse events (AEs). Most (84; 97%) had CGI item 4 score < 3 indicating switch did not interfere with functioning; three experienced drug-related AEs interfering with functioning (score = 3). 62% patients improved on Patient Global Impression of Change, assessing effectiveness. AEs occurring ≥ 5%: application site pruritus (10%), application site erythema (7%), dizziness (7%), dyskinesia (7%), erythema (6%), pruritus (6%). Unified Parkinson’s Disease Rating Scale II and III, Parkinson’s Disease Sleep Scale-2 and Pittsburgh Sleep Quality Index were unchanged. Numerical improvements in ‘off’ time, awakenings and nocturias were observed.

Conclusions: Switch from pramipexole or ropinirole to rotigotine (up to 14 mg/24 h) was feasible and possibly associated with some benefit.     

The Role of Muscarinic Receptors in the Pathophysiology of Mood Disorders: A Potential Novel Treatment?

The central cholinergic system has been implicated in the pathophysiology of mood disorders. An imbalance in central cholinergic neurotransmitter activity has been proposed to contribute to the manic and depressive episodes typical of these disorders. Neuropharmacological studies into the effects of cholinergic agonists and antagonists on mood state have provided considerable support for this hypothesis. Furthermore, recent clinical studies have shown that the pan-CHRM antagonist, scopolamine, produces rapid-acting antidepressant effects in individuals with either major depressive disorder (MDD) or bipolar disorder (BPD), such as bipolar depression, contrasting the delayed therapeutic response of conventional mood stabilisers and antidepressants. This review presents recent data from neuroimaging, post-mortem and genetic studies supporting the involvement of muscarinic cholinergic receptors (CHRMs), particularly CHRM2, in the pathophysiology of MDD and BPD. Thus, novel drugs that selectively target CHRMs with negligible effects in the peripheral nervous system might produce more rapid and robust clinical improvement in patients with BPD and MDD.     

Plasma dilution improves cognition and attenuates neuroinflammation in old mice

Our recent study has established that young blood factors are not causal, nor necessary, for the systemic rejuvenation of mammalian tissues. Instead, a procedure referred to as neutral blood exchange (NBE) that resets signaling milieu to a pro-regenerative state through dilution of old plasma, enhanced the health and repair of the muscle and liver, and promoted better hippocampal neurogenesis in 2-year-old mice (Mehdipour et al., Aging 12:8790–8819, 2020). Here we expand the rejuvenative phenotypes of NBE, focusing on the brain. Namely, our results demonstrate that old mice perform much better in novel object and novel texture (whisker discrimination) tests after a single NBE, which is accompanied by reduced neuroinflammation (less-activated CD68⁺ microglia). Evidence against attenuation/dilution of peripheral senescence-associated secretory phenotype (SASP) as the main mechanism behind NBE was that the senolytic ABT 263 had limited effects on neuroinflammation and did not enhance hippocampal neurogenesis in the old mice. Interestingly, peripherally acting ABT 263 and NBE both diminished SA-βGal signal in the old brain, demonstrating that peripheral senescence propagates to the brain, but NBE was more robustly rejuvenative than ABT 263, suggesting that rejuvenation was not simply by reducing senescence. Explaining the mechanism of the positive effects of NBE on the brain, our comparative proteomics analysis demonstrated that dilution of old blood plasma yields an increase in the determinants of brain maintenance and repair in mice and in people. These findings confirm the paradigm of rejuvenation through dilution of age-elevated systemic factors and extrapolate it to brain health and function.