Ammonia is predominantly generated in the gut by intestinal bacteria and enzymes and detoxified primarily in the liver. Since the 1930s, ammonia has been identified as the principal culprit in hepatic encephalopathy (HE). Many physicians utilize serum ammonia to diagnose, assess severity, and determine the resolution of HE in patients with chronic liver disease (CLD) despite research showing that ammonia levels are unhelpful in all of these clinical circumstances. HE in patients with CLD is a clinical diagnosis of exclusion that should not be based on ammonia levels.
Background Accumulating evidence shows evidence of efficacy with the combination of vorinostat and bortezomib in solid tumors. We previously examined a once-daily continuous dosing schedule of vorinostat in combination with bortezomib which was well tolerated in cycles 1 and 2; however, there was concern regarding the tolerability through multiple cycles. This study was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib. Methods Vorinostat was initially administered orally twice daily on days 1–14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at dose level 1, thus the protocol was amended to administer vorinostat intermittently twice daily on days 1–4 and 8–11. Results 29 patients were enrolled; 13 men and 16 women. Common cancer types included sarcoma, pancreatic, colorectal, GIST, and breast. The most common Grade 3–4 toxicities at any dose level included thrombocytopenia, fatigue, increased ALT, elevated INR, and diarrhea. DLTs in the intermittent dosing scheduled included thrombocytopenia and fatigue. The Cmax and AUC for the intermittent dosing regimen were similar to those observed in the daily dosing. In this heavily pretreated population, stable disease was observed in patients with sarcoma, colorectal adenocarcinoma and GIST. Conclusions The MTD was established at vorinostat 300 mg BID on days 1–4 and 8–11 and bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 of a 21 day cycle. Tolerability was not improved with the intermittent dosing schedule of vorinostat when compared to continuous dosing.
BackgroundElderly patients, in particular, have been reported to develop psychiatric side effects from antibiotics. Clarithromycin, quinolones, sulfamethoxazole-trimethoprim, isoniazid, penicillin, and cephalosporins have been reported to cause psychosis. This case report bridges a void in the medical literature with regards to the psychiatric adverse effects of imipenem-cilastatin.Case presentationA 64-year-old Hispanic man in septic shock due to urinary tract infection was initiated on imipenem-cilastatin and mechanically ventilated, following admission to hospital. His mentation was normal for 72 hours after extubation and discontinuation of sedatives and opioids, following which he was noted to be in acute psychosis. Our patient’s imipenem-cilastatin dose had been increased 24 hours prior to his violent visual and auditory hallucinations because his renal function had improved. The physical examination and laboratory tests did not reveal evidence of a new central nervous infection or endocrinopathy. His mentation improved after his antibiotic was switched to ceftriaxone, based on culture and sensitivity testing. Similar psychiatric symptoms developed 2 months later when he was treated with imipenem for a recurrent urinary tract infection. His symptoms again resolved with modification of his antibiotic regimen.ConclusionsEndocrine dysfunctions (thyroid, adrenal, and pituitary disorders) and toxic ingestions are medical disorders known to cause brief psychotic episodes. Fluoroquinolones, penicillins, and trimethoprim-sulfamethoxazole are common antibiotics associated with this rare adverse effect. Several pharmacokinetic hypotheses have been proposed for this adverse effect: (1) N-methyl-D-aspartate receptor hypofunctioning, (2) sequential blockade of folic acid production, (3) inhibition of prostaglandin E2 and proinflammatory cytokine production, (4) increased central dopamine turnover, and (5) accumulation of toxic levels of the drug. Pre-existing psychopathology, relevant comorbidities, slow acetylation status, and increased permeability of the blood–brain barrier have been suggested to make patients more prone to developing psychosis. According to the literature, this psychiatric manifestation resolves within 2 weeks of discontinuing the offending agent. There appears to be underreporting of the psychiatric manifestations of imipenem-cilastatin, contrary to post-marketing surveillance data. It is imperative that physicians recognize these psychiatric side effects of antibiotics, because they are a fundamental treatment option.
A 67-year-old woman with a history of lung adenocarcinoma presented with 3 weeks of redness, pain, swelling and skin changes in her right breast. Her vital signs and physical examination were within physiological limits except for the right breast. She had extensive red streaks radiating from the right nipple with peau d'orange appearance of her overlying skin. Her breast was tender on examination and did not have any associated cervical or axillary lymphadenopathy. Her mammography revealed thickening of the skin, increased parenchymal markings and shrinkage the breast. Multiple skin biopsies demonstrated moderately differentiated lung adenocarcinoma with lymphovascular invasion. The patient made an informed decision to undergo radiotherapy following discussion with her oncologist and breast surgeon. She succumbed to her illness 2 months after the diagnosis of metastasis to her breast.
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