Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0013362 (dysarthria)
 3,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

R115777 is a nonpeptidomimetic enzyme-specific inhibitor of farnesyl protein transferase (FT) that was developed as a potential inhibitor of Ras protein signaling, with antitumor activity in preclinical models. This study was a phase 1 trial of orally administered R115777 in 35 adults with poor-risk acute leukemias. Cohorts of patients received R115777 at doses ranging from 100 mg twice daily (bid) to 1200 mg bid for up to 21 days. Dose-limiting toxicity occurred at 1200 mg bid, with central neurotoxicity evidenced by ataxia, confusion, and dysarthria. Non-dose-limiting toxicities included reversible nausea, renal insufficiency, polydipsia, paresthesias, and myelosuppression. R115777 inhibited FT activity at 300 mg bid and farnesylation of FT substrates lamin A and HDJ-2 at 600 mg bid. Extracellular signal-regulated kinase (ERK), an effector enzyme of Ras-mediated signaling, was detected in its phosphorylated (activated) form in 8 (36.4%) of 22 pretreatment marrows and became undetectable in 4 of those 8 after one cycle of treatment. Pharmacokinetics revealed a linear relationship between dose and maximum plasma concentration or area under the curve over 12 hours at all dose levels. Weekly marrow samples demonstrated that R115777 accumulated in bone marrow in a dose-dependent fashion, with large increases in marrow drug levels beginning at 600 mg bid and with sustained levels throughout drug administration. Clinical responses occurred in 10 (29%) of the 34 evaluable patients, including 2 complete remissions. Genomic analyses failed to detect N-ras gene mutations in any of the 35 leukemias. The results of this first clinical trial of a signal transduction inhibitor in patients with acute leukemias suggest that inhibitors of FT may have important clinical antileukemic activity. (Blood. 2001;97:3361-3369)
 ...
PMID:Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. 1136 25

Whipple disease is a relapsing systemic illness caused by Tropheryma whippelii. Central nervous system involvement occurs in 5%-40% of all patients. Hypothalamic manifestations occur in 31% of Whipple encephalopathy, including polydipsia, hyperphagia, change in libido and insomnia. We report a case of a 48-year-old man with severe insomnia, depression, dementia, dysarthria, myoclonic movements of the limbs and ophthalmoplegia. The diagnosis of Whipple encephalopathy was confirmed by PCR analysis of blood and faeces. He received a full dose of antibiotic treatment. Despite clinical improvement, resolution of the lesions detected in MRI scan of the brain and negative results of the PCR in blood, faeces and cerebrospinal fluid six months later, insomnia persisted and finally subsided after the administration of carbamazepine (600 mg/day). Our case supports the finding that carbamazepine might be useful in the treatment of insomnia associated with Whipple encephalopathy.
 ...
PMID:An unusual case of insomnia associated with Whipple encephalopathy: first case reported from Greece. 1608 32

Diabetes mellitus develops in about 10% of acromegalic patients, usually secondary to insulin resistance caused by growth hormone excess. Diabetic ketoacidosis is a result of relative insulin deficiency and is a rare feature of acromegaly. Here, we present one case of this disorder. A 57-year-old man came to the emergency room due to 2 weeks of dizziness. He also had polyuria, polydipsia, nausea, diplopia, blurred vision and dysarthria. His plasma glucose level was 32.06 mmol/L, plasma osmolarity was 322 mOsm/L, arterial pH was 7.30, level of bicarbonates was 18 mmol/L, urine ketones was 4+, and HbA1c was 14.1%. No specific cause for the development of this metabolic derangement could be found. He displayed clinical features of acromegaly during admission, which was confirmed by an elevated growth hormone level and pituitary macroadenoma shown on magnetic resonance imaging. The patient underwent total transsphenoid tumor removal 2 weeks later; plasma glucose levels became normal thereafter.
 ...
PMID:Diabetic ketoacidosis in a patient with acromegaly. 1790 70

A 42-year-old woman, with a 12-year history of bipolar disorder was referred to our department due to tremor, sedation, dysarthria, polyuria and polydipsia. She had been on lithium monotherapy during the last 3 years. On admission, her cognitive status was intact, and neither depression nor euphoria was reported. Lithium plasma levels were 1.6 mEq/L, whereas creatinine and urea levels were 2.8 IU/L and 110 IU/L, respectively. The patient did not take other medications or misused lithium. Lithium was immediately discontinued. Ultrasound scans of the urinary tract were suggestive of bilateral hydronephrosis secondary to bladder contraction and cystoscopy-guided bladder biopsy revealed glandular cystitis a benign tumour into the bladder's wall, which impeded the bladder's contraction leading to hydronephrosis and subsequent toxic lithium plasma levels. The patient was switched to valproate and was referred for surgical excision of the lesion. One year later, she was in good physical and mental health under treatment with valproate (1000 mg/day). This is the first case report of glandular cystitis leading to lithium intoxication by impairing renal function. Acute renal failure leading to lithium intoxication would be possible. However, a thorough imaging, endoscopical and histological study revealed glandular cystitis as the cause of renal impairment. Although physicians are alert about lithium's toxicity and a monitoring of renal function is routinely prescribed, little focus has been made on the integrity of the urinary tract. We suggest that urinary tract imaging should be part of the routine work-up in patients presenting with symptoms and signs of lithium intoxication, since concomitant urinary tract lesions might occasionally be the cause of renal impairment leading to reduced lithium excretion.
 ...
PMID:Glandular cystitis and lithium intoxication in a patient with bipolar disorder. 2279 15