LY 2365109 hydrochloride

[Phase I study of gemcitabine hydrochloride (LY 188011) combination therapy with cisplatin in the patients with non-small cell lung cancer].[Pubmed:10396316]

Gan To Kagaku Ryoho. 1999 Jun;26(7):898-907.

The combination Phase I study of gemcitabine hydrochloride with cisplatin was conducted in the patients with non-small cell lung cancer (NSCLC) at 5 investigation sites. Gemcitabine was administrated on day 1, 8 and 15 and cisplatin on day 1 of each 28-day cycle. The dosage of cisplatin was fixed to 80 mg/m2 and the dosage of Gemcitabine was gradually escalated in 3 dosing level from 600, 800 to 1,000 mg/m2. The maximum tolerated dose (MTD) and the recommended dose was determined with Continual Reassessment Method. For each dose level, 6 cases, 3 cases and 6 cases were registered respectively and all 15 cases were evaluable. In the dose level 3 with 1,000 mg/m2 of gemcitabine and 80 mg/m2 of cisplatin, grade 4 neutropenia was observed as DLT in 3 out of 6 cases, thus dose level 3 was considered as MTD and the recommended dose. Major adverse events were leukopenia, neutropenia, nausea/vomiting and anorexia. The incidence of such adverse events seemed to be dose-dependent and especially the grade of neutropenia seemed to be more serious as the dose increased. Also, the grade of liver function tests abnormal seemed to be more serious as the dose increased but the incidence as well as the grade did not have tendency of dose-dependent in another events including renal function tests abnormal. On the other hand, as to the efficacy PR was observed in 4 out of 15 cases. Based upon the results, it is necessary to discuss further the efficacy in the recommended dose in the combination therapy of gemcitabine and cisplatin.

[An early phase II study of gemcitabine hydrochloride (LY 188011). Gemcitabine Cooperative Study Group for Early Phase II].[Pubmed:8937492]

Gan To Kagaku Ryoho. 1996 Nov;23(13):1813-24.

An early phase II cooperative study of Gemcitabine Hydrochloride (abbreviated to "gemcitabine" herewith) was conducted in patients with a variety of solid tumors (i.e., lung cancer, gastric cancer, pancreatic cancer, colon/rectum cancer, cervical cancer, ovarian cancer and breast cancer) at 56 institutions. The aim of the first step (Step I) was to investigate the feasibility of gemcitabine in a variety of different solid tumors, including lung cancer regarding efficacy and safety. The aim of the second step (Step II) was as a result of step I (Responses were observed) to continue to investigate the efficacy and safety of gemcitabine in chemonaive patients with non-small cell lung cancer. As a Step I study, gemcitabine was administered once weekly at a dose of 800 mg/m2 for a consecutive 3-week period followed by a week of rest, in multiple courses. Among the 29 eligible patients with lung cancer, partial response (PR) was achieved in 3 patients (25.0%, 95% confidence interval: 5.5-57.2%) out of 12 chemonaive patients. Adverse reactions (grade 3 or higher) seen in 29 patients with lung cancer were neutropenia (27.6%), leukopenia (13.8%), decreased hemoglobin (13.8%), thrombocytopenia (10.3%), malaise (6.9%), anorexia (3.4%), nausea/vomiting (3.4%), diarrhea (3.4%), dyspnea (3.4%) and interstitial pneumonia (3.4%). In other types of solid tumors, PR was achieved in 2 (8.7%) out of 23 eligible patients with cervical cancer and in 1 (5.3%) of 19 eligible patients with ovarian cancer, while the use of analgesics became unnecessary in 1 patient with pancreatic cancer. Incidence as well as severity of main adverse reactions in these patients were comparable to those seen in patients with lung cancer. A Step II study, in which gemcitabine was administered once weekly at a dose of 1,000 mg/m2 to chemonaive patients with non-small cell lung cancer, was conducted, referring to the results of Step I and clinical studies conducted overseas. The results of the Step II study demonstrated PR in 5 (14.3%, 95% confidence interval: 4.8 - 30.3%) out of 35 eligible patients with non-small cell lung cancer and that the main adverse reactions were comparable to those seen in the Step I study, posing no tolerability problems in particular.

Changes in motor activities induced by microinjections of the selective dopamine agonists LY 171555, quinpirole hydrochloride, and SK&F 38393 into the habenula nucleus.[Pubmed:3495009]

Pharmacol Biochem Behav. 1987 Mar;26(3):643-6.

The effects on behaviour of microinjections into the habenula complex of selective agonists for dopamine D-1 (SK&F 38393) and D-2 (LY 171555) receptors were documented in a holeboard, open-field test. The D-2 agonist reduced grooming responses, locomotor activity and rearing behaviour. In contrast, the D-1 agonist increased rearing and locomotor activity but was without effect on grooming responses. Neither drug produced significant effects on inspective hole exploration. The data extend findings of behavioural consequences of central D-1 receptor activation and provide direct evidence in support of the functional and behavioural importance of intrahabenular dopamine receptor sites. The findings are consistent with suggestions for feedback regulation of habenular efferents to midbrain dopaminergic neurons. Effects of both receptor agonists on some responses but not others indicates potential complex interactions between D-1 and D-2 receptors within the habenula.

Neurochemical and behavioral profiling of the selective GlyT1 inhibitors ALX5407 and LY2365109 indicate a preferential action in caudal vs. cortical brain areas.[Pubmed:18602930]

Neuropharmacology. 2008 Oct;55(5):743-54.

Selective inhibitors of the glycine transporter 1 (GlyT1) have been implicated in central nervous system disorders related to hypoglutamatergic function such as schizophrenia. The selective GlyT1 inhibitors ALX5407 (NFPS) and LY2365109 {[2-(4-benzo[1,3]dioxol-5-yl-2-tert-butylphenoxy)ethyl]-methylamino}-acetic acid increased cerebrospinal fluid levels of glycine and potentiated NMDA-induced increases in dialysate levels of neurotransmitters in the prefrontal cortex (PFC) and the striatum. However, higher doses produced both stimulatory and inhibitory effects on motor performance and impaired respiration, suggesting significant involvement of cerebellar and brain stem areas. A dual probe microdialysis study showed that ALX5407 transiently elevated extracellular levels of glycine in the PFC with more sustained increases in the cerebellum. In support of these findings, immuno-staining with pan-GlyT1 and GlyT1a antibodies showed a higher abundance of immunoreactivity in the brain stem/cerebellum as compared to the frontal cortical/hippocampal brain areas in four different species studied, including the mouse, rat, monkey and human. In addition, the inhibitory effects of ALX5407 on cerebellar levels of cGMP in the mouse could be reversed by the glycine A receptor antagonist strychnine but not the glycine B receptor antagonist L-701324. We propose that the adverse events seen with higher doses of ALX5407 and LY2365109 are the result of high GlyT1 inhibitory activity in caudal areas of the brain with sustained elevations of extracellular glycine. High levels of glycine in these brain areas may result in activation of strychnine-sensitive glycine A receptors that are inhibitory on both motor activity and critical brain stem functions such as respiration.