LY 456236 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.

Anticonvulsant effects of LY456236, a selective mGlu1 receptor antagonist.[Pubmed:16011839]

Neuropharmacology. 2005;49 Suppl 1:188-95.

Several lines of evidence suggest that mGlu1 metabotropic glutamate receptors may be involved in seizure disorders such as epilepsy. For example, the mGlu1 agonist DHPG produces limbic seizures and group I antagonists such as 4C3HPG and 4CPG are anticonvulsant when administered intracerebrally. The purpose of the present experiments was to characterize the anticonvulsant effects of the selective mGlu1 receptor antagonist LY456236 in mice and rats. In male and female DBA/2 mice, LY456236 produced a dose-related inhibition of sound-induced clonic-tonic seizures. In male CF1 mice, LY456236 produced a dose-related inhibition of tonic extensor seizures in the threshold electroshock model, and limbic seizures in the 6-Hz focal seizure model. However, this antagonist did not inhibit clonic seizures produced by pentylenetetrazol. In amygdala-kindled male Sprague-Dawley rats, LY456236 produced dose-related decreases in behavioral and electrographic seizures at threshold stimulus intensity. In addition, LY456236 produced a dose-related increase in the stimulus intensity required to produce generalized seizures. Taken together, the present results support the conclusion that mGlu1 receptor antagonists such as LY456236 may have clinical utility in the treatment of epilepsy and other seizure disorders.