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calcium channel	1

Salts of linogliride with reduced solubilities were prepared and evaluated as potential candidates for extended-release oral dosage forms. A once-daily dose of 300-800 mg was intended. Seven acids were selected: p-acetamidobenzoic, benzoic, p-hydroxybenzoic, 3-hydroxy-2-naphthoic, 1-napsylic, pamoic, and p-toluenesulfonic acids but only four salts were able to be prepared in suitable quantities for evaluation: linogliride pamoate, p-hydroxybenzoate, 3-hydroxy-2-naphthoate, and 1-napsylate. The pH-solubility profiles of the four new salts, free base, and fumarate salt were compared over the pH 1.43-8.3 range and the intrinsic dissolution rates of the four new salts and the free base were determined at pH 1.43, 4.4, and 7.5. The range of the pH-solubility profile and intrinsic dissolution rates of the p-hydroxybenzoate salt were less than the free base and fumarate and higher than the other three new salts. The pH-solubilities and intrinsic dissolution rates of the 1-napsylate salt were pH-independent. The solubilities and intrinsic dissolution rates of the pamoate and 3-hydroxy-2-naphthoate were higher at pH 1.4-3.4 than at higher pH. At pH 4.4 and higher, the solubilities were essentially the same, in the 1-2 mg/mL range. The intrinsic dissolution rates were also very low and not very different. Dissolution studies with capsules containing 800 mg doses of the pamoate, 1-napsylate, free base, and fumarate performed in a dissolution medium of pH beginning at 2.2 and ending at 6.8 demonstrated that the pamoate and 1-napsylate salt forms dissolved slower and could be useful as extended-release forms.

01 Oct 1990·The Journal of pharmacology and experimental therapeutics

Antinociceptive action of McN-5195 in rodents: a structurally novel (indolizine) analgesic with a nonopioid mechanism of action.

Article

Author: Hageman, W E ; Carson, J R ; Vaught, J L ; Persico, F J ; Raffa, R B ; Blum, P S ; Carmosin, R J ; Shank, R P

McN-5195 [(+/-)-trans-3-(2-bromophenyl)-octahydroindolizine] inhibited at nontoxic doses the nociceptive response in tail-pinch, tail-flick and 48 degrees C hot-plate tests of mice, with ED50 values of 38.2, 33.9 and 30.9 mg/kg i.p., respectively, and of rats, with ED50 values (i.p.) of 33.2 mg/kg (tail-flick) and 33.3 mg/kg (hot-plate). The compound was p.o. active in the acetylcholine-induced irritant test (ED50 = 20.1 mg/kg) in mice and the air-induced irritant test (ED50 = 33.2 mg/kg) in rats. McN-5195 blocked thalamic activity (multiunit recordings from the ventral posterolateral nucleus) evoked by noxious stimulation of the contralateral hindlimb of anesthetized rats, but did not alter thalamic activity during non-noxious stimulation. The antinociceptive action of McN-5195 was not blocked by naloxone and was not diminished in morphine-tolerant animals. McN-5195 did not affect arachidonate metabolism and was not active against carrageenan-induced paw edema or in an adjuvant arthritis test in rats. McN-5195 did not bind to opiate, serotonin S1 or S2, dopamine D2, alpha-1, alpha-2, beta adrenergic or gamma-aminobutyric acid-A receptors and did not inhibit the synaptic uptake of norepinephrine, serotonin, dopamine or gamma-aminobutyric acid. McN-5195-induced antinociception was not affected by reserpine or phentolamine pretreatment and was not reduced in clonidine-tolerant animals. Ketanserin and yohimbine inhibited McN-5195-induced antinociception by an indirect mechanism. Tolerance did not develop to chronic administration of McN-5195 (120 mg/kg 3 times per day for 10 days). We conclude that McN-5195 is a structurally novel (indolizine) antinociceptive agent that produces its analgesic action via a nonopioid mechanism, not involving products of arachidonate metabolism.

01 Sep 1989·The Journal of pharmacology and experimental therapeutics

Effect of the fatty acid oxidation inhibitor methyl palmoxirate (methyl 2-tetradecylglycidate) on recovery from insulin-induced hypoglycemia in diabetic dogs.

Article

Author: Altszuler, N ; Inman, M ; Tutwiler, G F ; Bowden, C R ; Tuman, R W

Methyl palmoxirate, an effective hypoglycemic agent administered p.o., has been shown to decrease hepatic glucose production secondary to inhibition of mitochondrial fatty acid oxidation. Because the ability to increase hepatic glucose production is an important counter-regulatory defense against hypoglycemia, we compared the ability of streptozotocin/alloxan-induced diabetic dogs treated p.o. with vehicle or methyl palmoxirate (2.5 mg/kg/day X 7 days) to recover from insulin-induced hypoglycemia. Hepatic glucose production and glucose utilization were determined by isotope dilution before and after acute reduction of plasma glucose by i.v. insulin injection (0.10 or 0.13 U/kg). Diabetic dogs treated with methyl palmoxirate for 6 days had lower overnight fasting plasma glucose levels than vehicle-treated animals (158 +/- 7 vs. 171 +/- 11, respectively, P less than .05). Plasma glucose at 4 hr after the last dose of drug decreased to 115 +/- 5 mg/dl, whereas glucose in the vehicle-treated dogs was unchanged (172 +/- 8 mg/dl). Recovery from insulin-induced hypoglycemia (nadirs of 58 +/- 5 and 42 +/- 4 mg/dl in the vehicle- and methyl palmoxirate-treated groups, respectively) was not significantly different between the two groups of dogs. Restoration of plasma glucose was primarily due to increased hepatic glucose production in both treatment groups, as glucose utilization did not fall significantly below baseline levels. Plasma glucagon levels increased in both vehicle- and methyl palmoxirate-treated dogs in response to hypoglycemia, indicating that release of an important counter-regulatory hormone was not compromised by drug treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

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Pipeline Snapshot as of 25 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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