dextromethorphan and Hypoglycemia

In this clinical trial, we investigated the blood glucose (BG)-lowering effects of 30, 60 and 90 mg dextromethorphan (DXM) as well as 100 mg sitagliptin alone versus combinations of DXM and sitagliptin during an oral glucose tolerance test (OGTT) in 20 men with T2DM. The combination of 60 mg DXM plus 100 mg sitagliptin was observed to have the strongest effect in the OGTT. It lowered maximum BG concentrations and increased the baseline-adjusted area under the curve for serum insulin concentrations in the first 30 min of the OGTT (mean ± standard deviation 240 ± 47 mg/dl and 8.1 ± 6.1 mU/l/h, respectively) to a significantly larger extent than did 100 mg sitagliptin alone (254 ± 50 mg/dl and 5.8 ± 2.5 mU/l/h, respectively; p < 0.05) and placebo (272 ± 49 mg/dl and 3.9 ± 3.0 mU/l/h, respectively; p < 0.001). All study drugs were well tolerated, alone and in combination, without serious adverse events or hypoglycaemia. Long-term clinical trials are now warranted to investigate the potential of the combination of 30 or 60 mg DXM and dipeptidyl peptidase-4 inhibitors in the treatment of individuals with T2DM, in particular as preclinical studies have identified the β-cell protective properties of DXM.

Topics: Aged; Blood Glucose; Cross-Over Studies; Dextromethorphan; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Glucose Tolerance Test; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Sitagliptin Phosphate

We investigated the functional characteristics of the NMDA receptor that modulates hypoxia/hypoglycaemia-induced striatal dopamine release. Dopamine release was detected by fast cyclic voltammetry in rat neostriatal slices. Four variables were measured: T(on) -- time from initiation of hypoxia/hypoglycaemia to the onset of dopamine release, Tpk -- time from onset to maximum, deltaDA/delta(t) -- rate of dopamine release and DAmax -- maximum extracellular dopamine concentration. In controls, T(on) = 164.9 +/- 1.7 s, Tpk = 20.9 +/- 0.9 s, deltaDA/delta(t) = 5.31 +/- 0.44 microM/s and DAmax = 79.1 +/- 2.5 microM (means +/- S.E.M., n = 203). Cis-4-(phosphonomethyl)piperidine-2-carboxylic acid (CGS 19755, 20 microM) lengthened, while N-methyl-D-aspartate (NMDA) (100 microM) shortened T(on). (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,1 0-imine hydrogen maleate (MK 801, 1 and 10 microM) and dextromethorphan (10 and 100 microM) increased Tpk and decreased DAmax. Neither glycine (100 microM), 7-chlorokynurenic acid (50 microM) nor 5-nitro-6,7-dichloro-1,4-dihydroquinoxaline-2,3-dione (ACEA 1021, 100 microM) had any effect although 7-chlorokynurenic acid blocked the effect of NMDA. Increasing [Mg2+] from 1.3 to 3.7 mM, increased Tpk and decreased deltaDA/delta(t). Dithiothreitol (1 mM) accelerated T(on) while 5.5-dithio-bis-(2-nitrobenzoic acid) (1 mM) delayed T(on). Neither drug affected Tpk, DAmax or deltaDA/delta(t). Neither spermidine (100 microM) nor arcaine (100 microM) affected T(on), Tpk or deltaDA/delta(t) although arcaine decreased DAmax. In conclusion, hypoxia/hypoglycaemia-induced dopamine release was influenced by an NMDA receptor although modulation of the glycine recognition site of the receptor was ineffective, as were agents acting at polyamine modulatory zones. These findings highlight differences between recombinant and native NMDA receptors and suggest caution in extrapolating molecular biology to functional studies.

Topics: Animals; Biogenic Polyamines; Dextromethorphan; Dizocilpine Maleate; Dopamine; Excitatory Amino Acid Antagonists; Hypoglycemia; Hypoxia; In Vitro Techniques; Magnesium; Male; Neostriatum; Rats; Rats, Wistar; Receptors, Glutamate; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Receptors, Phencyclidine