ABSTRACT
The potential of the aldose reductase inhibitor ponalrestat (600 mg daily) to ameliorate diabetic neuropathy was evaluated in 259 diabetes mellitus patients with peripheral neuropathy (defined by abnormal vibration perception threshold and abnormal peroneal motor conduction velocity) in a double-blind placebo-controlled clinical trial running for 18 months. Overall, no beneficial effect of ponalrestat on vibration perception thresholds, nerve conduction velocities, and nerve action potential amplitudes was detected. Because vibration perception thresholds and conduction velocities in median, peroneal, and sural nerves did not deteriorate in the placebo group, the potential of ponalrestat to prevent the expected deterioration in peripheral nerve function that occurs with an increased duration of diabetes was not tested. Patients with an abnormal heart rate reaction to standing (abnormal 30:15 ratio; n = 84) on ponalrestat did not deteriorate in this autonomic nerve function test as shown in those on placebo. In conclusion, ponalrestat did not improve peripheral nerve function in diabetes mellitus patients with signs of peripheral neuropathy, although it did ameliorate a deterioration in autonomic nerve function in diabetic patients with signs of autonomic neuropathy.
Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Autonomic Nervous System/physiopathology , Diabetic Neuropathies/drug therapy , Peripheral Nerves/physiopathology , Phthalazines/therapeutic use , Autonomic Nervous System/drug effects , Diabetic Neuropathies/physiopathology , Female , Glycated Hemoglobin/analysis , Heart Rate , Humans , Male , Middle Aged , Motor Neurons/physiology , Neural Conduction , Perception , Peripheral Nerves/drug effects , Placebos , Valsalva ManeuverABSTRACT
The standardization of methodology and the provision of age-related reference values have been addressed for the design of and interpretation of data from a multicentre neuropathy trial. Age-related reference values were generated from 120 healthy volunteers. Vibration perception thresholds (VPT) deteriorated significantly with age (p less than 0.001). Patients were selected on the basis of age-related abnormal VPT and peroneal motor nerve conduction velocity. They were assessed at the beginning and end of a placebo run-in period (baseline data). The coefficients of variation (CV%) for VPT at the medial malleolus (16.81 per cent, n = 316) and great toe (19.23 per cent, n = 313) were lower compared to results in healthy volunteers (29.7 per cent and 20.8 per cent, respectively, n = 49). The CV% for expiratory:inspiratory (E:I) ratio (4.82 per cent, n = 215), Valsalva manoeuvre (10.84 per cent, n = 249) and 30:15 ratio (7.73 per cent, n = 292) from patients corresponded to those recorded in volunteers (7.6 per cent, n = 45 11.0 per cent, n = 49 9.5 per cent, n = 48, respectively). Most patient values for VPT at the great toe fell beyond the 95 centile line for volunteers. E:I ratio for volunteers showed a more variable relationship with age, although patient values appeared to be located below the 5 centile line for volunteer data.
Subject(s)
Diabetic Neuropathies/physiopathology , Peripheral Nerves/physiopathology , Adult , Age Factors , Aged , Female , Humans , Male , Middle Aged , Neural Conduction , Neurologic Examination , Peripheral Nerves/physiology , Reference Values , SensationABSTRACT
The cardiovascular actions of two pyrethroids, deltamethrin and cismethrin, were assessed using the pithed rat, the isolated working heart, and perfused mesentery preparations. Deltamethrin but not cismethrin, increased mean arterial pressure and differential pressure in the pithed rat, and the aortic output and mean systolic aortic pressure in the working heart. Reserpine pretreatment reduced, but did not abolish, the pressor response to deltamethrin in the pithed rat and working heart, but did not reduce the increase in aortic output following deltamethrin in the working heart. In the perfused mesentery, deltamethrin did not modify the action of exogenous noradrenaline, but increased the response to 10 Hz stimulation. It is concluded that the cardiovascular effects of deltamethrin are due to both increased catecholamine release in peripheral vascular beds, and to a direct positive inotropic effect on the heart. The results also provide a distinction between the action of the two pyrethroids in terms of their cardiovascular activity.
Subject(s)
Cardiovascular System/drug effects , Insecticides/pharmacology , Pyrethrins/pharmacology , Animals , Blood Pressure/drug effects , Decerebrate State , In Vitro Techniques , Ion Channels/drug effects , Male , Myocardial Contraction/drug effects , Nitriles , Rats , Sodium/metabolismSubject(s)
Pyrethrins/toxicity , Animals , Male , Mephenesin , Pyrethrins/antagonists & inhibitors , RatsABSTRACT
Sodium chloride (155 mM) and N-acetyl cysteine (6 mM) were recirculated through the colons of anaesthetized rats. Mucus accumulated in the perfusion fluid which was changed at intervals to allow mucus output to be estimated by measurement of hexose. The output of mucus could be stimulated by intravenous administration of the cholinergic drugs carbachol and bethanechol; this effect was inhibited by atropine. Mucus output could also be stimulated by intravenous 5-hydroxytryptamine. This was not a muscarinic cholinergic effect because atropine did not prevent it. Neither did methysergide inhibit it; but chlorpromazine did. Precursors of 5-hydroxytryptamine, 5-hydroxytryptophan and L-tryptophan, also stimulated mucus output if given in high dosage. The results suggest that in this preparation mucus output can be stimulated by two distinct mechanisms, one cholinergic, the other involving 5-hydroxytryptamine and perhaps 5-hydroxytryptophan.
