ICONOTIDE (FORMERLY SNX-111, Neurex Pharmaceuticals, Menlo Park, Calif) is the synthetic equivalent of-conopeptide MVIIA, a 25-amino-acid polybasic peptide present in the venom of Conus magus, a marine snail. 1 Ziconotide produces potent antinociceptive effects 2 by selectively binding to N-type voltage-sensitive calcium channels 3,4 on neuronal somata, dendrites, dendritic shafts, and axon terminals, thus blocking neurotransmission from primary nociceptive afferents. Ziconotide is the first selective Ntype voltage-sensitive calcium channel blocking agent to be tested in clinical trials. There is no evidence of tolerance to ziconotide 5 or of addictive behavior in animals (Elan Pharmaceuticals Inc, unpublished data), and the drug must be administered intrathecally to maximize antinociceptive effectiveness and minimize sympatholysis. 6

Fenoldopam increased renal blood flow in a dose-dependent manner compared with placebo, and, at the lowest dose, significantly increased renal blood flow occurred without changes in systemic blood pressure or heart rate. These findings will be useful in designing future studies exploring the role of fenoldopam in preventing or treating renal failure in patients who are not hypertensive.

SNX-111, administered intrathecally by continuous, constant-rate infusion, produced dose-dependent pain relief in a 43-year-old male patient with a 23-year history of intractable deafferentation and phantom limb pain secondary to brachial plexus avulsion and subsequent amputation. Dizziness, blurred vision, and lateral-gaze nystagmus were dose-dependent side effects that resolved with decreasing dose levels. Complete pain relief was achieved in this patient without side effects after dose adjustment. We conclude that SNX-111 is a potent analgesic, antihyperesthesic, and antiallodynic agent. Controlled studies of SNX-111 in patients with malignant and nonmalignant pain syndromes are warranted and are under way.

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The ability of a series of synthetic analogues of omega-conopeptides MVIIA (SNX-111) and TVIA (SNX-185) to prevent electrically-evoked norepinephrine release from rat tail artery and hippocampal slice preparations was determined in an effort to identify voltage-sensitive calcium channel (VSCC) blockers that selectively target N-type VSCCs in central nervous system tissue. Electrical field stimulation (3 Hz, 1 ms in duration. 80 V for 1 min) caused a high and consistent tritium outflow from rat tail artery and hippocampal slice preparations preloaded with [3H]-norepinephrine. All conopeptides, chosen for their selective affinities for high-affinity SNX-111 binding sites (i.e., N-type VSCCs) over high-affinity omega-conopeptides MVIIC (SNX-230) binding sites (i.e., P/Q-type VSCCs), produced a concentration-dependent inhibition of calcium dependent electrically-evoked tritium outflow from both tail arteries and hippocampal slices: IC50s ranged from 1.2 nM to 1.2 microM. Blocking potencies (IC50s) in the tail artery assay were significantly correlated with those measured in the hippocampal slice preparation (r = 0.91, P = 0.00000012). There was a significant correlation between IC50s for blockade of hippocampal norepinephrine release and the inhibition of high-affinity [125I]-SNX-I11 binding in rat brain synaptosomes (r = 0.76, P = 0.00028). Blockade of hippocampal norepinephrine release was not significantly correlated with the inhibition of high-affinity SNX-230 binding (r = 0.46, P = 0.056). Maximum inhibition of tritium outflow in the tail artery assay was 22+/-1.4% of control, approximating the value (20.9+/-16.0% of control) obtained in the absence of extracellular Ca2+. In contrast, the maximum inhibition of tritium release from hippocampal slices was 36.8+/-2.5% of control (P < 0.05, compared to that of the tail artery assay). These results suggest that (1) N-type VSCCs alone mediate low frequency electrical stimulation-evoked neurotransmitter release from peripheral sympathetic efferents (tail artery) while both N-type and non-N type(s) mediate neurotransmitter release from CNS neurons (hippocampus); and (2) analogues of omega-conopeptides MVIIA and TVIA do not differentiate between N-type VSCCs mediating norepinephrine release from central and peripheral neural tissues.

SNX-111 is the first neuronal N-type, voltage-sensitive calcium channel (VSCC) blocker to enter clinical drug development. Areas of potential therapeutic utility include treatment of nociceptive and neuropathic pain and neuroprotection after ischemic brain injury. The data presented demonstrate that SNX-111 is biologically active in humans and indicate for the first time a neurophysiologic function of N-type VSCCs in humans.

The effect of the renin inhibitor enalkiren (Abbott-64662) was evaluated in eight normal volunteer subjects on a standardized sodium diet (100 mmol/day) by measurement of various components of the renin-angiotensin system and drug levels in plasma. On day 1, vehicle and doses of 0.001, 0.003, and 0.01 mg/kg i.v. were administered within 2 minutes at 90-minute intervals. On day 2, vehicle and doses of 0.01, 0.03, and 0.1 mg/kg i.v. were given. With the higher doses, blood pressure tended to decrease slightly with no change in heart rate. Plasma renin activity and plasma angiotensin-(l-8)octapeptide (angiotensin II) fell markedly in a dose-dependent manner. Inhibition of plasma renin activity was maximal 5 minutes after administration of the drug and persisted 90 minutes after the doses of 0.03 and 0.1 mg/kg. Not surprisingly, there was a close correlation between plasma renin activity and plasma angiotensin II levels (r=0.81, n=28, p<0.001). In contrast, active and total renin measured directly by monoclonal antibodies rose in dose-related fashion in response to renin inhibition. Pharmacokinetic parameters were calculated using the plasma drug concentrations obtained up to 6 hours after the 0.1 mg/kg dose. By means of a two-compartment model, plasma mean half-life of the drug was estimated at 1.60±0.43 hours. (Hypertension 1989;13:941-947) O ver the last decade, inhibition of the reninangiotensin system by converting enzyme inhibition has proved very effective for the treatment of hypertension and congestive heart failure.12 Converting enzyme inhibitors block the generation of angiotensin II, a potent pressor hormone. Because converting enzyme is identical to kininase II, it also contributes to the inactivation of the vasodilator hormone bradykinin.3 Accordingly, converting enzyme inhibition does not provide a totally specific means of blocking the reninangiotensin system. Furthermore, the disappearance of angiotensin II from the plasma triggers counterregulatory mechanisms that tend to limit the efficacy of angiotensin converting enzyme (ACE) inhibition. Thus, renin secretion is stimulated and, as a consequence, plasma angiotensin I is elevated. Even in the presence of pronounced ACE inhibition, some angtiotensin II may still be generated. More specific tools for blocking of the reninangiotensin system would be useful. Renin inhibitors have the theoretical advantage of specificity since renin has no known substrate other than angiotensinogen.5 So far, at least experimentally, renin has been blocked by means of various approaches: specific renin antibodies, 6 phospholipids, 78 peptides related to the renin prosegment, 9 pepstatin and its derivatives, 1011 and analogues of the renin substrate. The latter are derived from the minimal sequence of angiotensinogen reacting with renin.12 Actual inhibitors of this class contain a reduced bond between two amino acids at the cleavage site of renin. 13 The inhibitors seem to act by mimicking the transition state of the substrate formed during hydrolysis. Such compounds hav...