Functional distinction between NGF-mediated plasticity and regeneration of nociceptive axons within the spinal cord.

Successful regeneration after injury requires either the direct reformation of the circuit or the formation of a bridge circuit to provide partial functional return through a more indirect route. Presently, little is known about the specificity of how regenerating axons reconnect or reconstruct functional circuits. We have established an in vivo Dorsal root entry zone (DREZ) model, which in the presence of Nerve Growth Factor (NGF), shows very robust regeneration of peptidergic nociceptive axons, but not other sensory axons. Expression of NGF in normal, non-injured animals leads to robust sprouting of only the peptidergic nociceptive axons. Interestingly, NGF-induced sprouting of these axons leads to severe chronic pain, whereas, regeneration leads to protective-like pain without chronic pain. Using this model we set out to compare differences in behavioral outcomes and circuit features between these two groups. In this study, we examined pre-synaptic and post-synaptic markers to evaluate the relationship between synaptic connections and behavioral responses. NGF-induced sprouting of calcitonin gene-related peptide (CGRP) axons resulted in a significant redistribution of synapses and cFos expression into the deeper dorsal horn. Regeneration of only the CGRP axons showed a general reduction in synapses and cFos expression within laminae I and II; however, inflammation of the hindpaw induced peripheral sensitization. These data show that although NGF-induced sprouting of peptidergic axons induces robust chronic pain and cFos expression throughout the entire dorsal horn, regeneration of the same axons resulted in normal protective pain with a synaptic and cFos distribution similar, albeit significantly less than that shown by the sprouting of CGRP axons.

Advances in cancer pain management.

Control of malignant pain and related symptoms is paramount to clinical success in caring for cancer patients. To achieve the best quality of life for patients and families, oncologists and palliative care clinicians must work together to understand problems related to psychologic, social, and spiritual pain. Pain is the primary problem targeted for control using the World Health Organization's (WHO) analgesic ladder. This article focuses on increased knowledge of analgesic action that may enable expansion of the WHO analgesic ladder to fulfill the broader objectives of palliative medicine. We discuss clinical experience with several classes of drugs that are currently used to treat cancer pain: 1) nonsteroidal anti-inflammatory drugs, with emphasis on cyclooxygenase-2 inhibitors; 2) opioid analgesics, with specific emphasis on methadone and its newly recognized value in cancer pain; 3) ketamine, an antagonist at N-methyl-d-aspartate receptors; and 4) bisphosphonates, used for pain resulting from bone metastases. New concepts that compare molecular actions of morphine at excitatory opioid receptors, and methadone at nonopioid receptor systems, are presented to underscore the importance of balancing central nervous system excitatory (anti-analgesic) versus inhibitory (analgesic) influences.

Advances in cancer pain management.

Control of malignant pain and related symptoms is paramount to clinical success in caring for cancer patients. To achieve the best quality of life for patients and families, oncologists and palliative care clinicians must work together to understand problems related to psychologic, social, and spiritual pain. Pain is the primary problem targeted for control using the World Health Organization's (WHO) analgesic ladder. This article focuses on increased knowledge of analgesic action that may enable expansion of the WHO analgesic ladder to fulfill the broader objectives of palliative medicine. We discuss clinical experience with several classes of drugs that are currently used to treat cancer pain: 1) nonsteroidal anti-inflammatory drugs (NSAIDs), with emphasis on cyclooxygenase-2 (COX-2) inhibitors; 2) opioid analgesics, with specific emphasis on methadone and its newly recognized value in cancer pain; 3) ketamine, an antagonist at N-methyl d-aspartate (NMDA) receptors; and 4) bisphosphonates, used for pain resulting from bone metastases. New concepts that compare molecular actions of morphine at excitatory opioid receptors, and methadone at non-opioid receptor systems, are presented to underscore the importance of balancing central nervous system excitatory (anti-analgesic) versus inhibitory (analgesic) influences.

PC-SPES, a dietary supplement for the treatment of hormone-refractory prostate cancer.

OBJECTIVE: To assess the effectiveness of PC-SPES, a dietary supplement containing eight herbal extracts, which is a popular alternative therapy among patients with hormone-refractory prostate cancer; anecdotal reports claim that this agent provides relief of metastatic pain, improvements in quality of life and reduction of prostatic specific antigen (PSA) level. PATIENTS AND METHODS: Sixteen men treated for advanced metastatic prostate cancer (stage D3) with either orchidectomy or a luteinizing-hormone releasing hormone agonist, with or without anti-androgen, were enrolled into a prospective clinical trial to evaluate the possible toxic and beneficial effects of PC-SPES. After hormone-ablative therapy had failed, and with established disease progression, all patients received supplemental treatment with PC-SPES (2.88 g daily) for 5 months. Hormonal therapy was continued throughout the trial to avoid the known withdrawal effect of anti-androgen on PSA levels. RESULTS: The supplemental intake of PC-SPES was associated with significant (P<0.05-0.01) improvements in quality-of-life measures, reductions in patient's pain ratings (P<0.05-0.01), and a decline in PSA levels (P<0.01), with no major side-effects. CONCLUSIONS: These results support the anecdotal reports of the beneficial effects of PC-SPES as a comparable alternative to current management regimens in hormone-refractory prostate cancer. However, no conclusions can be drawn about the long-term effects of this new herbal therapy.

Hyperalgesic and analgesic actions of morphine, U50-488, naltrexone, and (-)-lobeline in the rat brainstem.

Morphine, U50-488, and (-)-lobeline produced dose-related shortening of a low-intensity thermally evoked tail avoidance response (LITETAR) (e.g., hyperalgesia) when microinjected into the dorsal posterior mesencephalic tegmentum (DPMT) of conscious rats. The hyperalgesic potency of (-)-lobeline was greater than either morphine or U50-488. With higher doses, morphine's hyperalgesic actions diminished and prolongation of the LITETAR (e.g., analgesia) was observed. Naltrexone produced analgesia in the DPMT that diminished with increasing dose. The hyperalgesic actions of morphine, U50-488, and (-)-lobeline further suggest the presence of kappaergic opioid and nicotinic mechanisms in the DPMT of rats. The hyperalgesic actions of U50-488, a highly specific opioid kappa-receptor agonist, strongly suggest the presence of a kappa-opioidergic hyperalgesic mechanism in the DPMT.

Cardiodepressant actions of combined diltiazem and propranolol in dogs.

The cardiovascular actions of combined intravenous (i.v.) diltiazem and propranolol were studied in barbiturate-anesthetized dogs. When given alone, diltiazem increased cardiac output (CO) and P-R interval duration (P-R) while decreasing mean arterial pressure (MAP), heart rate (HR), and systemic vascular resistance (SVR). Propranolol alone decreased CO and HR while increasing SVR. With the same i.v. doses, combined infusion of diltiazem and propranolol rapidly resulted in depression of CO to levels similar to those achieved with propranolol beta-adrenoceptor blockade alone. The combination decreased MAP to levels achieved with diltiazem-induced calcium channel blockade. P-R increased beyond the durations produced by either drug given alone. Pharmacokinetic interactions were not apparent, although slight increases in propranolol plasma concentrations were observed during combined drug infusions. These studies support clinical observations that the cardiovascular effects resulting from a combination of diltiazem and propranolol may be attributed to the characteristic cardiovascular actions of each individual drug.

Pharmacologic characteristics of a medullary hyperalgesic center.

The effects of ethylketazocine, U-50,488, morphine and (-)-nicotine administered both i.p. and into the mid-fourth ventricle of intact rats were investigated using a conventional high intensity tail-flick reflex and one evoked with a lower intensity thermal stimulus. The sensitivity of the low intensity thermally evoked tail avoidance reflex was several times that of a high intensity tail-flick reflex in detecting the analgesic activity of morphine and yielded valid assays and relative potencies between morphine (1), EKC (18.76) and U-50,488 (0.23) when the drugs were administered ip. When the opioid drugs were administered into the fourth ventricle they produced a dose-related shortening of the latency of the low intensity thermally evoked tail avoidance reflex. (-)-Nicotine, when administered into the mid-fourth ventricle, produced analgesia in low doses and hyperalgesia in high doses. Naltrexone and mecamylamine, when administered into the fourth ventricle, produced a dose-related analgesia. Doses of naltrexone and mecamylamine which antagonize maximally hyperalgesic doses of (-)-nicotine and ethylketazocine did not produce analgesia; however, larger doses produced analgesia. These observations suggest that analgesic doses do not involve prototypic kappa opioidergic or nicotinic mechanisms. These data confirm the existence of a medullary hyperalgesic center which may have both mu and kappa opioidergic as well as nicotinic mechanisms. Furthermore, these data indicate that this medullary hyperalgesic mechanism may have spontaneous or evoked tone and provide an explanation for the analgesic action of naltrexone and mecamylamine.

Analgesic actions of local anesthetics and cobalt chloride in the rat brain stem.

A low-intensity thermally evoked tail avoidance reflex (LITETAR) was used to study changes in nociceptive response produced by local anesthetics and cobalt chloride microinjected into the dorsal posterior mesencephalic tegmentum (DPMT) of conscious rats. Dose-related prolongation of the LITETAR (e.g., analgesia) was observed when lidocaine, cocaine, and bupivacaine were administered into the DPMT. Analgesic actions were also demonstrated when cobalt chloride was microinjected into the DPMT. The analgesic actions of these different neuronal suppressants provide support for the hypothesis that there exists tonic activity of hyperalgesic processes in the rat brain stem.

Analgesic actions of dynorphin A(1-13) antiserum in the rat brain stem.

This study was performed to evaluate the effects of dynorphin A(1-3) antiserum when microinjected into an active hyperalgesic region within the rat brain stem. When administered within the dorsal posterior mesencephalic tegmentum (DPMT) of intact conscious rats, dynorphin A(1-13) antiserum produced rapid onset and persistent prolongation of a low intensity thermally evoked tail avoidance response (LITETAR). These analgesic actions of the dynorphin A(1-13) antiserum appeared to be dose dependent. These studies support previous hypotheses about the existence of tonically active brain stem opioid hyperalgesic process. Further, the results provide indirect evidence for a potential role of brain stem dynorphin(s) in facilitating pain.

Thermally evoked tail avoidance reflex: input-output relationships and their modulation.

Latency to onset and magnitude (angular displacement) of thermally evoked tail avoidance reflexes (TETAR) to graded thermal stimuli were measured in pentobarbital-treated and untreated rats. The latency to onset was inversely and the magnitude was directly proportional to the thermal stimulus intensity. Pentobarbital prolonged the latency to onset of the TETAR to low by not high stimulus intensities. Activation of (-)-nicotine sensitive brainstem hyperalgesic processes shortened the latency and increased the magnitude of the TETAR. The hyperalgesic actions of (-)-nicotine were most demonstrable at lower thermal stimulus intensities. These studies suggest that the TETAR is graded in intensity as the stimulus intensity is increased and that the response evoked by different intensities of stimulus probably involve common neurophysiologic mechanisms.

Opioid and nicotinic analgesic and hyperalgesic loci in the rat brain stem.

The effects of (-)-nicotine and ethylketazocine (EKC) on the latency of a low-intensity thermally evoked tail avoidance response were evaluated at different midline mesencephalic, pontomedullary and medullary sites of conscious intact rats. Guide cannulae were implanted surgically at six anterior-posterior stereotaxic locations (AP, -4.4 to +2.8) and drugs were microinjected (0.5 microliter) at different depths in each region. The analgesic effects of naltrexone and mecamylamine were evaluated at those sites exhibiting sensitivity to the hyperalgesic actions of (-)-nicotine and EKC. Additional experiments evaluated the validity and reproducibility of the low-intensity thermally evoked tail avoidance response and a low intensity hot plate response in detecting hyperalgesia. The chemostimulation studies suggest that there are opioid and nicotinic hyperalgesic processes distributed throughout the dorsal regions of the posterior mesencephalic and pontomedullary brain stem. The relative hyperalgesic potency of (-)-nicotine appears to exhibit a gradient from the dorsal posterior mesencephalic tegmentum to the midmedullary region, whereas only analgesia was produced more rostrally, in the central gray, or caudally within the posterior medulla. Within regions intermediate between the dorsal posterior, mesencephalic tegmentum and posterior medulla, (-)-nicotine produced biphasic dose-response and time action curves. The effects of EKC were similar to those of (-)-nicotine at most sites although (-)-nicotine was 55 times more potent than EKC when administered in the most active hyperalgesic regions.2+ may differ from region to region.

Conscious state comparisons of the effects of the inhalation anesthetics and diltiazem, nifedipine, or verapamil on specialized atrioventricular conduction times in spontaneously beating dog hearts.

The effects of enflurane (ENF), halothane (HAL), and isoflurane (ISO) on specialized atrioventricular (AV) conduction times were contrasted to awake (control) in 22 chronically instrumented dogs. Dogs were studied with and without diltiazem (DIL), nifedipine (NIF), vehicle for NIF (VEH), or verapamil (VER). These calcium channel blockers (CCB) were administered iv to achieve clinically effective steady-state plasma levels in awake dogs. CCB plasma levels in awake dogs, subsequently anesthetized with ENF (N = 10), HAL (N = 10), or ISO (N = 11), were: DIL = 94 +/- 13 to 124 +/- 9 ng/ml, NIF = 4 +/- 1 to 7 +/- 2 ng/ml, VER 108 +/- 23 to 147 +/- 9 ng/ml. Anesthetized dogs had approximate two-fold increases in plasma levels of DIL or VER. There was no anesthetic effect on plasma levels for NIF. In the absence of CCBs, HAL increased AV nodal conduction time (AVN) compared to awake. There was a 4-10% increase in His-Purkinje (HP) and ventricular (VENT) conduction time with each anesthetic. The CCBs did not alter HP or VENT in awake dogs, but AVN was increased 15-23% by DIL and 28-38% by VER. Three of ten dogs with VER developed complete heart block or AV junctional escape rhythm at each level of ENF. One dog with VER developed type I, 2 degrees (Wenckebach) AV block at each level of HAL and ISO. No dogs with DIL had heart block or escape rhythms during anesthesia. In anesthetized dogs without heart block or escape rhythms, the increase in AVN with VER ranged from 46 to 69%, and with DIL from 36 to 55%. The CCB had no added effects on HP or VENT with any anesthetic. Finally, there were no effects of NIF alone or with the anesthetics on specialized conduction that could not be attributed to VEH. The authors conclude that with the inhalation anesthetics, antiarrhythmic plasma levels of DIL or VER prolong AV nodal most compared to infranodal conduction time. Additionally, heart block or escape rhythms appear more likely with VER and any of the potent inhalation anesthetics.

Nifedipine-propranolol interaction: dependence of cardiovascular effects on plasma drug concentrations.

The relationships between plasma drug concentrations and cardiovascular effects during combined administration of nifedipine and propranolol were evaluated in dogs anesthetized with thiopental. Three received small intravenous (i.v.) doses of nifedipine followed by propranolol, and 6 were given higher doses of nifedipine followed by propranolol; in 5, the order of drug doses was reversed, with propranolol administration followed by nifedipine. When dosing regimens that produced stable plasma levels of both drugs were used, the observed effects were closely related to the plasma concentrations of the individual agents. When small doses of nifedipine were combined with propranolol, at plasma levels associated with a significant degree of beta-adrenoceptor blockade, moderate decreases in spontaneous heart rate and cardiac output as well as increases in atrioventricular conduction time were produced. With higher doses of nifedipine, combined infusion with propranolol resulted in more pronounced depression in cardiac function, characterized by decreases in cardiac output, heart rate, and mean pulmonary arterial pressure, as well as increases in atrioventricular conduction time. When propranolol administration was followed by nifedipine, similar dose-dependent cardiovascular effects resulted, with profound toxicity apparent when large doses of nifedipine were used. These studies in an acute anesthetized dog model suggest that the magnitude of cardiovascular depression resulting from nifedipine and propranolol in combination is dependent on the plasma concentrations of both agents. Furthermore, in the presence of beta-adrenoceptor blockade, the direct effects of nifedipine on myocardial conducting tissue, which are usually absent when this calcium antagonist is given alone, may become apparent and result in depression of atrioventricular and sinoatrial nodal functions.

Hemodynamic and pharmacokinetic aspects of the interactions between verapamil and pindolol.

Combined administration of verapamil, a phenylalkylamine calcium-entry antagonist, with a pure beta-adrenoceptor blocker, propranolol, produces profound cardiovascular depression associated with decreased hepatic clearance of both drugs. We have therefore studied the combination of verapamil and pindolol, a beta-adrenoceptor blocker with intrinsic sympathomimetic activity (ISA), to evaluate whether or not the property of ISA will confer protection from the usual toxic effects observed with verapamil and a beta-adrenoceptor blocking agent. In an anesthetized dog model, dosing regimens which produced stable plasma concentrations of either verapamil and/or pindolol resulted in drug effects which were closely related to the plasma levels of the individual agents. When pindolol was combined with verapamil, profound depression of cardiac pump function occurred, similar to that previously found with propranolol. Further, plasma concentrations of verapamil promptly increased into a toxic range during combined administration with pindolol. In summary, since the cardiovascular depression resulting from verapamil and pindolol in combination is similar to that which occurs with verapamil and propranolol, ISA does not appear to obviate the toxic effects of verapamil and a beta-adrenoceptor agent in combination.

Kinetics and dynamics of calcium entry antagonists in systemic hypertension.

The calcium-entry antagonists verapamil, diltiazem and nifedipine (and their analogs) are all eliminated by hepatic metabolism and the rate of disposition is dependent on the rate of liver blood flow. During long-term administration, the profound hemodynamic effects of these agents result in changes in hepatic blood flow in association with decreases in arterial pressure, and either increases or decreases in measured cardiac output. This alters the drug's rate of delivery to the site of elimination, with concomitant changes in systemic clearance and a prolongation in elimination half-life. The pharmacokinetic data determined after initial single doses, therefore, only suggest the kinetic characteristics during long-term administration, because this profile depends on the drugs' sustained effects on liver blood flow. The elimination half-life of all 3 prototypical calcium antagonists is probably significantly prolonged during long-term dosing with clinically effective regimens. Patients with hepatic disorders in which liver blood flow is altered, such as cirrhosis, have profound changes in pharmacokinetics with both short- and long-term administration of verapamil and are likely to have similar changes with other calcium antagonists. During short-term administration, the plasma concentrations of verapamil and other calcium antagonists relate closely to the observed hemodynamic (and electrophysiologic) effects. With long-term administration, however, these correlations are much less impressive. When given in tablet form, nifedipine lowers blood pressure roughly in proportion to plasma levels between 20 and 200 ng/ml; verapamil plasma levels between 80 and 800 ng/ml are associated with antihypertensive efficacy. Plasma level measurements, therefore, are not of clinical importance as guides to antihypertensive therapy, except to identify noncompliance or abnormal patterns of drug handling.

Aspects of the clinical pharmacology of nifedipine, a dihydropyridine calcium-entry antagonist.

Although nifedipine has been characterized in terms of its general vasodilatory effects, this dihydropyridine must still be regarded as investigational with regard to available pharmacokinetic and pharmacodynamic data. Although limited studies are available, it is clear that the pharmacokinetic and pharmacodynamic data reported are quite variable among subjects. Further, it appears that single dose elimination kinetics may be of little predictive value with regard to the kinetic characteristics present during chronic drug administration. It is also possible that the plasma level-effect correlations for the drug may differ with single and sustained dosing regimens. At the present time the lack of definitive data to define the relationships between plasma levels of nifedipine and associated drug effects suggests that measurement of drug levels in plasma serves primarily as a research tool and to identify patient noncompliance or abnormal absorption of the drug. Finally, since the prototype of this class, nifedipine, has been shown to have the potential for non-linear kinetics during chronic dosing, dihydropyridine analogs should be subject to extensive pharmacokinetic and pharmacologic evaluation during both single and chronic dosing studies, prior to widespread clinical use.

Cardiovascular and pharmacokinetic consequences of combined administration of verapamil and propranolol in dogs.

Verapamil and propranolol, alone and in combination, were given intravenously to anesthetized dogs to analyze the interaction between drug-induced cardiovascular effects and the resulting changes in pharmacokinetics. Dosing regimens were used that produced steady state plasma levels of both drugs, and the observed effects were clearly related to the plasma concentrations of the agents. When given alone, at stable "therapeutic" levels in plasma, verapamil or propranolol decreased spontaneous heart rate, increased atrioventricular conduction time, and had opposite effects on cardiac output. At the same doses, the combined infusion of the 2 drugs rapidly resulted in profound depression in cardiac function; in addition, plasma concentrations of both agents increased into ranges associated with cardiovascular toxicity. When verapamil doses were reduced, combined infusion with propranolol decreased atrioventricular conduction and cardiac output, but drug plasma concentrations (and associated effects) remained stable. When reduced doses of propranolol were added to infusion of verapamil, similar effects on cardiovascular function occurred, but plasma drug levels increased progressively throughout the remainder of the study period. In all combinations studied, beta blockade with propranolol decreased liver plasma flow and, therefore, the systemic clearance of verapamil. The in vitro effects of propranolol on verapamil metabolism were small, although significant, and not clinically relevant. These acute studies suggest that the hemodynamic effects resulting from verapamil and propranolol in combination may significantly diminish clearance of 1 or both drugs, thereby resulting in accumulation during continued administration, increased drug effects with increasing plasma concentrations, and potentially lethal drug toxicity.

Pharmacodynamic comparison of verapamil and nifedipine in anesthetized dogs.

The relationships between steady-state plasma concentrations of verapamil or nifedipine and the resultant hemodynamic and electrophysiologic effects were evaluated in anesthetized, instrumented dogs. In different groups of animals, the drugs were given intravenously by loading-maintenance infusions designed to rapidly achieve and sustain stable plasma drug concentrations, over four different target ranges which span those found in clinical use of these agents. Plasma levels of nifedipine varied from 5 to 125 ng/ml, and those of verapamil, from 40 to 500 ng/ml. Nifedipine produced no apparent effects on the surface electrocardiogram. Verapamil dosing resulted in progressive prolongation of the PR interval as plasma drug levels increased from 40 to 250 ng/ml; at higher drug levels, complete atrioventricular block occurred. At the highest plasma concentrations used, the maximal vasodilation produced by both drugs was approximately equal, with mean aortic pressure levels falling to 50-60% of control values. The effects of the two agents on cardiac pump performance, however, differed: nifedipine administration produced dose-related increases in cardiac output at all plasma drug concentrations studied; the effects of verapamil were critically dependent upon drug levels in plasma, with cardiac output increased above control values at drug concentrations between 40 and 250 ng/ml, and progressively depressed at higher plasma levels of the drug. As a result, the calculated systemic vascular resistance declined progressively during nifedipine administration, while after verapamil doses, this parameter varied inversely with observed effects on cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of phenobarbital and SKF-525A on in vitro hepatic metabolism of verapamil and nifedipine.

Both verapamil and nifedipine are first-generation calcium-entry antagonist drugs which are eliminated by hepatic metabolism. To evaluate the effects of enzyme induction and suppression on the biotransformation of these compounds, liver homogenate fractions were prepared from male Fisher (F344) rats, which were either untreated, or injected intraperitoneally with phenobarbital or with SKF-525A prior to sacrifice. Known concentrations of verapamil or nifedipine were incubated with the 9,000 g supernatant, and the quantity of unchanged drug remaining after 10 min was measured. SKF-525A pretreatment significantly decreased the elimination (disappearance) rate of both calcium-entry antagonist compounds. Phenobarbital increased the rate of disappearance of verapamil, but had no effect on that of nifedipine. Difference spectra of hepatic microsomes to which verapamil had been added revealed a concentration-dependent, saturable interaction between drug and enzymes with spectral changes characteristic of "type I' substrates for cytochrome P-450 monooxygenase(s). The spectral characteristic of microsomes to which nifedipine was added could not be determined because of drug absorption at 350-500 nm. These data imply that verapamil metabolism is mediated by the cytochrome P-450 monooxygenase(s), and that nifedipine metabolism likely involves hepatic enzyme systems other than those known to be induced by phenobarbital.

Pharmacokinetics of calcium-entry blockers.

Effective use of drugs in therapy depends not only on clinical acumen but also on the availability of relevant pharmacokinetic and pharmacodynamic data. Such information assists in development of safe dosing regimens, prediction of abnormal handling of drugs in states of disease and disorder and anticipation of drug interactions. For the calcium-entry blocking agents now available in the United States (verapamil, nifedipine and diltiazem), these data appeared well after clinical patterns of use evolved. Nonetheless, their relevance continues to be demonstrated by the dependence of each agent on intact liver blood flow and function for normal rates of elimination; by the nonlinear kinetic characteristics for verapamil and diltiazem (and probably for nifedipine, as well) and the derivative implications for decreased dosing frequency requirements; and by observations now appearing on the relation between plasma drug levels and drug effects, both therapeutic and toxic. Such data are discussed herein, with emphasis on those aspects that impact on the clinical use of the calcium-entry antagonists.