Biomedical subjects

R J Tallarida

Publications and source records attributed to R J Tallarida.

At least 19 recordsLinked to original sources

PubMed2004

GABAA receptors modulate cannabinoid-evoked hypothermia.

Cannabinoids evoke hypothermia by stimulating central CB(1) receptors. GABA induces hypothermia via GABA(A) or GABA(B) receptor activation. CB(1) receptor activation increases GABA release in the hypothalamus, a central locus for thermoregulation, suggesting that cannabinoid and GABA systems may be functionally linked in body temperature regulation. We investigated whether GABA receptors modulate the hypothermic actions of [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one] (WIN 55212-2), a selective cannabinoid agonist, in male Sprague-Dawley rats. WIN 55212-2 (2.5 mg/kg im) produced a rapid hypothermia that peaked 45-90 min postinjection. The hypothermia was attenuated by bicuculline (2 mg/kg ip), a GABA(A) antagonist. However, SCH 50911 (1-10 mg/kg ip), a GABA(B) blocker, did not antagonize the hypothermia. Neither bicuculline (2 mg/kg) nor SCH 50911 (10 mg/kg) by itself altered body temperature. We also investigated a possible role for CB(1) receptors in GABA-generated hypothermia. Muscimol (2.5 mg/kg ip), a GABA(A) agonist, or baclofen (5 mg/kg ip), a GABA(B) agonist, evoked a significant hypothermia. Blockade of CB(1) receptors with SR141716A (2.5 mg/kg im) did not antagonize muscimol- or baclofen-induced hypothermia, indicating that GABA-evoked hypothermia does not contain a CB(1)-sensitive component. Our results implicate GABA(A) receptors in the hypothermic actions of cannabinoids and provide further evidence of a functional link between cannabinoid and GABA systems.

Animals↗

PubMed2003

L-NAME (N omega-nitro-L-arginine methyl ester), a nitric-oxide synthase inhibitor, and WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], a cannabinoid agonist, interact to evoke synergistic hypothermia.

Cannabinoids evoke profound hypothermia in rats by activating central CB(1) receptors. Nitric oxide (NO), a prominent second messenger in central and peripheral neurons, also plays a crucial role in thermoregulation, with previous studies suggesting pyretic and antipyretic functions. Dense nitric-oxide synthase (NOS) staining and CB(1) receptor immunoreactivity have been detected in regions of the hypothalamus that regulate body temperature, suggesting that intimate NO-cannabinoid associations may exist in the central nervous system. The present study investigated the effect of N(omega)-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, on the hypothermic response to WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenylcarbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], a selective cannabinoid agonist, in rats. WIN 55212-2 (1-5 mg/kg, i.m.) produced dose-dependent hypothermia that peaked 45 to 90 min post-injection. L-NAME (10-100 mg/kg, i.m.) by itself did not significantly alter body temperature. However, a nonhypothermic dose of L-NAME (50 mg/kg) potentiated the hypothermia caused by WIN 55212-2 (0.5-5 mg/kg). The augmentation was strongly synergistic, indicated by a 2.5-fold increase in the relative potency of WIN 55212-2. The inactive enantiomer of WIN 55212-2, WIN 55212-3 [S-(-)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-napthanlenyl) methanone mesylate] (5 mg/kg, i.m.), did not produce hypothermia in the absence or presence of L-NAME (50 mg/kg), confirming that cannabinoid receptors mediated the synergy. The present data are the first evidence that drug combinations of NOS blockers and cannabinoid agonists produce synergistic hypothermia. Thus, NO and cannabinoid systems may interact to induce superadditive hypothermia.

Animals↗

PubMed2002

N-methyl-D-aspartate antagonists and WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-i,j]quinolin-6-one], a cannabinoid agonist, interact to produce synergistic hypothermia.

CB(1) cannabinoid receptors mediate profound hypothermia when cannabinoid agonists are administered to rats. Glutamate, the principal excitatory neurotransmitter in the central nervous system (CNS), is thought to tonically increase body temperature by activating N-methyl-D-aspartate (NMDA) receptors. Because NMDA antagonists block cannabinoid-induced antinociception and catalepsy, intimate glutamatergic-cannabinoid interactions may exist in the CNS. The present study investigated the effect of two NMDA antagonists on the hypothermic response to WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-i,j]quinolin-6-one], a selective cannabinoid agonist, in rats. WIN 55212-2 (1-10 mg/kg i.m.) produced dose-dependent hypothermia that peaked 60 to 180 min postinjection. Dextromethorphan (5-75 mg/kg i.m.), a noncompetitive NMDA antagonist, or LY 235959 [(-)-6-[phosphonomethyl-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-2-carboxylate]](1-4 mg/kg i.m.), a competitive and highly selective NMDA antagonist, evoked hypothermia in a dose-sensitive manner, suggesting that endogenous glutamate exerts a hyperthermic tone on body temperature. A dose of dextromethorphan (10 mg/kg) that did not affect body temperature by itself potentiated the hypothermic response to WIN 55212-2 (1, 2.5, or 5 mg/kg). The enhancement was strongly synergistic, indicated by a 2.7-fold increase in the relative potency of WIN 55212-2. Similarly, a dose of LY 235959 (1 mg/kg) that did not affect body temperature augmented the hypothermia associated with a single dose of WIN 55212-2 (2.5 mg/kg), thus confirming that NMDA receptors mediated the synergy. We have demonstrated previously that CB(1) receptors mediate WIN 55212-2-evoked hypothermia in rats. The present data are the first evidence that NMDA antagonists exert a potentiating effect on cannabinoid-induced hypothermia. Taken together, these data suggest that interactions between NMDA and CB(1) receptors produce synergistic hypothermia.

Animals↗

PubMed2001

Possible mechanism of hypothermia induced by intracerebroventricular injection of orphanin FQ/nociceptin.

Orphanin/nociceptin (OFQ/N), a 17-amino-acid peptide, is an endogenous peptide, the receptor for which is similar to mu-, delta- and kappa-opioid receptors ( approximately 65% homology). Reports indicate that OFQ/N can block the antinociception induced by mu-, delta- and kappa-opioid agonists in the rat and in the mouse, indicating that there is a functional interaction between opioid receptors and OFQ/N receptors in the nervous system. It is well known that activation of the mu- and kappa-opioid receptors results in hyperthermia and hypothermia, respectively, in Sprague-Dawley rats. The present studies were designed to examine effects of OFQ/N on body temperature (Tb) and explore whether the mechanism of T(b) change induced by OFQ/N involved the opioid system. The results show that (1) i.c.v. injection of a high dose of OFQ/N (9-18 micro g) produces hypothermia in adult rats; (2) OFQ/N (1.8 micro g, i.c.v., t=+30 s after morphine) can decrease morphine-induced hyperthermia; (3) neither the opioid receptor antagonist, naloxone (10 mg/kg, s.c., t=-15 s before OFQ/N) nor the kappa-opioid receptor antagonist nor-BNI (1 micro g/5 microl, i.c.v., t=-30 s before OFQ/N) reduces the hypothermia induced by i.c.v. injection of OFQ/N at dose of 18 micro g (P>0.05); (4) 60 micro g/5 microl AS oligo (i.c.v. treatment on days 1, 3 and 5) against OFQ/N receptors significantly reduces the hypothermia induced by i.c.v. injection of 9 micro g OFQ/N (P<0.01). These results suggest that the hypothermia induced by i.c.v. injection of a high dose of OFQ/N (9 or 18 micro g) is mediated, at least partially, by its own receptor, independent or downstream of opioid receptors in the rat brain and that OFQ/N probably acts as a physiological antagonist to reduce morphine-induced hyperthermia.

Animals↗

PubMed2001

Unexpected and pronounced antinociceptive synergy between spinal acetaminophen (paracetamol) and phentolamine.

Acetaminophen was administered to mice by spinal (intrathecal, i.t.) injection alone or with phentolamine (11.3 microg = 0.03 micromol). Acetaminophen produced dose-related antinociception in the abdominal irritant test with an ED(50) value of 137.2 microg (0.9 micromol) Phentolamine had no effect. For combined administration, the potency of acetaminophen was significantly increased (ED50=24.4 vs. 137.2 microg), indicative of multiplicative interaction and strong synergism. These results reveal the significant and surprising interaction of spinal cord adrenoceptors or ion channel subtypes with acetaminophen-induced antinociception.

Acetaminophen↗

PubMed2001

Drug synergism: its detection and applications.

Two drugs that produce overtly similar effects will sometimes produce exaggerated or diminished effects when used concurrently. A quantitative assessment is necessary to distinguish these cases from simply additive action. This distinction is based on the classic pharmacologic definition of additivity that, briefly stated, means that each constituent contributes to the effect in accord with its own potency. Accordingly, the relative potency of the agents, not necessarily constant at all effect levels, allows a calculation using dose pairs to determine the equivalent of either agent and the effect by using the equivalent in the dose-response relation of the reference compound. The calculation is aided by a popular graph (isobologram) that provides a visual assessment of the interaction but also requires independent statistical analysis. The latter can be accomplished from calculations that use the total dose in a fixed-ratio combination along with the calculated additive total dose for the same effect. Different methods may be used, and each is applicable to experiments in which a single drug is given at two different sites. When departures from additivity are found, whether in "two-drug" or "two-site" experiments, the information is useful in designing new experiments for illuminating mechanisms. Several examples, mainly from analgesic drug studies, illustrate this application. Even when a single drug (or site) is used, its introduction places it in potential contact with a myriad of chemicals already in the system, a fact that underscores the importance of this topic in other areas of biological investigation.

Animals↗

PubMed2000

Discovery of "self-synergistic" spinal/supraspinal antinociception produced by acetaminophen (paracetamol).

The mechanism of the analgesic action of one of the world's most widely used drugs-acetaminophen (paracetamol)-remains largely unknown more than 100 years after its original synthesis. Based on the present findings, this elusiveness appears to have resulted from experimental strategies that concentrated on a single target site or mechanism. Here we report on the use of analyses that we previously developed to investigate possible brain/spinal-cord site-site interaction in acetaminophen-induced antinociception. Spinal (intrathecal) administration of acetaminophen to mice produced dose-related, naloxone-insensitive antinociception with an ED(50) value of 137 (S.E. = 23) microgram = 907 (S.E. =153) nmol. In contrast, supraspinal (i.c.v.) acetaminophen administration had no effect. However, combined administration of acetaminophen in fixed ratios to brain and spinal cord produced synergistic antinociception, ED(50) = 57 (S.E. = 9) microgram, that reverted toward additivity, ED(50) = 129 (S.E. = 23) microgram, when the opioid antagonist naloxone was given spinally (3.6 microgram = 10 nmol) or s.c. (3.6 mg/kg). These findings demonstrate for the first time that acetaminophen-induced antinociception involves a "self-synergistic" interaction between spinal and supraspinal sites and, furthermore, that the self-synergy involves an endogenous opioid pathway.

Acetaminophen↗

PubMed1999

Loss of antiallodynic and antinociceptive spinal/supraspinal morphine synergy in nerve-injured rats: restoration by MK-801 or dynorphin antiserum.

The co-administration of morphine at spinal (i.th.) and supraspinal (i.c.v.) sites to the same rat produces antinociceptive synergy, a phenomenon which may underlie the clinical analgesic utility of this drug. In animals with peripheral nerve injury, however, the antinociceptive potency and efficacy of i.th. morphine is significantly decreased. Here, the possible loss of spinal/supraspinal morphine antinociceptive synergy and relationship to elevation of spinal dynorphin content was studied. Ligation of lumbar spinal nerves resulted in elevated dynorphin in the ipsilateral lumbar and sacral spinal cord. In sham-operated rats supraspinal/spinal co-administration of morphine produced synergistic antinociception which was unaffected by i.th. MK-801 or dynorphin A((1-17)) antiserum. In nerve-injured rats, i.th. morphine was inactive against tactile allodynia and showed diminished in potency against acute nociception without supraspinal/spinal antinociceptive synergy. Antiserum to dynorphin A((1-17)) or the non-competitive NMDA antagonist MK-801 increased the antinociceptive potency of i.th. morphine, restored supraspinal/spinal morphine antinociceptive synergy and elicited a dose-related i.th. morphine antiallodynic action. These agents did not demonstrate antinociceptive or antiallodynic activity alone and did not alter morphine actions in sham-operated animals. The loss of spinal/supraspinal antinociceptive synergy and lack of antiallodynic activity of spinal morphine appear to be due to the elevation across multiple spinal segments of dynorphin following nerve injury. Pathological actions of elevated dynorphin may directly or indirectly modulate the NMDA receptor, result in a loss of supraspinal/spinal morphine synergy and may thus account for the decreased clinical analgesic efficacy of morphine in peripheral neuropathies.

Analgesics, Opioid↗

PubMed1999

Response surface analysis of synergism between morphine and clonidine.

Graded doses of morphine sulfate and clonidine hydrochloride were administered intrathecally to mice that were then tested for antinociception in the 55 degrees C tail immersion test. The dose-effect relations of each compound were used in calculations that permitted the construction of a three-dimensional plot of the expected additive effect (vertical scale) against the planar domain of dose pairs representing combinations administered simultaneously. This additive response surface became the reference surface for viewing the actual effects produced by three different fixed-ratio combinations of the drugs that were used in our tests. Each combination produced effects significantly greater than indicated by the additive surface, thereby illustrating marked synergism and a method for quantifying the synergism. This quantification, measured by the value of the interaction index (alpha), was found to be dependent on the fixed-ratio combination; accordingly, the actual response surface could not be described by a single value of the index alpha. Furthermore, we found that application of the common method of isoboles gave estimates of the index that agreed well with those obtained from the more extensive surface analysis. These results confirm earlier studies, which found synergism for these drugs while also providing surface views of additivity and synergism that form the basis of isobolographic analysis.

Algorithms↗

PubMed1999

Interaction between medullary and spinal delta1 and delta2 opioid receptors in the production of antinociception in the rat.

Previous work supports the existence of two types of delta opioid receptor (delta1 and delta2) and a role of both subtypes in the spinal cord and the ventromedial medulla (VMM) in the production of antinociception. Although it is well established that spinal and supraspinal mu opioid receptors interact in a synergistic manner to produce antinociception, little is known about the interaction of delta opioid receptors. This study used isobolographic analysis to determine how delta1 and delta2 opioid receptors in the VMM interact with their respective receptors in the spinal cord to produce antinociception. Concurrent administration of the delta1 opioid receptor agonist [D-Pen2,D-Pen5]enkephalin at spinal and supraspinal sites in a fixed-dose ratio produced antinociception in an additive manner in the tail-flick test. In contrast, concurrent administration of very low doses of the delta2 opioid receptor agonist [D-Ala2,Glu4]deltorphin at spinal and medullary sites produced antinociception in a synergistic manner. However, as the total dose of [D-Ala2,Glu4]deltorphin increased, this interaction converted to additivity. These observations suggest that different mechanisms mediate the antinociceptive effects of different doses of delta2 opioid receptor agonists. The difference in the nature of the interaction produced by delta1 and delta2 opioid receptor agonists provides additional evidence for the existence of different subtypes of the delta opioid receptor. These results also suggest that delta2 opioid receptor agonists capable of crossing the blood-brain barrier will be more potent or efficacious analgesics than delta1 opioid receptor agonists after systemic administration.

Analgesics, Opioid↗

PubMed1997

Synergism between buprenorphine and cocaine on the rotational behavior of the nigrally-lesioned rat.

Buprenorphine, a partial mu-opioid receptor agonist, has been proposed as a treatment for cocaine abuse. However, studies in animals have produced conflicting results on the nature of the interaction between buprenorphine and cocaine. In some studies, buprenorphine attenuated the effects of cocaine and in others it enhanced them. The purpose of the present study was to evaluate the interaction of buprenorphine and cocaine on the rotational behavior of the nigrally-lesioned rat. Both buprenorphine (0.003-0.1 mg/kg) and cocaine (1.0-30 mg/kg) alone produced dose-dependent increases in rotational behavior. Buprenorphine produced long-lasting turning with a peak at 60 min after administration, while cocaine produced turning that peaked immediately after administration and lasted for about 2 h. To distinguish simple additivity from other possible outcomes, we determined the relative potency of each drug alone, using a defined level of effect: 150 turns above the saline control in 4 h. This effect was produced by 10.0 mg/kg cocaine alone and by 0.0175 mg/kg buprenorphine alone. Based on these results, fixed ratio combinations were tested and the experimentally derived effects were compared to the theoretically additive values, using an isobolographic analysis. The fixed ratio combinations of the two drugs tested produced turning greater than predicted from simple additivity. This finding provides statistically-supported evidence for synergism between the actions of buprenorphine and cocaine.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1997

Theory and statistics of detecting synergism between two active drugs: cocaine and buprenorphine.

This article discusses the theory and statistical aspects in the design and analysis of experiments to detect synergism between two drugs that produce overtly similar effects. The current analysis extended and simplifies previously published work in this area. Application is made to a study by Kimmel et al. in this issue that examined the combined action of buprenorphine and cocaine in producing turning in rats having unilateral nigrostriatal lesions produced by 6-hydroxydopamine. The use of turning as an endpoint is unusual in quantitative studies of synergism in that no clear maximum effect (turning), could be elicited. Data from the turning study are analyzed statistically and reveal that the combination of buprenorphine and cocaine in each of two fixed ratio mixtures tested is synergistic for this effect.

Animals↗

PubMed1997

Efficient designs for studying synergistic drug combinations.

Distinguishing between pharmacologically additive and synergistic drug combinations requires experimental designs and statistical analyses that often require appreciable numbers of animals and much experimenter time. The current study employed a design in which individual dose-effect data from each drug were translated into theoretically additive total dose combinations, in a fixed drug proportion, in order to produce a composite additive dose-effect relation that could be compared with that of an actual mixture having the same proportion. Results from this approach, using a combination of intrathecal doses of morphine and clonidine, were virtually identical to those using isobolographic analysis of the same data set. Both analyses showed significant synergism for this combination and, in each method, it was not necessary to constrain the drug regression lines to parallelism. In contrast to the isobole approach, the use of the composite additive dose-effect relation also allows observation of the interaction over a range of effects while reducing the size of the data sets needed.

Analgesia↗

PubMed1997

Antivasoconstrictor and antiaggregatory activities of picotamide unrelated to thromboxane A2 antagonism.

Picotamide is a dual thromboxane (Tx) A2 receptor antagonist/Tx synthase inhibitor although some observations suggest an anti-vasoconstrictor effect independent of TxA2 inhibition/antagonism. The aim of our study was to assess whether picotamide antagonises vascular contractions induced by different vasoactive substances in vitro. Picotamide inhibited competitively the contraction of rabbit aortic rings induced by the TxA2 mimetic U46619 (pA2 = 3.59) but also the contractions induced by phenylephrine (pA2 = 3.93) and serotonin (5-HT) (pA2 = 5.81) although in a not competitive way. Picotamide did not inhibit potassium-induced contractions, thus excluding aspecific effects on vascular smooth muscle. Picotamide inhibited 5-HT-induced platelet aggregation in vitro with an IC50 (212 microM) similar to that found when other aggregating stimuli are used, but it did not affect shape change (IC50 > 1 mM) suggesting that the effects of picotamide can not be ascribed to 5-HT2-receptor antagonism; in the same experimental conditions neither a Tx-receptor antagonist (BM13.177) nor a dual Tx-receptor antagonist/synthase inhibitor (ridogrel) affected 5-HT-induced platelet responses. Our studies demonstrate that picotamide exerts antivasoconstrictor and platelet inhibitory effects unrelated to TxA2 antagonism. This activity may contribute to the anti-thrombotic/anti-ischaemic effects of the drug in vivo.

Animals↗

PubMed1996

Use of a mu-antisense oligodeoxynucleotide as a mu opioid receptor noncompetitive antagonist in vivo.

We examined whether mu-antisense (AS) oligodeoxynucleotide (oligo) treatment can be used in a manner similar to the mu-selective irreversible antagonist beta-funaltrexamine (beta-FNA) for in vivo pharmacology. Rats were injected intracerebroventricularly (icv) with a mu-AS or a missense (MS) oligo on days 1, 3, 5, 7, and 9 and were tested for the antinociceptive effect of sc injection of morphine on days 2, 4, 6, 8, and 10 in the cold water tail-flick (CWT) test. In another set of experiments, rats were also tested for the antinociceptive action of morphine twenty-four hours after icv injection of beta-FNA. Both beta-FNA and mu-AS produced rightward shifts in the dose-effect curves of morphine. In addition, pretreatment with 2.5 micrograms or more of beta-FNA or the mu-AS oligo for 5-9 days (but not for 1-3 days) reduced the maximal analgesic effect of morphine. The approximate fraction of functional receptor remaining for morphine was determined with the method of Furchgott to be 49.5% following 2.5 micrograms of beta-FNA; that after 5 days of the mu-AS oligo treatment was 50.8%. The results suggest that the mu-AS oligo can be used in the same manner as highly selective, irreversible mu opioid receptor ligands. Thus, properly designed AS oligos against receptors are of particular benefit when irreversible antagonists are not available. AS oligos represent a new class of selective and powerful pharmacological antagonists.

Animals↗

PubMed1996

Testing for synergism over a range of fixed ratio drug combinations: replacing the isobologram.

An isobologram is a Cartesian plot of pairs of doses that, in combination, yield a specified level of effect. It is a convenient and presently popular way of graphically displaying results of drug-combination and similar studies, because paired values of experimental points that fall below or above the line connecting the axial points (usually ED50 values) denote supra- and sub-additive combinations, respectively. However, an isobologram does not fulfill the criteria for standard least squares regression analysis. It is thus less useful for addressing questions related to the range of combination ratios over which synergy occurs. We describe herein a substitute for the isobologram in which log(total-dose) is plotted against the proportion of a component in a combination. One advantage is that a nonlinear curve-fitting procedure and determination of the confidence interval of a single parameter allow the determination of departure from additivity over a range of fixed proportion mixtures. An example is given of the combination of two analgesics (acetaminophen and tramadol hydrochloride). Another advantage of the new method is the reduction of animal use.

Acetaminophen↗

PubMed1996

Transient loss of dopamine autoreceptor control in the presence of highly potent dopamine agonists.

The concentrations of endogenous ligands generally remain in a bounded range around a basal level, a manifestation of control. The dopaminergic system is an excellent example of a control system in which a negative feedback signal is associated with receptor occupancy of a D2-like dopamine autoreceptor. A consequence of the control theory is that autoreceptor occupancy by an agonist results in dopamine levels below the basal, whereas similar stimulation by a dopamine competitive antagonist results in an increase of dopamine to levels above the basal. These consequences of control theory were tested and verified in the rat striatum by infusing graded doses of either the agonist, quinpirole, or the antagonist, sulpiride, into the rat striatum via a microdialysis probe and sampling dopamine and metabolite levels at various times after the start of infusion. Control was maintained even at the very highest doses of these compounds, i.e., striatal dopamine concentration rose in response to the antagonist and fell in response to the agonist. In contrast, administration of each of two high affinity dopamine agonists, 7-OH-DPAT and PPHT showed dose-dependent control only up to certain doses. Above these doses the dopamine concentration actually increased to levels well above basal, an indication of loss of control. These findings suggest that the control of this endogenous ligand does not extend to the very highest levels of autoreceptor occupancy.

Animals↗

PubMed1995

Current and historical mortality from cancer and cardiovascular disease in relation to age: U.S. and world values.

Data from the World Health Organization, U.S. Vital Statistics, the Historical Abstracts of the United States and the census of the United States were used to compare current world and states data on cancer death rate and age with historical data that shows the changing percentage of elderly. Current annual death rates from malignant neoplastic disease among the 73 countries for which data exist are highly correlated with the percent of the population > or = 60 yrs of age and a virtually identical relation exists presently among the 50 states of the U.S. The current world and states data provide a remarkably accurate snapshot of U.S. cancer death rates over the past century during which time the U.S. elderly population increased substantially. Data on U.S. lung cancer death rates since 1940 were similarly examined and these historical numbers also show good agreement with current values among countries that today span the same proportion of elderly that the U.S. had over this period. The agreement of current and historical CA death rate and age contrasts sharply with the picture that emerges when cardiovascular death rates and death rate from all causes are examined. The geographic and time invariance seen in the cancer data seems inconsistent with identical exposure to carcinogens and suggests that biological aging is an important intrinsic factor in cancer.

Aged↗