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PubMed1981

Pharmacologic studies of anticancer drugs with the human tumor stem cell assay.

To optimize the human tumor stem cell assay (HTSCA) for clinical and research purposes we have carried out in vitro pharmacology studies. Useful observations were made in four areas. (1) Drug assay design: The predictive accuracy of the HTSCA depends on the in vitro testing of drug concentrations of less than 10% of those which are pharmacologically achievable with standard in vivo drug doses. The use of unrealistically high in vitro concentrations can accurately predict clinical drug resistance, but is likely to yield high false-positive rates of clinical response prediction. (2) Drug scheduling: For certain schedule-dependent drugs, as well as those with a prolonged plasma half-life and those used according to a repeated daily schedule, prolonged in vitro exposure (rather than 1 h) may be needed to provide an adequate in vitro design. For an accurate prediction of sensitivity of tumor colony-forming units (TCFUs) to continuous drug contact in the agar, concentrations should be in the range of 1/300 that used for the standard 1-h exposure prior to plating. (3) Drug combinations: In preliminary studies of combination chemotherapy in vitro we commonly observed at least additive effects with low doses of cis-platinum plus either vinblastine or adriamycin. (4) Drug bioactivation: Rat liver microsomes or S-9 fraction were used to activate cyclophosphamide for in vitro effect, and satisfactory dose-response curves were observed for the inhibition of TCFUs. Such pharmacologic studies will be required for a wide variety of standard and new agents and will probably become a regular aspect of investigation of new anticancer drugs.

Antineoplastic Agents↗
PubMed1996

Can a pharmacological pain analysis be used in the assessment of chronic low back pain?

A battery of pharmacological tests was used to differentiate the pain in patients with chronic low back pain (CLBP) referred for pain diagnosis and assessment of whether surgery was indicated or not. Forty patients (mean age 39 years, range 22-51 years) suffering from CLBP (mean pain duration 5.9 years, range 1-12 years) participated. Three pharmacological approaches were used: (1) intravenous infusion of morphine, (2) intravenous infusion of lidocaine and (3) a diagnostic epidural opioid blockade. The patients were tested in a single-blind, placebo-controlled fashion. The pain was considered nociceptive if it decreased by 50% or more in response to both intravenous morphine and epidural fentanyl, but increased in response to intravenous naloxone. The pain was considered neuropathic if it decreased by 50% or more in response to both intravenous lidocaine and the epidural local anaesthetic. Patients who registered a pain decrease of 50% or more in response to saline were classified as placebo responders. Those who registered less than 50% pain decrease in all the tests were considered nonresponders. According to the results of the tests, 16 of the patients were classified as having nociceptive pain, 8 neuropathic pain, 2 were placebo responders, 10 non-responders and 4 were unclassified. The results support the idea that this battery of pharmacological tests can be used in the classification of CLBP patients into different pain categories. This approach may prove useful as a guide for further patient evaluation and as a basis for choice of a suitable treatment strategy.

Adult↗
PubMed1996

Molecular and pharmacological identity of the alpha 2D-adrenergic receptor subtype in bovine retina and its photoreceptors.

The rat cA2-47 gene encodes the pharmacologically defined alpha 2D-adrenergic receptor (alpha 2D-AR) subtype. Previously, the expression of its mRNA was shown in bovine retina by amplification through the reverse transcription-polymerase chain reaction (RT-PCR) of a region corresponding to the rat alpha 2D-AR, amino acid (aa) residues 382-439, indicating the presence of this subtype in this neural tissue. In the present study, the structure of this gene has been probed and the encoded receptor subtype has been characterized in bovine retina and its photoreceptor cells. The deduced aa sequence of the two bovine gene fragments, aa residues 290-375 and aa residues 392-434, demonstrates 77% overall identity with the rat alpha 2D-AR subtype and 80% overall identity with the mouse alpha 2D-AR. The receptor encoded by the bovine gene was expressed in the retina and its photoreceptors with the typical pharmacological characteristics established for the rat alpha 2D-AR subtype: The receptor bound rauwolscine with a KD of 14 nM in the retina and with that of 19 nM in the photoreceptor cells; the binding association rate constant, k+1, for the ligand was 0.012 min-1, the dissociation rate constant, k-1, was 0.14 min-1 and the half-time for dissociation was 5 min. Oxymetazoline displaced the bound [3H]-rauwolscine with an EC50 value of 85 nM, while SK & F 104078, and prazosin displaced the bound [3H]-rauwolscine with the respective IC50 values of 900 nM and 3000 nM. The other alpha 2-AR subtypes -alpha 2A-AR, alpha 2B-AR, alpha 2C-AR-were not detected in the retina and its photoreceptors. Thus, this study shows that the bovine alpha 2D-AR gene is a structural variant of the rat and mouse genes, that the bovine gene encodes the typical pharmacologically defined alpha 2D-AR subtype, that this subtype is present in its exclusive form in the bovine retina and its photoreceptors, where it may be presynaptic in nature.

Adrenergic alpha-Agonists↗
PubMed1980

Lateralization of neuroleptic-induced dyskinesia indicates pharmacologic asymmetry in the brain.

Since the two hemispheres of the human brain are asymmetrical for various cognitive and perceptual functions, a pharmacological as well as the known anatomical differentiation between the two hemispheres may underly the asymmetrical functions. A lateralization of the dyskinetic states consequent to long-term usage of large doses of neuroleptics would be indicative of a pharmacologic asymmetry in the brain hemispheres. Seven of eight right-handed psychiatric patients had greater right-than left-sided dyskinesias, a finding which pointed to pharmacological vulnerability in the left dominant hemisphere.

Adult↗
PubMed1982

Prediction of the Bobon clinical profile of neuroleptics from animal pharmacological data.

Canonical correlation analysis has been used for the comparison of a representative set of animal pharmacological data on 24 neuroleptics with a set of clinical data on the Bobon classification of neuroleptics. The pharmacological data include several measures of antidopaminergic, antiserotonergic, antihistaminergic and antinoradrenergic activities. The clinical data include several therapeutic effects and side-effects of neuroleptics using the six-point scale of the Bobon classification system. Good correlations were found for the first two pairs of canonical variables. Using these correlations, it was possible to make quantitative predictions of the clinical profiles of 21 neuroleptics based on their animal pharmacological data.

Animals↗
PubMed1983

The 'direct' pharmacological effects of heroin on operant responding and activity: the yoked-operant procedure.

The present study demonstrates a method which enables separation of the 'direct' pharmacological effects of heroin on activity and operant responding from the 'indirect' reinforcing effects of heroin. Experiment I was carried out at 0.1 mg/kg heroin with naive male albino Wistar rats (N = 21) from a La Trobe University (Bundoora, Australia) colony. Experiments II and III were carried out at 0.05 mg/kg (N = 21) and 0.2 mg/kg (N = 21) heroin doses with Wistar rats from a Monash University (Clayton, Australia) colony. Each experiment consisted of a 5-day pre-training period and a 10-day experimental period. Food-contingent operant behaviour was shaped in 14 animals during the first 4 days of the pre-training period. On day 5, baseline data was taken. Pairs of animals were then randomly yoked to one of seven naive 'executive' animals and the executive animals were allowed to self-inject heroin. Each self-injection of heroin by an executive animal led to a simultaneous injection of heroin to a yoked-heroin animal, and a simultaneous injection of saline to a yoked-saline animal. Results of 1-h data showed a significant decrement in food-contingent operant behaviour only for the yoked-heroin animals in the 0.2 mg/kg and 0.05 mg/kg groups. A significant decrement in both food-contingent operant behaviour and activity was found for the yoked-heroin animals at all three doses studied when data from the first half of 1-h sessions only was examined. It was concluded that the rate of self-injection demonstrated by executive animals was limited by the direct pharmacological effects of heroin on activity, and that the impairment of responding for food reflected this direct pharmacological effect of heroin. A theoretical model of reinforcement strength was subsequently proposed.

Animals↗
PubMed1981

Relationship between plasma delta-9-tetrahydrocannabinol concentration and pharmacologic effects in man.

The relationship between each of two pharmacologic effects (tachycardia and psychological "high") of delta-9-tetrahydrocannabinol (THC) and plasma THC concentration was investigated in three male and three female experienced marihuana smokers. Each subject smoked 1% THC cigarette on two occasions separated by 2 h. Heart rate and subjective psychological self-rating were determined frequently throughout the 4 h study period. Data were analyzed by calculating the area under the parameter versus time curves, constructing hysteresis plots, and calculating the decay rate constants from pharmacologic effect versus time plots. In both males and females, dose inhaled and psychological response were apparently equivalent for the first and second cigarettes. While all subjects exhibited marked tachycardia in response to the first cigarette, heart rate in both male and female subjects was not increased as markedly during the second cigarette. Interestingly, female subjects had less tachycardiac response than males during the second cigarette. Hysteresis plots revealed that both heart rate and subjective psychological effect were elicited in an effect compartment which was "deep" relative to the reference plasma compartment. The time courses of tachycardiac and psychological responses lagged behind the plasma THC concentration-time profile. Zero-order decay rate constants for subjective psychological rating did not change substantially from the first to second cigarette. This study suggest that plasma THC concentration is a poor predictor of simultaneously occurring physiological and psychological pharmacologic effects.

Adult↗
PubMed1989

Preclinical pharmacology of the anthrapyrazole analog oxantrazole (NSC-349174, piroxantrone).

Oxantrazole (now designated as piroxantrone) is an anthrapyrazole analog under evaluation as a potentially useful anthracycline-like antitumor agent. In preparation for phase I clinical trials, we characterized certain aspects of oxantrazole preclinical pharmacology, including plasma stability, murine pharmacokinetics, in vitro/in vivo metabolism, and DNA damage following incubation with human tumor cells in culture. Oxantrazole was relatively unstable in fresh mouse and dog plasma and particularly unstable in fresh human plasma (t 1/2 less than 5 min at 37 degrees C). Its decomposition in plasma was prevented by the addition of ascorbic acid, suggesting oxidative degradation. Following rapid i.v. administration of oxantrazole to mice, plasma elimination was best described by a two-compartment open model with an elimination-phase half-life, total body clearance, and steady-state volume of distribution of 330 min, 458 ml/min per m2, and 87.9 l/m2, respectively. The c x t value calculated following i.v. administration of 90 mg/m2 oxantrazole to mice was 177 micrograms-min/ml. This value was subsequently used in a pharmacologically guided dose-escalation scheme for the oxantrazole phase I clinical trial. Oxantrazole was converted to a polar conjugate, presumably a beta-glucuronide, by rat but not mouse hepatic microsomal preparations and in vivo by the mouse. Oxantrazole introduced protein-associated DNA strand breaks following incubation with a human rhabdomyosarcoma cell line. Repair of the damage was complete by 15 h. Clinical pharmacologic studies are currently under way in conjunction with the phase I clinical trial of oxantrazole.

Animals↗
PubMed1977

Relationship between plasma concentrations and pharmacological effects of labetalol.

In healthy normal subjects following the administration of labetalol the pharmacological effects were measured and compared with the plasma concentrations achieved. The inhibition of exercise induced tachycardia and inhibition of exercise induced increases in systolic pressure were significantly related to the administered dose of labetalol. Labetalol was rapidly absorbed from the gastrointestinal tract and peak plasma concentrations occurred two hours after oral administration. There was a linear correlation (r = 0.84) between the logarithm of the plasma concentration and the maximum inhibition of exercise tachycardia at two hours. After intravenous administration there was an immediate reduction in systolic and diastolic blood pressure with a concomitant small increase in heart rate. There was a rapid decline in the associated plasma concentration but the pharmacological effects were maintained in excess of two hours. Our findings are consistent with those of others who have studied the relationship between pharmacological events and plasma concentrations after single doses of other adrenoceptor blocking drugs.

Administration, Oral↗
PubMed1978

Pharmacological alterations of coronary collateral circulation; implication to the steal-phenomenon.

Measurements of resistances were performed on different parts of coronary vessels, including spontaneous collaterals in anesthetized dogs, following ligation and embolization of the descending branch of the left coronary artery. The normal situation was compared with the state of maximal pharmacological dilatation. The pharmacological dilatation decreased the collateral resistance by 24% in spite of the fact that the collaterals supplied an infarcted area in this case; the precollateral resistance, which chiefly consists of large vessels was also diminished. The collateral perfusion pressure is not only dependent on the aortic pressure, but also on the flow rate in the corresponding large coronary vessel and thereby on the ratio of precollateral to postcollateal resistance. A decrease of the collateral perfusion pressure causes an insufficient perfusion of the area supplied by the collaterals only when the pressure fall is not compensated for by an adequate decrease in the collateral resistance and when the ratio of the collateral to the nutritive resistance increases. Thus, both, the extent of the pressure fall across the precollateral resistance and the dilating capacity of the collaterals determine whether is not a pharmacological dilatation of the coronary vascular bed results in an insufficient supply of an infarcted area, i.e. in a so called "Steal-phenomenon". The results show further, that the given physical model of the microcirculation satisfactorily approximates the observed behaviour of the vascular system.

Animals↗
PubMed1975

[Studies on the degree of hypoxic and pharmacological coronary dilation (author's transl)].

On 11 isolated dog hearts, perfused with arterial blood of a donor dog, the degree of hypoxic dilatation and the maximum coronary blood flow achieved by adenosine were compared. The maximum coronary blood flow under adenosine infusion amounted to 455ml/minx100g, that means an increase of about 600% of the normal flow. If coronary venous pO2 was below 5mm Hg coronary blood flow was increased to 420ml/minx100g, which is 93% of the pharmacologically achieved maximum increase of the coronary blood flow. The difference between the maximum hypoxic and the maximum pharmacological dilatation is due to the method; it is caused by an increase of the extravascular component of coronary resistance under the influence of catecholamines in the case of hypoxic dilatation. It is pointed out that in order to achieve a maximum hypoxic dilatation oxygen pressure has to be below the critical value. It can be concluded that the intravascular component of coronary resistance is as low under hypoxic as under pharmacological dilatation.

Adenosine↗
PubMed1988

Physical versus pharmacological counter-measures. Studies on febrile rabbits.

128 experiments were carried out on febrile rabbits at air temperatures of 8, 18, 24 and 30 degrees C in order to analyze the thermoregulatory effects and mechanisms of physical and/or pharmacological counter-measures. Fever was achieved by injection of 0.1 micrograms Salmonella typhi endotoxin (LPS)/kg into an ear vein. As the pharmacological counter-measure, injections of acetylsalicylic acid (ASA) into an ear vein were chosen. For the physical counter-measure, cooling thermodes (5 degrees C) were constructed for the abdominal skin, for the ear and for the rectum. ASA injections had no effect on the first fever maximum, even if applied 20 to 60 min before the LPS injection, but eliminated the second fever maximum. Of course, the additional hyperthermia observed at 30 degrees C ambient temperature could not be eliminated by the injections. On the other hand, cooling procedures can obviously not affect the pyrogen-induced temperature increase, but reduce the hyperthermic effect of a higher ambient temperature. Rectal cooling was more effective than ear or abdominal skin cooling. Abdominal cooling evoked an increase in metabolic heat production. Application of combined physical and pharmacological counter-measures achieved the strongest and quickest reduction of the second maximum, whereas the first maximum was not affected, as in all other experiments. The study emphasizes the necessity of taking into account the time course of the effector mechanisms in order to discriminate between hyperthermic and febrile components of temperature increase. In the initial phase cooling measures would evoke unwanted regulatory responses of the effectors, whereas during the second febrile maximum they would achieve a quicker reduction of core temperatures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Pharmacology of calcium release from sarcoplasmic reticulum.

Calcium release from sarcoplasmic reticulum (SR) has been elicited in response to additions of many different agents. Activators of Ca2+ release are here tentatively classified as activators of a Ca2+-induced Ca2+ release channel preferentially localized in SR terminal or as likely activators of other Ca2+ efflux pathways. Some of these pathways may be associated with several different mechanisms for SR Ca2+ release that have been postulated previously. Studies of various inhibitors of excitation-contraction coupling and of certain forms of SR Ca2+ release are summarized. The sensitivity of isolated SR to certain agents is unusually affected by experimental conditions. These effects can seriously undermine attempts to anticipate effects of the same pharmacological agents in situ. Finally, mention is made of a new preparation ("sarcoballs") designed to make the pharmacological study of SR Ca2+ release more accessible to electrophysiologists, and some concluding speculations on the future of SR pharmacology are offered.

Animals↗
PubMed1994

Intraperitoneal 5-fluoro-2'-deoxyuridine with escalating doses of leucovorin: pharmacology and clinical tolerance.

In a preceding study, we established the tolerance and pharmacokinetic behavior of 5-fluoro-2'-deoxyuridine (FdUrd) given by the intraperitoneal (IP) route. A dose of 3 g daily x 3 days was found satisfactory for Phase II study and exploration of biochemical modulation. Therefore, the current study was conducted to study the tolerance and pharmacokinetics of such a dose-schedule and route of FdUrd combined with escalating doses of leucovorin (LV). Fourteen patients were entered and 13 were evaluable for tolerance determination. Pharmacologic determinations of IP FdUrd and 5-Fluorouracil (FUra) derived from it and LV were obtained by HPLC methods on 11 occasions. Findings were compared with the preceding study of FdUrd alone. LV did not appear to alter the tolerance of IP FdUrd even in the four patients receiving the highest dose of LV (640 mg). Toxicities included nausea, vomiting, and rarely neutropenia and diarrhea. Pharmacokinetic parameters indicate a parallel rate of egress of FdUrd and LV from the peritoneal cavity. The pharmacologic advantage for FdUrd is at least 3 logs as previously reported and one log for LV. Evidence of antitumor effect was noted particularly among untreated patients with gastrointestinal primaries. We conclude that IP FdUrd 3 g and LV in doses of up to 640 mg x 3 days are well tolerated. Since FdUrd is more potent, has an even greater hepatic clearance and shows greater potential for modulation with LV than FUra, it may be the preferred fluoropyrimidine for subsequent studies via the IP route in the treatment of carcinomas with prominent peritoneal spread. The pharmacologic advantage for leucovorin is limited but it is a good marker for peritoneal clearance since it parallels FdUrd clearance.

Abdominal Neoplasms↗
PubMed1985

Combined behavioral and pharmacological treatment of essential hypertension.

Fifty-two pharmacologically treated hypertensive patients were randomized to one of four treatment groups: (1) diastolic blood pressure biofeedback, (2) progressive deep muscle relaxation training, (3) self-directed relaxation training, or (4) medication alone. Data collection occurred during baseline, treatment, and 1-year follow-up phases in a laboratory, a medical clinic, and the patient's own home. Patients from all four groups combined showed mean blood pressure reductions of -10.2/-5.5 mm Hg on clinic recordings and -2.4/-.7 mm Hg on home recordings, which were maintained throughout the follow-up period. There were no significant differences among the four groups in terms of blood pressure reduction. Patients given adjunctive behavioral treatment showed significantly larger reductions in medication usage compared to patients treated with medication alone, but there were no significant differences among the three behaviorally treated groups. Patients who showed medication reductions did not show subsequent blood pressure elevation. The results suggest that combined behavioral and pharmacological therapy may be superior to pharmacological therapy alone in the treatment of essential hypertension.

Adult↗
PubMed1983

Kinetics of d-tubocurarine disposition and pharmacologic response in rats.

After bolus intravenous dosing of d-tubocurarine (d-TC) to rats, the twitch heights of the tibialis anterior muscle indirectly stimulated were followed, and its decrease was defined as pharmacologic response of d-TC. The relation between dose and response intensity was found to be well described with Hill's equation. According to a theory proposed by Smolen, Hill's equation was also applicable to the biophase d-TC concentration-response relation; the time courses of the relative biophase d-TC concentration indicated linear kinetics with dose levels less than or equal to 0.15 mg/kg and the occurrence of dose-dependent disposition with 0.30 mg/kg. After bolus i.v. dosing of 3H-d-TC, plasma d-TC concentration obeyed a dose-independent two compartment model with doses less than or equal to 0.15 mg/kg, but not with 0.30 mg/kg. This finding matched the above estimated with pharmacologic data. The active metabolite was not found in plasma and urine. The extent of d-TC plasma protein binding was independent of the wide range of plasma levels and its mean (+/- SD) value was 30.5 (+/- 3.8). Plasma d-TC levels and pharmacologic response intensity were well correlated by Hill's equation and a three compartment model (the general two and the biophase compartments) in the dose range less than or equal to 0.15 mg/kg.

Animals↗
PubMed1979

Multiple receptor responses: a new concept to describe the relationship between pharmacological effects and pharmacokinetics of a drug: studies on clonidine in the rat and cat.

The time course of an observed pharmacological effect is affected not only by the kinetics of the drug levels at the site of action but also by parameters such as the slope and maximum effect of the functional relationship between drug level and response. Using clonidine as a test drug, it was found that the kinetics of its effects on blood pressure and pain responses cannot be described by the time course of clonidine levels in the blood, brain, or the hypothetical tissue compartment of the two-compartment characteristics of this drug. However, the results can be explained assuming that the observed pharmacological effects of a drug are composed of the sum of responses from at least two receptor sites with different slopes and maximal effects. The effect of intravenously administered clonidine on blood pressure in the rat was found to be related to the blood concentrations at least at two receptor sites with opposite effects, one leading to a hypertensive and the other to a hypotensive response. Predictions indicate that a maximum decrease of arterial blood pressure is obtained when the steady-state blood concentration of clonidine is about 1 ng/ml and that no effect is seen at 10 ng/ml. Higher levels will produce an increase of the pressure. The kinetics of the analgesic effect of clonidine in the rat could best be related to the brain levels if the observed effect was considered to be derived from the sum of activity at two receptor sites each producing analgesia. The kinetics of the effects of clonidine on the nictitating membrane of the cat was found to be determined by the kinetics of the drug in the peripheral compartment of the two-compartment open model. Consideration of multiple receptor responses is suggested for future studies on the relationship between the kinetics of drug levels and pharmacological responses.

Animals↗
PubMed1977

[The influence of plasma protein binding on distribution and pharmacological activity of tranquilizers of the benzodiazepine group (author's transl)].

This paper discusses the problem if the plasma protein binding of benzodiazepine derivatives can influence distribution and pharmacological activity of the drugs. The distribution of the benzodiazepines in the organism is influenced not only by the plasma protein binding of the drugs, but also by several other factors, especially since the drugs are mostly lipophilic. Thus, an effect of the plasma protein binding on the distribution can only be expected if the benzodiazepine derivative is highly bound to the plasma proteins. Thus results have been shown only for diazepam and chlordiazepoxid, which indicate an effect of the plasma protein binding on distribution and pharmacological activity, for example the existence of a direct correlation between unwanted CNS depressions and low plasma albumin concentrations and a direct correlation between the plasma protein binding and the biological half-life. There are no observations available on a displacement of other drugs from their binding to plasma proteins by benzodiazepines. The observed displacement of thyroid hormones from their binding to plasma proteins seems to have only a significance for thyroid function tests in vitro. It was shown that benzodiazepines decrease the amount of L-tryptophan bound to serum albumin in vitro and in vivo and increased therewith the L-tryptophan concentration in the brain. At present it can not be confirmed if these observations bear any significance on the pharmacological activity of the drugs. But these experiments demonstrate the significance of the use of albumin as a model for the interaction of drugs with tissue or receptorproteins.

Anti-Anxiety Agents↗