Quantitative assessment of the microstructure of rat behavior: II. Distinctive effects of dopamine releasers and uptake inhibitors

The effects of four indirect dopamine agonists,d-amphetamine (0.25–4.0 mg/kg), cocaine (2.5–40.0 mg/kg), GBR 12909 (10.0–30.0 mg/kg), and nomifensine (5.0–20.0 mg/kg), on the behavioral organization of movements in an unconditioned motor paradigm were investigated in rats. The extended scaling hypothesis using the fluctuation spectrum of local spatial scaling exponents was used to quantify the geometrical characteristics of movements. The results reveal a qualitatively similar disruption of behavioral organization by lower doses of these drugs. Specifically, rats treated withd-amphetamine (<2.0 mg/kg), cocaine (<20.0 mg/kg), GBR 12909 (<20.0 mg/kg), or nomifensine (<10.0 mg/kg) exhibited a reduced range in the fluctuation spectrum, reflecting a predominance of meandering movements with local spatial scaling exponents between 1.3 and 1.7. This reduction was accompanied dynamically by a reduced predictability of movement sequences as measured by the dynamical entropy,h. By contrast, higher doses of these drugs produced distinctly different changes in behavioral organization. In particular, 4.0 mg/kgd-amphetamine and 40.0 mg/kg cocaine increased the fluctuation range, reflecting relative increases in both straight and circumscribed movements that are interpreted as a combination of spatially extended and local perseveration. In contrast, high doses of 30.0 mg/kg GBR 12909 and 20.0 mg/kg nomifensine induced only local perseveration. High doses ofd-amphetamine, cocaine, GBR 12909 and nomifensine reduced the dynamical entropy,h, indicating an increased predictability of the movement sequences. These results suggest that the generic behavioral change induced by low doses of dopamine agonists is characterized by a reduced variety of path patterns coupled with an increased variability in sequential movement sequences. The differential effects of higher doses of these drugs may be due to their influences on other neurotransmitter systems or differential affinities for different dopamine subsystems.     

Effect of serum protein binding on pharmacokinetics and anticoagulant activity of phenprocoumon in rats

The relationship among serum protein binding, kinetics of elimination, distribution, and anticoagulant activity of phenprocoumon was investigated in 25 selected outbred Sprague-Dawley rats which differed in the extent of serum protein binding of this drug. In addition, the serum protein binding of phenprocoumon was altered in inbred Lewis rats by continuous treatment with tolbutamide. This drug was found to displace phenprocoumon from serum proteins without affecting its intrinsic clearance. The serum free fraction values (f_s)of the selected Sprague-Dawley rats ranged from 0.0053 to 0.0145. There were positive and linear correlations between f_s and the first-order elimination rate constant (k), f_s and total clearance (CL _total ),and f_s and the liver/plasma concentration ratio (L/P ratio) of phenprocoumon. The free fraction values in the liver tissue (f _I )showed twofold variations and were not related to f_s.The half-effective plasma concentrations (C _p50% )of total phenprocoumon (i.e., the concentrations necessary to inhibit the prothrombin complex synthesis rate by 50%) decreased with increasing f_s.The C_p50% values of total drug varied eightfold between the animals but those of free drug only 3.5- fold. The total anticoagulant effect per dose (AE/dose), as reflected by the magnitude of the area above the prothrombin complex activity vs. time curve in the plasma, varied only 1.5- fold between the rats and was not related to f_s.Continuous treatment of inbred Lewis rats with tolbutamide led to an increase of f_s (twofold), k (1.3-fold), V_d (1.5-fold), and CL_total (twofold). The intrinsic clearance (CL _intr )remained unaffected. There was no significant increase of f_L but a twofold increase of the L/P ratio. AE/dose and the C_p50% values of free drug in tolbutamide-treated rats were not significantly different from those of control rats. Thus an increase of the free fraction of phenprocoumon in the serum of rats is followed by a proportional increase of the total clearance. This prevents a concomitant rise of the free drug concentration. Consequently, the total anticoagulant effect per dose remains almost unaffected by about threefold variations in the serum free fraction values of this drug.This work was supported by the Deutsche Forschungsgemeinschaft: it is part of the Ph.D. thesis for D. T.     

Dopamine depletion augments endogenous opioid-induced locomotion in the nucleus accumbens using bothμ1 andδ opioid receptors

The aim of this study is to analyze further the opioid receptor subtypes involved in the augmentation of behavioral activity after dopamine depletion in the nucleus accumbens of rats. Initially, the opioid receptors involved in the augmentation of locomotion produced by endogenous opioids were evaluated by microinjection of kelatorphan, an inhibitor of proteolytic enzymes that inactivates enkephalin, with or without specific antagonists forμ ₁ orδ-opioid receptors, naloxonazine or naltrindole, respectively. Kelatorphan produced a dose-dependent increase in horizontal photocell counts and vertical movements. At all doses examined the behavioral response was augmented in rats sustaining accumbal dopamine lesions. The augmentation in dopamine-depleted rats was partially blocked by naloxonazine or naltrindole. Since the motor stimulant response to intra-accumbens microinjection of theδ-opioid agonist, [d-penicillamine^2,5]-enkephalin, was not augmented in a previous study, we tested the behavioral response to a new endogenousδ-opioid agonist, [d-Ala²] deltorphin I. The locomotor response to deltorphin was slightly augmented in dopamine-depleted rats. These data suggest that the augmentation in the motor response elicited by endogenous opioids after dopamine lesions in the nucleus accumbens involves bothμ ₁ andδ-opioid receptors.     

The desirability function in evaluation of the response of phytoplankton communities to toxicants

The response of phytoplankton communities to copper, cadmium, zinc, and pentachlorophenolate in 2⁴-factorial experiments were investigated. Seven experiments lasting from three to five days were carried out. During each experiment, 16 bottles were incubated in situ. Different species had different responses to the toxicants. For evaluation of the response of the whole community the desirability function was used. The densities of abundant species in the control bottle were used as a reference and considered as desirable. All exceptions more than one standard deviation from the control were considered detrimental. The value of the overall desirability function D was calculated as a geometrical mean of the values of the desirability function for n single species D = (d₁d₂…d_n)^1/n. The overall desirability function values in the factorial experiments were treated by regression analyses. In all experiments, the responses of the phytoplankton community to the toxicants were similar. In general, copper caused the greatest change in phytoplankton communities.     

Behavioural effects of amphetamine in a small primate: Relative potencies of the d- and l-isomers

Acute administration of d-amphetamine (up to 8 mg/kg) or l-amphetamine (up to 12 mg/kg) in the marmoset results in a dose-dependent increase in small head movements (checking), an almost total suppression of activities including eating, grooming, playing, and social interaction, but little change in the amount of movement. Severe stereotypy is seen at high doses of both isomers. The d-isomer has approximately twice the potency of the l-isomer in increasing checking behaviour.     

The effects of MDMA and other methylenedioxy-substituted phenylalkylamines on the structure of rat locomotor activity.

The effects of acute subcutaneous injections of methylenedioxy-substituted phenylalkylamines in rats were tested in an unconditioned motor behavior paradigm using the Behavioral Pattern Monitor (BPM). Based on a previously developed scaling hypothesis and the associated temporal and spatial scaling exponents (alpha and d), the effects of racemic and S(+) 3,4-methylenedioxyamphetamine (MDA), racemic, S(+) and R(-) 3,4-methylenedioxymethamphetamine (MDMA), racemic N-methyl-1-(1,3-benzodioxol-5yl)-2-butanamine (MBDB), racemic N-ethyl-3,4-methylenedioxyamphetamine (MDEA), 2,5-dimethoxy-4-iodoamphetamine, and methamphetamine were characterized using the d-alpha plane. Three distinct dose-response patterns were observed. 1) S(+) and (+/-)MDA had pronounced dose-dependent effects on the structure of motor behavior, which were characterized by long-straight path movements and minimal changes in the amount of motor behavior. 2) (+/-)MDMA and (+/-)MBDB dose-dependently changed patterns of movements towards long-straight paths together with dose-dependent increases in the amount of motor activity. 3) S(+)MDMA and (+/-)MDEA produced dose-related increases in the amount of motor activity with minimal changes of the movement patterns in the BPM. Comparisons with the existing drug discrimination, operant, and biochemical literature on these compounds lead to the conclusion that the observed effects in the d-alpha plane do not simply reflect the different effects of these compounds as dopamine or serotonin (5-HT) releasers or reuptake inhibitors and do not parallel their different abilities to exhibit hallucinogen-like effects. Instead, indirect 5-HT1 effects appear to contribute substantially to the differential changes in the amount and structure of motor behavior induced by the phenylalkylamines. This conclusion may provide an encouraging rationale to develop postsynaptically effective "entactogens," a potential new drug category as adjunctive psychotherapeutics.     

Systemic bioavailability and pharmacokinetics of methylprednisolone in patients with rheumatoid arthritis following ‘high-dose’ pulse administration

The absolute and relative bioavailability of two methylprednisolone formulations (capsules and suspension) was determined along with its pharmacokinetics in four arthritic female patients, following an unconventional high-dose pulse of 1 g. Plasma concentrations of the drug were measured by a sensitive and specific high-performance liquid chromatographic (HPLC) procedure. The disposition of methylprednisolone from plasma following intravenous (i.v.) infusion of its succinate ester appeared monoexponential with a mean half-life of 2·4 h and an apparent volume of distribution (V_d) of 50 1 (0·871 /kg). The total body clearance (Cl) averaged 15·121/h. Absolute bioavailability was assessed by comparing the areas under the plasma concentration time curves (normalized to dose) following oral administration of capsule or suspension with those of intravenous administration. No significant difference (p > 0·2) was observed when systemic availability (f, expressed in per cent) following administration of drug in capsule (f = 49·35 per cent) was compared with that obtained following the administration of drug in a suspension (f = 58·26 per cent). The difference in the observed and predicted f may be due to incomplete absorption, hepatic and/or extrahepatic metabolism of methylprednisolone. Subjective evaluation showed no side effects of this high-dose pulse therapy in any of the patients.     

Aromatic glycosides from the flower buds of Lonicera japonica

Six new glycosides (1–6) have been isolated from the flower buds of Lonicera japonica. Their structures including the absolute configurations were determined by spectroscopic and chemical methods as ( ? )-2-hydroxy-5-methoxybenzoic acid 2-O-β-d-(6-O-benzoyl)-glucopyranoside (1), ( ? )-4-hydroxy-3,5-dimethoxybenzoic acid 4-O-β-d-(6-O-benzoyl)-glucopyranoside (2), ( ? )-(E)-3,5-dimethoxyphenylpropenoic acid 4-O-β-d-(6-O-benzoyl)-glucopyranoside (3), ( ? )-(7S,8R)-(4-hydroxyphenylglycerol 9-O-β-d-[6-O-(E)-4-hydroxy-3,5-dimethoxyphenylpropenoyl]-glucopyranoside (4), ( ? )-(7S,8R)-(4-hydroxy-3-methoxyphenylglycerol 9-O-β-d-[6-O-(E)-4-hydroxy-3,5-dimethoxyphenylpropenoyl]-glucopyranoside (5), and ( ? )-4-hydroxy-3-methoxyphenol β-d-{6-O-[4-O-(7S,8R)-(4-hydroxy-3-methoxyphenylglycerol-8-yl)-3-methoxybenzoyl]}-glucopyranoside (6), respectively.     

Comparison of the pharmacologic effects of N-allylnormetazocine and phencyclidine: Sensitization,cross-sensitization,and opioid antagonist activity

The effects of phencyclidine (PCP) on locomotor activity were compared to those of the stereoisomers of N-allylnormetazocine (NAN) after acute administration to rats. PCP produced swaying and falling movements, increased sniffing behavior, and enhanced horizontal locomotor activity. d-NAN also induced swaying, falling, sniffing behavior and locomotion, and decreased rearing behavior. l-NAN decreased rearing activity, depressed locomotion, antagonized morphine antinociception and precipitated the morphine-withdrawal syndrome. Sensitization to drug-induced sniffing, rearing and locomotion developed after four daily injections of PCP, d-NAN or l-NAN in rats. Rats which were sensitized to PCP-induced locomotion, sniffing, and rearing were also cross-sensitized to both d-NAN and l-NAN. Animals sensitized to the effects of either d- or l-NAN exhibited cross-sensitization to PCP. There was little evidence that the cross-sensitization between the three agents was stereoselective. These data indicate that the acute effects of PCP are similar to those of d-NAN, but differ from l-NAN, the only agent of the three with opioid antagonist properties. The data further indicate that as sensitization to the motor effects develops during repeated administration of PCP, d-NAN or l-NAN, the differences among the three agents become less apparent.     

Two new steroidal saponins from Tribulus terrestris

Two new steroidal saponins and two known flavonoid glycosides were isolated from the fruits of Tribulus terrestris. Their structures were assigned by spectroscopic analysis and chemical reaction as 26-O-β-d-glucopyranosyl-(25R)-5α-furostan-12-one-3β,22α,26-triol-3-O-β-d-glucopyranosyl (1 → 2)-β-d-glucopyranosyl(1 → 4)-β-d-galactopyranoside (1), 26-O-β-d-glucopyranosyl-(25S)-5α-furostan-22-methoxy-2α,3β,26-triol-3-O-β-d-glucopyranosyl(1 → 2)-β-d-glucopyranosyl(1 → 4)-β-d-galactopyranoside (2), kaempferol-3-gentiobioside (3), and isorhamnetin-3-gentiobioside (4).     

Synthesis and anti-nociceptive and anti-inflammatory effects of gaultherin and its analogs

The synthesis of gaultherin (1) and its analogs was carried out to provide 11 glycosides under phase-transfer catalytic conditions. The activities of all synthesized compounds were evaluated by nitric oxide production inhibitory assay in vitro. Methyl 2-O-(4-O-β-d-galactopyranosyl)-β-d-glucopyranosylbenzoate (5f) showed significantly anti-nociceptive and anti-inflammatory effects by the evaluation in vivo. Structure–activity relationships within these compounds were discussed.     

d-Amphetamine-induced “Floating limb” syndrome in young rhesus monkeys

Acuted-amphetamine administration to young rhesus monkeys (N=10) caused a motor syndrome of hypoactivity and chorea-like postures and motor movements which we have termed floating limb. Frequently after subcutaneous injections of 0.3 or 0.6 mg/kgd-amphetamine, an affected monkey raised one or both legs or arms and held the limb(s) motionless in the air. Affected limbs were usually returned to a normal position if they appeared to enter the animal's visual field. In other cases, the monkey assumed bizarre and contorted postures which were held for prolonged periods. Such postures were often accompanied by gentle repetitive brushing of the ears and facial hair with extremities of the affected limbs. Quantification of the frequency of these movements showed that they occurred regularly for 90–150 min afterd-amphetamine. Hydroxyamphetamine, a peripherally-acting amphetamine analog, did not induce floating limb, indicating that the behavior was probably mediated by central actions ofd-amphetamine. A similar disorder has been reported occasionally in other studies with monkeys and cats. It may be related to the chorea that is seen in humans after the use of amphetamine and other stimulants.d-Amphetamine treatment in young monkeys may provide a viable model of human choreoathetoid disorders induced by disease or drug use.     

指数程序升温药物稳定性试验

介绍了一种新的程序升温(指数程序升温)药物稳定性预测加速试验方法及计算方法。在这一新的程序升温方法中,温度每升高10℃,升温速率将增大2～4倍:dT/dt=a^(T-T₀)/10·(dT/dt)₀,使药物在高温和低温范围内的降解程度尽可能一致,提高了试验准确度。采用单因素优选法和数值积分法处理试验数据,避免了任何近似处理,使计算结果准确可靠。与线性升温、倒数升温和对数升温加速试验进行了对比,结果表明,指数程序升温法的准确性优于其它3种升温法。     

Evaluation of equilibrium dialysis volume shifts: A comment

Previous authors have presented in this journal an equation defining the fractional shift in volume (f_s)as a general equation implying applicability to a wide variety of circumstances. The equation concerned actually applies only when the starting volumes before dialysis are equal. A better general definition is given by f_s=(volume shift)/(starting volume of protein solution).     

Prediction of Poly(Ethylene) Glycol-Drug Eutectic Compositions Using an Index Based on the van't Hoff Equation

Purpose. To define an index based on the van't Hoff equation that can be used as a screening tool for predicting poly(ethylene) glycol (PEG)-drug eutectic composition. Methods. Phase diagrams of PEG with ritonavir, ibuprofen, fenofibrate, naproxen, and griseofulvin were constructed using differential scanning calorimetry, hot stage microscopy and powder X-ray diffractometry. Previously reported phase diagrams were also used to test the predictive capability of the index. Results. This work shows that a modified van't Hoff equation can be used to model the drug liquidus line of these phase diagrams. The slope of the liquidus line depends on the melting point (T^f _d) and heat of fusion (H^f _d) of the drug and describes the initial rate at which the eutectic or monotectic point is approached. Based on this finding, a dimensionless index I_c was defined. The index can be calculated from the melting points of the pure components and heat of fusion of the drug. In addition to the compounds listed above, the index was found to predict the eutectic composition for flurbiprofen, temazepam and indomethacin. These compounds range over 150°C in T^f _d, and from 25-65kJ/mole in H^f _d. Conclusion. Using I_c the approximate eutectic composition for eight different compounds was predicted. The index provides a useful screening tool for assessing the maximum drug loading in a drug-polymer eutectic/monotectic formulation.     

The effect of N-substituted alkyl groups on the anticonvulsant activities ofN-Cbz-α-amino-N-alkylsuccinimides

For the purpose of defining the effects of theN-substituted alkyl groups on the anticonvulsant activities ofN-Cbz-α-aminosuccinimides, various (R)-and(S)-N-alkyl substitutedN-Cbz-α-aminosuccinimides (1 and2) were prepared from the corresponding (R)-and(S)-N-Cbz-aspartic acid by using known reaction and were evaluated the anticonvulsant activies in the MES and PTZ tests, including their neurotoxicities. The most active compound in the MES test was(R)-N-Cbz-α-amino-N-methylsuccinimide (1b) (ED₅₀=52.5 mg/kg, Pl-3.2). And in case of the PTZ test,(R)-N-Cbz-α-amino-N-ethylsuccinimide (1c) was the most active compound (ED₅₀=32.5 mg/kg, Pl=3.1). The order of anticonvulsant activities of these compounds against the MES test, as judged from the ED₅₀ values for theR series (1), wasN-methyl >N-isobutyl > non-substituted >N-ethyl,N-allyl >N-benzyl compound; for theS series (2)N-methyl >N-allyl > non-substituted >N-isobutyl >N-ethyl >N-benzyl compound. The anticonvulsant activities in the PTZ tests of these compounds exhibited somewhat different pattern; for theR series (1)N-ethyl >N-methyl >N-isobutyl> non-substituted >N-allyl >N-benzyl compound in order of decreasing activity; forS series (2)N-ethyl >N-allyl, non-substituted >N-isobutyl >N-methyl >N-benzyl compound in order of decreasing activity.     

From piecewise to full physiologic pharmacokinetic modeling: Applied to thiopental disposition in the rat

Physiologically based pharmacokinetic modeling procedures employ anatomical tissue weight, blood flow, and steady tissue/blood partition data, often obtained from different sources, to construct a system of differential equations that predict blood and tissue concentrations. Because the system of equations and the number of variables optimized is considerable, physiologic modeling frequently remains a simulation activity where fits to the data are adjusted by eye rather than with a computer-driven optimization algorithm. We propose a new approach to physiological modeling in which we characterize drug diposition in each tissue separately using constrained numerical deconvolution. This technique takes advantage of the fact that the drug concentration time course, C_T(t), in a given tissue can be described as the convolution of an input function with the unit disposition function (UDF _T) of the drug in the tissue, (i.e., C _T (t)=(C _a (t)Q _r )*UDF _r (t) whereC _a(t) is the arterial concentration,Q _T is the tissue blood flow and * is the convolution operator). The obtained tissue unit disposition function (UDF) for each tissue describes the theoretical disposition of a unit amount of drug injected into the tissue in the absence of recirculation. From theUDF, a parametric model for the intratissue disposition of each tissue can be postulated. Using as input the product of arterial concentration and blood flow, this submodel is fit separately utilizing standard nonlinear regression programs. In a separate step, the entire body is characterized by reassembly of the individuals submodels. Unlike classical physiologic modeling the fit for a given tissue is not dependent on the estimates obtained for other tissues in the model. Additionally, because this method permits examination of individualUDF _s, appropriate submodel selection is driven by relevant information. This paper reports our experience with a piecewise modeling approach for thiopental disposition in the rat. Supported in part by Grant RO1-AG04594 from the National Institute of Aging and the Anesthesia/Pharmacology Research Foundation.     

Predicting the Effect of Renal Function on Systemic Clearance: Is a Simple Scaling Method Sufficient?

PurposeTo employ a simple scaling method to predict systemic or oral clearance for drugs that are primarily renally cleared knowing the fraction eliminated in urine (f_e) and a patient's renal function relative to healthy controls (S_GFR).MethodsObservations evaluating drug clearance as a function of creatinine clearance for renally cleared drugs (f_e >0.3) were obtained from literature sources. The analysis comprised of 82 unique drugs from 124 studies including 31 drugs with replicate studies. A simple scaler for renal function was employed and compared to the linear regression of available data. For drugs in which replicate studies were available, the ability of the linear regression (Cl vs Cl_CR) from one pharmacokinetic study was used to predict observations from an assigned replicate and compared to the scaling approach.ResultsFor patients categorized as severe kidney disease (Cl_CR fixed at 20 ml/min), the scalar tended to over predict some observations, but 92% of the predictions were within 50–200% of the observed data. For drugs with available replicates, the scalar was as good or better in predicting the influence of Cl_CR on systemic clearance from a separate study when comparing against the linear regression approach.ConclusionA scaling approach to account for alterations in drug clearance appears to have its advantages and represents a simple and generalizable method for guiding dose adjustments in patients with decreased renal function for drugs that are renally cleared (f_e >0.3). In addition to its use in clinical practice, validation of this approach may have implications in facilitating more efficient drug development processes for designing dose-adjusted pharmacokinetic studies in patients with renal disease.     

Ritanserin attenuates anorectic,endocrine and thermic responses tod-fenfluramine in human volunteers

This study investigated the role of the 5-HT_2/1C receptor antagonist ritanserin ond-fenfluramine (d-FF) induced changes in food intake, prolactin (PRL) secretion and oral temperature in 12 healthy male volunteers. The study was double blind and placebo controlled. Food intake was measured using an automated food dispenser.d-FF (30 mg) significantly reduced fat intake. While ritanserin (5 mg) had no effect when given alone it abolished thed-FF induced reduction in fat intake. In addition, ritanserin abolished thed-FF induced rise in PRL and oral temperature. The results suggest that 5-HT₂ or 5-HT_1C receptors mediate the effects ofd-fenfluramine on appetite, prolactin secretion and temperature in humans.     

Design and synthesis of some novel 3-[5-(4-substituted) phenyl-1,3,4-oxadiazole-2yl]-2-phenylquinazoline-4(3H)-ones as possible anticonvulsant agent

A novel series 7(a–f) 3-[5-(4-substituted) phenyl-1,3,4-oxadiazole-2yl]-2 phenylquinazoline-4(3H)-ones have been synthesized and screened for its anticonvulsant and neurotoxic activity. After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight 2,3-disubstituted-quinazolin-4(3H)-ones were examined in the maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. Spectroscopic data were consistent with the structure of newly synthesized compounds. The neurotoxicity was assessed using the rotorod method. In the prepared series, 7a was found to be active in the MES screen at 0.5 h, whereas 7f showed anticonvulsant activity at both 0.5 and 4 h.