Influence of honey on orally and intravenously administered diltiazem kinetics in rabbits

Effect of honey on plasma concentration of diltiazem after oral and intravenous administration in rabbits, has been studied. For oral study, single dose of diltiazem (5 mg/kg, p.o.) along with saline was administered to New Zealand white rabbits (n=8). Blood samples were collected at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6 and 8 hr after drug administration from marginal ear vein. After a washout period of one week, diltiazem was administered with honey (2.34 ml/kg; p.o.) and the blood samples were collected as above. To the same animals honey (2.34 ml/kg; p.o.) was continued once daily for 7 days. On 8th day, honey and diltiazem were administered simultaneously and blood samples were collected at similar time intervals as mentioned above. For intravenous study the pharmacokinetic was done in each animal on two occasions. The first study was done after single dose administration of diltiazem (5 mg/kg; i.v.) along with saline (2.34 ml/kg; p.o.). Blood samples were collected at 0, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4 and 6 hr after i.v. diltiazem administration. The same animals were treated with honey (2.34 ml/kg; p.o.) for seven days. On day 8, the second study was carried out with single dose i.v. administration of diltiazem along with honey (2.34 ml/kg; p.o.) and blood samples were collected. In the oral study, single dose administration of honey decreased the AUC and Cmax of diltiazem associated with significant increase in clearance and volume of distribution when compared to saline treated group. After one week administration of honey, diltiazem kinetic data showed further reduction in AUC and Cmax and increase in clearance and volume of distribution. In the i.v. study also, multiple dose administration of honey significantly reduced the AUC and increased the clearance value of diltiazem. The results suggest that honey may decrease the plasma concentration of diltiazem after its oral or i.v. administration in rabbits.     

Effects of calcium channel blockers on bupivacaine-induced toxicity

The purpose of this study was to investigate the influence of calcium channel blockers on bupivacaine-induced acute toxicity. For each of the three tested calcium channel blockers (diltiazem, verapamil and bepridil) 6 groups of mice were treated by two different doses, i.e. 2 and 10 mg/kg/i.p., or an equal volume of saline for the control group (n=20); 15 minutes later, all the animals were injected with a single 50 mg/kg/i.p. dose of bupivacaine. The convulsant activity, the time of latency to convulse and the mortality rate were assessed in each group. The local anesthetic-induced mortality was significantly increased by the three different calcium channel blockers. The convulsant activity of bupivacaine was not significantly modified but calcium channel blockers decreased the time of latency to obtain bupivacaine-induced convulsions; this effect was less pronounced with bepridil.     

Neuroprotection of Pramipexole in UPS Impairment Induced Animal Model of Parkinson’s Disease

Pramipexole (PPX), a dopamine (DA) receptor D3 preferring agonist, has been used as monotherapy or adjunct therapy to treat Parkinson’s disease (PD) for many years. Several in vitro and in vivo studies in neurotoxin-induced DA neuron injury models have reported that PPX may possess neuroprotective properties. The present study is to evaluate the neuroprotection of PPX in a sustained DA neuron degeneration model of PD induced by ubiquitin–proteasome system (UPS) impairment. Adult C57BL/6 mice were treated with PPX (low dose 0.1 mg/kg or high dose 0.5 mg/kg, i.p, twice a day) started 7 days before, and continued after microinjection of proteasome inhibitor lactacystin in the medial forebrain bundle for a total 4 weeks. Animal behavior observation, and pathological and biochemical assays were conducted to determine the neuroprotective effects of PPX. We report here that PPX treatment significantly improves rotarod performance, attenuates DA neuron loss and striatal DA reduction, and alleviates proteasomal inhibition and microglial activation in the substantia nigra of lactacystin-lesioned mice. PPX can increase the levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor and induce an activation of autophagy. Furthermore, pretreatment with D3 receptor antagonist U99194 can significantly block the PPX-mediated neuroprotection. These results suggest that multiple molecular pathways may be attributed to the neuroprotective effects of PPX in the UPS impairment model of PD.     

Endothelin-induced sudden death and the possible involvement of platelet activating factor (PAF)

Endothelin (5 nmol/kg, i.v.) caused a transient hypotension followed by a lasting hypertension in rats. However, an abrupt fall in the blood pressure was observed in most rats 6 to 30 min after the injection of endothelin and sudden death followed with lethality noted over 60 min. An abnormal electrocardiogram (ECG) (ventricular arrhythmias) was observed in rats injected with endothelin. Endothelin (i.v.) also caused sudden death in mice. Pretreatment (5 or 60 min) with specific PAF antagonists, CV-6209 (0.1-3 mg/kg, i.v.) and WEB 2086 (30 mg/kg, p.o.), and a calcium channel blocker, diltiazem (60 mg/kg, p.o.) prevented death and attenuated the ECG changes induced by endothelin, but CV-6209 did not prevent the blood pressure changes induced by endothelin. CV-6209 (0.5-3 mg/kg, i.v.), WEB 2086, diltiazem and dexamethasone (5 mg/kg, i.v.) protected mice against the death induced by endothelin. On the other hand, aspirin (cyclooxygenase inhibitor, 100 mg/kg, p.o.) did not protect mice from the death. Thus, endothelin is a highly toxic peptide with cardiotoxic effects, and PAF may be involved in the pathogenesis of the sudden death.     

Effects of amlodipine, diltiazem, and verapamil on the anticonvulsant action of topiramate against maximal electroshock-induced seizures in mice

To assess the effect of 3 calcium channel antagonists (amlodipine, diltiazem, and verapamil) on the anticonvulsant action of topiramate (a new generation antiepileptic drug) in the mouse maximal electroshock seizure (MES) model. Amlodipine (20 mg/kg) significantly enhanced the anticonvulsant activity of topiramate in the MES test in mice, reducing its ED50 value from 54.83 to 33.10 mg/kg (p < 0.05). Similarly, diltiazem (5 and 10 mg/kg) markedly potentiated the antiseizure action of topiramate against MES, lowering its ED50 value from 54.83 to 32.48 mg/kg (p < 0.05) and 28.68 mg/kg (p < 0.01), respectively. In contrast, lower doses of amlodipine (5 and 10 mg/kg) and diltiazem (2.5 mg/kg) and all doses of verapamil (5, 10, and 20 mg/kg) had no significant impact on the antiseizure action of topiramate. Pharmacokinetic verification of the interaction of topiramate with amlodipine and diltiazem revealed that neither amlodipine nor diltiazem affected total brain topiramate concentration in experimental animals, and thus, the observed interactions were concluded to be pharmacodynamic in nature. The favorable combinations of topiramate with amlodipine or diltiazem deserve more attention from a clinical viewpoint because the enhanced antiseizure action of topiramate was not associated with any pharmacokinetic changes in total brain topiramate concentration.     

Flumazenil and bupivacaine-induced toxicity: inverse agonist type activity

The purpose of this study was to investigate the influence of flumazenil on bupivacaine-induced acute toxicity, 10 groups of mice were previously treated by a 1, 0.5, 0.25 and 0.125 mg/kg single dose of flumazenil or saline 15 minutes before an injection of bupivacaine (50 mg/kg: exp. 1 and 60 mg/kg: exp.2). The convulsant activity, the period of latency to convulse and the induced mortality were assessed in each group. The bupivacaine-induced mortality was increased by flumazenil. Also, the convulsant activity was increased by flumazenil and the period of latency to convulse was proportionally decreased with increasing doses of flumazenil for the two tested doses of bupivacaine.     

Effects of acute and chronic nicotine on elevated plus maze in mice: involvement of calcium channels

The current experiments examined the anxiety-related effects of acute and repeated nicotine administration using the elevated plus maze test in mice. Nicotine (0.1 mg/kg s.c., 5 and 30 min after injection; 0.5 mg/kg, s.c., 5 min after injection) had an anxiogenic effect, shown by specific decreases in the percentage of time spent on the open arms and in the percentage of open arm entries. Tolerance developed to this anxiogenic action after 6 days of daily nicotine administration (0.1 mg/kg, s.c.). Five minutes after the seventh injection, an anxiolytic effect was observed, i.e., specific increases in the percentage of time spent on the open arms and in the percentage of open arm entries. L-type voltage-dependent calcium channel antagonists nimodipine (5 and 10 mg/kg, i.p.), flunarizine (5 and 10 mg/kg, i.p.), verapamil (5, 10, 20 mg/kg) and diltiazem (5, 10, 20 mg/kg, i.p.) were also injected prior to an acute low dose of nicotine or to each injection of chronic nicotine. Our results revealed that calcium channel blockers dose-dependently attenuated both an anxiogenic effect of nicotine as well as the development of tolerance to this effect. Our results suggest that neural calcium-dependent mechanisms are involved in the anxiety-related responses to acute and chronic nicotine injection that may ultimately lead to addiction and smoking relapse in human smokers.     

Pharmacokinetic and pharmacodynamic interactions between simvastatin and diltiazem in patients with hypercholesterolemia and hypertension

Pharmacokinetic and pharmacodynamic interactions between simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and diltiazem, a calcium antagonist, were investigated in 7 male and 4 female patients with hypercholesterolemia and hypertension. The patients were given, for one in a three consecutive 4-week periods, oral simvastatin (5 mg/day), oral simvastatin (5 mg/day) combined with diltiazem (90 mg/day), and then oral diltiazem (90 mg/day), respectively. The area under the plasma concentration versus time curve up to 6 hours post-dose (AUC0-6h) and maximum plasma concentrations (Cmax) of the drugs, serum lipid profiles, blood pressures and liver functions were assessed on the last day of each of the three 4-week periods. After the combined treatment period, Cmax of HMG-CoA reductase inhibitor was elevated from 7.8 +/- 2.6 ng/ml to 15.4 +/- 7.9 ng/ml (P < 0.01) and AUC0-6h from 21.7 +/- 4.9 ng x hr/ml to 43.3 +/- 23.4 ng x hr/ml (P < 0.01), while Cmax of diltiazem was decreased from 74.2 +/- 36.4 ng/ml to 58.6 +/- 18.9 ng/ml (P < 0.05) and its AUC0-6h from 365 +/- 153 ng x hr/ml to 287 +/- 113 ng x hr/ml (P < 0.01). Compared to simvastatin monotherapy, combined treatment further reduced LDL-cholesterol levels by 9%, from 129 +/- 16 mg/dl to 119 +/- 17 mg/dl (P < 0.05). No adverse events were observed throughout the study. These apparent pharmacokinetic interactions, namely the increase of HMG-CoA reductase inhibitor concentration by diltiazem and the decrease of diltiazem concentration by simvastatin, enhance the cholesterol-lowering effects of simvastatin during combined treatment.     

Dexamethasone as Adjuvant to Bupivacaine Prolongs the Duration of Thermal Antinociception and Prevents Bupivacaine-Induced Rebound Hyperalgesia via Regional Mechanism in a Mouse Sciatic Nerve Block Model

Background

Dexamethasone has been studied as an effective adjuvant to prolong the analgesia duration of local anesthetics in peripheral nerve block. However, the route of action for dexamethasone and its potential neurotoxicity are still unclear.

Methods

A mouse sciatic nerve block model was used. The sciatic nerve was injected with 60ul of combinations of various medications, including dexamethasone and/or bupivacaine. Neurobehavioral changes were observed for 2 days prior to injection, and then continuously for up to 7 days after injection. In addition, the sciatic nerves were harvested at either 2 days or 7 days after injection. Toluidine blue dyeing and immunohistochemistry test were performed to study the short-term and long-term histopathological changes of the sciatic nerves. There were six study groups: normal saline control, bupivacaine (10mg/kg) only, dexamethasone (0.5mg/kg) only, bupivacaine (10mg/kg) combined with low-dose (0.14mg/kg) dexamethasone, bupivacaine (10mg/kg) combined with high-dose (0.5mg/kg) dexamethasone, and bupivacaine (10mg/kg) combined with intramuscular dexamethasone (0.5mg/kg).

Results

High-dose perineural dexamethasone, but not systemic dexamethasone, combined with bupivacaine prolonged the duration of both sensory and motor block of mouse sciatic nerve. There was no significant difference on the onset time of the sciatic nerve block. There was “rebound hyperalgesia” to thermal stimulus after the resolution of plain bupivacaine sciatic nerve block. Interestingly, both low and high dose perineural dexamethasone prevented bupivacaine-induced hyperalgesia. There was an early phase of axon degeneration and Schwann cell response as represented by S-100 expression as well as the percentage of demyelinated axon and nucleus in the plain bupivacaine group compared with the bupivacaine plus dexamethasone groups on post-injection day 2, which resolved on post-injection day 7. Furthermore, we demonstrated that perineural dexamethasone, but not systemic dexamethasone, could prevent axon degeneration and demyelination. There was no significant caspase-dependent apoptosis process in the mouse sciatic nerve among all study groups during our study period.

Conclusions

Perineural, not systemic, dexamethasone added to a clinical concentration of bupivacaine may not only prolong the duration of sensory and motor blockade of sciatic nerve, but also prevent the bupivacaine-induced reversible neurotoxicity and short-term “rebound hyperalgesia” after the resolution of nerve block.     

Transport of alovudine (3'-fluorothymidine) into the brain and the cerebrospinal fluid of the rat, studied by microdialysis

Extracellular unbound concentrations of alovudine were sampled by microdialysis in order to study the transport of alovudine between the blood and the brain and the cerebrospinal fluid (CSF) in the rat. The AUC (area under the curve) ratio CSF/blood was higher than the brain/blood ratio after i.v. infusion of alovudine 25mg/kg/hr after a loading dose of 25 mg/kg in 5 minutes (n=4). Neither i.v. infusion of thymidine (25 mg/kg/hr, n=5; 100 mg/kg/hr, n=2) nor acetazolamide (50 mg/kg i.p. bolus followed by 25 mg/kg i.p. every second hour, n=3) influenced the brain/blood AUC ratio after alovudine 25 mg/kg s.c. injection compared to controls (n=5). Finally, perfusion through the microdialysis probe with thymidine (1000 microM, n=3) had also no effect on the brain/blood AUC ratio after alovudine 25 mg/kg s.c. Because neither thymidine nor acetazolamide has significant influence on the ability of alovudine to penetrate the blood-brain barrier in the rat, neither thymidine transport nor carboanhydrase dependent CSF production appear to be major determinants of the blood-brain concentration gradient. Thus, it is concluded that alovudine reaches the extracellular fluid of the brain not by cerebrospinal fluid, but via the cerebral capillaries and that the existence of a concentration gradient over both blood-brain and CSF-brain barrier can probably be explained by the presence of an active process pumping alovudine out from the brain.     

Beneficial effect of trimebutine and N-monodesmethyl trimebutine on trinitrobenzene sulfonic acid-induced colitis in rats

The use of local anesthetics, such as lidocaine, has been proposed in the treatment of distal ulcerative colitis. Trimebutine maleate (TMB) displays a local anesthetic activity higher than that of lidocaine in rabbit corneal reflex. TMB and nor-TMB its main metabolite in human show similar affinity to that of bupivacaine toward sodium channel labeled by [3H]batrachotoxin and block sodium currents in sensory neurons from rat dorsal root ganglia. The aim of this study was to evaluate the effects of TMB and nor-TMB in comparison to lidocaine and bupivacaine in a rat model of acute colonic inflammation induced by trinitrobenzene sulfonic acid (TNBS). A single intracolonic instillation of TNBS (50 mg/kg dissolved in ethanol 30%) led to early plasma extravasation then macroscopic damage (hyperemia and necrosis), increased colonic weight and tissular MPO, a marker of neutrophilic infiltration. Local administration of TMB at dose of 3 to 60 mg/kg, 30 min before, 24 and 48 h after colitis induction, significantly reduced the severity of colitis. Nor-TMB (1, 3, 10, 30 mg/kg) as well as lidocaine (1, 3, 10 mg/kg) dose-dependently reduced colitis while bupivacaine at 10 mg/kg did not affect it significantly. In contrast systemic administration of TMB, nor-TMB and lidocaine at 10 mg/kg had no significant effect. Furthermore, local administration of TMB (30 mg/kg) and lidocaine (10 mg/kg) significantly reduced plasmatic extravasation. In conclusion, intracolonic treatment with TMB and nor-TMB improved acute experimental TNBS-induced colitis in rat and these effects could be explained by their local anesthetic activity.     

Synthesis and evaluation of hydrolyzable hyaluronan-tethered bupivacaine delivery systems

Local anesthetics are useful for reducing acute pain, but their short duration precludes them from use in solely managing postoperative pain. To prolong the duration of local anesthesia, we conjugated bupivacaine to native hyaluronan (HA) and divinyl sulfone cross-linked Hylan A (Hylan B particles) using a hydrolyzable linker incorporating an imide. Bupivacaine was prepared for conjugation to HA by forming the acryl imide derivative. Separately, the carboxyl group of HA was reacted with nipsylethylamine (NEA) using carbodiimide-mediated coupling to provide HA-NEA that was subsequently reduced with tris(2-carboxyethylphosphine) hydrochloride to yield HA carrying a free sulfhydryl (HA-SH). The HA-bupivacaine conjugate was assembled by reacting HA-SH with acrylbupivacaine. Characterization of the conjugates showed 22% degree of modification by 1 mol of carboxyl. In vitro release studies comparing bupivacaine admixed in HA with bupivacaine conjugated to HA showed half-lives of 0.4 +/- 0.1 h, and 16.9 +/- 0.2 h, respectively, and the bupivacaine was released chemically unaltered as confirmed by LC-MS. In vivo studies to assess the duration of anesthetic activity were performed in a rat sciatic nerve blockade model. For these studies, bupivacaine was conjugated to Hylan B following a similar procedure, and the degree of modification obtained was 14%. Free bupivacaine (3 and 16 mg/kg) and free bupivacaine (3 mg/kg) admixed with Hylan B particles showed nerve block over 4, 9, and 6 h, respectively. Free bupivacaine (3 mg/kg) admixed with bupivacaine (13 mg/kg) conjugated to Hylan B particles showed a four to 5-fold longer impairment of motor function over the free bupivacaine formulations with a total block time of 19 h. Bupivacaine conjugated to Hylan B particles has the potential to prolong the duration of local anesthesia.     

Effect of praseodymium chloride on liver microsomal enzymes of rats

A single i.v. dose (5 mg/kg) of a light lanthanon, praseodymium, prolonged the duration of hexobarbital-induced sleep and zoxazolamine-induced paralysis, as well as it modified pharmacokinetic parameters of hexobarbital and zoxazolamine, in rats. Half-lives (t1/2) and area under the curve (AUC) were increased, while elimination coefficient (beta) and clearance (Cl) were decreased. However, in daily doses of 1 mg/kg i.p. for 15 days, praseodymium did not alter pharmacological effects and pharmacokinetic parameters. The in vitro hydroxylation of hexobarbital and zoxazolamine by liver microsomes was inhibited when the animals were treated previously with a single i.v. dose (5 mg/kg) of praseodymium chloride. In these animals, the amount of cytochromes P-450 and b5 were reduced significantly, whereas that of NADPH-cytochrome c reductase remained unchanged. The pretreatment of animals with phenobarbital normalized the microsomal enzyme impairment caused by praseodymium.     

Food-drug interaction of (-)-epigallocatechin-3-gallate on the pharmacokinetics of irinotecan and the metabolite SN-38

The aim of the present study was to investigate the effect of (-)-epigallocatechin-3-gallate (EGCG) on the pharmacokinetics of irinotecan (CPT-11) and its metabolite SN-38. EGCG was potentially used to modulate the ATPase activity of P-glycoprotein (P-gp). Experimental Sprague-Dawley rats were treated with EGCG (20mg/kg, i.v.) 10min before CPT-11 (10mg/kg, i.v.) administration, whereas the control group received CPT-11 (10mg/kg, i.v.) only. The biological samples were prepared by the protein precipitation and detected by HPLC-fluorescence detection which provided a good separation of CPT-11 and SN-38 within 10min. The pharmacokinetic data indicate that the area under the plasma concentration-time curves (AUC) of CPT-11 and SN-38 were increased by 57.7 and 18.3%, and AUC in bile were decreased by 15.8 and 46.8%, respectively, for the group pretreated with EGCG. The blood to bile distribution ratio (AUC(bile)/AUC(blood)) was significantly reduced after group coadministration of EGCG, it can be seen that the bile efflux transport system of CPT-11 and SN-38 may be markedly reduced by the treatment of EGCG which plays the role of P-gp inhibitor. In conclusion, EGCG was found to inhibit the transport of CPT-11 and SN-38 into the biliary elimination and their half-lives in plasma could be substantially prolonged. Based on the food-drug interaction, persons taking daily nutritional supplements should be warned of this interaction possibility.     

Protective effect of diltiazem hydrochloride on the occurrence of alloxan- or streptozotocin-induced diabetes in rats.

This study demonstrated that 20 mg/kg of the Ca2+ channel blocker, diltiazem hydrochloride, administered by intraperitoneal injection 15 min before 200 mg/kg of alloxan given by the same route to induce diabetes, served to suppress disease onset completely in rats. Even though 48-h fasting promoted the onset of alloxan diabetes, 40 mg/kg of diltiazem hydrochloride completely prevented the occurrence of diabetes induced by intraperitoneal injection of 200 mg/kg of alloxan. Forty mg/kg of the same agent, however, failed to prevent the onset of diabetes induced by the intravenous injection of streptozotocin (50 mg/kg). From the fact that Ca2+ channel blockers such as nicardipine, verapamil and bepridil have a similar suppressive effect on the occurrence of alloxan diabetes, one may readily infer that this action is characteristic of Ca2+ channel blockers. Moreover, the results suggest the close connection of Ca2+ in the occurrence of alloxan diabetes in rats.     

Blockade of substance P (neurokinin 1) receptors enhances extracellular serotonin when combined with a selective serotonin reuptake inhibitor: an in vivo microdialysis study in mice

Abstract Substance P antagonists of the neurokinin-1 receptor type (NK1) are gaining growing interest as new antidepressant therapies. It has been postulated that these drugs exert this putative therapeutic effect without direct interactions with serotonin (5-HT) neurones. Our recent microdialysis experiment performed in NK1 receptor knockout mice suggested evidence of changes in 5-HT neuronal function (Froger et al. 2001). The aim of the present study was to evaluate the effects of coadministration of the selective 5-HT reuptake inhibitor (SSRI) paroxetine with a NK1 receptor antagonist (GR205171 or L733060), given either intraperitoneally (i.p.) or locally into the dorsal raphe nucleus, on extracellular levels of 5-HT ([5-HT]ext) in the frontal cortex and the dorsal raphe nucleus using in vivo microdialysis in awake, freely moving mice. The systemic or intraraphe administration of a NK1 receptor antagonist did not change basal cortical [5-HT]ext in mice. A single systemic dose of paroxetine (4 mg/kg; i.p.) resulted in a statistically significant increase in [5-HT]ext with a larger extent in the dorsal raphe nucleus (+ 138% over basal AUC values), than in the frontal cortex (+ 52% over basal AUC values). Co-administration of paroxetine (4 mg/kg; i.p.) with the NK1 receptor antagonists, GR205171 (30 mg/kg; i.p.) or L733060 (40 mg/kg; i.p.), potentiated the effects of paroxetine on cortical [5-HT]ext in wild-type mice, whereas GR205171 (30 mg/kg; i.p.) had no effect on paroxetine-induced increase in cortical [5-HT]ext in NK1 receptor knock-out mice. When GR205171 (300 micro mol/L) was perfused by 'reverse microdialysis' into the dorsal raphe nucleus, it potentiated the effects of paroxetine on cortical [5-HT]ext, and inhibited paroxetine-induced increase in [5-HT]ext in the dorsal raphe nucleus. Finally, in mice whose 5-HT transporters were first blocked by a local perfusion of 1 micro mol/L of citalopram into the frontal cortex, a single dose of paroxetine (4 mg/kg i.p.) decreased cortical 5-HT release, and GR205171 (30 mg/kg i.p.) reversed this effect. The present findings suggest that NK1 receptor antagonists, when combined with a SSRI, augment 5-HT release by modulating substance P/5-HT interactions in the dorsal raphe nucleus.     

Diltiazem enhances food intake and gastrointestinal function in rats

The present study was to investigate the effects of diltiazem, a ghrelin receptor agonist, on food intake and gastrointestinal functions in rats. Rats were intragastrically administered with diltiazem solution (daily 16 mg/kg, 30 mg/kg or 80 mg/kg, 30 d), and the rats with saline as control. To detect the effects of diltiazem on food intake and body weight, the average daily food intake and body weight were recorded, and the serum metabolic hormones of plasma growth hormone (GH) and neuropeptide Y (NPY) were tested by radioimmunoassay. By means of the spectrophotometer and the modified Mett's method, the effects of diltiazem on rat's gastrointestinal function and pepsin activity were tested, respectively. In addition, the gastric juice's acidity of rats was detected by titration and the secretion amount was calculated. The results showed that the food intake and body weight were maximally promoted by diltiazem at the dose of 30 mg/kg daily (30 d). The average daily food intake and body weight were significantly increased, and the serum concentrations of GH and NPY were also remarkably increased in diltiazem-treated groups compared with those in control group. The results also showed that the gastric emptying rate, gastric acid secretion and the activity of pepsin were significantly increased in diltiazem-treated group compared with those in control group. These results suggest that diltiazem induces enhancement of eating, in the same time, it can also stimulate the gastrointestinal function and regulate growth of rat.     

Augmented behavioral response and enhanced synaptosomal calcium transport induced by repeated cocaine administration are decreased by calcium channel blockers

Recent studies suggest that calcium influx via L-type calcium channels is necessary for psychostimulant-induced behavioral sensitization. In addition, chronic amphetamine upregulates subtype Cav1.2-containing L-type calcium channels. In the present studies, we assessed the effect of calcium channel blockers (CCBs) on cocaine-induced behavioral sensitization and determined whether the functional activity of L-type calcium channels is altered after repeated cocaine administration. Rats were administered daily intraperitoneal injections of either flunarizine (40 mg/kg), diltiazem (40 mg/kg) or cocaine (20 mg/kg) and the combination of the CCBs and cocaine for 30 days. Motor activities were monitored on Day 1, and every 6th day during the 30-day treatment period. Daily cocaine administration produced increased locomotor activity. Maximal augmentation of behavioral response to repeated cocaine administration was observed on Day 18. Flunarizine pretreatment abolished the augmented behavioral response to repeated cocaine administration while diltiazem was less effective. Measurement of tissue monoamine levels on Day 18 revealed cocaine-induced increases in DA and 5-HT in the nucleus accumbens. By contrast to behavioral response, diltiazem was more effective in attenuating increases in monoamine levels than flunarizine. Cocaine administration for 18 days produced increases in calcium uptake in synaptosomes prepared from the nucleus accumbens and frontal cortex. Increases in calcium uptake were abolished by flunarizine and diltiazem pretreatment. Taken together, the augmented cocaine-induced behavioral response on Day 18 may be due to increased calcium uptake in the nucleus accumbens leading to increased dopamine (DA) and serotonin (5-HT) release. Flunarizine and diltiazem attenuated the behavioral response by decreasing calcium uptake and decreasing neurochemical release.     

Plasmodium chabaudi: in vivo effects of Ca2+ antagonists on chloroquine-resistant and chloroquine-sensitive parasites

The effects of Ca2+ antagonists, verapamil, nicardipine, and diltiazem, on susceptibility to chloroquine were examined in mice infected with chloroquine-sensitive and chloroquine-resistant lines of Plasmodium chabaudi. In mice that received no chloroquine, daily injections of 50 mg/kg of verapamil, nicardipine, or diltiazem did not affect the growth of both sensitive and resistant parasites. When mice were injected daily with verapamil plus 2 to 3 mg/kg chloroquine, the chloroquine-sensitive parasite became more susceptible to chloroquine than the parasite in mice given chloroquine alone. On the other hand, in mice infected with chloroquine-resistant parasites, verapamil severely suppressed the growth of the parasite when accompanied by daily injections of 2 to 3 mg/kg of chloroquine, at which doses resistant parasites grew steadily in the absence of verapamil, indicating reversal of chloroquine resistance. This reversal was dose-dependent between 5 and 50 mg/kg of verapamil. Daily injections of nicardipine or diltiazem at 50 mg/kg also reversed resistance to chloroquine in resistant parasites. These results indicate that Ca2+ antagonists increase the susceptibility to chloroquine in a sensitive line of P. chabaudi and reverse chloroquine resistance in a resistant line.