Interactions of carbon tetrachloride and promethazine in the rat—I: Effects of promethazine on the concentrations of carbon tetrachloride in blood and liver,and on the production of chloroform

The effects of Promethazine (PM, 78 μmoles/kg body wt, i.p.) on the concentrations of CCl₄ in samples of blood and liver of male, fasted rats after oral dosing with CCl₄ have been determined. With an administered dose of CCl₄ of 13 moles/kg body wt the concentrations of CCl₄ in the blood and liver were measured using gas chromatography with a flame ionisation detector. It was found that Promethazine delayed absorption of CCl₄ from the gastro-intestinal tract by approximately 2 hr as judged by blood levels of CCl₄; the maximum blood concentration (C_max) and the total absorption of ccl₄ (assessed by the area under the plot of blood concentration vs time during the first 6 hr after administration of CCl₄) were not significantly changed by Promethazine treatment. Liver and blood measurements were carried out on each rat in this series and the ratio of the CCl₄-concentrations in liver: blood were found to lie within the range 8–12 when studied in the absence of Promethazine treatment.Gas chromatography with electron capture was used on serial samples of blood from the same rat to measure CCl₄ and CHCl₃ concentrations following oral administration of 13, 6.5 or 1.3 mmoles CCl₄/kg body wt. The increase in blood CCl₄ levels at all doses of CCl₄ administered was delayed by about 2 hr by administration of Promethazine. The maximum blood concentrations of CCl₄ and total amount absorbed (judged by area under the plot of blood concentration vs time) were dose-related to the amount of CCl₄ administered with or without Promethazine administration. Blood concentrations of CHCl₃ were relatively constant over the range of CCl₄-doses used indicating that the metabolic production rate of CHCl₃ is saturated at rather low doses of CCl₄ administered.     

The development and performance of a radioimmunoassay for the analysis of ZM 213,689, the major metabolite of meropenem—a carbapenem antibiotic—in plasma and urine

The development of a radioimmunoassay for the analysis of ZM 213, 689, the major metabolite of meropenem found in the plasma and urine of rat, dog and humans, is described. The assay is rapid in order to minimise the effect of degradation of meropenem to ZM 213,689 in biological samples and has a working range of 0.08–3.5 mg l⁻¹ (RSD ⩽ 15%). The antibody was specific for ZM 213,689 with cross-reactivity to meropenem of only 0.4%. The synthesis of the immunogen and radiotracer involved a novel approach due to the multifunctional nature of ZM 213,689.     

Two enzymes for the detoxication of organophosphorus compounds—Sources,similarities, and significance

An enzyme in E. coli that hydrolyzes diisopropylphosphorofluoridate (DFP) has now been found to hydrolyze the nerve gas 1,2,2-trimethylpropylmethylphosphonofluoridate (soman) many times faster. With either substrate the E. coli enzyme is stimulated manyfold by 10⁻³ m Mn²⁺. These criteria are combined and applied to this, and to a superficially similar but distinctly different, enzyme found in squid nerve. The results suggest that while several tissues of the squid contain only this second kind of DFP hydrolyzing enzyme, termed squid type DFPase, many other sources including E. coli contain a mixture of squid type DFPase (the name not strictly indicative of source) and the other DFP hydrolyzing enzyme, now termed Mazur type DFPase. Procedures for the purification of Mazur type DFPase from hog kidney, while increasing the specific activity for DFP hydrolysis may actually have been enriching the purified material in the squid type DFPase. Because E. coli has the highest soman hydrolyzing capacity of any source so far examined, this organism is a promising source for the development of new purification procedures for Mazur type DFPase.     

Effect of the active principle of garlic—Diallyl sulfide—On cell viability,detoxification capability and the antioxidation system of primary rat hepatocytes

The objectives of this study were to investigate the effects of various concentrations and incubation time intervals of diallyl sulfide (DAS), an active principle of garlic, on cell viability, and glutathione (GSH) concentration and its related enzymes activities in rat hepatocytes. According to the results of lactate dehydrogenase (LDH) leakage and microscopic examination, 0.5 or 1 mM DAS treatment did not have any adverse effects on the viability of hepatocytes. Intracellular GSH contents of cells treated with 0.5 and 1 mM DAS (58.6 and 66.4 nmol GSH/mg protein, respectively) were higher than in the controls (54.2 nmol GSH/mg protein), around 8–23%, at 24 hr of incubation; a significant difference (P < 0.05) was observed for 1 mM DAS treatment at 48 hr. This phenomenon is beneficial to the detoxification and antioxidation capabilities of hepatocytes. Further, when the hepatocytes were treated with 0.5 or 1 mM DAS, the activities of glutathione S-transferase (GST), glutathione peroxidase (GPx) and glutathione reductase (GRd) were almost the same as those of the controls. On the other hand, treatment with 5 mM DAS was associated with a significant decrease (P < 0.05) in cell viability, namely in increased LDH leakage (50% at 24-hr treatment), significant changes in the morphology of the hepatocytes, low intracellular GSH level (45% lower than in the controls at 24-hr treatment), and low activities of GST, GPx and Grd.     

Naltrexone and β-funaltrexamine antagonism of the antinociceptive and response rate-decreasing effects of morphine, dezocine, and d-propoxyphene

  Rationale: Patterns of competitive and insurmountable antagonism provide important data to guide the classification and characterization of different types of opioid agonists as well as infer the mechanism of action for agonists. Objective: Experiments with the competitive antagonist, naltrexone, and the insurmountable antagonist, β-funaltrexamine (β-FNA), were conducted to determine whether the antinociceptive and rate-decreasing effects of the opioid agonists dezocine and d-propoxyphene are 1) mediated through μ opioid receptors in rats, and 2) differ from morphine with respect to relative efficacy. Methods: The rat tail-withdrawal assay was used to measure antinociception and a fixed ratio 20 (FR20) schedule of food delivery was used to measure rate suppression. Results: Naltrexone (0.01–1.0 mg/kg) was approximately equipotent as an antagonist of the antinociceptive and rate-decreasing effects of both morphine and dezocine and as an antagonist of the antinociceptive effects of d-propoxyphene. Naltrexone failed to block the rate-decreasing effects of d-propoxyphene. β-FNA (5 and 10 mg/kg) also antagonized the antinociceptive and rate-decreasing effects of morphine and dezocine as well as the antinociceptive effects of d-propoxyphene. β-FNA failed to produce a dose-dependent antagonism of the rate-decreasing effects of d-propoxyphene. Conclusions: These data suggest that the antinociceptive effects of morphine, dezocine, and d-propoxyphene and the rate-decreasing effects of morphine and dezocine are mediated through μ opioid receptors. Overall, high doses of β-FNA produced a greater degree of antagonism of the behavioral effects of dezocine than morphine or d-propoxyphene, confirming other reports that dezocine is a lower efficacy agonist than morphine. Additionally, the degree of antagonism produced by β-FNA was greater for the antinociceptive effects of all three compounds than for the rate-decreasing effects. Received: 14 August 1998 / Final version: 4 December 1998     

Mood disorders and serotonin transporter density in ecstasy users—the influence of long-term abstention, dose, and gender

Rationale Neurotoxic effects of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) on the serotonin (5-HT) system have been described in animals and humans, but little is known about long-term effects of ecstasy use on mood.Objectives To investigate short-term and long-term effects of ecstasy use on mood and its association with 5-HT neurotoxicity, dose, and gender in humans.Methods Fifteen moderate ecstasy users, 23 heavy ecstasy users, 16 former heavy ecstasy users and 15 drug-using, but ecstasy-naive controls were included. Mood was assessed using the Composite International Diagnostic Interview (CIDI) and the Beck Depression Inventory (BDI). Outcomes were correlated with 5-HT transporter (SERT) density, assessed with [¹²³I]-CIT single photon emission computed tomography (SPECT).Results The prevalence of mood disorders assessed by CIDI did not differ between all groups. The overall test for differences in BDI scores between groups was near significance (P=0.056), with BDI scores higher in former heavy ecstasy users than in ecstasy-naive controls (P=0.045). BDI scores were correlated with the total number of ecstasy tablets used (r=0.310; P=0.021). No associations between CIDI or BDI outcomes and SERT density or gender were observed.Conclusions These results suggest that ecstasy use is not associated with clinical depression (CIDI). However, the number of ecstasy tablets taken lifetime was associated with higher BDI scores for depressive mood, and this relationship seemed to persist after ecstasy use had stopped. We did not find that depressed mood in ecstasy users was associated with decrease in SERT density. Prospective studies are needed to establish the causal relationship between ecstasy use and depressed mood.     

Correlation between the effects of salbutamol on contractions and cyclic AMP content of isolated fast — and slow — contracting muscles of the guinea pig

Summary The effects of isoprenaline and salbutamol on incomplete tetanic contractions of the isolated soleus (slow contracting) and extensor digitorum longus (EDL-fast-contracting) muscles of the guinea pig were studied and an attempt made to correlate these effects on contractility with changes in cyclic AMP concentrations. Salbutamol was 10–12 times less potent than (±)isoprenaline in decreasing the force of subtetanic contractions in the soleus and between 5–6 times less potent in increasing the force of subtetanic contractions in the EDL.This observation plus the lack of activity of both the selective ₁-adrenoceptor antagonist (atenolol) and the selective ₁ agonist (H 133/22) in the EDL implies involvement of ₂-adrenoceptors in these responses of the muscles to isoprenaline and salbutamol. The soleus muscle was about 6–12 times more sensitive to effects of -adrenoceptor agonists than the EDL. In concentrations which produced effects on muscle contractility, salbutamol significantly elevated cyclic AMP concentrations in both types of muscle. These effects were antagonised by propranolol. It seems clear that the contrasting effects of sympathomimetic amines on slow — and fast contracting muscle are mediated through a common mechanism — elevation of cyclic AMP. Possible explanations of this apparent paradox are discussed.     

Care of the stroke patient—communication between the community pharmacist and prescribers in the Republic of Ireland

Objective This study sought to examine the perceptions that community pharmacists have of communication with prescribers in both primary and secondary care in Ireland, with respect to care of stroke patients. Setting Community pharmacies across Ireland, stratified into the four representative administrative regions. Method Survey using a structured postal questionnaire. Main outcome measure Perceptions of communication with prescribers based in primary and secondary care; pharmacy and pharmacy premises demographics. Results A response rate of 52% (n = 314) was achieved. Community pharmacists’ perceptions of information provision from secondary care were low, the majority (83%) never received any information from the hospital, although they would welcome it. Communication with hospital based prescribers was considered by most (93%) to be poor. The majority (greater than 75%) of respondents expressed a desire for greater information provision concerning a stroke patient’s medication and diagnostic information. Pharmacists’ perceptions of interaction with general practitioners were generally regarded as good (63%) although information provision in both directions between pharmacist and general practitioner could be improved. Conclusion The findings of this study indicated that community pharmacists perceive that there is room for improvement in the communication between themselves and prescribers in the primary and secondary care settings, concerning the care of the stroke patient. This highlights the need for the development of formal communication channels between community pharmacists and other members of the healthcare team involved in the care of the stroke patient. However, the challenges of communicating patient information across healthcare sectors are recognized.     

Combinatorial investigation of the effects of the incorporation of Ti, Si, and Al on the performance of α-Fe2O3 photoanodes

The effect of adding small amounts of Ti, Si, and Al on the photoelectrochemical activity of α-Fe(2)O(3) is investigated using a high-throughput combinatorial method. Quantitative ink jet printing is used to pattern iron oxide and dopant precursors onto conductive glass substrates. Subsequent pyrolysis yields a library of doped iron oxide electrodes that are screened for photoelectrolysis activity by immersing in an electrolyte and scanning a laser over the electrodes to map the photocurrent response. When Si and Al are individually added to iron oxide at the levels we studied, the photoelectrolysis activity decreased whereas low levels of Ti addition enhanced the photocurrents. Synergistic effects were observed resulting in enhanced photocurrents when multiple impurities were added to α-Fe(2)O(3).     

Microstructure of Tablet—Pharmaceutical Significance,Assessment, and Engineering

Purpose

To summarize the microstructure – property relationship of pharmaceutical tablets and approaches to improve tablet properties through tablet microstructure engineering.

Method

The main topics reviewed here include: 1) influence of material properties and manufacturing process parameters on the evolution of tablet microstructure; 2) impact of tablet structure on tablet properties; 3) assessment of tablet microstructure; 4) development and engineering of tablet microstructure.

Results

Microstructure plays a decisive role on important pharmaceutical properties of a tablet, such as disintegration, drug release, and mechanical strength. Useful information on mechanical properties of a powder can be obtained from analyzing tablet porosity—pressure data. When helium pycnometry fails to accurately measure true density of a water-containing powder, non-linear regression of tablet density—pressure data is a useful alternative method. A component that is more uniformly distributed in a tablet generally exerts more influence on the overall tablet properties.

Conclusion

During formulation development, it is highly recommended to examine the relationship between any property of interest and tablet porosity when possible. Tablet microstructure can be engineered by judicious selection of formulation composition, including the use of the optimum solid form of the drug and appropriate type and amount of excipients, and controlling manufacturing process.

     

Pharmacology and Toxicology of Major Constituents of Marijuana—On the Metabolic Activation of Cannabinoids and Its Mechanism

Many oxidative metabolites of tetrahydrocannabinols (THCs), active components of Cannabis sativa L. (Cannabinaceae), were pharmacologically potent, and 11‐hydroxy‐THCs, 11‐oxo‐Δ⁸‐THC, 7‐oxo‐Δ⁸‐THC, 8β,9β‐epoxyhexahydrocannabinol (EHHC), 9α,10α‐EHHC and 3'‐hydroxy‐Δ⁹‐THC were more active than THC in pharmacological effects such as catalepsy, hypothermia and barbiturate synergism in mice, indicating that these metabolites are active metabolites of THCs. Cannabidiol (CBD), another major component, was biotransfomred to two novel metabolites, 6‐hydroxymethyl‐Δ⁹‐THC and 3‐pentyl‐6, 7, 7a, 8, 9, 11a‐hexahydro‐1, 7‐dihydroxy‐7,10‐dimethyldibenzo[b,d]oxepin (PHDO) through 8R,9‐epoxy‐CBD and 8S, 9‐epoxy‐CBD as intermediates, respectively, identified by us. Both metabolites have some pharmacological effects comparable to Δ⁹‐THC. Cannabinol (CBN), the other major component, was mainly metabolized to 11‐hydroxy‐CBN by hepatic microsomes of animals including humans. The pharmacological effects of the metabolite were higher than those of CBN demonstrating that 11‐hydroxylation of CBN is an activation pathway of the cannabinoid as is the case in THCs. Tolerance developed to catalepsy, hypothermia and pentobarbital‐induced sleep prolonging effects of Δ⁸‐THC and its active metabolite, 11‐hydroxy‐Δ⁸‐THC. Reciprocal cross‐tolerance also developed to pharmacological effects and the magnitude of tolerance development produced by the metabolite was significantly higher than that by Δ⁸‐THC indicating that 11‐hydroxy‐Δ⁸‐THC has important role not only in the pharmacological effects but also its tolerance development of Δ⁸‐THC. THCs and their metabolites competed with the specific binding of CP‐55,940, an agonist of cannabinoid receptor, to synaptic membrane from bovine cerebral cortex. The Ki value of THCs and their metabolites were closely parallel to their pharmacological effects in mice. A novel cytochrome P450 (cyp2c29) was purified and identified for the first time by us as a major enzyme responsible for the metabolic activation of Δ⁸‐THC at the 11‐position in the mouse liver. cDNA of cyp2c29 was cloned from a mouse cDNA library and its sequence was determined. All of major P450s involving the metabolic activation of Δ⁸‐THC at the 11‐position are belonging to CYP2C subfamily in mammalian liver.     

Effects of pinacidil on cerebral and mesenteric arteries —influence of the endothelium

Summary The effect of pinacidil on the contractile response to stepwise increases of the extracellular K⁺ concentration ([K⁺]₀) was investigated in isolated segments of human pial and mesenteric arteries and rabbit basilar and mesenteric arteries. The [K⁺]_O eliciting half maximum contraction (EC₅₀) was lower in human pial (18 mM) and rabbit basilar (27 mM) arteries than in human (33 mM) and rabbit (32 mM) mesenteric arteries, respectively. The -adrenoceptor blocker, prazosin, increased the EC₅₀ value for K⁺ from 27 to 40 mM and reduced the maximum response in rabbit mesenteric arteries, but had no effect on the K⁺-induced contraction in rabbit basilar arteries, indicating a substantial noradrenergic component of the K⁺ response in the former arteries. Removal of the endothelium decreased the EC₅₀ value for K⁺ from 27 to 15 mM in rabbit basilar arteries, whereas the K⁺ sensitivity was unaffected in rabbit mesenteric arteries. Pinacidil shifted the K⁺ concentration-response curve to the right in human and rabbit cerebral and mesenteric arteries. In rabbit basilar arteries, but not in mesenteric arteries, the shift was larger in the absence than in the presence of an intact endothelium. When endothelium-denuded rabbit arteries were compared, the inhibitory effect of pinacidil was larger in basilar than in mesenteric arteries. Thus, pinacidil inhibits K⁺-induced contractions in both cerebral and mesenteric arteries, but appears to act preferentially on endothelium-denuded rabbit basilar arteries. Provided that endothelial damage and depolarization-induced vasoconstriction are of pathophysiological importance in cerebrovascular disorders such as stroke and cerebral ischemia secondary to vasospasm after subarachnoid hemorrhage, pinacidil may have a therapeutic potential. Correspondence to E. D. Hogestatt at the above address     

Postexposure management and treatment of anthrax in dogs—Executive councils of the American academy of veterinary pharmacology and therapeutics and the American college of veterinary clinical pharmacology

Dogs are generally at low risk of developing disease following exposure to anthrax. When disease does occur, it appears associated with oral exposure to the bacteria leading to massive swelling of the head, neck, and mediastinal regions. Death is due to toxemia and shock. For animals at high risk, such as search and rescue dogs with a known exposure, doxycycline at 5 mg/kg orally once daily for 45 to 60 days is suggested as a prophylactic treatment. Additional information on the diagnosis, prevention, and treatment of the disease in dogs is presented.     

Transdermal Penetration of Vasoconstrictors—Present Understanding and Assessment of the Human Epidermal Flux and Retention of Free Bases and Ion-Pairs

Purpose. As reductions in dermal clearance increase the residence time of solutes in the skin and underlying tissues we compared the topical penetration of potentially useful vasoconstrictors (VCs) through human epidermis as both free bases and ion-pairs with salicylic acid (SA). Methods. We determined the in vitro epidermal flux of ephedrine, naphazoline, oxymetazoline, phenylephrine, and xylometazoline applied as saturated solutions in propylene glycol:water (1:1) and of ephedrine, naphazoline and tetrahydrozoline as 10% solutions of 1:1 molar ratio ion-pairs with SA in liquid paraffin. Results. As free bases, ephedrine had the highest maximal flux, Jmax = 77.4 ± 11.7 g/cm²/h, being 4-fold higher than tetrahydrozoline and xylometazoline, 6-fold higher than phenylephrine, 10-fold higher than naphazoline and 100-fold higher than oxymetazoline. Stepwise regression of solute physicochemical properties identified melting point as the most significant predictor of flux. As ion-pairs with SA, ephedrine and naphazoline had similar fluxes (11.5 ± 2.3 and 12.0 ± 1.6 g/cm²/h respectively), whereas tetrahydrozoline was approximately 3-fold slower. Corresponding fluxes of SA from the ion-pairs were 18.6 ± 0.6, 7.8 ± 0.8 and 1.1 ± 0.1 respectively. Transdermal transport of VC's is discussed. Conclusions. Epidermal retention of VCs and SA did not correspond to their molar ratio on application and confirmed that following partitioning into the stratum corneum, ion-pairs separate and further penetration is governed by individual solute characteristics.     

Levcromakalim- and Isoprenaline-induced Relaxation of Human Isolated Airways—Role of the Epithelium and of K+ Channel Activation

Summary: In this study we have investigated the mechanism of action of levcromakalim and isoprenaline in human isolated airways with respect to the K⁺ channels they activate and the possibility that these smooth muscle relaxants activate K⁺ channels on the airway epithelium. Mechanical removal of the epithelial layer (mean percentage of epithelium present 20±3%, n=20 tissues) did not affect the relaxation responses to levcromakalim or isoprenaline, either in terms of maximal relaxation or sensitivity. Whilst having no effect on isoprenaline-induced relaxation, studied from basal tone, the ATP-sensitive K⁺ channel blocker BRL 31660 (10, 30 and 50 μM) reduced relaxation responses induced (from basal tone) by levcromakalim from 74±6% (of the maximal response to isoprenaline) to 48±12% (n=7), 9±9% (n=4) and 0 (n=4), respectively. Charybdotoxin, a blocker of high conductance Ca²⁺-activated K⁺ channels, at concentrations of 30 and 100 nM, had no effect on either levcromakalim- or isoprenaline-induced relaxation responses and yet charybdotoxin was active at K_Ca channels in outside-out patches of hippocampal granule cells. Moreover, tetraethylammonium (10 mM) inhibited neither isoprenaline- nor levcromakalim-induced relaxation. This study has demonstrated that the relaxation responses elicited in human bronchus to isoprenaline and levcromakalim are likely to be the result of direct effects on the smooth muscle with no contribution from epithelial receptors or K⁺ channels. The actions of levcromakalim appear to be mediated only via activation of K_ATP channels. Further, we have made the important observation that, under the experimental conditions of our study, isoprenaline does not activate the K_Ca channel to produce relaxation in human bronchus.     

Effects of tyrosine kinase inhibitor,genistein, and phosphotyrosine—phosphatase inhibitor,orthovanadate, on Ca2+-free contraction of uterine smooth muscle of the rat

• 1.1. The effects of a protein-tyrosine kinase inhibitor, genistein, and a protein-tyrosine phosphatase inhibitor, orthovanadate, were tested on the Ca²⁺-free contraction of the estrogen-dominated rat, which has been proved to be induced mainly via protein kinase C entirely independently of Ca²⁺.
• 2.2. Genistein (30 μM) significantly inhibited the contraction indicating participation of tyrosine kinase activity in the contraction.
• 3.3. Orthovanadate caused contraction concentration-dependently and augmented the Ca²⁺-free contraction at concentrations of more than 1 μM. The contraction by orthovanadate was not inhibited so significantly by genistein (30 μM).
• 4.4. Possible participation of tyrosine kinase activity in Ca²⁺-free contraction is discussed in addition to the formerly reported participation of protein kinase C.