Chemical characteristics and significant antitussive effect of the Erigeron canadensis polyphenolic polysaccharide-protein complex.

ETHNOPHARMACOLOGICAL RELEVANCE: Erigeron canadensis has been used in traditional medicine to treat a variety of respiratory diseases, including acute upper and lower respiratory tract infections and cough-related asthma. There is as yet no relevant experimental or clinical study in the scientific literature evaluating the efficacy of plants in these disorders. AIM OF THE STUDY: To investigate the active ingredients in Erigeron canadensis, a complex isolated from flowering parts of a plant was tested for airway defense reflexes, in particular for cough reflexes and airway reactivity. Both were experimentally induced by a chemical irritant that simulated the inflammatory conditions of their formation. MATERIAL AND METHODS: The polyphenolic polysaccharide-protein (PPP) complex was isolated from the flowering parts of Erigeron canadensis by hot alkaline extraction and a multi-stage purification process. The antitussive activity was confirmed as a decrease in the number of citric acid-induced coughs and the bronchodilator effect was verified as a decrease in specific airway resistance (sRaw) in conscious guinea pigs. RESULTS: The dark brown Erigeron complex with a molecular weight of 38,000 g/mol contained phenolics (13.2% wt%), proteins (16.3% wt%), and uronic acids (6.3% wt%). The neutral carbohydrate part of Erigeron consisted mainly of xylose (12.1 wt%), glucose (13.3 wt%), arabinose (24.1 wt%), and galactose (41.0 wt%) residues. Arabinogalactan and 4-OMe-glucuronoxylan have been found to be the major polysaccharides in the Erigeron complex. Using a method of chemically-induced cough reflex and guinea pigs test system the Erigeron complex exhibited statistically significant, the dose-dependent antitussive activity, which was similar to that of the centrally-acting opioid agonist codeine. CONCLUSION: Pharmacological tests have revealed a new pharmacodynamic effect of the Erigeron complex, namely an antitussive effect. Its activity was most pronounced in comparison with all previously tested compounds from other medicinal plants and approached the effect of codeine, the most potent antitussive used in clinical practice. The results provide the scientific basis for the application of this herb in traditional medicine.

The research of the possible mechanism and the treatment for capsaicin-induced cough.

Unexplained chronic cough (UCC) affects millions of patients worldwide. New therapeutic approaches to this condition are urgently needed, since current treatment options provide only symptomatic relief. Cough reflex hypersensitivity has been shown to play an important role in the pathogenesis of UCC. The transient receptor potential vanilloid type 1 (TRPV1) is present on peripheral terminals of airway sensory nerves and modulation of its activity represents a potential target for the pharmacological treatment of UCC. The aim of this study was to explore the efficacy and the possible mechanism of SB705498, a TRPV1 antagonist, for cough in a capsaicin-induced cough animal model (i.e. guinea pigs). Induction of cough by capsaicin was successfully implemented in the guinea pigs, and the animals that met the inclusion criteria were randomly divided into four treatment groups: (1) Saline inhalation group (NSInh group, N = 10, negative control group), (2) Codeine phosphate intraperitoneal injection group (CPInp group, N = 10, positive control group), (3) SB705498 inhalation group (SBInh group, N = 10), (4) SB705498 intragastric administration group (SBIng group, N = 10). After treatment with above compounds, the capsaicin-induced cough experiment was performed again. The cough numbers and the cough incubation periods were recorded to evaluate the antitussive effect of SB705498. Enzyme-linked immunosorbent assay (ELISA) testing and Immunohistochemistry (IHC) staining for substance P (SP), calcitonin gene related peptide (CGRP) and neurokinin A (NKA) expression in lung and brain tissues were performed as an indication of neurogenic inflammation. Hematoxylin-Eosin (H&E) staining was used to observe the pathology morphology of lung and brain tissues. When the CPInp, SBInh and SBIng groups were compared to the NSInh group, the cough numbers were significantly reduced (p < .001), while the cough incubation periods were significantly prolonged (P < .001). In addition, the expression of SP, CGRP and NKA in lung and brain tissue was reduced (P < .05). None of the animals in the four groups exhibited lung and brain parenchymal inflammation. The results from this study showed that SB705498 had a significant antitussive effect, could reduce the neurogenic inflammation by reducing the expression of SP, CGRP and NKA in a capsaicin-induced cough model of guinea pigs. The results further indicated that TRPV1 played an important role in UCC and SB705498 might be a promising therapeutic agent for UCC.

Pain Treatment Practices of Community-Dwelling Black Older Adults.

Black older adults often experience disparities in pain treatment that results in unmet pain needs. The aims of this study were to assess the pain management experiences of a group of community dwelling Black older adults and identify gaps in clinical practice. A qualitative, descriptive design was employed using the methodology of ethnography. The setting was an urban, low-income, community elderly housing high-rise facility. Participants included facility residents (n = 106); of these, 20 completed structured qualitative interviews. The Brief Pain Inventory and qualitative interviews were used to determine pain prevalence, treatment practices, and barriers. Eighty-six percent of the participants had severe pain with a mean worst pain rating of 7 on a 0 to 10 scale. Pain interfered moderately with general activity (5.59), walking (5.73) and normal work (5.70), also measured on 0 to 10 scales. Participants preferred non-opioid analgesics, topical over-the-counter treatments, and nonpharmacological interventions such as prayer/meditation, and exercise for treatment. Medications most commonly used by participants for pain management included, hydrocodone with acetaminophen (28.6%), nonsteroidal anti-inflammatory drugs (13.2%), acetaminophen with codeine (12%), and tramadol (9.9). Qualitative interviews revealed that pain management barriers were centered around communication concerns about side effects, fears of addiction, and provider mistrust. A communication gap exists between patients and providers. Discussing patient treatment preferences, providing balanced treatment information, and following-up with patients on treatment plan effectiveness by phone can improve how pain is managed for Black older adults.

Codeine and opioid metabolism: implications and alternatives for pediatric pain management.

PURPOSE OF REVIEW: Use of perioperative opioids for surgical pain management of children presents clinical challenges because of concerns of serious adverse effects including life-threatening respiratory depression. This is especially true for children with history of obstructive sleep apnea. This review will explore current knowledge of clinically relevant factors and genetic polymorphisms that affect opioid metabolism and postoperative outcomes in children. RECENT FINDINGS: Within the past several years, an increasing number of case reports have illustrated clinically important respiratory depression, anoxic brain injuries and even death among children receiving appropriate weight-based dosages of codeine and other opioids for analgesia at home setting particularly following tonsillectomy. Several national and international organizations have issued advisories on use of codeine in pediatrics, based on cytochrome P450 family 2 subfamily D type 6 (CYP2D6) pharmacogenetics. We have discussed the pros and cons of alternatives to codeine for pain management. SUMMARY: Although routine preoperative genotyping to identify children at risk and personalized opioid use for pediatric perioperative pain management is still a distant reality, current known implications of CYP2D6 pharmacogenetics on codeine use shows that pharmacogenetics has the potential to guide anesthesia providers on perioperative opioid selection and dosing to maximize efficacy and safety.

A new potent analgesic agent with reduced liability to produce morphine tolerance.

The therapeutic use of opioids is limited by the development of tolerance to the analgesic effect and the cellular and molecular mechanisms underlying this phenomenon are still not completely understood. For this reason the search for new analgesic derivatives, endowed with lower tolerance, is always an active field. The newly synthesized 14-O-Methylmorphine-6-sulfate (14-O-MeM6SU) shows high efficacy in in vitro assays and a strong analgesic action in the rat tail flick test. The aim of present work was to investigate: the analgesic effect of 14-O-MeM6SU in mouse tail-flick test; the tolerance to analgesic effect of 14-O-MeM6SU compared to morphine in mice, the effects of test compounds on glutamatergic neurotransmission by measuring spontaneous excitatory postsynaptic currents (sEPSCs) of layer V pyramidal cells from rat prefrontal cortices; and the effect of acute and chronic 14-O-MeM6SU treatments on opioid receptor gene expression in SH-SY5Y neuroblastoma cells expressing µ-opioid (MOP) and nociceptin/opioid receptor-like 1 (NOP) receptors. 14-O-MeM6SU was 17 times more potent than morphine in analgesia and had long duration of action in analgesic dose equipotent to morphine. Mice were treated subcutaneously (s.c.) either with 200 µmol/kg morphine or with 14-O-MeM6SU (12 µmol/kg) twice daily for three days. The magnitude of tolerance or cross-tolerance indicated by the shift in antinociceptive ED50 measured was greater for morphine compared to 14-O-MeM6SU. Subsequent to behavioral testing, patch-clamp experiments in layer V pyramidal neurons of rat prefrontal cortical slices in the presence of bicuculline were performed. Both 14-O-MeM6SU (0.1 µM) and morphine (1 µM) decreased the frequency of sEPSCs, indicating reduction of glutamate release. The effect of the novel compound was reversed by the opioid receptor antagonist naloxone, indicating an opioid mediated action. In contrast, the amplitude was not affected. Finally, gene expression data showed a dose dependent down-regulation of MOP receptor after 24h and 48 h exposure to 14-O-MeM6SU. Interestingly, no changes were detected for NOP receptor gene expression. The specific lack of this effect could be related to the lower tolerance development to analgesic effect of 14-O-MeM6SU. Furthermore, 14-O-MeM6SU displayed high intrinsic efficacy possibly an important factor in the observed effects. Further, the observed inhibition of glutamatergic signaling might be attributed also to the reduction of opioid tolerance. Based on our results the development of a new clinically important, safe analgesic agent might be possible.

Chemical and pharmacological profiles of Echinacea complex.

Echinacea purpurea has a long history in traditional medicine. To verify the pharmacological efficacy of active principles, a polysaccharide-phenolic-protein complex has been isolated from flowering parts of herb by alkaline extraction. It showed on GPC and HPLC one peak of molecular mass around 10 kDa. Chemical and spectroscopic analyses revealed carbohydrate, phenolic and protein contents in Echinacea complex. Pharmacological tests have shown its marked cough suppressing and bronchodilatory effects. The antitussive effect of Echinacea was similar to the narcotic drug codeine and the bronchodilatory effect was more significant than salbutamol, the antiasthmatic drug used in a clinical practice. Pharmacodynamic study shows the beneficial effects of Echinacea complex on the respiratory system and highlights the great potential for development of antitussive and bronchodilatory drugs from natural sources.

Analgesic effects of rosemary essential oil and its interactions with codeine and paracetamol in mice.

OBJECTIVE: The use of herbal medicinal products in the management of pain has been increasing steadily in recent years, often in combination with conventional analgesics, which can induce significant interactions. In traditional medicine, rosemary was used as mild analgesic, for relieving renal colic pain and dysmenorrhea. The aim of our study was to examine analgesic effects of rosemary essential oil and its pharmacodynamic interactions with codeine and paracetamol in mice. MATERIALS AND METHODS: The identification and quantification of chemical constituents of the essential oil isolated from air-dried aerial parts of rosemary were carried out by GC/FID and GC/MS. The hot plate test was performed on NMRI mice by placing them individually on hot plate and assessing their response to the thermal stimulus. RESULTS: In this research, we identified 29 chemical compounds of the studied rosemary essential oil, and the main constituents were 1,8-cineole, camphor, and α-pinene. Administration of investigated essential oil increased significantly the latency time of animal response to heat-induced pain between 20th and 50th minute of the test, when compared to saline-treated group. Rosemary essential oil in the dose of 20 mg/kg was shown to be more efficient than in the dose of 10 mg/kg, in combinations with both codeine and paracetamol. CONCLUSIONS: Our findings support the use of rosemary in the management of pain and indicate a therapeutic potential of rosemary essential oil in combination with analgesic drugs. The mechanisms involved in analgesic effects of rosemary essential oil and the potential influence on cytochromes and drug metabolism should be more in-depth investigated.

Antitussive activity of Withania somnifera and opioid receptors.

Arabinogalactan is a polysaccharide isolated from the roots of the medicinal plant Withania somnifera L. It contains 65% arabinose and 18% galactose. The aim of the present study was to evaluate the antitussive activity of arabinogalactan in conscious, healthy adult guinea pigs and the role of the opioid pathway in the antitussive action. A polysaccharide extract was given orally in a dose of 50 mg/kg. Cough was induced by an aerosol of citric acid in a concentration 0.3 mol/L, generated by a jet nebulizer into a plethysmographic chamber. The intensity of cough response was defined as the number of cough efforts counted during a 3-min exposure to the aerosol. The major finding was that arabinogalactan clearly suppressed the cough reflex; the suppression was comparable with that of codeine that was taken as a reference drug. The involvement of the opioid system was tested with the use of a blood-brain barrier penetrable, naloxone hydrochloride, and non-penetrable, naloxone methiodide, to distinguish between the central and peripheral mu-opioid receptor pathways. Both opioid antagonists acted to reverse the arabinogalactan-induced cough suppression; the reversion was total over time with the latter antagonist. We failed to confirm the presence of a bronchodilating effect of the polysaccharide, which could be involved in its antitussive action. We conclude that the polysaccharide arabinogalactan from Withania somnifera has a distinct antitussive activity consisting of cough suppression and that this action involves the mu-opioid receptor pathways.

In vivo antitussive activity of a pectic arabinogalactan isolated from Solanum virginianum L. in Guinea pigs.

ETHNOPHARMACOLOGICAL RELEVANCE: Solanum virginianum L. is used for the management of fever, bronchial asthma and cough for thousands of years. While the link to a particular indication has been established in human, the active principle of the formulation remains unknown. Herein, we have investigated a polysaccharide isolated from its leaves. MATERIALS AND METHODS: Utilizing traditional aqueous extraction protocol and using chemical, chromatographic, spectroscopic and biological methods we have analysed an antitussive pectic arabinogalactan isolated from its leaves. RESULTS: The water extracted polymer (WEP) is a highly branched arabinogalactan containing, inter alia, (1,3)-, (1,6)- and (1,3,6)-linked ß-Galp residues, terminal-, (1,5)- and (1,3,5)-linked units of α-Araf together with (1,2)- and (1,2,4)-linked Rhap. In vivo investigation on the citric-acid induced cough efforts in guinea pigs shows that the antitussive activity of the orally administered pectic arabinogalactan is greater than codeine phosphate. Remarkably, this macromolecule neither altered specific airway smooth muscle reactivity significantly nor it induced considerable change on levels of NO in expiratory flow in guinea pigs. CONCLUSIONS: Thus, traditional aqueous extraction method provides a molecular entity, which induces antitussive activity without addiction: this could represent an attractive approach in phytotherapeutic management.

Effects of opioids on local anesthesia in the rat: a codeine and tramadol study.

Opioids are central analgesics that act on the CNS (central nervous system) and PNS (peripheral nervous system). We investigated the effects of codeine (COD) and tramadol (TRAM) on local anesthesia of the sciatic nerve. Eighty Wistar male rats received the following SC injections in the popliteal fossa: local anesthetic with epinephrine (LA); local anesthetic without vasoconstrictor (LA WV); COD; TRAM; LA + COD; LA + TRAM; COD 20 minutes prior to LA (COD 20' + LA) or TRAM 20 minutes prior to LA (TRAM 20' + LA). As a nociceptive function, the blockade was considered the absence of a paw withdraw reflex. As a motor function, it was the absence of claudication. As a proprioceptive function, it was the absence of hopping and tactile responses. All data were compared using repeated-measures analysis of variance (ANOVA). Opioids showed a significant increase in the level of anesthesia, and the blockade duration of LA + COD was greater than that of the remaining groups (p < 0.05). The associated use of opioids improved anesthesia efficacy. This could lead to a new perspective in controlling dental pain.

Effects of opioids on local anesthesia in the rat: a codeine and tramadol study

Opioids are central analgesics that act on the CNS (central nervous system) and PNS (peripheral nervous system). We investigated the effects of codeine (COD) and tramadol (TRAM) on local anesthesia of the sciatic nerve. Eighty Wistar male rats received the following SC injections in the popliteal fossa: local anesthetic with epinephrine (LA); local anesthetic without vasoconstrictor (LA WV); COD; TRAM; LA + COD; LA + TRAM; COD 20 minutes prior to LA (COD 20' + LA) or TRAM 20 minutes prior to LA (TRAM 20' + LA). As a nociceptive function, the blockade was considered the absence of a paw withdraw reflex. As a motor function, it was the absence of claudication. As a proprioceptive function, it was the absence of hopping and tactile responses. All data were compared using repeated-measures analysis of variance (ANOVA). Opioids showed a significant increase in the level of anesthesia, and the blockade duration of LA + COD was greater than that of the remaining groups (p < 0.05). The associated use of opioids improved anesthesia efficacy. This could lead to a new perspective in controlling dental pain.

Characterization and biological activity of Solidago canadensis complex.

Polyphenolic-polysaccharide-protein complex has been isolated from flowers of Solidago canadensis L. by hot alkaline extraction procedure. Compositional analyses of S canadensis complex revealed the presence of carbohydrates (43 wt%), protein (27 wt%), phenolics (12 wt%), uronic acids (10 wt%) and inorganic material (8 wt%). The carbohydrate part was rich in neutral sugars (81 wt%) while uronids were determined in lower amount (19 wt%). Monosaccharide analysis of carbohydrate part revealed the presence of five main sugar components, i.e. rhamnose (~23 wt%), arabinose (~20 wt%), uronic acids (~19 wt%), galactose (~17 wt%) and glucose (~14 wt%), and indicated thus the presence of rhamnogalacturonan and arabinogalactan in S. canadensis complex. HPLC analysis of complex showed one single peak of molecule mass at 11.2 kDa. Antitussive activity tests, performed in three doses of Solidago complex, showed the reduction of the number of cough efforts in the dose-dependent manner. Higher doses (50 and 75 mg/kg b.w.) were shown to be by 15 and 20% more effective than that of lower one (25mg/kg b.w.). However, the antitussive effect of the highest dose (75 mg/kg b.w.) was by 10% lower in comparison with that of codeine, the strongest antitussive agent. Besides, the highest dose of the complex (75 mg/kg b.w.) significantly decreased values of specific airways resistance and their effect remained longer as that of salbutamol, a representative of classic antiasthmatic drugs.

Acute and chronic pretreatment with essential oil of peppermint (Mentha × piperita L., Lamiaceae) influences drug effects.

The appearance of common and self-initiative usage of various herbal preparations in everyday practice and life imposes the question of possible interactions with drugs. This survey examined the influence of acute and chronic peppermint oil (PO--Mentha × piperita L., Lamiaceae; prepared as emulsion for oral use) on pentobarbitone-induced sleeping time, analgesic effect of codeine and impairment of motor coordination caused by midazolam in mice. The chemical profile of essential oil was determined by GC-MS. Applied doses of PO were 0.1 and 0.2 mL/kg. Chronic PO intake (in both doses) led to significant decrease of analgesic effect of codeine, while acute intake of PO did not change this effect. Acute PO pretreatment in higher dose caused significant prolongation of pentobarbitone-induced sleeping time, while it was significantly shortened by chronic PO pretreatment at the same dose. Midazolam effect was enhanced and prolonged significantly by chronic PO intake at higher dose, while acute intake of PO did not change this effect. Gut motility was increased only by acute intake of higher PO dose. Regarding the fact that PO produces changes in tested drug effects, the interaction between drugs and phytopreparations containing PO should be additionally followed/confirmed in humans.

Where are the new cough treatments: a debriefing of recent clinical proof-of-concept trials with the NOP agonist SCH 486757.

Cough continues to be one of the top reasons why patients seek medical attention from health care providers. The prescription antitussive market is dominated by opioids, such as codeine that produces inconsistent efficacy and is often accompanied by significant side effect liabilities. Consequently, cough represents an unmet medical need and an underserved market. Yet, against the backdrop of increasing cough research, the development of novel treatments has been exceptionally challenging with dextromethorphan being the last US drug approved for cough almost a half century ago. We support the position that an unambiguous and actionable 'road map' that clearly delineates the pathway forward for new cough suppressants from basic research to and beyond clinical proof-of-concept studies will be an important aspect for future success of this pharmacological class of drug. Pivotal to the establishment of such a road map will be the review of lessons learned from antitussive agents that have been recently progressed to proof-of-concept trials. In the present commentary, we briefly discuss observations and challenges pertaining to SCH 486757, a selective orally active NOP agonist that has recently advanced to human antitussive testing.

In vivo anti-tussive activity and structural features of a polysaccharide fraction from water extracted Withania somnifera.

AIM OF THE STUDY: Anti-tussive drugs are amongst the most widely used medications worldwide; however no new class of drugs has been introduced into the market for many years. The present study aims at evaluating the structural features and in vivo anti-tussive activity of a polysaccharide fraction from water extracted Withania somnifera. MATERIALS AND METHODS: Herein, we have analyzed water extracted material of Withania somnifera using chemical, chromatographic, spectroscopic and biological methods. RESULTS: A polysaccharide fraction (F3) containing arabinosyl, galactosyl and galacturonosyl residues were obtained by anion exchange chromatography of the water extracted material. This polymer is branched and contained (1,5)-/(1,3,5)-linked arabinofuranosyl, (1,3)-/(1,6)-/(1,3,6)-linked galactopyranosyl residues together with small amount of terminal rhamnopyranosyl and terminal arabinofuranosyl residues. Peroral administration of this pectic arabinogalactan in a dose of 50 mg kg(-1) body weight (b.w.) decreased the number of cough efforts induced by citric acid in guinea pigs like that of codeine. CONCLUSIONS: This study provides a scientific basis for the past and present ethnomedical uses of this plant.

Elenoside increases intestinal motility.

AIM: To study the effects of elenoside, an arylnaph-thalene lignan from Justicia hyssopifolia, on gastro-intestinal motility in vivo and in vitro in rats. METHODS: Routine in vivo experimental assessments were catharsis index, water percentage of boluses, intestinal transit, and codeine antagonism. The groups included were vehicle control (propylene glycol-ethanol-plant oil-tween 80), elenoside (i.p. 25 and 50 mg/kg), cisapride (i.p. 10 mg/kg), and codeine phosphate (intragastric route, 50 mg/kg). In vitro approaches used isolated rat intestinal tissues (duodenum, jejunum, and ileum). The effects of elenoside at concentrations of 3.2 x 10(-4), 6.4 x 10(-4) and 1.2 x 10(-3) mol/L, and cisapride at 10(-6) mol/L were investigated. RESULTS: Elenoside in vivo produced an increase in the catharsis index and water percentage of boluses and in the percentage of distance traveled by a suspension of activated charcoal. Codeine phosphate antagonized the effect of 25 mg/kg of elenoside. In vitro, elenoside in duodenum, jejunum and ileum produced an initial decrease in the contraction force followed by an increase. Elenoside resulted in decreased intestinal frequency in duodenum, jejunum, and ileum. The in vitro and in vivo effects of elenoside were similar to those produced by cisapride. CONCLUSION: Elenoside is a lignan with an action similar to that of purgative and prokinetics drugs. Elenoside, could be an alternative to cisapride in treatment of gastrointestinal diseases as well as a preventive therapy for the undesirable gastrointestinal effects produced by opioids used for mild to moderate pain.

Modification by L-NAME of codeine induced analgesia: possible role of nitric oxide.

Objectives were to investigate the effect of nonselective nitric oxide synthase (NOS) inhibitor, L-NAME on codeine-induced analgesia and to see the role of NO in its antinociceptive effect. Also, to see if L-NAME can potentiate the antinociceptive response of sub-effective dose of codeine and to explore if opioid receptors have some role to play in L-NAME effects. Mice were injected with selected doses of codeine or other selected agents intraperitoneally and the latency to hot plate was recorded at zero, 15, 30, and 60 min of the treatments. The antinociceptive response of codeine (10 mg/kg, i.p.) was studied in comparison to those of the NOS inhibitor, L-NAME, and of nitric oxide donor, sodium nitroprusside (SNP). Assessment of nitrates and nitrites (NOx) in the sera of treated mice were also made. Codeine (20 mg/kg dose), induced analgesia significantly and dose dependently only after 15 min. L-NAME at 20, 40, and 80 mg/kg dose levels significantly changed the nonanalgesic effect of codeine (10 mg/kg) to highly significant analgesia. The effect of L-NAME 40 mg/kg was significantly higher than the other two doses and was almost equal to that of the higher dose of codeine. Naloxone itself did not show any intrinsic effect but almost abolished the L-NAME-codeine induced analgesia. Similarly, SNP (1 mg/kg) reversed the decrease in reaction time by L-NAME-codeine to its control values, significantly. Pretreatment with L-NAME rendered the nonanalgesic dose of codeine significantly analgesic almost in an equal potency to the high dose of codeine alone and indicate that the NO modulatory effect on the opioid analgesic codeine is probably, at least in part, through opioid receptors.

Effects of some Malian medicinal plants on the respiratory tract of guinea-pigs.

Crossopteryx febrifuga, Pteleopsis suberosa and Entada africana are used in Mali traditional medicine for fever and various respiratory diseases. We have investigated the effects of these three drugs in the form of a decoction on the respiratory tract using different experimental models. On citric acid-induced cough in guinea-pigs, the three drugs significantly decreased the number of coughs at the doses of 250 (P < 0.01), 500 (P < 0.05; P < 0.01) and 1000 (P < 0.01) mg kg(-1). The percent inhibition was respectively 62.86, 69.03 and 77.44% for C. febrifuga, 57.80, 53.90 and 61.40% for E. africana, and 37.13, 42.44 and 73.72% for P. suberosa. Codeine phosphate (10 mg kg(-1)) used as reference drug showed an inhibition of 76.32%. E. africana (1000 mg kg(-1)) reduced (65% inhibition) significantly (P < 0.05) bronchoconstriction induced by histamine (99.25% and 34.00% for control and extract, respectively). Furthermore, E. africana (1000 mg kg(-1)) provoked a bronchodilatation response when administered under basal conditions. On antigen-induced bronchospasm, C. febrifuga protected (54% inhibition) sensitized guinea-pigs with a pulmonary ventilation pressure (PVP) of 24.87% (control value < 55.00%). P. suberosa was inactive in both experimental models. The reference drug, disodium cromoglycate (10 mg kg(-1), i.v.) protected significantly (P < 0.05) with a PVP of 12.00% (78% of inhibition). This study confirmed the traditional use of these plants in the treatment of cough and other respiratory disorders.

Analgesia by dihydrocodeine is not due to formation of dihydromorphine: evidence from nociceptive activity in rat thalamus.

Dihydrocodeine is increasingly used in slow-release preparations for the treatment of chronic pain on step 2 of the "analgesic ladder" of the World Health Organization. Dihydrocodeine is suggested to act after O-demethylation to dihydromorphine. To test this possibility, experiments were carried out on rats under urethane anesthesia in which nociceptive activity was evoked by electrical stimulation of afferent C fibers in the sural nerve and recorded from neurons in the ventrobasal complex of the thalamus. Dihydrocodeine administered by intravenous injection reduced the evoked nociceptive activity in a dose-dependent manner. Like morphine, dihydrocodeine was capable of completely suppressing the evoked activity. Maximum depression was caused by 2 mg/kg, and the ED50 is 0.47 mg/kg. Naloxone (0.2 mg/kg) reversed the effect of dihydrocodeine (2 mg/kg). To inhibit O-demethylation of dihydrocodeine to dihydromorphine, metyrapone or cimetidine (50 mg/kg) was injected intraperitoneally 20 min before dihydrocodeine (1 and 2 mg/kg). This failed to markedly reduce the effect of dihydrocodeine. Dihydromorphine injected intravenously also reduced the evoked activity in a dose-dependent way. Maximum depression occurred at a dose of 4 mg/kg, and the ED50 is 0.97 mg/kg. Dihydrocodeine and dihydromorphine were equieffective when administered by intrathecal injection at a dose of 100 microg. It is concluded that dihydrocodeine causes analgesia independent of biotransformation to dihydromorphine.

Differential effect of codeine on coughs caused by mechanical stimulation of two different sites in the airway of guinea pigs.

We studied the difference in the effects of codeine on coughs caused by mechanical stimulation to the larynx and to the bifurcation of the trachea in lightly anaesthetized guinea pigs. Mechanical stimulation to the larynx or the bifurcation of trachea caused a stable cough response. The response was reproducible over 60 min, when stimulation was repeatedly applied at 20-min intervals. No significant difference was found between the amplitudes of the responses to mechanical stimulation of the larynx and of the tracheal bifurcation. Codeine, 10, 20 and 50 mg/kg, dose dependently depressed the coughs caused by larynx stimulation. The antitussive, however, failed to depress the cough caused by stimulation to the tracheal bifurcation, although a large dose, 50 mg/kg, significantly depressed the cough. In capsaicin-treated guinea pigs, codeine at 20 mg/kg significantly depressed the cough caused by stimulation to the tracheal bifurcation. The present results suggest that cough caused by mechanical stimulation to the larynx might be more sensitive to codeine treatment than cough caused by stimulation to the bifurcation of trachea. Furthermore, it is suggested that coughs caused by mechanical stimulation to both sites might consist of at least two components as regards their pharmacological nature.