Laxative management in ambulatory cancer patients on opioid therapy: a prospective, open-label investigation of polyethylene glycol, sodium picosulphate and lactulose.

Constipation and the laxatives polyethylene glycol (PEG), sodium picosulphate (SPS) and lactulose (L) were investigated in outpatients with cancer and on opioid therapy. Randomly selected patients were enrolled in a prospective, controlled, open-label trial. Endpoints were number of patients taking laxatives >28 days, number of patients with a stool-free interval >72 h (sfi72), dosage, numerical rating scale (NRS) for constipation, and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) questionnaire scores. The 348 patients had comparable demographic and medical data. In this ambulatory population, mobility scores remained unaffected. Constipation incidence was 5.7%, with sfi72 42, mean NRS 2.3557 and mean QoL 2.1. A total of 53.2% discontinued their laxative medication. Laxative use correlated with higher opioid usage (morphine-equivalent mg/day: no laxative 98.2, SPS 128.2, PEG 139.9, L 154.5). PEG was the most frequently prescribed laxative (PEG 27.3%, SPS 10.3%, L 9.2%). PEG (sfi72 12.6%, NRS 2.2, QoL 2.1) and SPS (sfi72 11.1%, NRS 2.7, QoL 2.2) proved more effective than L (sfi72 15.5%, NRS 3.8, QoL 2.5). In spite of opioid therapy, the incidence of constipation was low in these ambulatory cancer pain patients at an early disease stage. For prevention of constipation, PEG or SPS is recommended instead of L.

[Modafinil for the treatment of cancer-related fatigue : an intervention study]. / Modafinil zur behandlung der tumorfatigue : eine interventionsstudie.

AIM: the authors conducted an open-label investigation examining the effects of modafinil in reducing fatigue in patients with cancer, undergoing cancer treatment, and receiving opioid therapy. METHODS: after approval by the local Ethics Committee and informed consent cancer patients who reported fatigue - defined as persistent tiredness interfering with usual functioning - were enrolled in the study. Once daily, patients received 100 mg open-label modafinil. The Fatigue Severity Scale (FSS), Epworth Sleepiness Scale (ESS), and a visual analogue scale (VAS, 0-10) were performed at baseline (t1), day 7 (t2), and day 28 (t3). Further assessment comprised the d2 Test of Attention (d2), the Hamilton Depression Scale (HAMD), the Eastern Cooperative Oncology Group-Score (ECOG), side effects, and patients' satisfaction with modafinil treatment. RESULTS: of the 37 patients who were enrolled, 29 completed all assessments in the study. Modafinil had a significant effect on the FSS (t1 44.6+/-12.2, t2 39+/-12.4, t3 35.3+/-13.8 (p=0.015), on the VAS (t1 6+/-3.1), t2 4.5+/-2.8, t3 3.7+/-2.8 (p=0.005), and an insignificant effect on d2 parameters of neurophysiological functioning and ESS. No differences were seen for ECOG and patients' satisfaction. No severe adverse effects were detected. CONCLUSION: modafinil improved alertness and cognitive skills in patients receiving cancer pain treatment by enhancing vigilance and cognitive performance. Although confirmation of this preliminary result is needed, these findings suggest that modafinil may improve quality of life in this patient population. However, in Germany the use of modafinil for fatigue is off-label and careful assessment of fatigue is needed prior to treatment. Randomized controlled trials are needed to confirm this evidence.

[Superior cervical ganglion: an anatomical variant. Are variations of the cranial carotid artery a risk factor for accidental intravascular injection?]. / Ganglion cervicale superius: eine anatomische Besonderheit. Variationen der A. carotis interna als Risiko einer akzidentellen intravasalen Injektion?

A variation of the cranial carotid artery is demonstrated in an anatomical specimen revealing possible complications of ganglionic local opioid analgesia at the superior cervical ganglion. Located in the area of the puncture site, a loop of the aberrant carotid artery adheres closely to the pharyngeal wall in the medial position, shortening the distance between the arterial lumen and the oral cavity to 5 mm. With an incidence of 25%, an aberrant carotid artery could possibly facilitate an accidental intravascular injection during ganglionic local opioid application at the superior cervical ganglion.

Less nausea, emesis, and constipation comparing hydromorphone and morphine? A prospective open-labeled investigation on cancer pain.

GOALS OF WORK: The purpose of this trial was to evaluate the effect of long-term treatment with either oral sustained-release hydromorphone (HM) or morphine (M) on nausea, emesis, and constipation. MATERIALS AND METHODS: In a prospective, open-labeled, controlled trial, 100 outpatients with cancer pain and treatment with HM or M were enrolled. Mobility, pain, and gastrointestinal symptoms were assessed by the ECOG performance status, selected items of the EORTC questionnaire and Numerical Rating Scales (NRS). Data were analyzed using descriptive and confirmatory statistics (paired t-test, chi square test, Poisson regression). MAIN RESULTS: Demographic and medical data were comparable in both treatment groups. Taking into account different conversion factors, opioid doses (M 94.4 mg/d vs. HM 137.6 [HM/M = 1:5], p = 0.05 and HM 206.4 [HM/M = 1:7.5], p = 0.0002, respectively) were higher under hydromorphone and NRS of pain (M 2.3 vs. HM 3.6, p = 0.0002) lower under morphine. Nausea and emesis did not attenuate in 33% of patients. NRS of nausea (M 2.5 vs. HM 1.5; p = 0.01), incidences of emesis (M 0.7/d vs. HM 0.1/d, p = 0.0001), the consumption of antiemetics (M 26 vs. HM 14, p = 0.01), and the number of constipated patients (M 8 vs. HM 2, p = 0.04) were higher in the morphine group. An extended use of substances for symptom control revealed constipating effects (M 31 vs. HM 13, p = 0.0003) and was associated with a higher incidence of constipation in the morphine group. CONCLUSIONS: Symptom control in outpatients with cancer pain may be complicated by a symptom controlling medication. Particularly, antiemetics revealed potentially constipating effects. Despite lower opioid doses, morphine provided a better pain control but produced more side effects. Comparing hydromorphone with morphine, it remains unclear if fewer incidences of constipation and nausea in the hydromorphone group were related to pharmacodynamic effects or to a less effective pain control with significantly higher NRS for pain. However, the conversion factor of oral hydromorphone and morphine needs to be questioned.

The effects of morphine on human 5-HT3A receptors.

5-HT3 receptors are ligand-gated ion channels that are involved in the modulation of emesis and pain. In this study, we investigated whether the opioid analgesic, morphine, exerts specific effects on human 5-HT3 receptors. Whole-cell patches from HEK-293 cells stably transfected with the human 5-HT3A receptor cDNA were used to determine the effects of morphine on the 5-HT-induced currents using the patch clamp technique. At negative membrane potentials, 5-HT induced inward currents in a concentration-dependent manner. The 5-HT3 receptor antagonist, ondansetron, (0.3 nM) reversibly inhibited the 5-HT-induced signals. Morphine reversibly suppressed 5-HT-induced peak currents as a function of concentration (IC50 = 1.1 microM, Hill coefficient = 1.2). The block by morphine decreased with increasing 5-HT concentrations, suggesting a competitive effect. In addition, the activation, as well as the inactivation, kinetics of the currents were significantly slowed in the presence of morphine. The morphine antagonist, naloxone, also inhibited 5-HT-induced currents (e.g., at 3 microM by 17%). The effects of morphine and naloxone were not additive. The potency of morphine and the competitivity of the blocking effect points to a specific mechanism at a receptor site rather than an unspecific membrane effect.

[Managing patients with chronic orofacial pain in the outpatient departments of dental and maxillofacial surgeons. Results of a survey]. / Versorgung von Patienten mit chronischem orofazialem Schmerz. Ergebnisse einer Befragung in ambulanten zahnärztlichen und Mund-Kiefer-Gesichts-Chirurgie-Einrichtungen.

OBJECTIVE: The aim of this study was to evaluate the significance attributed by dental and maxillofacial surgeons to the ambulatory management of chronic orofacial pain syndromes. MATERIALS AND METHODS: All the dentists and oral and maxillofacial surgeons working in ambulatory capacities within a county of the German Rhine Area were asked to answer a questionnaire on demographic data, diagnostic and therapeutic principles, and the use of analogue scales, surgical, minimal-invasive or pharmacological procedures. RESULTS AND DISCUSSION: Seventy-two ambulatory institutions reported 985 patients suffering from temporomandibular disorders (40.2%), headache-syndromes associated with facial pain (18.2%), and atypical odontalgia respectively phantom tooth pain (17.0%). Patients were characterized by prior dental treatment or trauma (41.9%), female gender (66.8%), middle age (81.1%, 20-60 years), very frequent change of therapists (54.6%) and long-term perseverance of pain (61.1% >6 months). Only 7% of therapists used visual or numerical analogue scales to assess pain intensity. Therapeutic procedures consisted of analgesics (15.7%) and further surgical procedures (47.7%). Pain therapists were rarely involved (12.5%). CONCLUSION: Dental and maxillofacial surgeons should apply an interdisciplinary and multimodal approach to diagnostics and therapy at an earlier stage in order to optimize the pain management of patients with chronic orofacial pain.

Pharmacological modification of sodium channels from the human heart atrium in planar lipid bilayers: electrophysiological characterization of responses to batrachotoxin and pentobarbital.

BACKGROUND AND OBJECTIVE: To investigate the effects of barbiturates on batrachotoxin-modified sodium channels from different regions of the human heart. Single sodium channels from human atria were studied and compared with existing data from the human ventricle and from the central nervous system. METHODS: Sodium channels from preparations of human atrial muscle were incorporated into planar lipid bilayers in the presence of batrachotoxin, a sodium channel activator. The steady-state behaviour of single sodium channels was recorded in symmetrical 500 mmol NaCl before and after the addition of pentobarbital 0.34-1.34 mmol. RESULTS: The batrachotoxin-treated human atrial sodium channel had an average single-channel conductance of 23.8 +/- 1.6 pS in symmetrical 500 mmol NaCl and a channel fractional open time of 0.83 +/- 0.06. The activation mid-point potential was -98.0 +/- 2.3 mV. Extracellular tetrodotoxin (a specific sodium channel blocking agent) blocked these channels with a k(1/2) = 0.53 micromol at 0 mV. Pentobarbital reduced the time average conductance of single atrial sodium channels in a concentration-dependent manner (ID50 = 0.71 mmol). In the same way, the steady-state activation was shifted to more hyperpolarized potentials (-10.6 mV at 0.67 mmol pentobarbital). CONCLUSIONS: The properties of batrachotoxin-modified sodium channels from human atrial tissue did not differ greatly from those described for ventricular sodium channels in the literature. Our data yielded no explanation for the observed functional diversity. However, cardiac sodium channels differ from those found in the central nervous system.

Human cardiac sodium channels are affected by pentobarbital.

BACKGROUND AND OBJECTIVE: To investigate the response to general anaesthetics of different sodium channel subtypes, we examined the effects of pentobarbital, a close thiopental analogue, on single sodium channels from human ventricular muscle and compared them with existing data from human brain channels. METHODS: Sodium channels from preparations of human ventricular muscle were incorporated into planar lipid bilayers in the presence of batrachotoxin, a sodium channel activator. Single channel currents were recorded in symmetrical 100 mmol L-1 and 500 mmol L-1 NaCl before and after the addition of the anaesthetic pentobarbital (0.34-1.34 mmol L-1). RESULTS: The blocking effect of pentobarbital on the fractional open time had an IC50 of 690 micromol L-1 in 500 mmol L-1 NaCl, whereas it had a significantly lower IC50 of 400 micromol L-1 in 100 mmol L-1 NaCl. Pentobarbital caused a significant shift of steady-state activation to hyperpolarized potentials (fmax = -42 mV, IC50 = 2 mmol L-1). This effect was independent of NaCl concentration. CONCLUSION: Despite pharmacological and electrophysiological differences between human cardiac and human brain sodium channels their responses to pentobarbital are similar. The finding of channel block being dependent on the electrolyte concentration is novel for sodium channels.

Single sodium channels from human ventricular muscle in planar lipid bilayers.

Sodium channels from human ventricular muscle membrane vesicles were incorporated into planar lipid bilayers and the steady-state behavior of single sodium channels were examined in the presence of batrachotoxin. In symmetrical 500 mM NaCl the averaged single channel conductance was 24.7 +/- 1.3 pS and the channel fractional open time was 0.85 +/- 0.04. The activation midpoint potential was -99.5 +/- 3.1 mV. Extracellular tetrodotoxin blocked the channel with a k(1/2) of 414 nM at 0 mV. In 7 out of 13 experiments subconductance states were observed (9.2 +/- 1.2 pS). When sodium chloride concentration was lowered to 100 mM, single channel conductance decreased to 19.0 +/- 0.9 pS, steady-state activation shifted by -17.3 +/- 5.1 mV, tetrodotoxin sensitivity increased to 324 nM, and sub-conductance states were invariably observed in single channel records (7.9 +/- 0.7 pS). In the planar lipid bilayer system the properties of cardiac sodium channels from different species are not very different, but there are significant differences between sodium channels from human heart and from human CNS.

Mitotic arrest of female germ cells during prenatal oogenesis. A colcemid-like, non-apoptotic cell death.

The sequence of events and a possible reason for germ cell death during oogenesis in the prenatal ovary were studied in rat and mouse embryos. ED 14-22 rat and ED 14-16 mouse embryos were studied using semithin sections for light microscopy and serial ultrathin sections for electron microscopy. In addition, the rat material was 3H-thymidine labelled for historadioautography and cytospin preparations of freshly obtained gonads were immunohistochemically analysed. During the transition from the proliferating oogonial stage to the meiotic prophase about 16% of the postmitotic oocytes do not pass the initial meiotic checkpoint on ED 18/19 in the rat (ED 15/16 in the mouse). These germ cells first show structural signs of mitosis; the diploid number of 'super-condensed' chromosomes are globally formed and are concentrated in the center of the cell. Although the germ cells show all morphological signs of living cells they never have mitotic spindles; the micro-tubulus-organisation-centres (MTOCs) are found peripherally and become concentrated, forming a single centrosomal body (acentriolar MTOC) as detected by immunohistochemistry for the centrosomal protein MPM2 and gamma-tubulin. EM studies show 25 nm tubule-like profiles within the MTOC bodies. The centrioles frequently lie separate from the MTOC material or are not present at all; the germ cells are apparently arrested in a prophase- or metaphase-like stage when they have reached the postmitotic G2/preleptotenal transition and are unable to enter meiosis. Forty-eight to 72 h after the first mitotically arrested germ cells are found, degeneration is seen in these germ cells. This second event, the germ cell death proper, shows neither criteria of apoptosis (cell shrinkage, marginal condensation of chromatin, DNA fragmentation) nor signs of necrosis (cell swelling, pycnosis, inflammation). Both arrested pro- and metaphase-like stages are found with signs of cell death and phagocytosis. The morphological signs of phagocytosis are found in neighbouring pregranulosa cells. The final heterocytotic bodies contain the remnants of the centrosomal (MTOC) material and DAPI-positive DNA material. The pregranulosa cells are mitotically silent during the phase when mitotic arrest and germ cell degeneration is found. The results suggest the presence of a hypothetical 'anti-spindle' factor, which under normal conditions is necessary for induction of meiotic prophase. The structural events of 'arrested mitosis' is reminiscent of those induced by the antimitotic, tubule-degrading drug colcemid. This type of arrest may inhibit meiosis of more than 33% prenatal germ cells and induce their cell death.

Distinct molecular sites of anaesthetic action: pentobarbital block of human brain sodium channels is alleviated by removal of fast inactivation.

Fast inactivation of sodium channel function is modified by anaesthetics. Its quantitative contribution to the overall anaesthetic effect is assessed by removing the fast inactivation mechanism enzymatically. Sodium channels from human brain cortex were incorporated into planar lipid bilayers. After incorporation, channels were exposed to increasing concentrations of pentobarbital (pentobarbitone), either before or after fast inactivation had been enzymatically removed using trypsin. Anaesthetic suppression of these channels with or without the fast inactivation site was compared by analysing single channel currents. Treatment with cytoplasmic trypsin alleviated two-thirds of the pentobarbital block on open channel probability (fractional channel open time). The hyperpolarizing shift in steady-state activation caused by pentobarbital was not affected by treatment with trypsin. Extracellular trypsin was ineffective. These results support a model of general anaesthetic action on sodium channels in which anaesthetics produce a concentration-dependent shift in the distribution between activated and inactivated states towards fast inactivation. Some pentobarbital effects remained after removal of inactivation. The results support a multi-mechanistic model of anaesthetic action on brain sodium channels.

Steady-state properties of sodium channels from healthy and tumorous human brain.

This extensive bilayer study of unpurified human brain channels from non-diseased and tumorous human brain involves more than 300 lipid bilayer experiments. Single channel conductances and subconductances, single channel fractional open times, the voltage-dependence of tetrodotoxin (TTX) block and the steady-state activation behavior of four different human brain synaptosomal preparations have been examined. Reproducible values have been obtained for the molecular electrophysiological parameters and their standard deviations, providing a database for future comparisons involving disease or drug-related changes in molecular sodium channel functions. In comparison with sodium channels from other species and under other experimental conditions, the bilayer system proved to be a reliable experimental setting. Despite the very different histology of the tissue probes, there were no significant differences in any of the examined electrophysiological features.

Blocking effects of the anaesthetic etomidate on human brain sodium channels.

Sodium channels from human brain tissue were incorporated into voltage-clamped planar lipid bilayers in presence of batrachotoxin and exposed to increasing concentrations of the intravenous anaesthetic drug etomidate (0.03-1.02 mM). Etomidate interacted with the sodium-conducting pathway of the channel causing a concentration-dependent block of the time-averaged sodium conductance (computer fit of the concentration-response curve: half-maximal blocking concentration, EC50, 0.19 mM; maximal block, block(max), 38%). This block of sodium-conductance resulted from two distinct effects (I) major effect: reduction of the sodium-channel amplitude and (II) minor effect: reduction of the fractional channel open-time. These results were observed at concentrations above clinically-relevant serum concentrations (up to 0.01 mM), suggesting only a limited role for human brain sodium channels in the mechanism of action of etomidate during clinical anaesthesia.

Germ cell kinetics during early ovarian differentiation: an analysis of the oogonial cell cycle and the subsequent changes in oocyte development during the onset of meiosis in the rat.

The aim of this study was the comparison between the mitoses of oogonia and the initial stages of oocyte meiosis. The structural alterations that the germ cell chromatin undergoes during the oogonial mitosis have been compared with those occurring during the G1- and S-phase just before meiosis. Using plastic embedded 1-microm sections of fetal rat ovaries (embryonic days = ED 14-20) labeled with 3H-thymidine and re-embedded for electron microscopy, a study of the structural conditions of the nuclear chromatin has been combined with a kinetic analysis of the oogonial cell cycle and the transitional period into the meiotic prophase. After ovarian differentiation (ED 14) the oogonia show a non-clonal, but strong proliferation. On ED 16, proliferation changes to a clonal pattern and decreases during ED 17. A final increase in 3H-thymidine incorporation on ED 18 characterizes the meiotic S-phase. On ED 19 the nuclear labeling drops to zero. The mitotic cycle of the oogonia lasts 16.5 hr and can be divided into 11 stages according to the concept of El-Alfy and Leblond [(1988) Am. J. Anat., 183:45-56] on the basis of the chromatin pattern. The S-phase (10.0 hours) extends from the telophase-interphase transition through the interphase to early prophase. The postmitotic G1- and S-phases show a more extensive duration, respectively 10 and 11.5 hours, and differ from their oogonial counterparts by the spherical shape of the nuclei from the very beginning. The chromatin pattern is similar until the end of the S-phase and lacks any prophase-like, preleptotenal chromatin condensation before the oocytes exhibit (pre-) leptotenal structures. Once the germ cell has completed a sequence of clonal mitotic divisions, it irrevocably progresses into meiosis. During an extended postmitotic period, the structural characteristics of meiosis emerge stepwise.

Primordial germ cells of the rabbit are specifically recognized by a monoclonal antibody labelling the perimitochondrial cytoplasm.

Instrumental for studies investigating the development of germ cells, and especially the separation of the germline in the early embryo, are molecular markers which reliably label germ cells and with which regulative factors of germ cell development may be analyzed. Here, we describe the monoclonal antibody PG-2, which is highly specific for the germ cells of the rabbit embryo and labels the perimitochondrial cytoplasm, as demonstrated by immunogold-silver staining. Identical expression patterns are found in germ cells of either sex from early organogenesis at 10 days post-conception (d.p.c.), when the germ cells leave the hindgut epithelium and settle in the gonadal anlage as primordial germ cells (PGCs), until the time immediately prior to birth (30 d.p.c.), when germ cells are either in their oogonial or prospermatogonial state. The antibody is the first to recognize specifically a cytoplasmic epitope in germ cells of a higher vertebrate and may well recognize the mammalian equivalent of the germ plasm found in invertebrates and lower vertebrates. The antibody can be used for early identification of PGCs and may be of help in the elucidation of mammalian germ cell development towards the gonial stages of spermatogenesis and oogenesis.

No evidence for specific opioid effects on batrachotoxin-modified sodium channels from human brain synaptosomes.

Human central nervous system (CNS) sodium channels modified by batrachotoxin and incorporated inter voltage-clamped lipid bilayers, were exposed to various concentrations of the opioid alfentanil (0.2-8.0 mM). Alfentanil caused a concentration-dependent and membrane potential independent reduction of the single channel amplitude and the fractional channel open-time. The weighted computer fit of the dose-response curve yielded a maximal conductance block of 50% with an EC50 of 1.3 mM. These effects occurred at levels beyond clinically relevant human serum/brain levels (0.003 mM) but within the predicted concentration range using the Meyer-Overton (lipid solubility/anaesthetic potency) correlation. Thus, human CNS sodium channels are probably not a main target site for the clinical effects of alfentanil but they provide a model system to estimate the proportion of the lipophilic interactions contributing to its overall effect.

[Do general anesthetics act on specific receptors?]. / Greifen Allgemeinanästhetika an spezifischen Rezeptoren an?

First of all, the meanings of the terms anaesthesia, anaesthetic and receptor are defined. Examples of anaesthetic actions in model systems are then described and compared with clinical actions of anaesthetics. When anaesthetics achieve a certain membrane concentration, they begin to influence membrane protein function in a nonspecific manner. If the anaesthetic drug possesses polar functional groups in addition to lipophilic ones, it may selectively affect membrane proteins and interact with them specifically. The absolute lipophilicity of a drug does not necessarily determine whether or not a drug is a suitable anaesthetic. Rather, it is important that the drug does not show undesirable side effects when it achieves a critical membrane concentration at which lipophilic interactions occur. There are examples of specific interactions of general anaesthetics with receptors as well as examples of nonspecific effects on membranes. Whether these interactions are important for anaesthesia remains to be seen.

Dissecting pentobarbitone actions on single voltage-gated sodium channels.

In order to begin separating the roles of membrane protein structure and membrane protein milieu in anaesthetic interactions a new planar lipid bilayer technology is being used. Membrane proteins such as sodium channels from diverse tissue sources are inserted into identical lipid and aqueous environments where they can be examined and compared electrophysiologically in great detail. The results obtained with pentobarbitone suggest that some anaesthetic interactions may be general and conserved, while other anaesthetic interactions may depend on the particular sodium channel isoform. Furthermore, the alteration of the membrane lipid composition can modulate anaesthetic effects. These results suggest that some cells may be more sensitive to anaesthetics than similar cells in other tissues which express a different sodium channel type or a different membrane environment. Therefore, caution must be exercised when generalizing findings concerning anaesthetic interactions with channels from one tissue or cell type to all other channel isoforms.