Economic burden of haematological adverse effects in cancer patients: a systematic review.

OBJECTIVE: Patients receiving cancer treatments commonly experience haematological adverse effects (AEs) related to chemotherapy or molecularly targeted therapies, which may be associated with high healthcare costs. The objective of this review was to summarise the published literature on the economic burden of neutropenia, thrombocytopenia and anaemia as AEs of cancer treatment. METHODS: A systematic search of the medical literature published between 1990 and 2006 was conducted using PubMed/MEDLINE, EMBASE, BIOSIS, related article links and supplemental searches. References selected for inclusion were prospective or retrospective studies specifically designed to examine the burden of illness, direct medical costs, indirect costs and/or cost drivers associated with neutropenia, thrombocytopenia and anaemia in adult cancer patients. All costs are reported as originally published and adjusted to 2006 US dollars. RESULTS: In the US, the cost of neutropenia ranged from $US 1893 (2006 value $US 2632) per outpatient episode to $US 38,583 ($US 49,917) per febrile neutropenia hospitalisation. For countries outside the US, the cost of neutropenia appeared to be lower. The cost of thrombocytopenia ranged from $US 1035 ($US 1395) to $US 5328 ($US 7635) per cycle or episode in the US. Costs attributable to anaemia ranged from $US 18,418 ($US 22,775) to $US 69,478 ($US 93,454) per year in the US. The costs of AEs for patients with haematological malignancies appeared to be up to 2-3 times higher than those for patients with solid tumours. Economic studies of the cost of haematological AEs specific to new molecularly targeted treatments for haematological malignancy have not been published. CONCLUSIONS: Chemotherapy-related haematological AEs result in a substantial economic burden on patients, payers, caregivers and society in general. Because of their burden, the frequency and severity of these toxicities should be one of the key factors in the selection of optimal treatments for patients with cancer, especially those with haematological malignancies. Future research is needed to assess the economic burden of AEs associated with new molecularly targeted treatments for haematological malignancies.

Influence of excitatory amino acid receptor antagonists and of baclofen on synaptic transmission in the optic nerve to the suprachiasmatic nucleus in slices of rat hypothalamus.

Electrical stimulation of the optic nerve evoked two positive waves with short latency, followed by a large negative wave in the suprachiasmatic nucleus of slices of hypothalamus of the rat. The latency to peak of the two positive waves and the large negative wave were 2.7 +/- 0.1, 6.1 +/- 0.1 and 10.3 +/- 0.5 msec, respectively. Only the large negative wave disappeared in low calcium Ca2+-high magnesium (Mg2+) Krebs solution and with the addition of tetrodotoxin (1 microM) all the waves disappeared. Baclofen inhibited the large negative wave in a dose-dependent manner but not the two positive waves. Excitatory amino acid antagonists also inhibited only the large negative wave, i.e. it was reduced to about 70% by 1 mM glutamic acid diethyl ester and to about 50% by both 1 mM 2-amino-4-phosphonobutyric acid and 1 mM DL-2-amino adipic acid. All waves were unaffected by 0.1 mM atropine, hexamethonium and curare. These results indicate that two positive waves, induced by stimulation of the optic nerve are attributed to nerve conduction and the large negative wave to the neurons of the suprachiasmatic nucleus, and that the neuronal pathway from the optic nerve to the suprachiasmatic nucleus may include aspartate and/or glutamate as an excitatory neurotransmitter.

Effect of monoamines on field potentials in the suprachiasmatic nucleus of slices of hypothalamus of the rat evoked by stimulation of the optic nerve.

The effects of the application of serotonin, histamine, noradrenaline and dopamine to the bath on field potentials in the suprachiasmatic nucleus evoked by stimulation of the optic nerve were studied using a hypothalamic slice. Stimulation of the contralateral optic nerve evoked fast positive and late large negative waves in the suprachiasmatic nucleus. The monoamines produced a dose dependent suppression of the amplitude of the negative wave but did not affect that of the positive waves, and the order of potency was serotonin greater than noradrenaline greater than dopamine greater than or equal to histamine. The negative wave was suppressed by phenylephrine (0.1-10 microM) in a dose-dependent manner, whereas it was unaffected by isoproterenol (0.1-10 microM). The suppression of the negative wave produced by the application of histamine and noradrenaline was antagonized by the H1-receptor antagonist, diphenhydramine and the alpha 1-receptor antagonists, phenoxybenzamine and phentolamine. Therefore, the suppression of the negative wave by histamine and noradrenaline was mediated by the H1-receptor and alpha 1-receptor, respectively. The present study indicates that monoamines may play an inhibitory role in the regulation of neurotransmission in the retinohypothalamic pathway to the suprachiasmatic nucleus.

Single unit response of suprachiasmatic neurons to arginine vasopressin (AVP) is mediated by a V1-like receptor in the hamster.

A large population of local circuit neurons within the suprachiasmatic nucleus (SCN) exhibit immunopositive staining for arginine-vasopressin (AVP). AVP has been reported to be released from SCN neurons in a circadian pattern that peaks during the subjective day. Using an in vitro hypothalamic slice preparation, the present study investigated how SCN neurons respond to AVP over the circadian cycle and whether the response to AVP is mediated by V1- or V2-like AVP receptors. Exposure of the slice to AVP 10(-8) M produced excitatory responses in 51% of the 74 SCN neurons examined. A statistically significant day-night difference in the percentage of SCN units responding to AVP was observed (chi 2 = 15.62; P less than 0.01). During the dark phase 73% were excited by AVP, while during the light phase only 24% had excitatory responses. The threshold concentration of AVP ranged from 10(-9) to 10(-10) M and 10(-7) to 10(-8) M during the dark and light phase, respectively. In a second experiment the effects of selective V1 and V2 agonists and antagonists were determined. A V1, but not a V2 receptor antagonist was found to block the effects of AVP on single unit activity. Similarly, a V1 but not a V2 receptor agonist mimicked the effects of AVP.(ABSTRACT TRUNCATED AT 250 WORDS)

Ca(2+)- and Cl(-)-dependent, NMDA receptor-mediated neuronal death induced by depolarization in rat hippocampal organotypic cultures.

The neurotoxicity induced by depolarization with high-K+ was investigated in rat hippocampal organotypic slice cultures. The exposure of cultures to 90 mM K+ solution for 30 min caused a severe neuronal injury in CA1 region while less damage was observed in CA3 and dentate gyrus over the following day. This neurotoxicity was prevented in a concentration dependent manner by NMDA antagonist MK-801 or CPP. Non-NMDA antagonist, DNQX, had no protective effect. Omission of Ca2+ from the exposure solution prevented the neurotoxicity. Voltage-dependent Ca2+ channel blockers, nifedipine and flunarizine, failed to prevent the neurotoxicity. These results suggest that the Ca2+ influx through the NMDA receptor is predominantly involved in this neurotoxicity. Apparent tissue swelling was observed immediately after the depolarization. This swelling was completely inhibited by omission of Cl- from the exposure solution, accompanied with complete protection against neurotoxicity. This suggests that Cl(-)-dependent tissue swelling also largely contributes to the neurotoxicity. Depolarization with application of MK-801 (10 microM) or omission of Ca2+ from the solution still caused apparent swelling, despite these treatment protected neuronal death. We hypothesize that Cl(-)-dependent tissue swelling may be involved in the release of the excitatory amino acid, which activates the NMDA receptor.

Testosterone alters the behavioral response of the medial preoptic-anterior hypothalamus to microinjection of arginine vasopressin in the hamster.

The medial preoptic-anterior hypothalamus (MPOA-AH) is necessary for expression of several testosterone-dependent behaviors including a form of hamster scent marking, called flank marking. Since arginine vasopressin (AVP) plays a critical role in the control of flank marking by the MPOA-AH the present study examined whether testosterone can influence the amount of flank marking produced by AVP microinjected into the MPOA-AH. The dose-dependent induction of flank marking by AVP was found to be reduced by approximately 50% in castrated male hamsters when compared to intact or testosterone-treated castrates. These data demonstrate that testosterone influences the amount of flank marking produced by AVP within the MPOA-AH.

Electrophysiological studies of the development of suprachiasmatic neuronal activity in hypothalamic slice preparations.

The rate and pattern of neuronal discharge in the suprachiasmatic nucleus (SCN) during developmental stages were studied and compared with those of the ventromedial (VMH) and the lateral hypothalamus (LHA) using rat hypothalamic slices. The firing rate of the SCN neurons was low on the 7th and 11th days; however, it dramatically increased by the 14th day to reach the adult rate, while firing rates of VMH and LHA neurons increased gradually with age. The discharge rate of neurons in the ventrolateral part of the SCN (VL-SCN) was higher than that of the dorsomedial SCN (DM-SCN) neurons in 14-, 21- and 70-100-day-old rats. Activity of the DM-SCN neurons on day 21 were unaffected by bilateral enucleation on the third day, while activity in the VL-SCN decreased; that of both parts was significantly decreased by a constant light schedule.

U-92032, a T-type Ca2+ channel blocker and antioxidant, reduces neuronal ischemic injuries.

Several diphenylmethylpiperazine derivatives are potential therapeutic agents for prevention of ischemic injuries in the heart and brain, because of their ability to block Ca2+ currents and their antioxidant activity. In this study, the current lead compound, U-92032 ((7-((bis-4-fluorophenyl)methyl)-1-piperazinyl)-2-(2-hydroxyethylamin o)- 4-(1-methylethyl)-2,4,6-cycloheptatrien-1-one), has been compared with flunarizine and nifedipine (well-known T- and L-type Ca2+ channel antagonists, respectively) for their effects on Ca2+ channels in a mouse neuronal cell line, N1E-115 cells, and their ability to preserve the phenomenon of long-term potentiation and to improve neurological symptoms in gerbil ischemic models. U-92032, like flunarizine, blocked transient Ba2+ currents (IBa) through T-type Ca2+ channels with no effect on nifedipine-sensitive non-inactivating currents. Transient IBa was reduced by U-92032 at a constant rate, the magnitude of which depended on the drug concentration, probably because of a time-dependent accumulation of the lipophilic drug in the membrane phase. For instance, the drug at 6 microM reduced IBa by 21% per min and abolished it in less than 5 min, about 3 times faster than flunarizine at the same concentration. Otherwise, U-92032 behaved like flunarizine, showing a use-dependent block without noticeable effects on the current-voltage relationship for transient IBa. Oral administration of U-92032 (1 and 25 mg/kg) or flunarizine (25 mg/kg), but not nifedipine (50 mg/kg), to gerbils 1 h prior to bilateral carotid artery occlusion, preserved long-term potentiation in hippocampal CA1 neurons, which were largely abolished by ischemia without the drug treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of the circadian rhythm of neuronal activity in suprachiasmatic nucleus of rat hypothalamic slices.

Development of the circadian rhythm of neuronal activity in the suprachiasmatic nucleus (SCN) was studied in rat hypothalamic slices. The firing rate of SCN neurons of 7- and 11-day-old rat pups was low during all of the day, whereas that of 14- and 21-day-old pups was high during daytime and low during nighttime. The present results suggest that the circadian rhythm of SCN neuronal activity is established between 11 and 14 days of age, corresponding closely to the time of onset of the other various hormonal and behavioral circadian rhythms.

Different effects of amino acids, acetylcholine and monoamines on neuronal activity of suprachiasmatic nucleus in rat pups and adults.

A study was undertaken of the effects of iontophoretically applied amino acids, acetylcholine and monoamines on suprachiasmatic nucleus (SCN) neurons of rat pups, at the 11th postnatal day, using a hypothalamic slice preparation. GABA and taurine inhibited 97 and 42% of SCN neurons, respectively, while glycine had no effect. Glutamate excited 68% of them. These effects were similar to those in adult rats. Serotonin and noradrenaline inhibited 6 and 10% of SCN neurons, respectively, in rat pups, whereas 32 and 26% of them were inhibited in adult rats. Acetylcholine excited 7% but inhibited 26% of SCN neurons in rat pups and these values were almost the same as those of adult rats. These results reveal that acetylcholine and amino acids regulate SCN neurons even in rat pups, whereas monoamines play an important regulatory role in SCN activity in adult rats only.

Effects of dibutyryl cyclic adenosine monophosphate and dibutyryl cyclic guanosine monophosphate on neuron activity of suprachiasmatic nucleus in rat hypothalamic slice preparation.

In order to elucidate the role of cyclic nucleotides in the suprachiasmatic nucleus, we examined the effect of dibutyryl cyclic AMP (c-AMP) and dibutyryl cyclic GMP (c-GMP) on single neuronal activity of the suprachiasmatic nucleus of the rat. A hypothalamic slice about 300 micron thick, including the suprachiasmatic nucleus, was cut coronally using a vibratome. By means of bath- as well as iontophoretic application, c-AMP and c-GMP caused mainly an inhibition and facilitation in suprachiasmatic neuronal activity, respectively. The present results suggest that c-AMP and c-GMP play an important role in regulation of suprachiasmatic neuronal activity as a second messenger and that these two nucleotides may function as a reciprocal messenger.

Inhibitory and excitatory effects of histamine on suprachiasmatic neurons in rat hypothalamic slice preparation.

The effects of histamine (HA) and serotonin (5-HT) on single neurons of the suprachiasmatic nucleus (SCN) in hypothalamic slices were investigated by iontophoretic application. Sixty-two of 181 cells were inhibited by HA, whereas 30 were excited. Forty-nine of 163 cells were inhibited by 5-HT, whereas 9 were excited. Pyrilamine, an H1-antagonist, slightly (2/7), and cimetidine, an H2-antagonist, strongly (10/13) antagonized the inhibitory effect of HA. The excitatory effect of HA was not antagonized by cimetidine (0/4), but was perfectly antagonized by pyrilamine (5/5). The present results suggest that HA and 5-HT play mainly an inhibitory role in the SCN neuronal activity, and that inhibition and excitation induced by HA may be mediated by H2- and H1-receptors, respectively.

The role of calcium ions in circadian rhythm of suprachiasmatic nucleus neuron activity in rat hypothalamic slices.

The role of calcium ions in maintaining the circadian rhythm of suprachiasmatic nucleus (SCN) neuron activity was investigated using rat hypothalamic slice preparations. In normal Krebs solution, the firing rate of SCN neurons was higher in the light period than in the dark period. In Ca2+-free Krebs solution, SCN neuron activity was low during all periods and did not show diurnal rhythm. These results suggest that the disappearance of circadian rhythmic change of SCN neuron activity in Ca2+-free Krebs solution may be due to the disappearance of synaptic transmission in the SCN.

The role of inositol trisphosphate-induced Ca2+ release from IP3-receptor in the rat suprachiasmatic nucleus on circadian entrainment mechanism.

Synchronization between the environmental lighting cycle and the circadian clock in the suprachiasmatic nucleus (SCN) is correlated with Ca2+ increase. The mechanism underlying the increase of Ca2+ and its relation to clock resetting are unknown. To address these issues, we examined the possibility whether inositol 1,4,5-trisphosphate receptor (IP3-R), which regulate intracellular Ca2+, was involved in the circadian rhythm component of the rat SCN. A novel IP3-induced Ca2+ release modulator, 2-amino-ethoxy diphenylborate (2APB), blocked optic nerve stimulation-induced neuronal field potentials in the SCN. Furthermore, glutamate-induced phase delay of the circadian firing pattern in the SCN was also blocked completely by 2APB in vitro. Together, these data suggest the possibility that IP3-induced Ca2+ release through IP3-R plays a role in the entrainment of the mammalian circadian clock, the SCN.

Morphometric characteristics of optic disk with disk hemorrhage in normal-tension glaucoma.

PURPOSE: To evaluate the morphometric characteristics of the optic disk in eyes with and without disk hemorrhage in normal-tension glaucoma. METHODS: This was a prospective study conducted at Gifu University Hospital of 50 eyes of 50 patients with normal-tension glaucoma (12 men, 38 women; age, 56.5 +/- 14.1 years) who had developed new disk hemorrhage at the time of enrollment and 58 eyes of 58 patients with normal-tension glaucoma (20 men, 38 women; age, 56.7 +/- 12.4 years) with no history of disk hemorrhage during the follow-up period of more than 2 years. Age and global indexes of the visual field were matched. We morphometrically compared the optic disk with and without hemorrhage using a scanning laser tomograph. Global and sector analyses were made of the optic disk structural parameters. RESULTS: There was no significant difference in the global values of the disk parameters between the disk hemorrhage and the nonhemorrhage groups. However, the inferotemporal values for the rim area, rim volume, mean retinal nerve fiber layer thickness, and retinal nerve fiber layer cross-section area in the disk hemorrhage group were significantly smaller than those in the nonhemorrhage group (P <.05). In the disk hemorrhage group, moreover, the values for the rim area, rim volume, and retinal nerve fiber layer cross-section area in the inferotemporal sector with hemorrhage were significantly smaller than those in the same sector without hemorrhage (P <.05). CONCLUSION: Localized damage of the disk rim and retinal nerve fiber layer at the inferotemporal sector was prominent in eyes with disk hemorrhage.

Single unit response of neurons within the hamster suprachiasmatic nucleus to neuropeptide Y.

The effect of neuropeptide Y (NPY) on the spontaneous discharge of neurons within the hamster (Mesocricetus auratus) suprachiasmatic nucleus (SCN) (N = 83) was determined using the hypothalamic slice preparation. The discharge of neurons within the ventral SCN recorded during the day was either excited (6/42), immediately inhibited (17/42), or transiently excited and then inhibited (10/42) by NPY 10(-7). During the night, NPY produced excitatory effects in 2/23 neurons, inhibition in 7/23 and excitation followed by inhibition in 4/23. A higher percentage of neurons was found to be unresponsive to NPY during the night than during the day. This difference approached but did not reach statistical significance. In the 18 neurons recorded within the dorsal SCN, NPY had little effect on spontaneous discharge during the day or night. These data indicate that bath application of NPY predominately inhibits the spontaneous discharge of SCN neurons recorded in the hypothalamic slice preparation.

Single unit response of neurons within the hamster suprachiasmatic nucleus to GABA and low chloride perfusate during the day and night.

Using the in vitro hamster hypothalamic slice preparation, the effects of GABA and 80% chloride (Cl-) reduced medium on the single unit activity of SCN neurons was investigated. GABA 10(-4) M produced inhibitory responses in 55% of the 69 SCN neurons examined. No statistically significant day-night difference was observed in either the percentage of SCN units responding to GABA, or in their threshold response. During the day 80% Cl- reduced medium had an excitatory effect on SCN neurons; however, following the return to normal Cl- concentrations a transient, but significant inhibition was observed. During the night, 80% Cl- reduced medium produced an excitatory response similar to that observed during the day, but no inhibition following return to the medium containing normal Cl- concentrations. Only during the night was Cl- reduced medium found to initiate activity in a dose-dependent manner in some silent cells. No significant day-night difference in response to 80% Cl- reduced medium occurred in neurons of the paraventricular nucleus of the hypothalamus. These results indicate that SCN neurons whose activity is mediated by Cl- may be involved in the control of circadian rhythms.

Optic nerve stimulation-induced increase of release of 3H-glutamate and 3H-aspartate but not 3H-GABA from the suprachiasmatic nucleus in slices of rat hypothalamus.

This study investigates the possibility of glutamate and/or aspartate as an excitatory transmitter in the retinohypothalamic fibers' terminal within the anterior hypothalamus, including the suprachiasmatic nucleus (SCN). We studied the release of 3H-Glu and 3H-Asp from the SCN of rat hypothalamic slices produced by optic nerve stimulation. Stimulation of the optic nerve released 3H-Glu, 3H-Asp but not 3H-GABA, while stimulation of the SCN released all three. These releases were suppressed in both Ca2+ free Krebs and tetrodotoxin (TTX) 1 microM containing Krebs. The present result with previous electrophysiological observations strongly suggest that glutamate and/or aspartate are included in this retinohypothalamic termination, while GABA is included in intrinsic and/or extrinsic neurons of the SCN, excluding the terminal of the retinohypothalamic fibers.

Effects of GABA and anxiolytics on the single unit discharge of suprachiasmatic neurons in rat hypothalamic slices.

The effects of gamma-aminobutyric acid (GABA), muscimol, baclofen and the anxiolytics; diazepam (DZP), flurazepam (FZP) and zopiclone on single-unit neural activities in the suprachiasmatic nucleus (SCN) were investigated using the rat hypothalamic slice preparation. Exposure of the slice to GABA 10(-4) M produced inhibitory responses in 65% of the 49 SCN neurons examined. The threshold concentration of GABA ranged from 10(-6) to 10(-4) M. Neurons responsive to GABA were not found to be restricted to a subdivision of the SCN, but were diffusely distributed throughout the nucleus. DZP, FZP and zopiclone produced responses similar to those of GABA. The inhibitory effects of GABA (10(-5) M) were potentiated by coadministration of DZP (10(-5) M). Muscimol and baclofen (10(-7) M to 10(-4) M) also inhibited SCN neuronal activity in a dose-dependent manner. Bicuculline (10(-5) M-10(-4) M) scarcely affected the baclofen-induced inhibition (1/6) but strongly antagonized the effects of muscimol (6/6), GABA (6/8) and DZP (4/5). These results suggest that the receptors mediating the inhibitory effects of GABA and anxiolytics within the SCN may be GABAA and/or GABAB or GABA-BDZ receptor complex, respectively.

Field potentials in the suprachiasmatic nucleus of rat hypothalamic slice produced by optic nerve stimulation.

Spatial profile of a projection from retina to the suprachiasmatic nucleus (SCN) was studied by electrophysiological method. Stimulation of contralateral optic nerve evoked the fast positive and late large negative waves in only the ventrolateral but not the dorsolateral parts of the posterior SCN. This result, in agreement with anatomical evidence suggests that the late negative wave is due to excitatory synaptic potential in the SCN and has a role for elevating the neuronal activity in the ventrolateral part of the posterior SCN daytime.