Lenograstim for the treatment of neutropenia in patients receiving ganciclovir for cytomegalovirus infection: a randomised, placebo-controlled trial in AIDS patients.

This phase IIa, randomised, single-blind, placebo-controlled study was conducted to determine the dose of recombinant human granulocyte colony-stimulating factor (lenograstim) suitable for use in AIDS patients. The study was conducted at 27 European AIDS/HIV centres, and recruited 69 AIDS patients with an initial episode or relapse of cytomegalovirus infection (neurological site excluded) and an absolute neutrophil count (ANC) < or = 1.0 x 10(9)/L upon diagnosis or between days 1 and 12 of ganciclovir (GCV) treatment. The patients were randomised to placebo (n = 14) or one of four lenograstim arms: 150 microg/m2/d (the standard onco-haematology dose, n = 13) or 100 (n = 13), 50 (n = 15), or 25 microg/m2/d (n = 14). In all groups, the planned dose of GCV was 10 mg/kg/d for 21 d. Median ANC at weeks 2 and 3 was significantly higher in each lenograstim group than in the placebo group (p = 0.05). At week 3, median ANC (x 10(9)/L) was 0.7 in the placebo group, compared with 6.0, 7.4, 4.5, and 2.0 in the 150, 100, 50, and 25 microg2/d lenograstim groups, respectively. Median ANC was not significantly different between the 150, 100, and 50 microg/m2/d lenograstim groups at any time point, but significantly higher in the 50 than in the 25 microg/m2/d group at weeks 2 (p = 0.05) and 3 (p = 0.02). Lenograstim was generally well tolerated, leading to no severe adverse events. In conclusion, lenograstim 50 microg/m2/d is suitable for the treatment of ganciclovir-induced neutropenia and is safe. These results should help the physician choose an optimal and cost-efficient regimen for patients with AIDS-related neutropenia when rHuG-CSF support is indicated.

Lenograstim as support for ACE chemotherapy of small-cell lung cancer: a phase III, multicenter, randomized study.

This phase III study was conducted to evaluate the usefulness of lenograstim as support for ACE (doxorubicin, cyclophosphamide, and etoposide) chemotherapy in previously untreated patients with small-cell lung cancer. Patients were randomized to receive up to six 3-week cycles of either ACE alone (n = 139) or ACE with lenograstim support (150 microg/m2/day subcutaneously, days 4-13, n = 141). Compared with the chemotherapy-alone group, the lenograstim support group was more likely to achieve neutrophil recovery (absolute neutrophil count, > or =1.5 x 10(9) cells/l) by day 14 (95.8-100% vs. 14.3-24.1% across the cycles) and less likely to experience at least one infectious episode (36.7 vs. 54.0%; p = 0.004), chemotherapy delay (51.8 vs. 56.2%; NS), or dose reduction (17.3 vs. 27.7%; p = 0.037). Objective response and event-free and overall survival rates were similar. Lenograstim was well tolerated. Lenograstim may allow the interval between cycles of ACE to be reduced to 2 weeks; such dose intensification may lead to more favorable objective response and survival rates.

Origin of the central entrainment of respiration by locomotion facilitated by MK 801 in the decerebrate rabbit.

In order to establish the origin of the central coupling between locomotion and respiration which operates in freely moving mammals during galloping, we sought experimental conditions that readily lead to such a coupling in decerebrate and curarised rabbit preparations. In such preparations, stimulation of the mesencephalic locomotor region (MLR) evokes locomotor activities, recorded from hindlimb muscle nerves, that are rarely totally coordinated with phrenic inspiratory activity. However, low doses (0.2 mg/kg i.v.) of MK 801, a non-competitive NMDA antagonist which has been shown to increase the activity of the spinal locomotion generators (Fenaux et al. 1991), dramatically enhanced this coupling during MLR stimulation in most experiments: 1/1 coupling was dominant but 2/1 and 3/1 couplings (i.e. two or three locomotor cycles per respiratory cycle) were also obtained. Compared with spontaneous respiratory activity, which was apneustic under these conditions, the respiratory period was drastically decreased during coupling. However, a further transection of the spinal cord at the C6 or C7 level, which isolated the spinal locomotion generators from the supraspinal levels, totally suppressed this reduction of the inspiratory period during MLR stimulation in the presence of MK 801. In experiments where locomotor activity was simultaneously recorded at forelimb and hindlimb levels, the 1/1 evoked locomotor-respiratory coupling remained after the lumbar cord had been isolated by L1 spinal transection. The present data do show that intact spinal mechanisms are required for entrainment to occur. They suggest either tha a common supraspinal drive cannot entrain locomotion and respiration when being depressed, or that respiration is entrained at the locomotor rate by the spinal locomotion generators.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of hindlimb muscle afferents involved in ventilatory effects observed in decerebrate and spinal preparations.

Neurogenic changes of phrenic activity have previously been observed during periodic passive motions of one hindlimb in decorticate, unanaesthetized and curarized rabbit preparations before and after high spinal transection (Palisses et al. 1988). In decerebrate and spinal preparations, we aimed to determine, through rhythmic electrical stimulation of hindlimb muscle nerves, which muscle afferents are involved in these effects. In decerebrate preparations, these electrical stimulations (trains of shocks at 80 Hz for 300 ms every second for 20 s) produced ventilatory effects when group I + II afferent fibres of either flexor or extensor nerves were stimulated together and more powerful changes as soon as group III fibres were recruited. Stimulation of group I fibres alone induced no such effects. When present, these changes in respiratory activity consisted of a maintained decrease of the respiratory period due to both inspiratory and expiratory time shortening; in addition, the amplitude of the phrenic bursts greatly increased at the onset of electrical stimulation. After spinal transection at C2 level and pharmacological activation by nialamide and DOPA, only short-lasting phrenic bursts developed spontaneously; the electrical stimulation of group II and mainly group III flexor afferent fibres induced large amplitude phrenic activity whereas the stimulation of the same extensor afferents was relatively ineffective. The activation of phrenic motoneurones during group III flexor afferent stimulation was closely linked to each 300 ms period of stimulation. While the phrenic effects obtained in the spinal preparations by natural and by electrical periodic stimulation are quite similar to each other, those produced in decerebrate preparations differ substantially.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of an NMDA-receptor antagonist, MK-801, on central locomotor programming in the rabbit.

NMDA has been shown to disclose spinal fictive locomotor activity in various in vitro preparations. In the present work the NMDA-mediated effects of endogenously released excitatory aminoacids (EAA) on fictive locomotion in the adult rabbit preparation were assessed in vivo using systemic injections of a non competitive NMDA-antagonist, MK-801. In acute low spinal and curarized preparations, the amplitude of the "spontaneous" fictive locomotor activities recorded from hindlimb muscle nerves after nialamide-DOPA pretreatment was much decreased in flexor and extensor nerves after MK-801 administration (0.25 mg/kg i.v.) whereas the locomotor period increased slightly. The more potent locomotor bursts, evoked by repetitive sural nerve stimulation at 10 Hz during 10 s, were differently affected after MK-801: the main effect was a lengthening of the locomotor period and a less drastic drop in the burst amplitude. These changes in the burst period were maximal for activities evoked by A fibre group stimulation (+100%) and less when C fibres were recruited (+70%). In decerebrate curarized preparations where the locomotor sequences were evoked either by sural nerve stimulation or by stimulation of the mesencephalic locomotor region, MK-801 (0.25 mg/kg i.v.) caused the same drop in burst amplitude (by at least 50%) as in the spinal preparation but, in contrast, it reinforced rhythmic bursting: this was revealed by a clear shortening (up to -65%) of the locomotor period and by the prolongation of rhythmic bursting after stimulation. All these effects obtained in decerebrate preparations were maximal 20-30 min after MK-801 injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for respiratory interneurones in the C3-C5 cervical spinal cord in the decorticate rabbit.

In mammals, it has long been considered that the bulbo-spinal inspiratory drive provided a direct (monosynaptic) excitation of phrenic motoneurones (Phr Mns). Although such connections have been demonstrated, recent indirect data strongly suggested that the main inspiratory drive is polysynaptic. We tried to directly demonstrate relay respiratory interneurones at the C3-C6 spinal cord level where the Phr Mn pool is located. The experiments were performed on decorticate, unanaesthetized, bilaterally vagotomized and curarized rabbits and the firing pattern of spinal interneurones was compared to the phrenic bursting. Dorsally and dorso-medially to the Phr Mn pool, different classes of inspiratory (54%) and expiratory (46%) interneurones could be identified in the ventral horn. Three classes of inspiratory interneurones were characterized and classified as "I all" (26%), "I late" (43%) and "I tonic" (29%) according to the terminology used by other authors for the bulbospinal inspiratory neurones which drive the spinal respiratory motoneurones. The expiratory interneurones could also be divided into 3 classes: "E all" (48%), "E late" (10%) and "E tonic" (41%). This first direct evidence of inspiratory interneurones at the C3-C6 spinal cord levels can account for the major polysynaptic excitation of the Phr Mns while the presence of numerous expiratory interneurones at this level suggests a polysynaptic bulbo-spinal inhibitory action onto the Phr Mns. These classes of inspiratory and expiratory interneurones did not always coincide with the bulbo-spinal classes of neurones described elsewhere.(ABSTRACT TRUNCATED AT 250 WORDS)

Reflex modulation of phrenic activity through hindlimb passive motion in decorticate and spinal rabbit preparation.

The neurogenic effect of passive hindlimb movement on phrenic nerve discharge was compared in decorticate unanaesthetized and curarized rabbit preparations prior to and after spinal transection. The question of how and where sensory information has access to the central respiratory network was addressed in each case. All passive motions, performed using a mechanical device, were of constant amplitude in a given preparation. The results clearly differed in decorticate and spinal preparations. In the decorticate vagotomized preparation, periodic passive motions led to an immediate shortening of the respiratory period which lasted throughout the periodic stimulation and stopped with its cessation; it did not depend on the frequency of the natural stimulation and was entirely due to a 20% shortening of the expiration time. Maintained full flexion or full extension both induced the same expiration time shortening, but limited to the first two to three respiratory cycles after onset and interruption of stimulation. After spinal transection at the C2 level, and moderate activation with DOPA, no phrenic activity developed in the absence of proprioceptive stimulation. Periodic hindlimb movements evoked simultaneous large bursts in both phrenic nerves during each extension; a 1:1 coordination of phrenic activity with the external imposed period (P) was observed for various P values. A strong phrenic activation could also be elicited through maintained full hindlimb extension but not through full flexion: this activation appeared as rhythmic discharge as long as extension was maintained. It is concluded that proprioceptive inputs act upon the medullary respiration generator and reset its own rhythm whereas, at the spinal level, they elicit an amplitude modulation at phrenic motoneuronal level without acting upon the rate of the spinal "respiration" generator itself; on the same phrenic motoneurons, a subthreshold central activation added to a subthreshold proprioceptive activation probably accounts for the phrenic bursting during maintained extension. Finally, the proprioceptive control from the hindlimb on phrenic activity is processed at different sites of the central respiratory network at medullary and at spinal level, and may depend on different input signals.

Different mechanisms involved in supraspinal and spinal reflex regulation of phrenic activity through chest movements.

The coordination of breathing activity with chest movements was compared in the same decorticate rabbit preparations prior to and after a transection at the C2 spinal level. Pharmacological activation was induced with a combination of nialamide and DOPA in the latter situation. The preparation was curarized and chest inflations and deflations were induced by a respirator whose parameters could be modified. In decorticate preparations, phrenic activity was coordinated 1:1 with the respirator period over a large range of imposed periods. Beyond the extreme values a new coupling was achieved with a ratio of either 1:2 or 2:1. Throughout the range of 1:1 coordination, phrenic bursting always happened at a preferred time in the respirator period, although this time differed for the various imposed periods. This coordinated activity required vagal inputs. After spinal transection the phrenic nerves were totally silent; DOPA administration allowed rhythmic activity to develop. In some preparations, phrenic bursts were coordinated 1:1 with the respirator period and remained so for all the imposed periods: the phase of these phrenic discharges relative to the respirator cycle was kept unchanged for the different periods. In addition, there was a modulation of amplitude superimposed on this 1:1 coupling. These spinal phrenic bursts were generally suppressed when the respirator was turned off. From these results, the coordination of phrenic activity with the respirator rate appears to be produced by different mechanisms in the decorticate and in the spinal preparations. In the decorticate animal the periodic vagal inflow reset the activity of the medullary inspiratory generator and entrains it at its own rate. The coordination observed in the spinal preparation results from a periodic peripheral activation of premotoneuronal or motoneural phrenic elements during inflation. If the central bursts provided by the spinal "respiration" generator can fire phrenic motoneurons above threshold, their timing is not dependent on the peripheral inflow; when the motoneurons are fired below threshold by these central inputs, they are probably summing together the central and peripheral excitations, which could account for the amplitude modulation of the coordinated phrenic bursts of pure reflex origin. Possible afferent pathways are discussed.

Changeover from alternate to synchronous bilateral pattern of the phrenic bursts entrained by fictive locomotion in the spinal rabbit preparation.

Phrenic bursting resulting from locomotor entrainment during fictive locomotion was shown previously in high spinal preparation after nialamide-DOPA administration. The temporal evolution of the bilateral pattern of phrenic vs locomotor activity is considered here. At variance with the bilateral locomotor pattern which is always alternate (fictive stepping), the pattern on both phrenic nerves changes with time after DOPA injection: first alternate, left and right phrenic bursts become synchronous. A study of ipsilateral phrenic-locomotor phase relationships allowed to disclose the way the transition from alternate to synchronous phrenic coupling was achieved: synchronism appeared as resulting from a strong facilitation on the overlapping parts of the bilaterally alternating phrenic bursts; this phase shifting, vs the ipsilateral locomotor pattern, accounts for the transfer of phrenic bilateral coupling.

Relationship between phrenic and hindlimb extensor activities during fictive locomotion.

In decorticate and in spinal curarized rabbit preparations, respiratory and locomotor rhythms can be closely related (1:1 coupling between successive periods), demonstrating central relationships between the two types of pattern generators. In both preparation types, phrenic discharges are highly correlated to the extensor activities.

[Existence of respiratory interneurons in the cervical spinal cord of the rabbit]. / Existence d'interneurones respiratoires dans la moelle cervicale du lapin.

A spinal "respiration" generator has been shown to fire phrenic motoneurones in rhythmic bursts. It is very likely driven through bulbo-spinal inspiratory neurones in intact preparations. Although no direct evidence for respiratory interneurones at the C4-C5 spinal levels has been obtained so far (except for Renshaw cells ), it is currently believed that only few inspiratory inputs to the phrenic motoneurones are transmitted monosynaptically from the medulla. We have tried here to record spinal interneuronal respiratory activities in decorticate, unanaesthetized, vagotomized and curarized rabbit preparations. Different functional categories of interneurones could be identified at the C4-C5 spinal levels: inspiratory and expiratory interneurons with various discharge patterns which rather well correspond to the functional categories of inspiratory and expiratory bulbo-spinal neurones described by Bianchi and Richter. In addition, multiunit inspiratory bursting could be followed over several 100 microns during each electrode penetration. The different categories of interneurones were encountered laterally from 700 to 1,000 microns, at depths ranging from 300 to 500 microns dorsally to the phrenic nucleus, down to the nucleus itself. These results indicate that part of the medullary inspiratory drive is channelled via spinal cord interneurones; they also suggest that an inhibition of phrenic motoneurones from the bulbo-spinal expiratory drive takes place via interneurones.