Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma.

PURPOSE: To evaluate the safety and efficacy of fludarabine plus rituximab in treatment-naive or relapsed patients with low-grade and/or follicular non-Hodgkin's lymphoma. PATIENTS AND METHODS: This was an open-label, single-arm, single-center phase II study enrolling 40 patients. During the first week of the study, patients received two infusions of rituximab 375 mg/m2 administered 4 days apart. Seventy-two hours after the second infusion of rituximab, patients received the first of six cycles of fludarabine chemotherapy (25 mg/m2/d for 5 days on a 28-day cycle). Single infusions of rituximab were administered 72 hours before the second, fourth, and sixth cycles of fludarabine, and two infusions of rituximab were given 4 weeks after the last cycle of fludarabine. Treatment duration was 26 weeks. RESULTS: An overall response rate of 90% (80% complete response rate) was achieved in the intent-to-treat population. Similar response rates were seen in treatment-naive and previously treated patients. The median duration of response has not been reached at 40+ months. The median follow-up time in this study is 44 months (range, 15 to 66 months). In patients positive for the 14;18 translocation in blood and/or marrow at enrollment, molecular remission was achieved in 88% of cases, with patients remaining negative for up to 4 years to date. Hematologic toxicity was manageable, and except for a 15% incidence of herpes simplex/zoster infections, infectious complications were rare. Nonhematologic toxicities were minimal. CONCLUSION: Rituximab plus fludarabine was well tolerated and associated with an excellent complete response rate, including molecular remissions, in patients with low-grade or follicular lymphoma.

Phase I and pharmacological study of the novel topoisomerase I inhibitor 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) administered as a ninety-minute infusion every 3 weeks.

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11; Irinotecan), a semisynthetic analogue of camptothecin (CPT) with broad preclinical antitumor activity, has demonstrated impressive activity in phase II trials in Japan in advanced small and non-small cell lung, colorectal, cervical, and ovarian carcinomas, as well as in refractory lymphomas and leukemias. In this phase I and pharmacological study, 90-min infusions of CPT-11 were administered every 3 weeks at doses ranging from 100 to 345 mg/m2 to patients with solid malignancies. Acute, severe, and refractory vomiting, diarrhea, and/or abdominal cramps associated with flushing, warmth, and diaphoresis occurred in the immediate posttreatment period at the 240-mg/m2 dose level in several patients who were not treated with premedications. The characteristics and temporal nature of these toxicities, the prompt resolution of symptoms following treatment with diphenhydramine, and the successful use of a premedication regimen consisting of ondansetron and diphenhydramine in preventing these acute effects suggest that vasoactive substances are involved in the mediation of these acute toxicities. With the routine use of these premedications, there was no single toxicity type that limited the escalation of CPT-11 doses. Instead, a constellation of severe hematological and gastrointestinal effects precluded the repetitive administration of CPT-11 at doses above 240 mg/m2, the maximum tolerated dose and recommended phase II dose on this schedule. Major responses were observed in patients with advanced colorectal, cervical, and renal cancers. The disposition of total CPT-11 in plasma was fit by a biexponential kinetic model with renal elimination accounting for 37 +/- 4% (SE) of total drug disposition. The Cmax for the active metabolite of CPT-11, 7-ethyl-10-hydroxycamptothecin (SN-38), was achieved at 2.2 +/- 0.1 h after treatment, and mean residence times for both CPT-11 and SN-38 were long, 9.1 and 10.0 h, respectively. Compared with topotecan, another CPT analogue under development, a larger proportion of total drug exposure was accounted for by the active lactone (closed-ring) forms of CPT-11 and SN-38; areas under the time-versus concentration curve for their respective lactone were 44 and 50% of areas under the time-versus-concentration curve for total CPT-11 and SN-38. Although intermittent dosing schedules appear to be superior to single dosing schedules for CPT and some CPT analogues in preclinical tumor models, the maintenance of biologically relevant concentrations of SN-38 for relatively long durations may negate the potential pharmacological benefits of intermittent and continuous administration schedules for CPT-11.(ABSTRACT TRUNCATED AT 400 WORDS)

Functional and morphological evidence for the existence of neurites from abdominal ganglion bag cell neurons in the head-ring ganglia of Aplysia.

Three lines of evidence are presented indicating that axons of the Aplysia neuroendocrine bag cells extend into the head-ring ganglia of the CNS. When the abdominal ganglion was bisected longitudinally, separating the two bag cell clusters, an afterdischarge induced in one cluster generated an afterdischarge in the other via activity through the head-ring ganglia to which each half abdominal ganglion was attached by connective nerves. This suggests that some axons of bag cells in each cluster communicate through the head-ring ganglia. Retrograde labelling of bag cells occurred when rhodamine-conjugated latex microspheres were injected into the cerebral or either pleural ganglion, a direct demonstration that bag cell axons extend into these ganglia. Finally, cell LP1 in the left pleural ganglion was inhibited during a bag cell afterdischarge, an action mimicked by application of alpha-bag cell peptide (alpha BCP). Since alpha BCP can act only close to its site of release due to susceptibility to peptidase activity, it is likely that LP1 inhibition is dependent on the local release of alpha BCP from bag cell neurites in the pleural ganglion. These results open new possibilities for how bag cell afterdischarges may be initiated and broaden the distribution of their effects.

Peptide B induction of bag-cell activity in Aplysia: localization of sites of action to the cerebral and pleural ganglia.

The bag cells of the marine mollusc Aplysia are model neuroendocrine cells involved in the initiation of egg laying and its associated behaviors, but the natural stimulus triggering bag-cell activity is not known. The atrial gland of A. californica, an exocrine organ in the reproductive tract, contains two structurally related peptides (A and B) which can induce an afterdischarge in vitro, and these peptides can be used to probe the central nervous system for sites where extrinsic excitatory input onto the bag-cell system might occur. These sites were identified in a series of lesion and ablation experiments. The entire central nervous system was removed from an animal and placed in a chamber with two compartments which could be independently perfused, allowing peptides (atrial gland extract or purified peptide B) to be selectively applied to specific regions of the nervous system while bag-cell activity was monitored using extracellular suction electrodes. Afterdischarges were consistently and reliably induced when peptides were applied to the cerebral ganglion, the pleural ganglia, the cerebropleural connectives, or the rostral 10-15% of the pleurovisceral connectives, provided that an intact neuronal pathway connected the site of peptide application with the bag cells. In contrast, afterdischarges were never observed when peptides were selectively applied to the buccal or pedal ganglia and only rarely observed when applied to the abdominal ganglion and caudal pleurovisceral connectives. These results support the hypothesis that bag-cell processes and/or neuron(s) presynaptically excitatory to the bag cells are located in the pleural and cerebral ganglia and narrow the region of the central nervous system where the critical initiator element(s) can be identified.

Effects of synthetic bag cell and atrial gland peptides on identified nerve cells in Aplysia.

We have examined the effects of peptides on the neuroendocrine bag cells, the R2 neuron and the left upper quadrant (LUQ) neurons of the abdominal ganglion of Aplysia californica. Peptides include those extracted from the atrial gland, a reproductive organ; those released by an afterdischarge of the bag cells; and 2 synthetic peptides: the amidated 9-amino acid C-terminal portion of atrial gland peptides A/B/ERH (B26-34), and the 8-amino acid alpha-bag cell peptide (alpha-BCP1-8). Peptides were applied by superfusion, arterial perfusion, pressure ejection from micropipettes, or by inducing a bag cell afterdischarge. Both alpha-BCP1-8 and B26-34 are able to produce a bag cell afterdischarge when applied to the abdominal ganglion but are not as effectively able to trigger the bag cells when applied selectively to the ganglia of the head ring. Peptides released by the bag cells inhibit R2 and LUQ neurons; whereas atrial gland extract mildly excites LUQ neurons and powerfully excites R2. The inhibitory effect of the LUQ cells and R2 following an afterdischarge of the bag cells is mimicked by alpha-BCP1-8. The excitatory effect of the atrial gland extract cannot be duplicated with B26-34. Rather, instead of having an excitatory effect on R2 and LUQ cells, B26-34 seems to mimick alpha-BCP1-8 and inhibit these neurons. Both peptides produce a membrane conductance increase in R2 and LUQ cells.

Aspects of copulatory behavior and peptide control of egg laying in Aplysia.

The atrial gland of the marine mollusc Aplysia is associated with the large hermaphroditic duct of the reproductive system and contains several peptides capable of inducing egg laying. The structure and function of these peptides are briefly reviewed. It has been hypothesized that during copulation the atrial gland of the female is stimulated by penile insertion to release its peptides, which in turn initiate events leading to egg deposition. To test this hypothesis we monitored reproductive activity over periods of weeks in individual, paired, and grouped A. brasiliana. It was found that copulation is not a necessary stimulus for egg laying, because individually housed Aplysia lay more eggs than when they are paired and allowed to copulate. Nor is copulation a sufficient stimulus, because the vast majority of copulations are not followed by egg laying. Simultaneous egg laying and female copulatory behavior were often observed with grouped and paired animals, but these events are probably not causally related. It is concluded that although the atrial gland contains at least three peptides that can induce egg laying, stimulation of this gland during copulation does not normally serve to initiate egg laying.

Does the Mauthner cell conform to the criteria of the command neuron concept?

The relationship between the Mauthner (M) cell action potential of the bullfrog tadpole and the rapid tail-flip was studied with electrophysiological and video-recording techniques. Single action potentials were elicited in the M-cell by vibratory stimulation or electrical stimulation of the eighth cranial nerve. These impulses were followed by a tail-flip to the side contralateral to the M-soma. Similarly, a tail-flip was produced by direct intracellular stimulation of the M-cell. Hyperpolarization of the M-soma blocked orthodromic action potentials and prevented the tail-flip. Therefore, the M-cell action potential appears to be sufficient and necessary to produce a rapid tail-flip which is associated with a naturally observed startle behavior.

Physiological properties of the penis retractor muscle of Aplysia.

The properties of the penis retractor muscle of Aplysia have been studied using intracellular, sucrose gap and tension recording. The fibers are of the invertebrate smooth muscle type and exhibit slow contractions which occur spontaneously or in response to stretch in isolated preparations. Individual muscle fibers are innervated by excitatory and inhibitory axons. A variety of sizes of excitatory and inhibitory junctional potentials can be recorded from them. The innervation is probably diffuse and functionally polyneuronal. The fibers are electrically coupled, permeable to potassium and chloride at rest, and exhibit no overshooting active responses. The muscle shows graded responses of depolarization and contraction proportional to strength of nerve stimulation. Facilitation and depression of junctional potentials are seen with various frequencies of nerve stimulation. Post-tetanic potentiation occurs with nerve stimulation at frequencies from 2 to 50 Hz and is suppressed in the presence of increased extracellular calcium concentrations.

Penis-retractor muscle of Aplysia: excitatory motor neurons.

Cobalt axonal iontophoresis and intracellular recordings were used to identify a cluster of several motor neurons innervating the penis-retractor muscle of Aplysia. Intracellularly recorded motor neuron action potentials elicited direct, one-for-one, constant latency excitatory junctional potentials (ejps) in individual muscle fibers. The axons of motor neurons could be recorded extracellularly in the penis-retractor nerve and stimulation of the nerve backfired the motor neurons. Perfusion of the ganglion, the muscle, or both with solutions of either increased Mg++/decreased Ca++ or increased Ca++ sea water indicated that the presumed motor neuron impaled was not a sensory cell and that interneurons were not intercalated in the pathway. Innervation of muscle fibers was found to be functionally polyneuronal and diffuse. The ejps were found to undergo marked facilitation with repetitive motor-neuron stimulation. The motor neurons were isolated in a distinct cluster in the right pedal ganglion. Their electrical activity was characterized by spontaneous irregular action potentials and a moderate input of postsynaptic potentials.