Administration Of Vincristine Research Articles

Inadvertent intrathecal administration of vincristine: are we fulfilling our roles as oncology pharmacists?

Inadvertent intrathecal administration of vincristine: are we fulfilling our roles as oncology pharmacists?

Pharmacokinetics of Vincristine in Infants with Acute Lymphoblastic Leukemia.

An understanding of vincristine (VCR) pharmacokinetics (PK) is important to achieve drug dosing that optimizes efficacy and minimizes toxicity. Limited information is available on the PK behavior of VCR in infants.Objectives: To determine the PK of VCR in infants, and to compare the PK parameters of infants to those in older children.Methods: A subset of 28 patients enrolled on the Pediatric Oncology Group 9407 infant leukemia study participated in this VCR PK study. PK samples were collected following the administration of VCR (0.05 mg/kg) i.v. push on week 1, day 1 of treatment. Twenty-eight patients, median age 7.1 months (range, 0.1–11.9 months) had blood samples collected for analysis of VCR concentrations at 5 minutes, and 0.5, 1, 4, and 24 h after drug administration. Samples were analyzed using a validated LC-MS method. A two-compartment model was fit to each patients data using Bayesian estimation (Adapt II software).Conclusions: PK parameters in infants < and > 6 months of age were similar. CL in this population ranged from 7.8–31 ml/min/kg and was correlated with body weight, however only 25% of the variability in VCR CL could be accounted for by this variable. CL and t1/2 values are similar to those previously reported in older children. Evaluation of pharmacokinetic/pharmacodynamic correlation is ongoing.Results:VCR (mean ± SD)AUC (mcg•hr/L )41.7 ± 19CL (ml/min/kg)19.2 ± 6Vc (L/kg)1.3 ± 1t 1/2 elimination (h)17.1 ± 8.3Kcp (hr-1)5.2 ± 1.7Kpc (hr-1)0.3 ± 0.14

In vivo administration of liposomal vincristine sensitizes drug-resistant human solid tumors.

Here we evaluated the antitumor efficacy of vincristine (VCR) encapsulated in sphingomyelin/cholesterol liposomes (SM/Chol) on drug-resistant human solid tumors. We firstly used the M14 human melanoma line and the counterpart resistant derivative, M14/R. The M14/R, selected after doxorubicin exposure, was cross resistant to VCR: the in vitro treatment with free VCR reduced the survival of M14, while M14/R line was completely resistant to VCR. Encapsulation in liposomes improved the efficacy of VCR in M14 cells and sensitized the M14/R line to the drug. Experiments in vivo confirmed these results. The treatment of M14 bearing mice with VCR resulted in marked reduction of tumor growth, while no antitumoral effect was observed in M14/R tumors. The administration of VCR encapsulated in liposomes was able to sensitize M14/R tumors to the drug, the antitumoral effect being comparable to that observed in M14 tumors after the same treatment. By injecting animals with the same dose of liposomal VCR fractionated into 3 daily injections and administering repeated cycles of treatment, to a marked improvement of the antitumor activity of liposomal VCR was observed. TUNEL assay in tumor sections indicated that the improved efficacy of liposomal VCR was related to the induction of massive necrosis and apoptosis. To confirm the efficacy of liposomal VCR on drug-resistant tumors, MCF7 breast and LoVo colon carcinomas, sensitive and resistant to VCR treatment, were also employed. The results showed that the treatment with liposomal VCR of mice bearing breast or colon resistant tumors reduced the tumor mass and delayed the tumor regrowth to the same extent observed in the sensitive counterpart. Together, these results demonstrate the ability of VCR encapsulated in liposomes in sensitizing drug resistant tumors of different histotypes.

Acute sixth-nerve palsy after vincristine therapy

The chemotherapeutic effectiveness of vincristine was first reported in 1962, and with its increased use the incidence of reported neurologic side effects has also increased. We reported a case of acute sixth-nerve palsy occurring soon after administration of vincristine for acute lymphoblastic leukemia (ALL), a previously unreported side effect.

Paclitaxel in early breast cancer: a viewpoint by Aman U. Buzdar.

1. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the Adjuvant combination chemotherapy in patients randomized trials. Lancet 1998; 352: 930-42 with early-stage breast cancer can reduce the risk of 2. Levine MN, Bramwell VH, Pritchard KI. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil recurrence and death.[1] Anthracycline-containing chemotherapy compared with cyclophosphamide, methotrexcombinations are superior to cyclophosphamideate, and fluorouracil in premenopausal women with nodepositive breast cancer. J Clin Oncol 1998; 16 (8): 2651-8 methotrexate-fluorouracil combinations.[2,3] In earli3. Misset JL, di Palma M, Delgado M. Adjuvant treatment of nodeer decades, to improve on the anthracycline-containpositive breast cancer with cyclophosphamide, doxorubicin, ing combinations, sequential administration of modfluorouracil, and vincristine versus cyclophosphamide, methotrexate, and fluorouracil: final report after a 16-year median estly active agents like methotrexate and vinblastine follow-up duration. J Clin Oncol 1996; 14 (4): 1136-45 was evaluated,[4] but with limited success in the 4. Hortobagyi GN, Yap HY, Blumenschein GR. Phase II evaluaadjuvant and neoadjuvant setting.[5,6] tion of vinblastine, methotrexate and calcium leucovorin rescue in patients with refractory metastatic breast cancer. Cancer The availability of taxanes provided new hope as 1983; 51 (5): 769-72

Altered temporal pattern of evoked afferent activity in a rat model of vincristine-induced painful peripheral neuropathy

It is known that the level of activity in nociceptive primary afferent nerve fibers increases in neuropathic conditions that produce pain, but changes in the temporal patterning of action potentials have not been analyzed in any detail. Because the patterning of action potentials in sensory nerve fibers might play a role in the development of pathological pain states, we studied patterning of mechanical stimulus-evoked action potential trains in nociceptive primary afferents in a rat model of vincristine-induced painful peripheral neuropathy. Systemic administration of vincristine (100 μg/kg) caused approximately half the C-fiber nociceptors to become markedly hyperresponsive to mechanical stimulation. Instantaneous frequency plots showed that vincristine induced an irregular pattern of action-potential firing in hyperresponsive C-fibers, characterized by interspersed occurrences of high- and low-frequency firing. This pattern was associated with an increase in the percentage of interspike intervals 100–199 ms in duration compared with that in C-fibers from control rats and vincristine-treated C-fibers that did not become hyperresponsive. Variability in the temporal pattern of action potential firing was quantified by determining the coefficient of variability (CV2) for adjacent interspike intervals. This analysis revealed that vincristine altered the pattern of action-potential timing, so that combinations of higher firing frequency and higher variability occurred that were not observed in control fibers. The abnormal temporal structure of nociceptor responses induced by vincristine in some C-fiber nociceptors could contribute to the pathogenesis of chemotherapy-induced neuropathic pain, perhaps by inducing activity-dependent post-synaptic effects in sensory pathways.

Inadvertent Intramuscular Administration of Vincristine: Lack of Untoward Effects without Any Treatment Except Administration of Hot Compresses

A seven-year-old boy with acute lymphoblastic leukemia received vincristine sulphate 1 mg, 1 ml intramuscularly, into his glutea, inadvertently, in the local hospital. The mother, applied hot compresses for 16 hours, starting 6.5 hours after the injection. Then, she told, the slight pain and the reddened area which developed around the injection site dissappeared completely and he turned back to his daily activities. His physical examination, 2 weeks after the injection and during his follow-up revealed no abnormality.

Neutropenia Associated with Vincristine and L‐Asparaginase Induction Chemotherapy for Canine Lymphoma

Vincristine (VCR) and L‐asparaginase (L‐ASP) are commonly used to treat canine lymphoma. As single agents, these drugs are not myelosuppressive. However, in combination, VCR and L‐ASP cause severe neutropenia in some dogs. It has been recommended that L‐ASP be administered 12–24 hours after VCR to minimize toxicity. The purpose of this retrospective study was to determine the prevalence of neutropenia after VCR/l‐ASP induction therapy for canine lymphoma and to evaluate risk factors for myelosup‐pression, especially the interval between VCR and L‐ASP administration. Medical records of 147 dogs were reviewed. L‐ASP was given 0 (n = 50), 6 (n = 23), 18 (n = 20), or 24 (n = 54) hours after VCR. Forty percent of the dogs were neutropenic 7 days after VCR/L‐ASP, and 18% had neutrophil counts of &lt;l,000 cells/μL. The median neutrophil count was 3,712 cells/μL (range 0— 30,968 cells/μL). No correlation was found between administration interval and day 7 neutrophil count (P= .84) or development of gastrointestinal signs, including vomiting (P= .80), diarrhea (P= .52), and decreased appetite (P= .30). No significant predictors of neutropenia were identified. Higher clinical stage and substage b were associated with decreased appetite after treatment (P= .04 and .01, respectively). Sixteen percent of the dogs were hospitalized. This study demonstrates that VCR/L‐ASP induction for canine lymphoma may result in neutropenia but that separation of VCR and L‐ASP administration may not be necessary to avoid toxicity.

Olfactory epithelium as a novel toxic target following an intravenous administration of vincristine to mice.

To delineate morphological characteristics of olfactory lesions induced by vincristine (VCR), a vinca alkaloid derivative with antitumor activity, male BALB/c mice were given a single intravenous injection of 1.95 mg/kg, an estimated 10% lethal dose (designated as day 1). The animals were serially sacrificed on days 2, 3, 5, 10, 15 and 60, and the nasal mucosa was examined histopathologically. Cell death was noted in the olfactory epithelia adjacent to the respiratory epithelia from days 2 to 5. Inflammatory responses were not detected throughout the observation periods. Cell death was identified as apoptotic by the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL) assay and electron microscopy. Mitotic figures and proliferating cell nuclear antigen (PCNA)-positive reactions were diffusely scattered in both the basal and sensory cells. On days 10 or after, no prominent histological abnormalities were noted in the olfactory epithelia, which suggests the aforementioned lesions were completely recovered. These results demonstrate that it is essential to perform histopathological evaluation of the nasal mucosa during an early preclinical stage for novel antitumor drugs, since olfactory lesions due to the certain compounds like VCR may not be detected by any other procedure.

Intrathecal Vincristine: Long-Term Survivor of Potentially Fatal Chemotherapeutic Error

Intrathecal Vincristine: Long-Term Survivor of Potentially Fatal Chemotherapeutic Error

Potentiation of vincristine toxicity by itraconazole in children with lymphoid malignancies

Eight consecutive paediatric patients with acute lymphoblastic leukaemia (ALL) (n=7) and T‐cell non‐Hodgkin's lymphoma (NHL) (n=1) presenting within a 5‐wk interval were started on a standard induction protocol which included weekly treatment with vincristine for 4 wk. Itraconazole was commenced as antifungal prophylaxis, 1–21 d after the first injection of vincristine. Within 2 to 4 wk, enhanced vincristine neurotoxicity was noted in all patients, abdominal cramps and constipation occurred most frequently, and one patient developed a bowel perforation associated with paralytic ileus. Hyponatraemia associated with SIADH was observed in three patients and four patients developed seizures. An additional patient with B cell NHL developed seizures 5 d after an injection of vincristine. Recovery was complete in all patients and ranged from 2 d to 15 wk. Conclusion: The extent and consistency of adverse effects documented in this study support the recommendation that concurrent administration of vincristine and itraconazole should be avoided.

Potentiation of vincristine toxicity by itraconazole in children with lymphoid malignancies.

Eight consecutive paediatric patients with acute lymphoblastic leukaemia (ALL) (n = 7) and T-cell non-Hodgkin's lymphoma (NHL) (n = 1) presenting within a 5-wk interval were started on a standard induction protocol which included weekly treatment with vincristine for 4 wk. Itraconazole was commenced as antifungal prophylaxis, 1-21 d after the first injection of vincristine. Within 2 to 4 wk, enhanced vincristine neurotoxicity was noted in all patients, abdominal cramps and constipation occurred most frequently, and one patient developed a bowel perforation associated with paralytic ileus. Hyponatraemia associated with SIADH was observed in three patients and four patients developed seizures. An additional patient with B cell NHL developed seizures 5 d after an injection of vincristine. Recovery was complete in all patients and ranged from 2 d to 15 wk. The extent and consistency of adverse effects documented in this study support the recommendation that concurrent administration of vincristine and itraconazole should be avoided.

An antimicrotubule agent, TZT-1027, does not induce neuropathologic alterations which are detected after administration of vincristine or paclitaxel in animal models

One of the major dose-limiting toxicities induced by antimicrotubule antitumor agents such as vinca alkaloids and taxanes is peripheral neuropathy. The neurotoxicity of TZT-1027 (a dolastatin 10 derivative antimicrotubule agent) was thus assessed using the animal models for antimicrotubule agent-induced neurotoxicity. Rabbits were intravenously given TZT-1027 or vincristine weekly for 5 weeks. In the mouse study, TZT-1027, vincristine or paclitaxel was intravenously given every 2 days and/or weekly. Despite the neuropathologic evidence such as myelinated axonal and fiber degeneration in the peripheral nerves and in the sensory tracts of the spinal cord following the treatment with vincristine or paclitaxel, no drug-induced alteration was observed in the TZT-1027 groups. Although there are reports that some other dolastatin derivatives with antimicrotubule activity showed no neurotoxic potential in humans, the present study represents the first demonstration in experimental animals that a dolastatin derivative has no, or at least a lower, neurotoxic potential compared to other antimicrotubule agents.

Motor nervous pathway function is impaired after treatment of childhood acute lymphoblastic leukemia: a study with motor evoked potentials.

The objective was to evaluate whether motor nervous pathways are affected when patients are treated for childhood acute lymphoblastic leukemia (ALL). Thirty-two children with ALL were studied at the end of treatment by means of motor evoked potentials (MEPs) elicited by magnetic stimulation (MS) transcranially and peripherally and underwent a detailed neurological examination. Thirty-two healthy children matched with them for age, sex, and height served as a control group. The latencies of the MEPs were significantly prolonged along the entire motor nervous pathway in the patients with ALL compared with the healthy controls, indicating demyelination in the thick motor fibres. The MEP amplitudes of the distal extremities elicited by stimulation at the brachial plexus and LV spinal level were significantly lowered in the patients treated for ALL, also indicating anatomical or functional loss of descending motor fibres and/or muscle fibres. The MEP amplitudes elicited by cortical MS showed wider variation and no clear abnormalities were found. Neurological signs and symptoms were common after treatment: 41% of the patients had depressed deep tendon reflexes, 31% had fine motor difficulties and 63% gross motor difficulties, and 34% had dysdiadochokinesia. The conduction delay within the peripheral nerve was related to the post-therapeutic interval after administration of vincristine and the lesions within the CNS to the number of injections of intrathecal methotrexate. The present results show adverse effects of the ALL treatment on the entire motor nervous pathways. In our experience, the measurement of MEPs by MS provides an objective, painless, and practical tool for assessing the treatment-related neurotoxicity in both the CNS and the peripheral nerves. These disturbances in the motor nervous pathways at the end of treatment raise the question of the long-term effects of ALL treatment on the motor nerve tracts, and have led us to employ MEPs to study these effects in long-term survivors of ALL.

ENHANCED VINCRISTINE NEUROTOXICITY FROM DRUG INTERACTIONS: Case Report and Review of Literature

This study reports observed toxicity in a child with acute lymphocytic leukemia who had received vincristine (VCR) with nifedipine and itraconazole. A 5-year-old-child with leukemia developed bilateral cranial nerve palsies, severe peripheral neuropathy involving upper and lower extremities, seizures, hypertension, heart failure, and syndrome of inappropriate antidiuretic hormone secretion after being treated with VCR, nifedipine, and itraconazole. Appropriate management of the above problems including discontinuation of VCR resulted in recovery from neurotoxic manifestations. Concurrent administration of VCR with nifedipine and itraconazole may enhance its neurotoxicity.

Craniofacial growth of immature rats following administration of vincristine and doxorubicin.

The aim of the present study was to investigate the possible short-term effect of two anti-neoplastic drugs, vincristine and doxorubicin, on the craniofacial skeleton in young rats. On the basis of findings from pilot experiments, one dose of 0.0375 mg/kg vincristine or 1.0 mg/kg doxorubicin was given parenterally to inbred Long-Evans/Turku rats at 10 or 30 days of age, and followed up until 30 or 50 days, respectively. Some 30-day-old rats received two additional doses of the drugs, 3 and 6 days after the first injection. Controls were given physiological saline. A total of 310 rats were used: 40 for the pilot study, 180 medicated, and 90 control animals for the experiment itself. The weights of the rats were recorded, a number of craniofacial dimensions were measured, and the neurocranial volume determined in the case of the most severely affected rats. The weight gain of the younger rats was retarded, as was that of the older rats that received repeated drug injections. Most dimensions of the craniofacial skeleton were significantly smaller in the vincristine-treated young animals, and following multiple injections of vincristine or doxorubicin also in the older ones when compared with the controls. Contrary to the general pattern, the measurements of the foramen magnum increased in the older rats, a feature associated with the decrease in brain cavity volume observed in those that received vincristine. These findings indicate that anti-neoplastic agents can have a short-term adverse effect on the craniofacial growth and that the morphological changes are differential, rather than uniform.

Damage to the cytoskeleton of large diameter sensory neurons and myelinated axons in vincristine‐induced painful peripheral neuropathy in the rat

Vincristine, along with other antimitotic chemotherapeutic drugs, produces a peripheral neuropathy in humans that is accompanied by painful paresthesias, dysesthesias, and occasionally hypoesthesia, and by hyporeflexia (Holland et al. [1973] Cancer Res. 33:1258–1264; McLeod and Penny [1969] J Neurol Neurosurg Psychiatry 32:297–304; Postma et al. [1993] J Neurooncol. 15:23–27; Sandler et al. [1969] Neurology 19:367–374). Systemic administration of vincristine causes swelling of unmyelinated axons and disorientation of axonal microtubules (Tanner et al. [1998a1998a] J Comp Neurol. 395:481–492) at a time when it also produces allodynia and mechanical hyperalgesia (Aley et al. [1996] Neuroscience 73:259–265; Authier et al. [1999] Neuroreport 10:965–968) and enhanced responsiveness in C-fibers in the rat (Tanner et al. [1998b] J Neurosci. 18:6480–6491). Because slowing of A-fiber conduction velocities had also been demonstrated (Tanner et al. [1998b] J Neurosci. 18:6480–6491), and mechanical hyperalgesia can occur secondary to damage to large diameter sensory afferents (Basbaum et al. [1991] Can J Physiol Pharmacol. 69:647–651; Coggeshall et al. [1993] Pain 52:233–242; Woolf and Mannion [1999] Lancet 353:1959–1964), we sought to determine whether vincristine also induced ultrastructural changes in myelinated A-fibers. Moreover, since systemic treatment with vincristine did not cause profound microtubule depolymerization in the unmyelinated axons of the peripheral nerve, we hypothesized that the drug's effects may be more extensive in the cell body, because in the spinal ganglion, the blood-nerve barrier is less restrictive. We used quantitative ultrastructural methods to analyze the microtubule cytoskeleton in myelinated axons in the mid-shaft of the saphenous nerve and in the sensory ganglion cells. Vincristine induced swelling of the whole nerve and an increase in the cross-sectional areas of myelinated axons but no loss of myelinated axons. There was a significant decrease in axonal microtubules, as well as microtubule disorganization, in myelinated fibers from vincristine-treated rats. In the spinal ganglion, vincristine induced swelling of large diameter sensory neurons and a build-up of neurofilaments in the cell bodies and proximal axons, suggestive of impaired anterograde axonal transport. J. Comp. Neurol. 424:563–576, 2000. © 2000 Wiley-Liss, Inc.

Potential Salvage Therapy for Accidental Intrathecal Vincristine Administration: A Preliminary Experimental Study

Background: Accidental intrathecal vincristine (VCR) administration results in severe neurotoxicity, usually fatal in outcome. No specific therapy for initrathecal VCR toxicity has been reported so far. In our recent report, complete in vitro degradation of VCR by hypochlorous acid (HOCl) was demonstrated. Methods: In this comparative study, we examined the in vivo effectivity of HOCl in the cerebrospinal fluid of 24 New Zealand rabbits following intracisternal VCR administration. Results: There were no significant clinical or histopathologic abnormalities in the control and HOCl groups; however, multiple necrotic foci on histopathological examination of brain sections in the VCR group were determined. There were significantly lower numbers of necrotic foci in brain sections of rabbits which received HOCl administration than those without therapy. Conclusion: Our results indicate that HOCl may reduce VCR neurotoxicity.

Distribution and inducibility of P-glycoprotein in the catfish: immunohistochemical detection using the mammalian C-219 monoclonal

Mounting evidence suggests that the P-glycoprotein (pgp) efflux pump may be a modulator of bioavailability and a mode of excretion for xenobiotics. Immunohistochemistry was utilized to examine the distribution and inducibility of a pgp like protein in catfish. Immunoreactivity to the MDR C-219 monoclonal antibody was noted primarily in bile canaliculi or bile preductules of the liver, discrete areas of the extratubular region of the kidney and the columnar epithelia of the intestine. Regional differences in pgp content were noted in the intestine with the distal region containing greater pgp levels than the proximal intestine. Dietary administration of vincristine, a prototypic pgp inducer and β-naphthoflavone an Ah agonist resulted in induction of the C-219 immunoreactivity in the liver and the distal intestine. These results are consistent in location and inducibility with pgp like proteins and support a possible relationship to xenobiotic absorption and/or excretion in the catfish.

Vincristine impairs platelet aggregation in dogs with lymphoma.

Platelet aggregation before and after administration of 0.5 mg/m2 of vincristine (VCR) was evaluated in 7 dogs with spontaneously occuring lymphoma. Aggregation on platelet-rich plasma separated from blood collected in 3.8% sodium citrate was performed using adenosine diphosphate (ADP), arachidonic acid (AA), and collagen (COL) as agonists. The slope for aggregation in response to ADP was significantly lower after administration of VCR (P = .032). Maximal aggregation after administration of VCR was significantly lower in response to ADP, COL, and AA (P = .03, P = .04, and P = .03, respectively).