Vinca Alkaloids

Most antimicrotubules agents are alkaloids, structurally complex plant-derived organic bases. Vinca alkaloids are the first widely used class of antimicrotubule agents in cancer chemotherapy. They are cell-cycle-specific vesicants derived from the pink periwinkle plant, Catharanthus roseus (L.) G. Don. Vincristine and vinblastine are the two representative compounds. Vinorelbine is a vinblastine semisynthetic derivative with broad antitumor activity as a single agent that may not be completely cross-resistant with vincristine and vin-blastine. Their antitumor and toxicity spectra vary significantly. This variability may arise from different tubulin isotypes, lipophilicity, or cellular retention.

Cytotoxicity of vinca alkaloids is principally related to the microtubular depolymerization by inhibiting microtubule assembly, resulting in metaphase arrest in G2 and M cell-cycle phases in dividing cells. This explanation is oversimplified, as the lowest drug concentration that induces metaphase arrest and antiproliferative effects results in little or no dis ruption of the mitotic spindle apparatus or depolymerization. The vinca alkaloids have pleitropic biologic effects not necessarily related to their effects on microtubules, such as inhibiting purine, DNA, RNA, and protein synthesis. They are also potent inhibitors of angiogenesis. As microtubules function in cell processes other than mitosis, vinca alkaloids also affect cells in the nonmitotic phases of the cell cycle.

Thse vinca alkaloids are primarily eliminated by hepatic metabolism and biliary excretion. Hepatic metabolism is principally mediated by P-450 CYP3A. Agents that can increase toxicity include l-asparaginase and CYP3A inhibitors such as erythromycin. On the other hand, they can reduce the bioavailability of certain drugs such as digoxin and phenytoin. Vinca alkaloids are administered intravenously. Vinorelbine is orally bioavailable, although a commercial formulation is not yet available. Vincristine has the longest terminal half-life and the lowest clearance rate, whereas vinorelbine has the shortest half-life and the highest clearance rate. Vinca alkaloids should never be administered intrathecally, as the global dissolution of brain and spinal cord neurofilaments that ensues is fatal.


Vincristine has the greatest affinity for tubulin and has the highest degree of intracellular accumulation among the vinca alkaloids. These characteristics, together with its pharmaco-kinetic properties, are implicated in the associated neurotox-icity. Neurotoxicity is cumulative and the severity is related to total dose and duration of therapy. Motor dysfunction is usually irreversible. Autonomic neuropathy may be manifest as ileus, constipation, urinary retention, orthostatic hypotension, or hypertension. Central effects, such as seizure and blindness, have been reported. Aside from drug discontinuation or dose/schedule modification, approaches to prevent or reduce neuropathy include the use of folinic acid and glu-tamic acid. Severe myelosuppression is rare. In therapy, vin-cristine is unique in that a single maximum dose delivered is typically limited to 2 mg to prevent and/or delay the development of neurotoxicity. It is an integral component in chemotherapy regimens for lymphomas, Ewing's sarcoma, rhabdomyosarcoma, leukemias, and neuroblastoma.

Vinblastine and Vinorelbine

Neurologic effects are much less common and severe with vinblastine and least with vinorelbine. Myelosuppression, especially neutropenia, is the major dose-limiting toxicity of both vinblastine and vinorelbine. Mucositis and stomatitis happen more frequently with vinblastine than vincristine. Constipation, as with vincristine, occurs frequently. Vin-blastine is an important component for regimens used in testicular carcinomas and lymphomas. Vinorelbine has demonstrated activity in advanced non-small cell lung cancer, breast cancer, and ovarian carcinomas as well as lymphomas.


Taxanes affect microtubules through a mechanism of action unique from the vinca alkaloids. Unlike the vinca alkaloids, which facilitate microtubule depolymerization, taxanes shift the dynamic equilibrium toward microtubule assembly, prevent depolymerization, and therefore suppress microtubu-lar reorganization. The binding site for taxanes is different from that for vinca alkaloids, GTP, podophyllotoxins, and colchicine. Sustained mitotic arrest at the metaphase-anaphase boundary, apoptosis, and antiangiogenesis may be observed even at low concentrations where increase in micro-tubule bundling is not seen. Taxanes also exert inhibitory effects on nonmitotic cell-cycle phases, attesting to the myriad functions subserved by microtubules. They have also been shown to be effective radiosensitizers. This radiosensi-tizing effect is most likely related to their ability to cause cell-cycle arrest in the G2 and M phases of the cell cycle, when tumor cells are highly susceptible to the effects of radiation. Taxanes are intravenously administered because of poor oral bioavailability, due in part to the constitutive overexpression of P-glycoprotein in enterocytes as well as the first-pass metabolism in the liver and/or intestines. They are widely distributed to almost all tissues and third-space fluid collections except the CNS. Plasma protein binding is high (more than 90%), and elimination half-lives are long. The principal route of metabolism is through the hepatic cytochrome P-450 system. Biliary excretion is the main route of elimination as renal clearance accounts for less than 10%. Dose reductions are therefore necessary in patients with hepatic dysfunction. Reversible and noncumulative neutropenia is the principal toxicity of the taxanes in clinical use.


The prototype taxane, paclitaxel, is a complex alkaloid ester initially isolated from the bark of the Pacific yew tree, Taxus brevifolia. It is currently a semisynthetic derivative from 10-deacetylbaccatin III and other precursors found in the needles of other more abundant Taxus species, such as the European yew, Taxus baccata. Paclitaxel binds to the N-terminal 31 amino acids of the b-tubulin subunit of the tubulin oligomers.98 Aside from its effects on the microtubular system, in vitro experiments also showed inhibition of endothelial cell proliferation, motility, and invasiveness in a dose-dependent manner. Paclitaxel also inhibits the production of matrix metalloproteinases, which are enzymes that degrade matrix and thereby contribute to tumor invasiveness.

Clinical activity and toxicity of paclitaxel is highly dose-and schedule-dependent. Early clinical studies of paclitaxel were limited to 24-hour infusion schedules largely due to the severity of hypersensitivity reactions on shorter infusion schedules. However, the development of effective premed-ication regimens enabled reevaluation of shorter infusion schedules. The extensive distribution and high affinity of taxanes to peripheral tissue may explain the lack of significant differences in antitumor activity between the short and protracted infusion schedules. Patients treated with higher doses and/or shorter infusion schedules are more prone to neurotoxicity as compared to those treated with longer infusion. In contrast, both dose and duration of infusion are directly proportional to the degree of myelosuppression. Weekly treatment (80-100mg/m2/week), although more inconvenient than the conventional once every 3 weeks schedule (135 mg/m2 over 24 hours or 175 mg/m2 over 3 hours), has gained clinical acceptance. Weekly administration not only results in dose-dense therapy, it achieves a higher dose intensity, total cumulative dose over a 3-week period being higher than could be given in one dose. Weekly administration results in less myelosuppression and allows for better control of toxicities, as a dose may be omitted but treatment resumed the following week. This regimen results in sustained exposure of tumor cells to paclitaxel and simulates "metronomic" dosing as well that enhances its antiangio-genic activity.

The severity of myelosuppression seems to be related to prolonged infusions. Because of poor aqueous solubility, pacli-taxel is formulated in polyoxyethylated castor oil (cremophor EL), which leaches the plasticizer out of polyvinylchloride containers and tubings. Cremophor, known to induce histamine release, is most likely responsible for the well-recognized hypersensitivity reactions seen with paclitaxel. Major anaphylactoid manifestations include bronchospasm, urticaria, and hypotension that usually occurs within 2 to 3 minutes after administration. The taxane structure itself may be contributory. Before the routine use of premedication with antihistamines and corticosteroids, severe acute hyper-sensitivity reactions occurred in 20% to 30% of patients treated with paclitaxel in early Phase I trials. With standard premedication, the incidence of major hypersensitivity reactions nowadays is low (less than 5%) and similar for the 3- or 24-hour infusion. Particularly pertinent to paclitaxel is its effect on atrioventricular conduction, as it causes brady-arrhythmias, which are mostly reversible and asymptomatic. A direct causal relationship observed between paclitaxel and ventricular and atrial tachycardias has yet to be proven. Combination of paclitaxel and doxorubicin results in a higher frequency of congestive heart failure than would have been expected from an equivalent cumulative dose of doxorubicin given alone.


Docetaxel is a more water-soluble taxane semisynthetically derived from 10-deacetylbaccatin III, obtained from the needles of the European yew (Taxus baccata). It is more potent than paclitaxel and has nearly twofold-higher affinity for the b-tubulin subunit. In comparative studies, docetaxel has been found to be 1.3- to 12-fold more cytotoxic in vitro than paclitaxel. It has linear pharmacokinetics at clinically relevant doses, and its maximal activity can be achieved with fairly rapid infusion, in contrast to paclitaxel. Schedule-dependent activity thus seems not to be evident with doc-etaxel. It is highly protein bound, primarily to a-acid glycoprotein. CYP3A4 and CYP 3A5 constitute the major cytochrome P-450 isoforms responsible for the bulk of its metabolism.

Major anaphylactoid reactions induced by docetaxel are similar to those seen with paclitaxel although, unlike pacli-taxel, docetaxel is suspended in a polysorbate 80 formulation. Whether the polysorbate or the taxane moiety itself or both are responsible for the hypersensitivity reactions is unclear. With corticosteroid and histamine antagonist premedication, incidence of major hypersensitivity reactions is reduced to 1% to 3%. Peripheral neuropathy is less common and less severe with docetaxel. Unlike paclitaxel, adverse cardiovascular events such as arrhythmias are rare with its use, and docetaxel can be combined with anthracyclines without excessive cardiac toxicity. On the other hand, fluid retention mimicking capillary leak syndrome characterized by edema, pleural effusions, ascites, or anasarca is noted with docetaxel, particularly at cumulative doses that exceed 400mg/m2. Doc-etaxel also causes an erythematous, pruritic maculopapular rash over the forearms and hands in up to 75% of patients. It is associated with palmar-plantar erythrodysesthesia that may respond to cooling or pyridoxine. Premedication with corticosteroids has been shown to reduce the incidence of dermatologic toxicities and fluid retention.

Constipation Prescription

Constipation Prescription

Did you ever think feeling angry and irritable could be a symptom of constipation? A horrible fullness and pressing sharp pains against the bladders can’t help but affect your mood. Sometimes you just want everyone to leave you alone and sleep to escape the pain. It is virtually impossible to be constipated and keep a sunny disposition. Follow the steps in this guide to alleviate constipation and lead a happier healthy life.

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