Pain-relieving properties of topically applied morphine on arterial leg ulcers: a pilot study.

OBJECTIVE: To assess whether topical morphine is pharmacologically effective in relieving pain from ulcers caused by arterial insufficiency and identify whether this effect is centrally or peripherally mediated. METHOD: The analgesic effect of a topically applied hydrogel containing 0.5% of morphine was evaluated in a double-blind, placebo-controlled, three-way crossover pilot study involving nine patients with painful arterial leg ulcers. All patients had a baseline pain intensity of at least 5 on a 10-point numeric rating scale. They received the following three treatments in random order: morphine hydrogel plus a subcutaneous (SC) placebo infusion; placebo gel plus a SC infusion of 5mg morphine over six hours and a placebo gel plus a SC placebo infusion. Each treatment lasted one day. Pain was assessed during the first 24 hours after application of the hydrogel and the start of the subcutaneous infusion. RESULTS: There was a statistically significant difference between average baseline pain scores and those reported during treatment, but this difference was not clinically relevant. The three treatments did not differ in terms of the pain relief provided. CONCLUSION: Topical morphine does not have a clinically relevant analgesic effect in patients with painful arterial leg ulcers. Further research should focus on ulcers of other aetiology.

In vitro modulation of cisplatin cytotoxicity by sparsomycin inhibition of protein synthesis.

Inhibition of protein synthesis can alter cellular responsiveness to the classical anticancer drugs. The in vitro response of Chinese hamster ovary (CHO) cells to cisplatin with or without sparsomycin (Sm) was studied with the use of [3H]leucine and [methyl-3H]thymidine incorporation and clonogenic assay. Pretreatment of exponentially growing CHO cells with 1 microgram Sm/ml for 3 or 5 hours decreased [3H]leucine incorporation by 20% and resulted in significant resistance to cisplatin (P = .005). Sm in a concentration of 10 micrograms/ml reduced [3H]leucine and [methyl-3H]thymidine incorporation after 3 hours by 92 and 84%, respectively, and resulted in potentiation of the cisplatin cytotoxicity (P = .004). This effect was the same in the case of nonproliferating cells (P = .005), while protection due to Sm (1 microgram/ml) was seen only during cell proliferation. Simultaneous incubation and postincubation with Sm proved to have much less or no potentiating effect on cisplatin. The mechanisms of both protection and potentiation are still not clear, but our data indicate that Sm is a promising drug for further studies on the modulation of the cancer cell response to classical anticancer drugs.

Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects.

The pharmacokinetics of a novel antipsychotic agent, risperidone, and the prolactin response were studied in 12 dextromethorphan-phenotyped healthy men after administration of 1 mg risperidone intravenously, intramuscularly, and orally. The formation of the equipotent major metabolite, 9-hydroxyrisperidone, exhibited CYP2D6-related polymorphism. The plasma area under the concentration-time curve from time zero to infinity ratio of 9-hydroxyrisperidone to risperidone averaged 3 (intravenous and intramuscular) and 6 (oral administration) in the extensive metabolizers and 0.2 in the poor metabolizers. Risperidone half-life was about 3 hours in extensive metabolizers and 22 hours in poor metabolizers. Risperidone absolute oral bioavailability was 66%. The pharmacokinetics of the active moiety (risperidone plus 9-hydroxyrisperidone) varied little among subjects (mean terminal half-life, 20 +/- 2 1/2 hours; absolute oral and intramuscular bioavailability, 100%). The prolactin response correlated best with the plasma active moiety, which showed little hysteresis. It is concluded that risperidone metabolic polymorphism on increased plasma prolactin is minimal and that the active moiety is clinically relevant.

Potential uses of topical opioids in palliative care--report of 6 cases.

Opioids used topically may exercise several useful clinical effects. Opioids may cause immediate local analgesia and also may work indirectly through decreasing the inflammation process. In this article we describe six patients treated with topical opioids because of cutaneous pain due to tumor infiltration. skin ulcers of malignant and non-malignant origin, severe oral mucositis, pain due to knee arthrosis and severe tenesmoid pain. In all but one case, topical morphine provided rapid relief which lasted usually for 7-8 h. The side effects of topical opioids were none or minimal. Possible mechanisms of topical analgesia are discussed.

Lipophilic analogues of sparsomycin as strong inhibitors of protein synthesis and tumor growth: a structure-activity relationship study.

Fourteen derivatives of sparsomycin (1) were synthesized. Six of them were prepared following a novel synthetic route starting from the L-amino acid alanine. Some physicochemical properties, viz. lipophilicity and water solubility, of selected derivatives were measured. The biological activity was tested in vitro in cell-free protein synthesis inhibition assays, in bacterial and tumor cell growth inhibition assays, and in the L1210 leukemia in vivo model in mice. Also for selected drugs the acute toxicity in mice was determined. Ribosomes from both an eukaryotic and a prokaryotic organism were used in the protein synthesis inhibition systems. A linear correlation between the lipophilicity parameters measured was observed. Water solubility and drug toxicity in mice were found to be linearly correlated with lipophilicity. All the derivatives studied are more lipophilic than 1. The deshydroxysparsomycin analogues (30-33) showed an interesting phenomenon: increase in hydrophobicity was accompanied by a considerable increase in water solubility. We found that an increase in hydrophobicity of the drug as a result of replacing the SMe group of 1 with larger alkylthio groups causes an increase in the biological activity of the drug. However, not only the hydrophobicity but also shape and size of the substituent are important; in the homologous series 1-9-10-11-12, 21-22-23-24, and 30-31-32-33, highest protein synthesis inhibitory and in vitro cytostatic activity is found with compounds 11, 23, and 32, respectively, and in comparison with the highly active n-butyl compound 10, the isomeric tert-butyl compound 13 is rather inactive. Polar substituents replacing the SMe group, i.e. Cl in 17 and 35, also render the molecule inactive. Substituting the bivalent sulfur atom for a methylene group decreases the drug's activity. This effect can be compensated for by increasing the length of the alkylsulfinyl side chain. The agreement between the results derived from cell-free and "in vivo" tests is good. The assays using ribosomes of bacterial and eukaryotic organisms give similar results although the latter seem to be more sensitive to changes in hydrophobicity of the drug. Our results confirm the presence of a hydrophobic region at the peptidyl transferase center of the ribosome; the interaction of sparsomycin with this region is more pronounced in the eukaryotic particles. The sparsomycin analogues 11, 23, and 30 show the highest antitumor activity against L1210 leukemia in mice, their median T/C values are 386, 330, and 216%, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Potentiation of cisplatin antitumor activity on L1210 leukemia s.c. by sparsomycin and three of its analogues.

Sparsomycin (Sm) is a known antibiotic derived from Streptomyces. Its potential antitumor activity stimulated the search for a synthetic production method and the development of new derivatives. In a recent screening investigation, three Sm analogues appeared to be more active and considerably less toxic than the parent drug. Sparsomycins became especially interesting when it was shown that Sm potentiates the antitumor activity of cisplatin. In the present study Sm and its three promising analogues: deshydroxy-Sm (dSm), ethyl-deshydroxy-Sm (EdSm) and n-pentyl-Sm (PSm) were studied for their cisplatin potentiating effect. The experiments were performed on CD2F1 mice inoculated with 10(6) L1210 cells s.c. Sparsomycins were administered i.p. 3 h before cisplatin on days 1, 5 and 9. Three of the drugs, Sm, dSm and PSm, showed no potentiating effect in this tumor model. At a dose of 10 mg/kg, EdSm potentiated cisplatin antitumor activity 2.8 times (P less than 0.01) without an increase in weight loss. These results warrant further investigation.

In vivo potentiation of cis-diamminedichloroplatinum (II) antitumor activity by pretreatment with sparsomycin.

The influence of protein synthesis inhibition by sparsomycin (Sm) on in vivo cisplatin activity has been studied on BALBc X DBA2: F1 mice bearing L1210 leukemia i.p. Sm alone at the dose range from 0.5 to 3.0 mg/kg did not significantly improve animal survival. Sm potentiated cisplatin activity only when given 3 or 6 h prior to cisplatin (P less than 0.001). Sm 0.5-1.5 mg/kg 3 h prior to cisplatin resulted in a significant prolongation of animal survival (P less than 0.001) and 66% cures in each group versus 0% due to cisplatin alone. Sm pretreatment decreased weight loss due to cisplatin suggesting that it probably is able to decrease cisplatin toxicity.

In vitro and in vivo anticancer activity of mitozolomide and sparsomycin in human tumor xenografts, murine tumors and human bone marrow.

The colony formation in agar of human tumor xenografts, of murine tumors and of human bone marrow was used as a test system to determine the in vitro activity of the two novel cytostatic agents, mitozolamide and sparsomycin. Mitozolomide was additionally studied in vivo in nine human tumor xenografts. The comparison of in vitro/in vivo activity allows an assessment of the relevant in vitro dose based on in vivo pharmacological behavior of a compound. Both compounds showed clear dose/response effects in vitro. A dose of 3 micrograms/ml mitozolomide, given by continuous exposure, was active (colony number of test less than 30% of the control group) in 12/42 (29%) human tumor xenografts as well as in the four murine tumors, P388, L1210, B16 melanoma and colon carcinoma 38, whereas the two human bone marrows showed no significant suppression of the ability to form colonies in culture. The comparison of in vitro with in vivo activity suggests that the in vitro dose of 3 micrograms/ml corresponds best to the activity observed in animal experiments. The highest activity was observed in small-cell cancer of the lung (4/5), followed by melanomas (2/7) and non-small-cell cancer of the lung (2/9). Furthermore, activity was found in a cancer of the large bowel, stomach, breast and in one sarcoma. In the treatment of nine human tumor xenografts growing subcutaneously in nude mice, mitozolomide effected a complete or partial remission in 6 out of 9 tumors. In comparison to standard drugs mitozolomide is one of the most effective compounds in these tumors. These data indicate that mitozolomide possesses potent broad-spectrum activity in human tumor xenografts. Sparsomycin (0.1 micrograms/ml, continuous exposure) was active in 11/46 (24%) human tumor xenografts and in 4/5 of the murine tumors, whereas the colony-forming capacity of four human bone-marrows showed no inhibition, suggesting that this dose level may be the relevant in vitro dose. However, the high in vitro activity in murine tumors is incompatible with the in vivo activity. In mice the only responsive tumor was leukemia P388, whereas the L1210, B16 melanoma and colon carcinoma 38 were resistant. At the dose level of 0.03 microgram/ml only 3/30 (10%) of the human tumor xenografts were sensitive. In an earlier clinical phase I study the dose-limiting adverse effect was eye toxicity and not bone-marrow suppression.(ABSTRACT TRUNCATED AT 400 WORDS)

Itch: scratching more than the surface.

In origin, itch can be cutaneous ("pruritoceptive", e.g. dermatitis), neuropathic (e.g. multiple sclerosis), neurogenic (e.g. cholestasis), mixed (e.g. uraemia) or psychogenic. Although itch of cutaneous origin shares a common neural pathway with pain, the afferent C-fibres subserving this type of itch are a functionally distinct subset: they respond to histamine, acetylcholine and other pruritogens, but are insensitive to mechanical stimuli. Histamine is the main mediator for itch in insect bite reactions and in most forms of urticaria, and in these circumstances the itch responds well to H(1)-antihistamines. However, in most dermatoses and in systemic disease, low-sedative H(1)-antihistamines are ineffective. Opioid antagonists relieve itch caused by spinal opioids, cholestasis and, possibly, uraemia. Ondansetron relieves itch caused by spinal opioids (but not cholestasis and uraemia). Other drug treatments for itch include rifampicin, colestyramine and 17-alpha alkyl androgens (cholestasis), thalidomide (uraemia), cimetidine and corticosteroids (Hodgkin's lymphoma), paroxetine (paraneoplastic itch), aspirin and paroxetine (polycythaemia vera) and indometacin (some HIV+ patients). If the remedies specified fail, paroxetine and mirtazapine should be considered. Ultraviolet B therapy, particularly narrow-band UVB, may be superior to drug treatment for itch in uraemia.

Pharmacokinetics and toxicology of sparsomycin in beagle dogs.

Sparsomycin is a cytotoxic drug exhibiting a broad spectrum of in vitro activity against murine tumors and many tumor cell lines. It also appears to be a potent stimulator of the antitumor activity of cisplatin against L1210 leukemia in vivo. However, because of its toxicity, the antitumor activity of sparsomycin on murine tumors in vivo has been disappointing. The purpose of our study was to investigate the pharmacokinetics of this drug as well as the possible mechanisms that produce sparsomycin toxicity. Tests on beagle dogs revealed that about 60% of the drug is eliminated by metabolic clearance, while 40% is eliminated by the kidneys. After a single bolus injection of 0.1 mg/kg sparsomycin without narcosis, sparsomycin was eliminated with a t beta 1/2 of 0.6-0.7 h, the AUC being 0.32-0.38 mg.h.l-1, and the volume of distribution (Vd) 0.26 l/kg. In addition to being subject to glomerular filtration, sparsomycin is probably also actively excreted and actively reabsorbed by the renal tubuli. Sparsomycin itself may inhibit its active tubular excretion, thus resulting in a decrease in the drug's renal clearance and its accumulation in the plasma. Sparsomycin appeared to be toxic primarily in the liver, disturbing its function and the synthesis of plasma proteins. Two out of five dogs developed hemorrhagic diathesis due to hypofibrinogenemia and deficiency of other blood-coagulation factors. Sparsomycin was not toxic to the bone marrow.

Understanding pruritus in systemic disease.

Many pruritic conditions do not originate in the skin, but are the result of systemic abnormality. Among the diseases that can cause pruritus are renal insufficiency, cholestasis, Hodgkin's lymphoma, polycythemia vera, solid tumors, and many others. Other pruritic conditions appear to be iatrogenic; opioid-induced pruritus may be the most important in palliative medicine. Successful treatment of the underlying condition usually relieves itch. But, with time, many diseases progress and treatment of the cause will be impossible. Topical treatments may be of limited value. Strategies involving systemic treatments include use of antidepressants, oral opioid antagonists, or cholestyramine. There is no one cure for all pruritic symptoms. Better understanding of mechanisms of pruritus may help develop better treatments.

Paroxetine for pruritus in advanced cancer.

Pruritus associated with malignancy may be one of the most bothersome symptoms in advanced cancer. Its control is still difficult to achieve and is a challenge to palliative medicine specialists. We describe five patients suffering from pruritus of different etiologies who responded rapidly to administration of paroxetine, a serotonin reuptake inhibitor, in a dose-dependent manner. Two patients experienced transient but severe nausea and vomiting. We suggest that paroxetine's antipruritic effect may be explained by rapid downregulation of the 5-HTs receptors, which may have an important role in the generation of pruritus and pain.

Modulation of the in vitro cytotoxicity of seven anticancer drugs by protein synthesis inhibition using sparsomycin.

Inhibitors of protein synthesis may modify cell response to cytotoxic drugs. The influence of protein synthesis inhibition using sparsomycin (Sm) on the cytotoxicity of seven classical cytotoxic drugs, 5-FU, ARA-C, MTX, doxorubicin, melphalan, bleomycin and vincristine, was studied. Preincubations, simultaneous incubations and postincubations with Sm were investigated in vitro on CHO cells. Preincubation with Sm antagonized the activity of the S phase specific drugs 5-FU, ARA-C, MTX as well as vincristine, while postincubation with Sm enhanced their effect. A similar pattern was observed with doxorubicin. Preincubation with Sm had a potentiated non-S phase specific like bleomycin and cisplatin, but not melphalan. Postincubation with Sm had a potentiating effect on bleomycin but had no effect on melphalan. These results indicate a strong, schedule dependent effect of Sm on various drugs and suggest some potentially useful combinations to be tested in vivo.

Preclinical pharmacokinetics of the antitumor antibiotic deshydroxy-sparsomycin in beagle dogs.

Sparsomycin (Sm) is a well known inhibitor of protein synthesis with anticancer potential. In order to minimize toxicity of this drug and increase its activity, several analogues were synthesized. Deshydroxy-Sm (dSm) appeared to be a good candidate for further investigations because of its lower toxicity and significantly higher antitumor activity in several ascitic tumors in mice. Pharmacokinetic evaluation in beagle dogs was performed using either single iv bolus or continuous infusion administrations. The drug was eliminated with a terminal t1/2 beta of 0.8 +/- 0.08 hours (48 +/- 5 minutes). The mean volume of distribution was 0.4 +/- 0.06 l.kg-1. The mean total body clearance was 6.4 +/- 0.8 ml.min-1.kg-1. The drug is eliminated mainly by the kidneys (54%). Active tubular secretion and active tubular reabsorption of the drug were observed. The pharmacokinetics was linear until the lethal dose. The results of this study provided additional data useful in selection of potentially useful analogues for further preclinical studies.

Studies on retinotoxic potential of a novel antitumor antibiotic--sparsomycin--in rats.

Sparsomycin (Sm) is a potent inhibitor of protein synthesis with an anticancer potential. Two years after its discovery in 1962 a phase I clinical trial revealed serious drug-induced retinotoxicity. The mechanism of this toxicity still remains unresolved; however, its understanding is important for the reintroduction of Sm or one of its analogues in clinical practice. If Sm penetrates the retina, its toxic effect should be seen as inhibition of a protein(s) vital for the visual function. Treatment of healthy albino rats and Royal College of Surgeon (RCS) rats with subtoxic doses of Sm was unable to produce ocular toxic effects. Disruption of the blood-retina barrier with sodium iodate allowed Sm to decrease opsin content by only 27%. These results strongly indicate that Sm might become retinotoxic solely upon extreme conditions such as permeabilization of the blood-retina barrier which may happen only in some rare pathological situations.

Ethical considerations in the treatment of pain in a hospice environment.

Most people treated in hospices suffer from pain. The hospice environment offers them a place where they may feel safe and get rest before they die. This particular environment was originally created to solve the many problems terminal patients encountered in busy modern hospitals. However, it is clear that solving some problems frequently means creating new ones. For people who are about to complete their life's journey, a hospice is a place of care and autonomy. Previous losses and severe spiritual distress complicate most of the severe pain conditions seen in hospices. In this paper, some specific ethical problems encountered in hospice practice will be discussed. Patients' autonomy with all its advantages and disadvantages will be highlighted. Acceptance of death may result in an active and creative attitude. Although scientific evidence of the processes taking place is still lacking, the modern hospice may be seen as a complementary, main-stream institution contributing to the development of whole medicine.

Oral opioids in the treatment of cancer pain.

Persistent severe cancer pain should be treated with opioid drugs, principally morphine. It can be administered orally, rectally and parenterally. Morphine is metabolised in the liver mainly to glucuronides, of which morphine-6-glucuronide is a powerful analgesic. Oral morphine should be administered regularly and in individualized doses. The use of morphine is frequently accompanied by adverse effects such as constipation, nausea, vomiting and sedation. Management of these is critical for successful pain treatment. Although alternatives are available none has any clear advantage over morphine in cancer pain, and should be reserved for special situations. Oral morphine is successful in more than 90% of cancer pain patients. Slow release morphine sulphate tablets (MS Contin) are often the best choice. For the few patients who need parenteral medication, continuous subcutaneous morphine sulphate infusion is generally the most suitable. Some pains are morphine resistant, especially those due to nerve injury. In these cases pain is best treated with tricyclic antidepressants and/or anticonvulsants.

[Laxative policy for terminal patients ineffective]. / Laxantiabeleid bij terminale patiënten ondoelmatig.

OBJECTIVE: To determine the prevalence of constipation and the use of laxatives in terminal patients. DESIGN: Retrospective. SETTING: Hospice Rozenheuvel, Rozendaal, the Netherlands. METHOD: Of patients who were admitted for terminal care between 1 January 1995 and 15 July 1996 the anamnestic data were recorded about presence of constipation and use of medicines, notably opioids and laxatives. RESULTS: The study population (n = 121) consisted of 65 male and 56 female patients. 95 patients (79%) suffered from cancer. The median survival time was 18 days (spread from 1-180 days). 58 (48%) of the patients were constipated at the time of admission and 62 (51%) used opioids. The opioid users were more often constipated (68% versus 27%; p < 0.001). 35 out of 62 (56%) opioid users were given laxatives. The laxative users, however, were more often constipated (65% versus 36%; p < 0.01). Neither in users nor in non-users of opioids did laxatives have any effect on presence of constipation. Of the laxative users 37 (73%) were given lactulose in a fixed dosage. CONCLUSION: Present laxative policy in terminal patients is ineffective. Monotherapy with fixed lactulose doses is not effective as a laxative in either users or non-users of opioids.

[Pruritus in cancer: uncommon, but sometimes worse than the pain]. / Jeuk bij kanker: zeldzaam, maar soms erger dan pijn.

Three patients, two females aged 45 and 56 years with metastasized breast carcinoma and one man aged 88 years with inoperable bronchial carcinoma, suffered from severe pruritus. This was only alleviated after treatment with paroxetine, a serotonin re-uptake inhibitor, or with tropisetron, a serotonin antagonist. The youngest woman then could be given chemotherapy, after which clinical recovery occurred, the other patients died, one week and 3 months, respectively, after start of the treatment. Pruritus is a relatively rare symptom in malignancies, but may be worse than pain. In the development and transmission of pruritus signals, in cholestatic icterus as well, serotonin appears to play a more important part than histamine.

[Delirium is certainly not an unavoidable complication of pain control in the terminal phase of life]. / Delirium door pijnbestrijding in de terminale levensfase kan worden vermeden.

In three terminal patients, a man aged 19 years who suffered from progressive osteosarcoma, a man aged 71 years with a small-cell pulmonary carcinoma, and a 68-year-old woman with cerebral metastases from a mammary carcinoma, delirium developed due to increased dosage of opioids for seemingly intractable pain (the first two patients) and dexamethasone (third patient). The delirium subsided after opioid rotation, administration of drugs for neuropathic pain, and treatment with an antipsychotic, respectively. This enhanced the patients' quality of terminal life and quality of dying. In terminal patients, analgesics-induced delirium must be considered, diagnosed and treated without delay.