Phase II trial of piroxantrone in metastatic breast cancer

Summary Thirty-two eligible patients with advanced metastatic breast cancer who had received no more than 1 prior chemotherapy regimen for metastatic disease (16 had received prior doxorubicin) were treated with piroxantrone at a dose of 120 mg/m² intravenously every 21 days. In the twenty-seven patients evaluable for response, two partial responses were seen. Toxicities observed were primarily hematologic with grade 3 or greater granulocytopenia occurring in 34% of the patients. One patient developed symptomatic congestive heart failure at a total cumulative dose of 960 mg/m². We conclude that piroxantrone given at this dose and schedule has minimal activity in patients with metastatic breast cancer.     

Age-related alterations of NMDA-receptor properties in the mouse forebrain: partial restoration by chronic phosphatidylserine treatment.

The effect of aging on the properties of N-methyl-D-aspartate (NMDA) receptors in the forebrain of female NMRI mice was investigated using the antagonist [3H]MK-801 as radioligand. Compared to young (3 months) mice, aged (20 months) mice showed changes of the properties of the NMDA receptor at three different levels: (1) the density was reduced by about 35%; (2) the efficacy of L-glutamate and glycine for stimulating specific [3H]MK-801 binding was enhanced, probably because more NMDA receptor-associated ion channels are closed under baseline conditions in the aged brain; (3) the affinity of L-glutamate and glycine to its binding sites at the NMDA receptor complex was also enhanced. Chronic treatment of aged mice with phosphatidylserine (20 mg/kg, i.p., once daily) for three weeks completely normalized enhanced efficacy and affinity of L-glutamate and glycine and elevated NMDA receptor density by approximately 25%. These findings are consistent with the assumptions that deficits of the NMDA receptor are one of the mechanisms of age-related cognitive impairment and that the beneficial effects of phosphatidylserine treatment on cognitive deficits of aged individuals might be partially due to the effects of this drug on age-related NMDA receptor deficits.     

Evaluation of Tissue-Engineered Skin (Human Skin Substitute) and Secondary Intention Healing in the Treatment of Full Thickness Wounds after Mohs Micrographic or Excisional Surgery

BACKGROUND: Human Skin Substitute (Apligraf, Organogenesis, Inc., Canton, MA) is a bi-layered tissue-engineered living biological dressing developed from neonatal foreskin. It consists of a bovine collagen matrix containing human fibroblasts with an overlying sheet of stratified human epithelium containing living human keratinocytes. Human Skin Substitute (HSS) appears to be immunologically inert, and has shown usefulness in the treatment of chronic and acute wounds. OBJECTIVE: Primary objectives were to evaluate the safety and efficacy of HSS in the treatment of full-thickness wounds in a prospective case series. Secondary objectives were to determine the rate of complete wound reepithelialization, incidence of complete wound healing, pain at wound site, overall cosmetic outcome, and patient satisfaction. METHODS: Fourteen patients were enrolled in the study, of which 12 were evaluable. HSS was applied in a blinded fashion to 6 of the patients immediately following Mohs or excisional surgery for skin cancer. The remaining 6 patients were allowed to heal by secondary intention. Both groups were evaluated at weekly appointments until complete reepithelialization occurred. During each evaluation, wound quality was assessed through the Vancouver Burn Scar Assessment Scale by the investigator and an independent blinded dermatologist. The investigator, blinded observer, and patient further evaluated the cosmetic outcome of the wound through the use of a Visual Analog Scale over a 6-month period. RESULTS: HSS patients and secondary intention patients were equivalent in comorbid factors such as pain, erythema, edema, exudate, infection, or hematoma between the groups. The incidence of complete wound healing at 6 months was 100% for both groups. Both groups also appeared to heal at similar rates, as defined by the complete reepithelialization of the wound. HSS patients ultimately resulted in more pliable and less vascular wounds as defined by the Vancouver Burn Scar Assessment Scale. Patient satisfaction with cosmetic outcome in both groups was positive at 6 months. CONCLUSIONS: HSS appears to be a safe, well-tolerated biological dressing with equivalent comorbid factors to secondary intention healing. HSS, however, seems to produce a more pliable and less vascular scar than those developed through healing by secondary intention. HSS also appears to produce more satisfactory cosmetic results when compared to secondary intention healing.     

Limited lists and the purchase of pharmaceutical products by government agencies in the RSA

The use of a limited list to restrict the range and type of medication used by medical institutions that operate under the auspices of the provincial authorities has been mooted as one possible method of cost containment. This study discusses the implementation of such measures in other countries and then quantifies the cost savings that might be obtained in the South African case. The possible savings are somewhat offset by other costs such a measure would introduce.     

The effect of oral dosing of xamoterol on systolic time intervals in man and xamoterol plasma concentrations in heart failure patients.

1. Six healthy male human volunteers of mean age 30.8 years (range 23-37) were given single oral doses of xamoterol (20, 50, 100 or 250 mg) and placebo with a 1 week interval between each dose. Xamoterol produced a significant decrease in systolic time intervals (QS2I, LVETI and PEPI) and a significant increase in systolic blood pressure indicating a positive inotropic effect on the heart at rest. The changes in QS2I were dose-related. Maximum decreases in QS2I were noted 1 to 2 h after dosing and were achieved with a dose of 100 mg. 2. In a second study, oral administration of xamoterol at 3 doses (100, 200 or 300 mg) and placebo were studied in 12 patients of mean age 60.4 years (range 52-73) with mild to moderate heart failure. Each dose was given twice daily for 7 days in a random order. Each dose of xamoterol produced a significant decrease in systolic time intervals indicating a positive inotropic effect on the heart at rest in patients with heart failure. It was not possible to distinguish between the effects of the three doses of xamoterol. 3. In heart failure patients, peak plasma concentrations of xamoterol occurred 1 to 2 h after dosing at all dosage levels and there was a linear relationship between dose and plasma concentration. 4. In both studies xamoterol was well tolerated and only minor adverse experiences were reported. 5. We conclude that, at rest, xamoterol has a positive inotropic effect on the heart when given orally to healthy volunteers or patients with mild to moderate heart failure.     

Differentiation between the stimulus effects of (+)-lysergic acid diethylamide and lisuride using a three-choice,drug discrimination procedure

The discriminative stimulus properties of (+)-lysergic acid diethylamide (LSD) and lisuride hydrogen maleate (LHM), were compared in a three-choice, water reinforced (FR 20) situation in which rats were required to press one lever following LSD (0.08 mg/kg), a second lever following LHM (0.04 mg/kg), and a third lever following saline. Reliable drug-appropriate responding was established in 72 sessions. Dose-response tests with LSD and LHM indicated that, as dose increased, the per cent of responding on the lever associated with the particular training drug also increased; little or no cross-transfer occurred between LSD and LHM. In generalization tests, the serotonin (5-HT) agonist quipazine substituted for LSD but not LHM while the dopamine (DA) agonist apomorphine mimicked LHM but not LSD; an unrelated compound, pentylenetetrazol (PTZ), produced responding on the saline-appropriate lever. In combination tests, 5-HT antagonists (e.g., BC-105 and low doses of pirenperone) blocked responding on the LSD lever while DA antagonists (e.g., haloperidol and much higher doses of pirenperone) blocked LHM-appropriate responding. These data suggest that the three-lever (D-D-N) procedure is similar to, but can be more sensitive than the two-lever (D-N) procedure (because it can differentiate between LSD and LHM); they therefore at least partially support the hypothesis that three-choice discriminations can be conceptualized as two separate, two-choice (D-N) discriminations (Jarbe and Swedberg 1982). The results also confirm suggestion that the stimulus effects of LSD and LHM are mediated by different mechanisms; the primary action of LSD is serotonergic (5-HT₂), while that of LHM is dopaminergic (White 1986).Some of these data were presented at the meeting of the Society of Neuroscience, Toronto, 1988 (Satellite Session of the Society for the Stimulus Properties of Drugs). They were also submitted (in somewhat different form) to the Graduate School of the University of South Carolina in partial fulfillment of the requirements for an MA degree (in Experimental Psychology)     

Haemodilution induces a hypercoagulable state

It has been suggested that haemodilution with saline may increase whole blood coagulation. This study was conducted in two parts. First, we investigated the effect of in vitro dilution of blood with saline on whole blood coagulation as measured by the thrombelastogram (TEG). Blood (4 ml) was diluted with 0.9% saline 1 ml and coagulation compared with that of an undiluted control specimen obtained concurrently from the same subject. In the second part, the study was repeated using a modified gelatin colloidal solution (Haemaccel) as the diluent. The r time, k time and r + k time were decreased relative to control in both diluent groups. The alpha angles were increased compared with control in both groups while maximum amplitude was unchanged in the Haemaccel diluted group. We conclude that haemodilution per se increases the coagulability of whole blood in vitro, but that saline haemodilution has a more marked effect on final clot strength.