A Case of Milk-Alkali Syndrome Caused by Diuretic-Induced Alkalosis and Polypharmacy.

Milk-alkali syndrome, which is characterized by hypercalcemia, metabolic alkalosis, and renal dysfunction, typically results from the ingestion of large amounts of calcium and absorbable alkaline products. However, these symptoms can also manifest when alkalosis and calcium loading occur simultaneously, owing to other factors. We report a case of milk-alkali syndrome caused by loop-diuretic-induced alkaline load and polypharmacy in an 85-year-old Japanese woman with multiple comorbidities, including osteoporosis, hypertension, type 2 diabetes, dyslipidemia, and Parkinson's disease. The patient regularly took 14 drugs, including calcium L-aspartate, eldecalcitol, celecoxib, and a fixed-dose combination of losartan and hydrochlorothiazide. Immediately before admission, furosemide was administered for the treatment of edema. The patient presented with chest discomfort, general malaise, and clinical signs of dehydration, hypercalcemia, hypophosphatemia, hypokalemia, and hypomagnesemia, accompanied by electrocardiogram abnormalities, renal dysfunction, and chloride-resistant metabolic alkalosis. The hypercalcemia was specifically induced by calcium L-aspartate and eldecalcitol. The hypomagnesaemia and hypophosphatemia were caused by diuretics and hypercalcemia. Thus, all the oral medications were discontinued, and rehydration and electrolyte correction therapy were administered. The final diagnosis was milk-alkali syndrome caused by the concomitant use of loop diuretics and other medications, without absorbable alkaline preparation use. This case underscores the importance of considering drug-related factors, checking concomitant medications, and being aware of the benefits, harmful effects, and side effects of polypharmacy in older adults with multimorbidity.

A Phase 2 Study of PCI-27483, a Factor VIIa Inhibitor in Combination with Gemcitabine for Advanced Pancreatic Cancer.

OBJECTIVES: Tissue factor overexpression is associated with tumor progression, venous thromboembolism, and worsened survival in patients with cancer. Tissue factor and activated factor VII (FVIIa) complex may contribute to tumor invasiveness by promoting cell migration and angiogenesis. The study objective was to evaluate safety, pharmacokinetics, and efficacy of PCI-27483, a selective FVIIa inhibitor. METHODS: This was an open-label, multicenter phase 2 trial of patients with advanced pancreatic cancer. Part A of the study was an intrapatient dose escalation lead-in portion in patients concurrently receiving gemcitabine, and in part B, patients were randomized 1: 1 to the recommended phase 2 dose combination PCI-27483-gemcitabine versus gemcitabine alone. RESULTS: Target international normalized ratio (between 2.0-3.0) was achieved following PCI-27483 treatment. Overall safety of PCI-27483-gemcitabine (n = 26) was similar to gemcitabine alone (n = 16), with a higher incidence of mostly low-grade bleeding events (65% vs. 19%). Progression-free survival (PFS) and overall survival (OS) were not significantly different between patients treated with PCI-27483-gemcitabine (PFS: 3.7 months, OS: 5.7 months) and those treated with gemcitabine alone (PFS: 1.9 months, OS: 5.6 months). CONCLUSIONS: Targeted inhibition of the coagulation cascade was achieved by administering PCI-27483. PCI-27483-gemcitabine was well tolerated, but superiority to single agent gemcitabine was not demonstrated.

Safety assessment of a novel active ingredient, acetyl aspartic acid, according to the EU Cosmetics Regulation and the Scientific Committee on Consumer Safety guidelines.

OBJECTIVE: Acetyl aspartic acid (A-A-A) was proposed as a new novel active ingredient for use in cosmetics. The safety of A-A-A was assessed by following an in-house-developed 'New Ingredient Testing Strategy', which was designed in accordance with the Scientific Committee on Consumer Safety (SCCS) notes of guidance and the requirements of Annex I of the EU Cosmetics Regulation. The aim of the project was to determine whether A-A-A was safe for use in cosmetics and to determine a maximum permitted safe level in the formulations. METHODS: A literature review was conducted, consulting over 40 different information sources. This highlighted a number of gaps which required testing data. A-A-A was tested for phototoxicity according to OECD test guideline 432, skin irritation according to OECD test guideline 439 and eye irritation according to OECD test guideline 437. Dermal absorption of A-A-A was measured according to OECD test guideline 428 and was used to calculate the margin of safety (MoS). Finally, A-A-A was tested in a human repeat insult patch test (HRIPT) and a 14-day in-use tolerance study. RESULTS: A-A-A was non-phototoxic and was non-irritating to skin and eyes in in vitro testing. Dermal absorption was calculated to be 5%. The MoS for A-A-A was 351, at a level of 5%, for all cosmetic product types, indicating no systemic safety toxicity concern. A-A-A at 5% under occlusive patch on a panel of 50 adult volunteers induced no skin irritation or allergic reaction in the HRIPT study. Finally, repeated application of A-A-A to the periocular area, twice per day for 14 days, in 21 female volunteers, demonstrated that 1% A-A-A was well tolerated following dermatological and ophthalmological assessment in a cosmetic formulation. CONCLUSION: A-A-A was assessed as safe by the cosmetic safety assessor for use in cosmetics at a level of 5% in all cosmetic product types, in line with the requirements of the EU Cosmetics Regulation and in accordance with the SCCS notes of guidance.

A randomized, double-blind, crossover, placebo-controlled comparative clinical trial of arginine aspartate plus adenosine monophosphate for the intermittent treatment of male erectile dysfunction.

Efficacy and safety of l-arginine aspartate 8 g combined with 200 mg of adenosine monophosphate (AA) with placebo (PL) alone for intermittent treatment of mild-to-moderate erectile dysfunction (ED) were compared. The study design was a double-blind, PL-controlled, two-way crossover randomized clinical trial with 26 patients. Efficacy was assessed by International Index of Erectile Function (IIEF) and two additional validated questionnaires [the Erection Hardness Score (EHS) and the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS). During each crossover period, separated by a 2-week wash-out period, drugs were administered orally, 1-2 h before sexual intercourse. Primary endpoint was a change in the IIEF. Secondary endpoints were patient and investigator assessments of treatment success. Investigators' and patients' assessment of efficacy was significantly improved by the combination vs. PL (p = 0.01 and p = 0.04 respectively]. EHS and EDITS questionnaires were both improved by the combination (p = 0.015 and p = 0.017 respectively). There was no significant difference in terms of tolerance between AA and PL or severe adverse events. ED patients demonstrated significant improvements in all IIEF domains with the exception of the Sexual Desire and Orgasmic Domains when treated with AA compared with PL. This pilot phase II study showed that the on-demand oral administration at a high dosage of l-arginine aspartate-adenosine monophosphate combination may be effective in patients with mild-to-moderate ED, is very well tolerated and could be tested as a safe first-line therapy in a larger size phase III study.

L-Cysteine and glutathione restore the reduction of rat hippocampal Na+, K+-ATPase activity induced by aspartame metabolites.

Studies have implicated aspartame (ASP) ingestion in neurological problems. The aim of this study was to evaluate hippocampal Na(+),K(+)-ATPase and Mg(2+)-ATPase activities after incubation with ASP or each of ASP metabolites, phenylalanine (Phe), methanol (MeOH) and aspartic acid (asp) separately. Suckling rat hippocampal homogenates or pure Na(+),K(+)-ATPase were incubated with ASP metabolites. Na(+),K(+)-ATPase and Mg(2+)-ATPase activities were measured spectrophotometrically. Incubation of hippocampal or pure Na(+),K(+)-ATPase with ASP concentrations (expected in the cerebrospinal fluid (CSF)) after ASP consumption of 34, 150 or 200mg/kg resulted in hippocampal enzyme activity reduction of 26%, 50% or 59%, respectively, whereas pure enzyme was remarkably stimulated. Moreover, incubation with hippocampal homogenate of each one of the corresponding in the CSF ASP metabolites related to the intake of common, high/abuse doses of the sweetener, inhibited Na(+),K(+)-ATPase, while pure enzyme was activated. Hippocampal Mg(2+)-ATPase remained unaltered. Addition of l-cysteine (cys) or reduced glutathione (GSH) in ASP mixtures, related with high/toxic doses of the sweetener, completely or partially restored the inactivated membrane Na(+),K(+)-ATPase, whereas the activated pure enzyme activity returned to normal. CSF concentrations of ASP metabolites related to common, abuse/toxic doses of the additive significantly reduced rat hippocampal Na(+),K(+)-ATPase activity, whereas pure enzyme was activated. Cys or GSH completely or partially restored both enzyme activities.

Freehand three-dimensional assessment of left ventricular volumes and ejection fraction with ultrasound contrast agent LK565.

AIMS: Accurate assessment of left ventricular function by determining left ventricular volumes and ejection fraction is important in evaluating the prognoses of patients with heart failure. Two-dimensional (2D) echocardiography suffers from low correlation with reference methods like ventriculography. Three-dimensionally (3D) assessed data have been proved to have better conformity. Endocardial border delineation remains a problem, however, especially in patients with suboptimal recordings. Few data exist on 3D-echocardiographic volumetry with ultrasound contrast agents (UCAs). We evaluated the second-generation UCA LK565 for its boundary-tracing capacities in freehand 3D echocardiography in a phase II clinical trial. Safety and efficacy of the novel contrast agent were also evaluated. METHODS AND RESULTS: Forty patients between the age of 42 and 77 were included in this trial. Left ventricular end-systolic and -diastolic volume (LVESV, LVEDV) and ejection fraction (EF) were determined by either 2D or 3D freehand second harmonic echocardiography with and without use of LK565. Parameters were compared statistically with ventriculography performed in 35 patients. Immune response to LK565 was evaluated by analysing phagocytosis capacity and kinetics of inflammatory cytokines (TNF-alpha, IL-4, IL-10, IFN-gamma). Patients were monitored for adverse events up to 72 h after application of the UCA. Calculated values for left ventricular volumes and ejection fraction correlated best for freehand 3D echocardiography in combination with LK565 (r=0.92 for LVEDV; r=0.96 for LVESV; r=0.94 for EF). Excellent left ventricular contrast enhancement was achieved for approximately 8 min. A reversible saturation of phagocytosis capacity for monocytes and neutrophils set in with a maximum peak at 6h. No significant increase in cytokine expression was observed. CONCLUSION: LK565 improves feasibility of endocardial border delineation in 3D echocardiography, leading to better correlation of left ventricular volumetry with reference methods. Efficacy and safety of LK565 are equivalent to those of conventional UCAs.

Immunological evaluation of the new stable ultrasound contrast agent LK565: a phase one clinical trial.

BACKGROUND: Ultrasound contrast agents (UCAs) allow the enhancement of vascular definition, thereby providing more diagnostic information. LK565 is a new second-generation UCA based on synthetic polymers of aspartic acid which is eliminated from the blood stream via phagocytosis. LK565 forms very stable air-filled microspheres and is capable of repeated passage through the pulmonary capillary bed after peripheral intravenous injection. This characteristic allows examination of the cardiac function or extracardiac vessel abnormalities up to 15 minutes. METHODS: A phase one clinical study was conducted on 15 healthy volunteers to identify the development of an undesirable immune response. Phagocytosis capacity, TNF-alpha secretion, and MHC class II upregulation of monocytes was monitored, as well as microsphere specific antibody development (IgM, IgG). Furthermore, the kinetics of the activation surface markers CD69, CD25, CD71, and CD11b on leukocytes were analyzed. RESULTS: Due to LK565-metabolism the administration of the UCA led to saturation of phagocytes which was reversible after 24 hrs. Compared to positive controls neither significant TNF-alpha elevation, neither MHC class II and activation surface markers upregulation, nor specific antibody development was detectable. CONCLUSION: The administration of LK565 provides a comfortable duration of signal enhancement, esp. in echocardiography, without causing a major activation cascade or triggering an adaptive immune response. To minimize the risk of undesirable adverse events such as anaphylactoid reactions, immunological studies should be included in clinical trials for new UCAs. The use of LK565 as another new ultrasound contrast agent should be encouraged as a safe means to provide additional diagnostic information.

Glutamate transporters and retinal excitotoxicity.

Glutamate appears to play a major role in several degenerative retinal disorders. However, exogenous glutamate is only weakly toxic to the retina when glutamate transporters on Müller glial cells are operational. In an ex vivo rat retinal preparation, we previously found that exogenous glutamate causes Müller cell swelling but does not trigger excitotoxic neurodegeneration unless very high concentrations that overwhelm the capacity of glutamate transporters are administered. To determine the role of glutamate transporters in Müller cell swelling and glutamate-mediated retinal degeneration, we examined the effects of DL-threo-beta-benzyloxyaspartate (TBOA), an agent that blocks glutamate transport but that unlike most available transport inhibitors is neither a substrate for transport nor a glutamate receptor agonist. We found that TBOA triggered severe retinal neurodegeneration attenuated by ionotropic glutamate receptor antagonists. TBOA-induced neuronal damage was also diminished by riluzole, an agent that inhibits endogenous glutamate release. In the presence of riluzole, to inhibit glutamate release plus TBOA to block glutamate uptake, the addition of low concentrations of exogenous glutamate triggered severe excitotoxic neuronal damage without inducing Müller cell swelling. We conclude that TBOA-sensitive glutamate transporters play an important role in regulating the neurodegenerative effects of glutamate in the rat retina.

[Therapy of cardiac arrhythmias. Clinical significance of potassium- and magnesium aspartate in arrhythmias]. / Therapie von Herzrhythmusstörungen. Die klinische Bedeutung von Kalium- und Magnesiumaspartat bei Arrhythmien.

UNLABELLED: Potassium and magnesium deficiencies usually coexist and represent a risk factor for cardiac arrhythmias. Serum levels--in particular of magnesium--are inconclusive for establishing a possible electrolyte deficiency. Basic treatment of arrhythmia should therefore include the administration of potassium and magnesium, since the benefit is great, and the possible side effects is negligible. A placebo-controlled study involving patients with cardiac arrhythmias revealed that appreciably fewer ventricular asystoles occurred after three weeks of treatment with potassium and magnesium aspartate, even when serum levels were within the normal range prior to initiating treatment. Patients older than 50, and those with previous coronary heart disease and/or myocardial infarction derived particular benefit from this form of treatment. CONCLUSION: These results underscore the key role played by potassium and magnesium in the treatment of cardiac arrhythmias.

Epileptic seizures induced by N-acetyl-L-aspartate in rats: in vivo and in vitro studies.

Tremor rat (tm/tm), the parent strain of spontaneously epileptic rat (SER: zi/zi, tm/tm), exhibits absence-like seizures characterized by 5-7 Hz spike-wave-like complexes on cortical and hippocampal electroencephalograms (EEG) after 10 weeks of age, prior to development of convulsive seizures. Recently, this animal model has been demonstrated to display a genomic microdeletion within the critical region of tm, where aspartoacylase hydrolyzing N-acetyl-L aspartate (NAA) is located, besides showing the ability to accumulate NAA in the brain. Therefore, the present study was performed to determine the involvement of NAA in the induction of epileptic seizures. When NAA (4 micromol) was applied intracerebroventricularly (i.c.v.) to normal Wistar rats, 4-10 Hz polyspikes and/or spike-wave-like complexes followed by absence-like seizure before persistent 1-5 Hz waxing high-voltage after-discharges were observed on cortical and hippocampal EEG. At a higher dose (8 micromol), NAA induced convulsive seizures. The absence-like seizures with polyspikes and/or spike-wave-like complexes on the EEG were also observed with i.c.v. NAA in premature tremor rats without seizures. The NAA-induced seizures in normal rats were antagonized by i.c.v. glutamic acid diethyl ester, a non-selective glutamate receptor antagonist. In addition, NAA applied to the bath rapidly induced a long-lasting depolarization concomitantly with repetitive firings in hippocampal CA3 neurons of normal rat brain slice preparations. These findings suggest that NAA is involved in the induction of absence-like seizures and/or convulsion, probably via glutamate receptors.

Effects of PALA on the pharmacokinetics of 5-fluorouracil.

N-(phosphonacetyl)-L-aspartate (PALA) modulates the activity of 5-fluorouracil (5-FU) by inhibiting pyrimidine biosynthesis. A cross-over study was conducted to determine whether PALA affects the pharmacokinetic parameters of 5-FU in patients given 5-FU/folinic acid (FA). Six patients (3 males, 3 females) aged 63 4.3 (mean SD) years (body surface area of 1.84 18 m2) with metastatic colorectal carcinoma were given two courses of treatment. The treatment consisted of 250 mg/m2 of PALA on day 1 followed by 20 mg/m2 FA and 400 mg/m2 5-FU (5 min i.v. bolus injection) on days 2-5 in one cycle of treatment (PALA+). In another treatment cycle, these doses of 5-FU and FA were given for all 5 days without PALA (PALA-). The two courses were given four weeks apart. It was determined by random selection whether the course with PALA was given before or after the course without PALA. Blood samples were collected over a period of three hours, starting from the beginning of 5-FU infusion on days 2 and 5 of both courses. Plasma concentrations of 5-FU were determined by an HPLC technique. Pharmacokinetic parameters were calculated using a non-compartmental model. While there were no significant differences between pharmacokinetic parameters in the PALA+ vs PALA- courses, there was a trend towards a decreasing area under the curve (AUC) and increasing clearance (Cl) in PALA+ courses of treatment.

PALA versus streptozotocin, doxorubicin, and MeCCNU in the treatment of patients with advanced pancreatic carcinoma.

Seventy-three eligible, chemotherapy-naive, ambulatory patients with advanced pancreatic carcinoma were allocated to one of two treatment regimens: 35 received PALA (1250 mg/m2 daily x 5 every 4 weeks) and 38 were given SAM (streptozotocin 400 mg/m2 i.v. daily x 5, doxorubicin 45 mg/m2 i.v. on day 1 and 22, and methyl CCNU 60 mg/m2 orally on days 1 and 22 every 6 weeks). Doses were modified for myelo-, gi-, or cardiotoxicity. Adequate organ, bone marrow and cardiac function; a measurable lesion; adequate caloric intake; and a life expectancy of 2 months were required for treatment on this trial. One patient on each regimen had a partial response for response rates of 3% (95% confidence intervals, 0.08 to 17%). Median survival on the PALA arm was 5 months and median time to treatment failure was 2.6 months. SAM patients experienced median overall and progression free survivals of 3.4 and 1.9 months, respectively. The severe toxicity observed was almost exclusively myelosuppression on both regimens. One patient receiving SAM had lethal leukopenic sepsis during the first cycle as the only treatment-related death. Neither PALA nor SAM offer any therapeutic utility to patients with advanced pancreatic cancer.

Modulation of 5-fluorouracil with methotrexate and low-dose N-(phosphonacetyl)-L-aspartate in patients with advanced colorectal cancer. Results of a phase II study.

Methotrexate (MTX) and N-phosphonacetyl-L-aspartate acid (PALA) have been shown to modulate the cytotoxic effects of 5-fluorouracil (5-FU). A phase II study was initiated to evaluate the feasibility, toxicity and efficacy of PALA/MTX and 5-FU in patients with metastatic colorectal cancer. 26 patients received PALA 250 mg/m2 as an intravenous 15-min infusion plus MTX 200 mg/m2 as a 30-min intravenous (i.v.) infusion on day 1 and 5-FU 600 mg/m2 as i.v. push on day 2. Cycles were repeated every 14 days and the 5-FU dose was escalated in the individual patient in steps of 100 mg/m2 for the third, fifth and seventh cycle in the absence of toxicity. 7 patients had received prior 5-FU-based chemotherapy while 19 patients were chemotherapy naive. Objective responses occurred in 23% of patients (1 CR, 5 PR of which 2 were pretreated), no change in 13 patients (50%) and tumour progression (6 patients) or toxic death (one patient) in 27%. Responses lasted for a median of 7 months (range 6-9), the median time to progression was 4 months and median survival 13 months. Toxicity was mainly gastrointestinal with diarrhoea and mucositis, and severe or life threatening in only 3 patients. In 3 patients an increase in serum glucose levels occurred while being treated with PALA/MTX and 5-FU. 2 patients with insulin-dependent diabetes had a 33% increase in insulin requirement and 1 patient with dietary-controlled diabetes died due to a ketoacidotic coma. PALA/MTX/5-FU in this dose and schedule is active in patients with colorectal cancer. Hyperglycaemia may be a potential side-effect of PALA-containing regimens especially in patients with diabetes. Careful monitoring of serum glucose levels in these patients is indicated.

Magnesium in the prophylaxis of migraine--a double-blind placebo-controlled study.

The migraine prophylactic effect of 10 mmol magnesium twice-daily has been evaluated in a multicentre, prospective, randomized, double-blind, placebo-controlled study. Patients with two to six migraine attacks per month without aura, and history of migraine of at least 2 years, were included. A 4-week baseline period without medication was followed by 12 weeks of treatment with magnesium or placebo. The primary efficacy end-point was a reduction of at least 50% in intensity or duration of migraine attacks in hours at the end of the 12 weeks of treatment compared to baseline. With a calculated total sample size of 150 patients, an interim analysis was planned after completing treatment of at least 60 patients, which in fact was performed with 69 patients (64F, 5M), aged 18-64 years. Of these, 35 had received magnesium and 34 placebo. The number of responders was 10 in each group (28.6% under magnesium and 29.4% under placebo). As determined in the study protocol, this was a major reason to discontinue the trial. With regard to the number of migraine days or migraine attacks there was no benefit with magnesium compared to placebo. There were no centre-specific differences, and the final assessments of treatment efficacy by the doctor and patient were largely equivocal. With respect to tolerability and safety, 45.7% of patients in the magnesium group reported primarily mild adverse events like soft stool and diarrhoea in contrast to 23.5% in the placebo group.

Phase I study of N-(phosphonacetyl)-L-aspartate with fluorouracil and with or without dipyridamole in patients with advanced cancer.

We conducted a combined biochemical modulation trial of N-(phosphonacetyl)-L-aspartate (PALA), dipyridamole (DP), and fluorouracil (5-FU) in patients with cancer. Eighty-eight patients with advanced cancer were entered into this Phase I trial. During the first part of the study, four doses of PALA (125, 250, 500, and 1000 mg/m2, administered on day 1) were evaluated to determine the PALA dose with maximal suppression of aspartate transcarbamylase (ATCase) activity that was clinically tolerable. Patients were randomized to receive DP (or no DP), 50 mg/m2, p.o. every 6 h on days 1-6, and all patients received 5-FU, 400 mg/m2, by bolus administration on days 2-5. Prior to and during therapy, WBCs were collected and assayed for ATCase activity. After the maximally tolerated PALA dose with 400 mg/m2 5-FU +/- 50 mg/m2 DP was defined, the 5-FU dose was escalated using the same administration schedule of 5-FU, PALA, and DP. The dose of 5-FU was escalated by 25% in each of the DP cohorts until dose-limiting toxicity was reached. ATCase activity was inhibited in a dose-dependent manner with PALA doses of 125, 250, 500, and 1000 mg/m2, resulting in 0, 13, 17, and 49% inhibition of ATCase activity. Only at the higher PALA doses (i.e., 500 and 1000 mg/m2) was ATCase activity suppressed during days 2-5, but the activity returned to pretreatment levels by day 15. Based on the clinical tolerance and significant suppression of ATCase activity, a PALA dose of 500 mg/m2 was selected for the 5-FU dose escalation phase. At a 5-FU dose of 625 mg/m2, dose-limiting toxicity (leukopenia, stomatitis, and diarrhea) occurred in both DP cohorts. We recommend that for this monthly treatment schedule, 500 mg/m2 PALA and 500 mg/m2 5-FU, with or without 50 mg/m2 DP, be used in subsequent Phase II trials.

Therapeutic availability of iron administered orally as the ferrous gluconate together with magnesium-L-aspartate hydrochloride.

Since in vitro experiments had excluded interactions between Fe-gluconate (Fe-gluc) and magnesium-L-aspartate hydrochloride (MAH) in aqueous solutions the present in vivo studies seemed to be justified. Animal studies: Rats were kept on magnesium-(Mg)- and iron-(Fe)- sufficient and deficient diets. The intragastral administration of Fe-gluc significantly increased plasma Fe after 3 h, either given alone, or in combination with MAH (inducing hypermagnesemia). Same results were obtained when fortified diets were offered to Fe/Mg-deficient animals. Human studies: The combination of Fe-gluc (2 x 50 mg Fe per day, per os) plus MAH (2 x 7.5 mmol Mg per day, p.o.) was well tolerated by healthy volunteers. Single dose experiments revealed that Fe-gluc alone and in combination with MAH increased plasma Fe levels during 3 h to the same extent. Two groups of pregnant women with moderately reduced hemoglobin levels either received Fe-gluc (out-patients) or its combination with MAH (at least temporarily hospitalised because of preterm labor). Treatments were well tolerated. Hemoglobin levels did not further decrease, as expected without Fe supplements, during the course of pregnancy, thus indicating the therapeutic availability of the electrolytes in both study groups. Progesterone-induced constipation is frequently observed during pregnancy; hence stool softening reported by 50% of the women receiving Fe-gluc plus MAH (versus 33% in the Fe-gluc group) can be regarded as desirable effect. It is concluded that MAH does not interfere with the enteral absorption of Fe-gluc when both electrolytes are orally administered together. Taking both electrolytes together instead of 2 to 3 h apart from each other, as actually recommended, means a less complicated dosage regimen and probably improves compliance.

Phase II trial of low-dose N-(phosphonacetyl)-disodium L-aspartic acid and high-dose 24-hour infusional 5-fluorouracil in advanced gastric adenocarcinoma. A Southwest Oncology Group study.

N-(phosphonacetyl)-disodium L-aspartic acid (PALA) demonstrates a synergistic antitumor effect when combined with 5-Fluorouracil (5-FU) in in vitro studies. In a Phase II trial, 23 eligible patients with unresectable or metastatic adenocarcinoma of the stomach were treated with weekly i.v. bolus PALA (250 mg/M2) followed 24 hours later by a 24-hour infusion of 5-FU (2600 mg/M2) for an initial period of 8 weeks. No objective responses were noted. PALA and 5-FU is inactive against gastric adenocarcinoma at the doses and schedule used in this trial.

Phase I trial of low dose N-phosphonacetyl-L-aspartic acid and high dose 5-fluorouracil administered concomitantly with radiation therapy for unresectable localized adenocarcinoma of the pancreas.

BACKGROUND: Preclinical and clinical data suggest that N-phosphonacetyl-L-aspartic acid (PALA) can augment the cytotoxic effects of 5-fluorouracil (5-FU). In addition, the combination of 5-FU and radiation therapy has been used with success in prolonging survival and providing palliation of symptoms in patients with advanced unresectable pancreatic carcinoma. This Phase I study was undertaken to determine the feasibility and evaluate the qualitative and quantitative toxicities of PALA and escalating doses of 5-FU administered concomitantly with radiation therapy in patients with locally advanced nonmetastatic pancreatic adenocarcinoma. METHODS: Ten previously untreated patients with advanced nonmetastatic adenocarcinoma of the pancreas were treated with 250 mg/m2 of PALA given as an intravenous bolus followed 24 hours later by 5-FU, which was given by continuous 24-hour infusion every week. The 5-FU doses were assigned according to a Phase I drug escalation (1000 mg/m2, 1300 mg/m2, and 1700 mg/m2). Radiation therapy was delivered concurrently with chemotherapy at a dose of 180 cGy per fraction (900 cGy per week) over 6 1/2 weeks. PALA and 5-FU were continued weekly after the end of radiation therapy, with disease assessments made every 8 weeks. Chemotherapy was continued until the disease progressed. RESULTS: All 10 patients were evaluable. The maximum tolerated dose (MTD) of 5-FU was 1300 mg/m2. Two of the four patients treated at the 1700 mg/m2 dose level experienced dose-limiting toxicities, nausea/vomiting and mucositis, respectively. Toxicities were mild to moderate at the 1000 mg/m2 and 1300 mg/m2 dose levels. Two patients treated with 5-FU at the 1300 mg/m2 dose level had complete responses, and one patient treated at the 1700 mg/m2 dose level had a partial response. The median survival was 12.5 months, and four patients survived more than 1 year. CONCLUSIONS: PALA and 5-FU administered concomitantly with radiation therapy is an active regimen in locally advanced, unresectable pancreatic cancer. Dose-limiting toxicities are nausea/vomiting and mucositis. The MTD of 5-FU is 1300 mg/m2. The regimen is well tolerated and administered in an outpatient setting.

Reduction of blood pressure with oral magnesium supplementation in women with mild to moderate hypertension.

In a double-blind controlled trial, 91 middle-aged and elderly women with mild to moderate hypertension who were not on antihypertensive medication were randomly assigned to treatment with magnesium aspartate-HCl (20 mmol Mg/d) or placebo for 6 mo. Magnesium aspartate-HCl in the given dose was well-tolerated and was not associated with an increased frequency of diarrhea compared with placebo. At the end of the study, systolic blood pressure had fallen by 2.7 mm Hg (95% CI -1.2, 6.7; P = 0.18) and diastolic blood pressure by 3.4 mm Hg (1.3, 5.6; P = 0.003) more in the magnesium group than in the placebo group. Blood pressure response was not associated with baseline magnesium status, as measured by dietary magnesium intake and urinary magnesium excretion. Urinary magnesium excretion in the magnesium group increased by 50% during the intervention period. No changes were seen in other biochemical indexes, including serum concentrations of total and high-density-lipoprotein cholesterol. The findings suggest that oral supplementation with magnesium aspartate-HCl may lower blood pressure in subjects with mild to moderate hypertension.

A phase I-II study of N-(phosphonacetyl)-L-aspartic acid (PALA) added to 5-fluorouracil and folinic acid in advanced colorectal cancer.

N-(phosphonacetyl)-L-aspartic acid (PALA) inhibits the enzyme L-aspartic acid transcarbamoylase (ATCase) which is important in de novo pyrimidine synthesis. Low dosages of PALA modulate the in vitro activity of 5-fluorouracil (5-FU) and PALA (250 mg/m2) inhibits pyrimidine synthesis in patients. PALA (250 mg/m2 day 1) was combined with an established 5-FU/folinic acid (FA) regimen [FA (200 mg/m2 over 2 h days 2 + 3) and bolus and 22 h infusional 5-FU (300-500 mg/m2 days 2 + 3)] without the need for dose reduction of 5-FU or FA. 35 patients were entered. Treatment was well tolerated; 4/27 patients experienced > or = ECOG grade 3 toxicity at full 5-FU dosage (500 mg/m2 bolus/infusion). However, the response rate in 33 evaluable patients was only 6.1% [95% confidence intervals (C.I.) 0.2-21.8%]. Median response duration was short (4 months, 95% C.I. 3-6 months) and overall median survival was 10 months (95% C.I. 7-16 months). Although PALA (250 mg/m2) can be combined with full dosage 5-FU/FA, the combination has poor activity in colorectal cancer.