Large Cumulative Doses Research Articles

Prostaglandin-Induced Antral Hyperplasia in Neonates: Clinical Experience and Dose-Response Characteristics

Antral hyperplasia (AH) induced by prostaglandins (PG) has been described by us recently in 5 infants with cyanotic heart disease receiving the drug. The purpose of the present study was to analyze 14 infants diagnosed as having AH either sonographically or pathologically in an attempt to characterize the dose-response characteristics of this adverse drug reaction, its clinical course and its optimal management. Infants with AH exhibiting large gastric aspirates have received a significantly lower cumulative dose (1,633 +/- 1,266 micrograms/kg) than those presented also with a palpable mass (3,458 +/- 1,703 micrograms/kg), (p < 0.01). While in general there is a dose-related clinical toxicity, variability in the location of the hyperplasia can explain cases of no apparent obstruction despite large cumulative doses of PG. In asymptomatic cases the antral hyperplasia, although visualized, it did not result in gastric outlet obstruction. In all cases followed by us to date, discontinuation of the PG has resulted in resolution of the clinical and sonographic findings. Nasojejunal tube was successfully attempted in several cases, preventing surgery in these very-high-risk infants.

Aminoglycoside induced ototoxicity in patients with cystic fibrosis

The improved survival of cystic fibrosis (CF) patients is partly due to intensive treatment for their chronic infections. Treatment usually includes intravenous and nebulised aminoglycoside antibiotics and they receive a large cumulative dose of these antibiotics over their lifetime. There is little information in the literature on the prevalence of ototoxicity due to aminoglycoside in these patients. We performed pure tone audiometry on 43 CF patients aged 14-42 years. Seven (16%) had bilateral sensorineural hearing loss (SNHL) for high frequency sounds, consistent with aminoglycoside induced ototoxicity. However, only 2 of these patients had documented toxic serum levels in the past. The identification of bilateral SNHL in one in six adult CF patients is a cause for concern. It may be that the high cumulative dose of aminoglycosides received by these patients may be causing inner ear injury in the absence of specific episodes of toxic serum levels.

Chemoprotectants for cancer chemotherapy.

Maximal dosing of cytotoxic chemotherapy drugs is often limited by the development of severe nonmyelosuppressive toxicities. Numerous studies have demonstrated that sulfur-containing nucleophiles can antagonize the dose-limiting effects of alkylating agents on the genitourinary tract. Examples include the use of sodium thiosulfate to prevent cisplatin-induced renal tubular necrosis and the use of sulfhydryl-containing compounds like N-acetylcysteine and 2-mercaptoethanesulfonate (mesna) to block oxazophosphorine-induced bladder toxicity. Mesna does not block the antitumor action of oxazophosphorines due to its rapid formation of the inactive dimer dimesna in the bloodstream. The active monomer is selectively reduced from dimesna in renal tubule cells, thereby limiting the inactivation of toxins like acrolein to the genitourinary tract. Recent clinical trials suggest that oral mesna has adequate bioavailability (roughly 50% by urinary thiol measurements) to prevent urotoxicity in high-dose ifosfamide regimens. In addition, mesna is stable in aqueous oral formulations. This may facilitate more convenient oral mesna dosing in protocols using high-dose cyclophosphamide or ifosfamide. Whereas agents like mesna and sodium thiosulfate complex directly with activated (electrophilic) alkylator species, chemoprotectants for the anthracyclines appear to complex with metal cofactors like iron, which are required for the production of cardiotoxicity. Several ethylenediaminetetraacetic-like agents have been evaluated, and a water-soluble piperazinyl derivative, ICRF-187, is currently undergoing clinical evaluation in patients receiving large cumulative doxorubicin doses. An initial clinical trial suggests that ICRF-187 can prevent doxorubicin-induced cardiomyopathy. As with mesna, ICRF-187 does not block the myelosuppressive or the antitumor effects of doxorubicin. Overall, these studies show that site-selective chemoprotection is now feasible for at least two major classes of anticancer agents.

Daunorubicin in patients with relapsed and refractory acute nonlymphoblastic leukemia previously treated with anthracycline.

While the efficacy of daunorubicin (DNR) in first induction of patients with acute nonlymphoblastic leukemia (ANLL) has been well documented, little data are available concerning the activity of DNR in patients with relapsed and refractory ANLL previously treated with anthracycline. We administered DNR (60 mg/m2/day for 3-5 days) in 21 patients with relapsed (n = 12) or refractory (n = 9) ANLL previously treated with anthracycline. The general response rate was 48%, with a complete response (CR) rate of 38%. Five of 12 patients with relapsed ANLL and 3 of 9 patients with refractory ANLL achieved CR. Among these cases with CR in refractory ANLL, the evolution of one patient is particularly illustrative since he had received previously a large cumulative dose of anthracycline (540 mg/m2) and has been shown to be refractory to high-dose cytosine arabinoside. This study suggests that previous administration of DNR or adriamycin does not induce significant resistance to anthracycline: DNR appears to be almost as efficient in patients with relapsed and refractory ANLL previously treated with anthracycline as in first induction.

Uric acid nephrolithiasis and acute renal failure secondary to streptozotocin nephrotoxicity

Uric acid nephrolithiasis developed in a 75-year-old man who had received a large cumulative dose of streptozotocin for treatment of metastatic islet cell carcinoma of the pancreas. Oligoanuric renal failure mediated by massive intraureteral uric acid deposits occurred despite normal serum concentrations of uric acid. This case implicates the uricosuric effects of streptozotocin in the pathogenesis of uric acid nephropathy and suggests that renal uric acid excretion should be monitored routinely in patients receiving large cumulative doses of this drug.

Hypomagnesemia following high-dose intracavitary cisplatin with systemically administered sodium thiosulfate.

Seventy-one patients receiving a minimum of two courses of high-dose intracavitary cisplatin (100-200 mg/m2/course) with i.v. thiosulfate administered to protect against cisplatin-induced renal insufficiency were retrospectively evaluated to examine the influence of thiosulfate and large cumulative doses of cisplatin on the incidence of hypomagnesemia. Only 8% of 50 patients who had normal serum magnesium levels prior to the initiation of the experimental program became hypomagnesemic during the therapeutic trial. Similarly, while 67% of the 21 patients with low initial serum magnesium levels remained hypomagnesemic, 33% had normal serum levels at the completion of therapy. It is suggested that the intravenous administration of thiosulfate might have been responsible for the strikingly low incidence of hypomagnesemia in this patient population. A prospective evaluation of the utility of sodium thiosulfate in preventing cisplatin-induced renal magnesium wasting appears indicated.

Phase I study of MVE-2 evaluating toxicity and biologic response modification capability.

A total of 21 patients were treated in a phase I trial using the biological response modifier MVE-2, a low molecular weight component of pyran copolymer. All patients received weekly IV MVE-2 infused over 2 h. Proteinuria, sometimes of nephrotic proportions, was the dose limiting toxicity, and was seen with increasing incidence as the cumulative dose of MVE-2 exceeded 2500 mg. Other toxicity with MVE-2 was minimal. Biologic response modification at tolerable doses was inconsistent, although several assays, particularly natural cell-mediated cytotoxicity, indicated enhanced activity at higher dosages of MVE-2. No objective tumor responses were observed. MVE-2 is not useful as a biological response modifier using our initial method of administration, since the dose limiting toxicity occurred at lower levels than were necessary to induce consistent biologic response modification. Following completion of the phase I study, we administered MVE-2 by 30-min infusion to 8 additional patients and did not detect proteinuria, in spite of large cumulative doses. It is possible that alternate schedules of MVE-2 administration could minimize proteinuria and allow the administration of dosages necessary for immunologic modification.

Evaluation of factors associated with glucocorticoid-induced osteopenia in patients with rheumatic diseases.

In 161 ambulatory rheumatic disease patients receiving long-term prednisone therapy, diaphyseal mass (DM) and metaphyseal mass (MM) of the forearm were measured by single photon absorptiometry, and bone radiographs were reviewed when available. Multivariate analysis of treatment and patient characteristics demonstrated that glucocorticoid-induced osteopenia (defined as an elevated DM:MM ratio) and bone fractures occurred with similar frequency in patients of each sex, in whites and blacks, in patients with various rheumatic diseases, and in patients receiving different regimens of prednisone therapy. However, large cumulative doses of prednisone were associated with elevated DM:MM ratios as well as with bone fractures, and menopause or age greater than or equal to 50 years (males or females) was associated with bone fractures. We conclude that long-term therapy with various prednisone regimens results in glucocorticoid-induced osteopenia and fractures. This affect is cumulative, occurs in all patient groups, and results in more bone fractures in certain groups.

Total lymphoid irradiation in kidney and liver transplantation in the baboon: prolonged graft survival and alterations in T cell subsets with low cumulative dose regimens.

Prolonged kidney and liver allograft survival was produced in baboons by low cumulative doses (500 to 1200 rad) of total lymphoid irradiation (TLI). Continuing normal graft function for more than 1 yr after transplantation was seen in 10 animals in this series. The longest survivor (greater than 4 years) rejected a third party kidney allograft in typically acute fashion 1 yr after the original transplantation. The dose-response effect was parabolic, with a cumulative dose of 800 rad given as twice weekly fractions of 100 rad each being the most effective. With smaller cumulative doses (500 or 600 rad) results were improved if TLI was administered as a larger number of smaller fractions. These regimens are free of the radiation related mortality observed in earlier studies with larger cumulative doses. As in previous studies, the injection of donor bone marrow was not essential for prolonged and continuing graft survival. The field irradiated was extensive, and included a substantial part of the of the hemopoietic bone. Restricting the field irradiated to that approximating what is used clinically in patients with Hodgkin's disease resulted in markedly poorer graft survival. Alterations in T cell subpopulations were studied in these baboons with the use of the anti-human monoclonal antibodies OKT11 (anti-total T cells), OKT4 (anti-T helper cells; Th), and OKT8 (anti-T suppressor/cytotoxic cells, Tsc), which cross-react with baboon lymphocytes. After completion of TLI but before transplantation, the relative percentage of Tsc cells fell and the percentage of Th and the Th/Tsc ratio rose. Transplantation was followed by an inversion of this ratio due to reciprocal changes in the percentages of Th and Tsc cells. This pattern persisted and increased until 6 mo after transplantation, when it reverted to that seen in untreated control animals. This was maintained in long surviving animals up to 17 mo after transplantation. Transplantation was also followed by a marked early increase in the percentage of Ia+ (OKIa1 anti-human monoclonal antibody) total T, T4+, and T8+ cells. If findings in the human, in which activated suppressor but no cytotoxic T cells are Ia+, can be extrapolated to the baboon, a possible explanation for the serial changes observed in the present studies may be that transplantation after TLI results in a polyclonal expansion of nonspecific suppressor T cells. These disappear with time leaving specific suppressor T cells that may be responsible for continuing graft acceptance. Formal proof of this hypothesis will require appropriate functional studies.

Potentially toxic serum lidocaine concentrations following spray anesthesia for bronchoscopy.

Serum lidocaine concentrations were measured in a series of ten patients during and after topical lidocaine spray anesthesia used for diagnostic fiberoptic bronchoscopy. Mean total dose of lidocaine ranged from 480-720 mg. Peak serum lidocaine concentrations averaged 3.6 micrograms/ml (range: 1.9 to 7.4 micrograms/ml), and were attained shortly after the start of the procedure. Repeated topical administration of lidocaine spray therefore may lead to large cumulative doses and serum concentrations which are in the therapeutic or potentially toxic range.

Aseptic osteonecrosis in children treated for acute lymphoblastic leukemia and aplastic anemia.

We report six children, five with acute leukemia and one with aplastic anemia, who during chemotherapy have developed severe aseptic bone necrosis. Although there is no definite proof, our data are highly suggestive of incriminating corticosteroid therapy in large cumulative doses as the main pathogenetic factor.

Secondary treatment of polycythemia rubra vera with 6-thioguanine.

6-thioguanine, an antimetabolite not potentiated by allopurinol, has been used in the treatment of 29 patients with polycythemia vera. All but two of the patients had been treated previously by venesection and/or radioactive phosphorus (32p) and/or alkylating agents. The usual dose was 40-160 mg daily alternate weeks according to individual response. The treatment period varied from 6-66 months (mean, 31 months). Of 27 evaluable patients 24 (89%) responded to treatment and at one year there was a significant fall in all blood count parameters. Seven patients relapsed while on treatment and four were withdrawn because of side effects. 6-thioguanine merits further evaluation in the management of polycythemia vera, particularly in those patients who have received large cumulative doses of 32p and/or alkylating agents and in whom an alternative mode of therapy is desirable.

The Safety of Treating Rheumatoid Arthritis With Aspirin

High-dose aspirin has long been considered first-choice therapy for the treatment of rheumatoid arthritis and other inflammatory rheumatic diseases.1Recently some clinicians have challenged this premise and suggested that the newer nonsteroidal anti-inflammatory agents, while more costly, are equally efficacious and less toxic.2They have emphasized less gastrointestinal toxic reaction and have suggested that these drugs be substituted for aspirin as a foundation of medical therapy. We have disagreed, noting the relatively short experience with the newer agents, as well as the emergence of a number of side effects with their continued use.3The subject of renal toxic reaction of aspirin and other nonsteroidal agents has been discussed in the literature. The article by Emkey and Mills in this issue ofThe Journal(p 55) examines the safety of long-term ingestion of large cumulative doses of aspirin from the standpoint of significant renal parenchymal disease. To decide

Comparisons of alum-precipitated and unprecipitated aqueous ragweed pollen extracts in the treatment of hay fever

In 1969 and 1970, groups of patients with ragweed hay fever never before treated were started on preseasonal courses of immunization with an alum precipitate of aqueous ragweed extract. A comparison between these two groups of patients and a similar group of patients treated with unprecipitated aqueous extract in 1968 shows that treatment with alum precipitate was safely initiated with fewer injections even though a higher dose was administered. The larger cumulative dose appeared to give better IgG antibody responses and greater relief of symptoms. A repeat preseasonal course the next year again required fewer injections of the alum-precipitated extract than a repeat course of aqueous extract.

Intracranial calcifications in childhood leukemia: An association with systemic chemotherapy

Children with acute lymphocytic leukemia were examined for evidence of intracranial calcifications with roentgenograms of the skull and computerized tomography. Of 39 children in their initial complete remission, ten were found to have subcortical cerebral calcifications. Significant associations were found between the presence of cerebral calcifications and systemic treatment with large cumulative doses of methotrexate.

Cardiovascular effects of prolonged delta-9-tetrahydrocannabinol ingestion.

In contrast to the tachycardia and unchanged or increased blood pressure seen after single doses, prolonged delta-9-tetrahydrocannabinol (THC) ingestion produced significant heart rate slowing and blood pressure lowering in hospitalized volunteers. Impaired circulatory responses to standing, exercise, Valsalva maneuver, and cold pressor testing suggest a state of sympathetic insufficiency. Marked weight gain was observed in all subjects, which has been shown to be related to fluid retention and plasma volume expansion. Tolerance developed to orthostatic hypotension, possibly related to plasma volume expansion, but did not develop to the supine hypotensive effects. Nearly complete tolerance developed to the tachycardia and psychological effects produced by smoked marijuana while ingesting THC. Electrocardiographic changes were minimal despite the large cumulative dose of THC. The hypothesis that THC has a biphasic effect on the sympathetic nervous system in man, producing excitation with single doses and inhibition with prolonged administration, is discussed.

The Quantitative Distribution Of Gold In Skin During Chrysotherapy

Gold concentrations in epidermis, dermis, and whole skin were measured by neutron activation analysis after formation of suction bullae in 8 patients who had received protracted cyrysotherapy. Epidermis contained 3% (median) of the gold content of whole skin. A direct correlation between cumulative gold dose and skin gold level was noted. These findings suggest that apparent gold concentrations in skin are influenced by the depth of the biopsy, that keratinous tissues have little affinity for gold, and that the gold storage capability of skin is not saturated by large cumulative doses of gold. The beneficial effect of gold in pemphigus may not be mediated at the site of blister formation.

HEADACHE POWDERS AND RENAL DISEASE.

An association between chronic analgesic ingestion and the occurrence of renal disease, first suggested by Spuhler and Zollinger in 1953, 1 has since been prominently reported in the European literature and has gained a measure of acceptance as a clinicopathologic entity. Acetophenetidin (Phenacetin) has been regarded by most authors as the likely offending agent, and a large cumulative dose of the drug has been consistently described in affected individuals. Detailed case reports from this country have been comparatively few. 2,3 We report herein three such patients, two of whom in addition were noted to have the interesting historical background of former chronic alcoholism. Case 1. —A 51-year-old man was admitted to the North Carolina Memorial Hospital for the first time May 17, 1960, in a stuporous state. He was known to have had mild hypertension for about one year. Three months before admission, he had noted the onset of mild

The effect of phenylephrine, methamphetamine, cocaine, and serotonin upon the adrenaline sensitive component of the reticular activating system

A series of sympathominetic agents and related substances were tested for their effect upon the EEG and blood pressure of the unanesthetized cat with mid-reticular coagulation. Adrenaline, noradrenaline, and phenylephrine all produced prompt, short-lasting and reproducible EEG activation and rise in blood pressure, but showed certain quantitative differences. Methamphetamine produced a feeble direct effect upon the EEG and blood pressure, and both responses showed tachyphylaxis. Both methamphetamine and cocaine were able to lower the threshold to adrenaline EEG activation ten-fold or more, and in large enough cumulative doses produced a sustained EEG activation which was abolished by further destruction of the mesencephalic tegmentum. Serotonin produced alternate phases of EEG activation and deactivation dissimilar in pattern to that produced by the sympathomimetic agents. It is postulated that the central nervous system stimulating properties of methamphetamine and cocaine observed clinically are due to their sensitizing effect upon adrenergic component of the reticular activating system.