Nonclinical Safety Profile of BMS-986001, a Nucleoside Transcriptase Inhibitor for Combination Retroviral Therapy.

Nucleoside reverse transcriptase inhibitors (NRTIs)/nucleotide reverse transcriptase inhibitors are key components of combination antiretroviral therapy for HIV infection. First-generation NRTIs are associated with mitochondrial toxicity in patients, mainly due to inhibition of human DNA polymerase γ (hDNA polγ) that manifests as adverse events such as lipodystrophy, lactic acidosis, myopathy, cardiomyopathy, or nephropathy in patients. In chronic nonclinical studies in rodents and nonrodents, eukaryotic (host) mitochondrial toxicity manifests as some drug-specific toxicities similar to human toxicity. BMS-986001, a novel thymidine analog with minimal hDNA polγ inhibition, has demonstrated antiretroviral activity in early clinical studies. The primary toxicity of BMS-986001 in rats and monkeys is bone marrow dyserythropoiesis with associated decreases in red blood cell mass. Additionally, at high doses, severe platelet reductions accompanied by cutaneous petechiae began during weeks 8 and 11 in 3 of 60 monkeys in chronic toxicity studies. In a 6-month study, platelet reductions required euthanasia of the 2 affected monkeys (300 mg/kg/d) at week 14, but with dose reduction (200 mg/kg/d) remaining monkeys had no platelet changes. One affected monkey (200 mg/kg/d) in a 9-month study completed dosing and its platelet counts recovered during a 1-month recovery. Formation of platelet-bound immunoglobulin in the presence of BMS-986001, together with rapid and complete platelet recovery in the absence of BMS-986001, suggested that platelet decreases in monkeys may be immune mediated. No findings indicative of mitochondrial toxicity were observed in rats or monkeys given BMS-986001, suggesting an improved safety profile compared to marketed NRTI or tenofovir disoproxil fumarate.

An ethanolic extract of black cohosh causes hematological changes but not estrogenic effects in female rodents.

Black cohosh rhizome (Actaea racemosa) is used as a remedy for pain and gynecological ailments; modern preparations are commonly sold as ethanolic extracts available as dietary supplements. Black cohosh was nominated to the National Toxicology Program (NTP) for toxicity testing due to its widespread use and lack of safety data. Several commercially available black cohosh extracts (BCE) were characterized by the NTP, and one with chemical composition closest to formulations available to consumers was used for all studies. Female B6C3F1/N mice and Wistar Han rats were given 0, 15 (rats only), 62.5 (mice only), 125, 250, 500, or 1000 mg/kg/day BCE by gavage for 90 days starting at weaning. BCE induced dose-dependent hematological changes consistent with a non-regenerative macrocytic anemia and increased frequencies of peripheral micronucleated red blood cells (RBC) in both species. Effects were more severe in mice, which had decreased RBC counts in all treatment groups and increased micronucleated RBC at doses above 125 mg/kg. Dose-dependent thymus and liver toxicity was observed in rats but not mice. No biologically significant effects were observed in other organs. Puberty was delayed 2.9 days at the highest treatment dose in rats; a similar magnitude delay in mice occurred in the 125 and 250 mg/kg groups but not at the higher doses. An additional uterotrophic assay conducted in mice exposed for 3 days to 0.001, 0.01, 0.1, 1, 10, 100 and 500 mg/kg found no estrogenic or anti-estrogenic activity. These are the first studies to observe adverse effects of BCE in rodents.

Macrocytosis is a predictor of resting lactate concentrations in persons on dideoxynucleoside therapy for HIV infection.

OBJECTIVES: Mitochondrial toxicity is an important toxicity of antiretroviral therapy and may manifest as elevated blood lactate. Macrocytosis has been hypothesized to act as a marker of mitochondrial toxicity in persons with HIV infection. As part of a larger study on markers of mitochondrial toxicity we evaluated the relationship between resting lactate and erythrocyte mean corpuscular volume (MCV). METHODS: We studied the effect of micronutrient supplementation on lactate metabolism in three groups: those with HIV on and not on dideoxynucleoside-containing antiretroviral therapy and those without HIV. As part of the study we measured resting lactate and erythrocyte MCV after a 14-h fast. RESULTS: Erythrocyte MCV was significantly higher among the 11 participants on antiviral therapy (109.3 femtoliters (fl)) compared to five controls without HIV (89.3 fl) and four controls with HIV not on antiviral therapy (88.3 fl). In addition a strong predictive relationship was seen between MCV and resting lactate (R(2)=0.548, p<0.01). CONCLUSIONS: Macrocytosis may be a marker of treatment-related mitochondrial dysfunction in persons on treatment for HIV. Evaluating patients for early evidence of mitochondrial dysfunction in resource-constrained settings could be facilitated by this marker.

Methionine in the treatment of nitrous-oxide-induced neuropathy and myeloneuropathy.

Two cases of severe myeloneuropathy and macrocytic anemia associated with a low serum level of vitamin B12 after prolonged exposure to nitrous oxide are reported. In both cases, the neurological manifestations worsened initially despite B12 supplementation, although in one case the use of methionine seemed to arrest the progression of the disease and accelerate recovery. This offers further support for the biochemical hypothesis of methionine synthetase inhibition by nitrous oxide and reproduces in man previously reported animal studies with methionine. Methionine may be an important first-line therapy in the initial treatment of neuropathy and myeloneuropathy induced by nitrous oxide, and has a hypothetical role in the treatment of subacute combined degeneration of the cord.

[Monitoring of several hematological parameters of the erythroid series in patients with HIV infection treated with zidovudine]. / Monitoraggio di alcuni parametri ematologici della serie eritroide in pazienti con infezione da HIV in trattamento con zidovudina.

Haematologic toxicity is the most common adverse effect related to long-term administration of zidovudine (AZT). We evaluated the kinetics of modifications of some haematologic parameters of erythroid series in 65 patients with HIV infection treated with AZT for a mean duration of 7.6 +/- 4.7 months (13 of them with a previous diagnosis of AIDS, 34 with ARC, 18 asymptomatic or with LAS/PGL), in order to correlate the observation and the evolution of these laboratory changes with the onset of severe anaemia. The development of macrocytosis occurs in a large majority of AZT-treated subjects, in spite of folate and vitamin B12 supplementation; the monitoring of erythrocytes distribution according to cellular volume and cellular haemoglobin concentration makes it possible to early recognize the occurrence of modification in erythropoiesis. There is no correlation between an elevated mean corpuscular volume and the development of severe anaemia (Hb less than or equal to 9 g/dl) in an individual patient; a fall in the reticulocyte count appears to be the earliest peripheral blood sign of the development of bone marrow toxicity.

[Macrocytic anemia as a possible adverse effect of fluoropyrimidines].

One hundred and thirty-seven cases of stomach cancer given fluoropyrimidines (UFT: 66 cases, Tegafur: 58 cases, 5-FU: 13 cases) after gastrectomy as the adjuvant chemotherapy were examined as to appearance of macrocytic anemia. The mean corpuscular volume (MCV) gradually elevated in all cases but seven after administration. Macrocytic anemia, defined by the elevation over 20% compared with both pre-operative and pre-administrative values of MCV, was developed 30.3% in UFT group, 8.6% in tegafur group and 30.8% in 5-FU group. The incidence was statistically higher in UFT group (p less than 0.01) and 5-FU group (p less than 0.05) than in tegafur group. The cause was attributed to fluoropyrimidine administration because the serum folate and vitamin B12 levels remained normal and the value of MCV normalized after cessation of administration. Each total dose to induce macrocytic anemia was potentially about 70g in UFT. 100g in tegafur and 30 g in 5-FU. In conclusion, periodical hematological examination is necessary for the patients given fluoropyrimidine preparations.

Intravascular haemolysis and renal impairment after blood transfusion in two patients on long-term 5-fluorouracil and mitomycin-C.

In a multicentre trial of adjuvant chemotherapy in gastric adenocarcinoma, a number of patients developed chronic haemolysis and renal failure following long-term treatment with 5-fluorouracil and mitomycin-C. This was exacerbated by blood transfusion, leading to an acute intravascular haemolytic state accompanied by rapid decline in renal function. One patient investigated extensively was treated with antiplatelet drugs, steroids, and fresh frozen plasma without success. At necropsy this patient and another had renal changes typical of the haemolytic-uraemic syndrome and no evidence of tumour recurrence. Long-term treatment with this drug combination is potentially dangerous, and routine monitoring of renal function is recommended.

Haematological changes during normal pregnancy: iron induced macrocytosis.

Haematological indices in 300 pregnant and 50 non-pregnant women were obtained by Coulter Counter analysis. In 47 women who did not receive iron supplements during pregnancy, haemoglobin concentration fell from a mean of 12-23 g/dl in early pregnancy to 11-04 g/dl at 34 weeks gestation, a level which was maintained until term. In the 153 women to whom iron supplements were given during pregnancy, the initial fall in haemoglobin concentration was less, was arrested by 28 weeks gestation and then rose to a level equivalent to the booking level. This different pattern in iron supplemented pregnancies was due to an increase in the red cell count together with a change in mean cell volume. Although the changed mean cell volume usually remained within the normal range in the group who did not take iron, a few women developed microcytosis which could reflect iron deficiency; a macrocytic change was noted in a small number of the women who received routine iron supplements and this could reflect iron "over sufficiency". The results are discussed in relation to the possible effects of giving routine oral iron to all pregnant women.