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PubMedDate not supplied

Thalidomide in human immunodeficiency virus (HIV) patients. A review of safety considerations.

The sedative thalidomide was withdrawn from the market 30 years ago because of its teratogenic and neurotoxic adverse effects. The compound was later discovered to be extremely effective in the treatment of erythema nodosum leprosum, a complication of lepromatous leprosy. This effect is probably due to a direct influence on the immune system, because thalidomide possesses no antibacterial activity. The compound is presently used as an experimental drug in the treatment of a variety of diseases with an autoimmune character, including recurrent aphthosis of nonviral and nonfungal origin in human immunodeficiency virus (HIV) patients. This article reviews the most important chemical and pharmacokinetic properties of thalidomide. The possible mechanisms of the nonsedative effects of thalidomide with respect to the safety of its use in HIV patients are discussed. Because the mechanism of the immunomodulatory effect of thalidomide is unknown, the possibility that the administration of this compound will accelerate the deterioration of the immunological status of HIV patients cannot be excluded. Clinical evidence suggests that thalidomide may aggravate the condition of patients with preexisting peripheral neuropathy. Hypersensitivity reactions to thalidomide may occur more frequently in HIV patients than in other patient groups. Because of the teratogenic activity of thalidomide, reliable contraception must be provided to female patients of childbearing age. Before the introduction of thalidomide therapy to an HIV patient presenting with oral ulcers, a fungal or viral origin of the lesions should be excluded. Thalidomide should not be used in patients with preexisting HIV-related peripheral polyneuropathy, polyradiculopathy or encephalopathy. In patients experiencing a complete remission, the discontinuation of thalidomide treatment and its reintroduction in the case of a relapse are preferable to maintenance therapy.

Female↗

PubMed2024

Clinical efficacy of thalidomide for various genotypes of beta thalassemia.

OBJECTIVE: The objective of this study was to investigate the therapeutic efficacy of thalidomide across various genotype presentations of β-thalassemia so as to facilitate the early screening of thalidomide-sensitive thalassemia cases and to understand the impact of iron overload on thalidomide. METHODS: From our initial sample of 52 patients, we observed 48 patients with β-thalassemia for two years after administration of thalidomide. This cohort included 34 patients with transfusion-dependent thalassemia (TDT) and 14 patients with non-transfusion-dependent thalassemia (NTDT). We recorded the values of hemoglobin (Hb), fetal hemoglobin (HbF), and serum ferritin (SF) in the baseline period and at 1, 3, 6, 12, 18, and 24 months after enrollment, as well as the pre- and post-treatment blood transfusion volume in all 48 cases. According to the increase in Hb levels from baseline during the 6-month observation period, the response to thalidomide was divided into four levels: main response (MaR), minor response (MiR), slow response (SLR), and no response (NR). A decrease in serum ferritin levels compared to baseline was considered alleviation of iron overload. We calculated the overall response rate (ORR) as follows: ORR = MaR + MiR + SLR/number of observed cases. RESULTS: The ORR was 91.7% (44/48 cases), and 72.9% showed MaR (35/48 cases). Among the 34 patients with TDT, 21 patients (61.8%) were free of blood transfusion, and the remaining 13 patients still required blood transfusion, but their total blood transfusion volume reduced by 31.3% when compared to the baseline. We found a total of 33 cases with 10 combinations of advantageous genes, which included 5 cases with βCD41-42/βCD17 and 6 cases with βCD41-42/β-28. Based on the treatment outcomes among the 48 cases in the observation group, there were 33 cases in the MaR group and 15 cases in the SLR/NR group. There was a difference in HbF between the two groups at baseline (P = 0.041). There were significant differences between the two groups in Hb and HbF at the time points of 6 and 12 months, respectively (P < 0.001). Compared to the baseline measurement, there was a significant decrease in the level of SF at months 12 and 24 (P < 0.001). CONCLUSION: In this study, we identified 10 β-thalassemia gene combinations that were sensitive to thalidomide. These gene combinations can be used for initial screening and to predict the therapeutic effect of thalidomide in clinical practice. We examined the therapeutic response to thalidomide and found that the administration of thalidomide in combination with standardized iron removal was more beneficial in reducing iron overload.

Humans↗

PubMed1977

A comparison of thalidomide and pentobarbital - new methods for identifying novel hypnotic drugs.

We have compared the sleep-producing effects of thalidomide and pentobarbital. In a dose range that did not produce ataxia, thalidomide increased slow wave sleep and rapid eye movement sleep in cats (2-8 mg/kg p.o.) and rats (16 mg/kg p.o.). Pentobarbital had hypnotic activity in the same dose range but produced ataxia also at these doses. Thalidomide reduced spontaneous activity of both mice and rats. This occurred over a dose range of 8 to 1000 mg/kg p.o., but plateaued at a level of activity well above the complete inactivity of anesthesia that occurred with pentobarbital at well above the complete inactivity of anesthesia that occurred with pentobarbital at doses (greater than or equal to 32 mg/kg p.o.) above the hypnotic range. Several simple screens for thalidomide-like activity have been described which, together, could facilitate the search for thalidomide-like hypnotics. Pentobarbital, at doses 3 to 10 times the hypnotic range, prevented audiogenic seizures in physically dependent rats withdrawn from sodium barbital but thalidomide did not substitute for barbiturates even at doses 30 times those that increased sleep. Thalidomide, but not pentobarbital, enhanced the sleep-producing effect of electrical stimulation of basal forebrain in cats. The latter two findings suggest that thalidomide probably has a mechanism of action different from that of pentobarbital and that this may involve the activation of a sleep center in the forebrain.

Animals↗

PubMed1992

Refractive evaluation in thalidomide embryopathy.

To evaluate the ocular findings associated with thalidomide embryopathy, we examined 86 of 100 Swedes who had a proven correlation between birth defects and the mother's intake of thalidomide during pregnancy. Cycloplegic refraction, keratometry, and axial length measurements were performed. The subjects were divided into four groups according to their physical malformations, giving a time frame for when in gestation the insult occurred (the sensitive phase for thalidomide is 20-36 days after conception). The results indicate a trend toward shorter and longer axial lengths, high refractive errors, and corneal astigmatism in thalidomide embryopathy compared to controls, and in addition there was a tendency for those anomalies to occur in the group with the earliest thalidomide-induced defects. It is suggested that thalidomide disturbs the growth and shape of the eye and that this effect is exerted early in its teratogenic period.

Abnormalities, Drug-Induced↗

PubMed1992

Improvements in solubility and stability of thalidomide upon complexation with hydroxypropyl-beta-cyclodextrin.

Thalidomide is in clinical use for the treatment of graft-versus-host disease in leukemia patients after bone marrow transplant. Low levels of the drug in plasma after oral administration have made an intravenous thalidomide formulation desirable. Thalidomide, however, is sparingly soluble in aqueous solution (50 micrograms/mL) and unstable. Complexation with hydroxypropyl-beta-cyclodextrin has significantly improved the aqueous solubility and stability of thalidomide. Results obtained with HPLC and 1H NMR spectrometry have demonstrated that the solubility is increased to 1.7 mg/mL and the half-life of a diluted solution is extended from 2.1 to 4.1 h. Hence, an intravenous thalidomide-hydroxypropyl- beta-cyclodextrin solution has the potential to significantly improve current therapy for graft-versus-host disease by providing sustained high levels of drug in the plasma.

Cyclodextrins↗

PubMed1977

[Fixed lupus erythematosus (its treatment with thalidomide)].

The results obtained from the first 20 cases of Discoid Lupus Erithematosus treated with Thalidomide showed evidence of its great efficacy, evident from the first 15 days of treatment. In the incipient cases the results were even spectacular. 2. The minimum dosage used by the authors seems to be adequate on the basis of the results obtained. 3. The precise mode of action of thalidomide but it is thought that in acts on the hypothalamus. 4. The intolerance to Thalidomide and its undesireable side effects consisted slight somnolence; only one case had fever, cephalea, arthralgia, vertigo, nausea and urticaria which is unknown made it necessary to discontinue the medication. 5. The teratogenic effect of thalidomide obliges us to redouble the vigilance in women in age of reproduction by using of parenteral contraceptives applied by or in presence of the investigator. This study included one case that started treatment during the 7th month of pregnancy, without any problem and with an excellent result. The patient gave birth to a healthy full term infant. 6. It is recognized that this preliminary study should be continued with a greater number of cases and that these should be continued for a longer follow-up evaluation. At the present time, the authors believe that thalidomide is the best treatment for Discoid Lupus Erythematosus.

Adolescent↗

PubMed1979

Unusual muscle abnormalities associated with thalidomide treatment in a rhesus monkey: a case report.

Unusual musculotendinous abnormalities were observed in the forelimbs of a rhesus monkey treated prenatally with thalidomide (10 mg/kg maternal body weight, gestation days 33, 34, and 35). Although the hindlimbs exhibited malformations typical of thalidomide dysmelia, the forelimbs appeared relatively normal externally. However, dissection revealed totally anomalous insertions of preaxial muscles of both forearms. Extensor muscles inserted on flexor surfaces even though normal sites of insertion were present and unoccupied. Radiographs revealed only minor ossification deficiencies in the carpus and distal radius. These observations suggest that thalidomide, given at the appropriate time, can disrupt condensation and splitting of pre-muscle masses without greatly disturbing condensation of corresponding preskeletal elements. These types of musculoskeletal relationships are unusual findings in congenital malformations of the limbs and have not been widely associated with thalidomide teratogenesis.

Abnormalities, Drug-Induced↗

PubMed1992

Thalidomide for the treatment of chronic graft-versus-host disease.

BACKGROUND: Allogeneic bone marrow transplantation is an accepted therapy for hematologic cancer, aplastic anemia, and inherited immunodeficiencies. Chronic graft-versus-host disease (GVHD) is the principal complication in patients surviving more than 100 days. Thalidomide has been shown experimentally to be effective in treating GVHD. METHODS: We treated 23 patients with chronic GVHD refractory to conventional treatment and 21 patients with "high-risk" chronic GVHD (identified as having at least two of the following three risk factors: chronic GVHD that has evolved from acute GVHD, lichenoid skin or mucous-membrane changes, and hepatic dysfunction. Such patients have a high mortality rate.) with thalidomide in a dose that produced a plasma level of 5 micrograms per milliliter two hours after administration. Therapy was continued for three months after a complete response or for six months after a partial response. RESULTS: The overall actuarial survival of all enrolled patients was 64 percent. Survival was 76 percent among the patients receiving salvage therapy for refractory GVHD and 48 percent among those with high-risk GVHD. A complete response was observed in 14 patients, a partial response in 12 patients, and no response in 18. Side effects were minor, most notably sedation in almost all patients. CONCLUSIONS: In this preliminary trial, thalidomide appeared to be safe and effective for the treatment of chronic GVHD. A trial comparing thalidomide with prednisone in patients with newly diagnosed chronic GVHD will be required to demonstrate its relative efficacy.

Adolescent↗

PubMed1992

Thalidomide's effectiveness in erythema nodosum leprosum is associated with a decrease in CD4+ cells in the peripheral blood.

Thalidomide is well documented as being an effective drug in the treatment of erythema nodosum leprosum (ENL). The mechanism of action of thalidomide in ENL as well as the pathogenesis of ENL are yet to be fully determined. Lepromatous leprosy patients experiencing ENL have been reported to have an increase in the ratio of CD4+ to CD8+ cells in their blood and ENL skin lesions. Thalidomide has been shown to cause a decrease in the ratio of CD4+ to CD8+ lymphocytes in the blood of healthy males. This decrease was due to a significant reduction in the numbers of Cd4+ lymphocytes and an apparent increase in the numbers of CD8+ lymphocytes. In this study, thalidomide's effectiveness in halting chronic ENL and arresting a relapse into ENL was consistently associated with a decrease in the numbers of CD4+ lymphocytes in the blood of 2 male lepromatous leprosy patients.

Adult↗

PubMed1976

[Genital malformations in thalidomide-damaged girls (author's transl)].

Due to the close morphological relationships and the dependence of the genital system on inductive impulses from the uropoietic system, the possibility of an increased incidence of malformations in the area of the female genitals for thalidomide-damaged children is to be expected. This suspicion is supported by the accumulation of reports of genital malformations in deceased children from mothers who took thalidomide-containing medicaments during the early weeks of pregnancy. - A 14-year-old patient with malformations of both upper extremities whose mother had taken thalidomide during the 6th to the 9th week of pregnancy presented at our hospital with complaints of cyclic pain in the lower abdomen. Although the ovaries and fallopian tubes were normally developed, the uterus and the vagina were absent in this patient. After this manuscript had been completed, we heard of 3 additional cases of genital malformation with a known thalidomide anamnesis.

Abnormalities, Drug-Induced↗

PubMed1975

The action of thalidomide on the peripheral nervous system of the embryo.

The mode of teratogenic action of thalidomide is unknown. A new radiological interpretation of thalidomide-induced limb malformations suggested that pathological changes should be sought in the sensory ganglia. Newborn rabbits with thalidomide-induced limb defects were examined histologically, and failure of maturation of dorsal root ganglion cells was demonstrated. This neuronal immaturity supports the radiological hypothesis of embryonic neuropathy, which is proposed as the underlying pathology of the limb deformities due to thalidomide.

Abnormalities, Drug-Induced↗

PubMed1977

The effects of thalidomide and two analogues on the regenerating forelimb of the newt.

Oral administration (3 mg/day) of thalidomide during the dedifferentiation and early limb-bud stages of newt forelimb regeneration produced a variety of specific limb deformities. Proximal and preaxial skeletal elements were the most severely malformed, e.g. preaxial hemimelia, severe proximal deformities, and preaxial polydactyly. Likewise, oral, daily doses (3 mg) of the teratogenic analogue, EM12, on days 7 and 8 following bilateral amputation caused the same incidence and type of forelimb abnormalities as did thalidomide. Conversely, the non-teratogenic analogue, EM87, when orally administered (3 mg/day) on days 7 and 8 post-amputation resulted in a low rate of limb deformities, similar in type to those seen in control regenerates. The type of limb deformities observed in the regenerating newt forelimb following thalidomide treatment nearly mimic those seen in the human and monkey syndromes. Therefore, the newt represents a possible model for investigating some of the problems associated with thalidomide teratogenesis.

Amputation, Surgical↗

PubMed1978

On the application of thalidomide as a block of functional groups of proteins in histochemical investigations.

An attempt was made to apply thalidomide as a block of functional protein groups in histochemical investigations. It was found that thalidomide slightly oxidizes thyrosine and blocks the SH groups mainly in the cytoplasm of rat liver. Contrary to N-ethyl-maleimide, thalidomide does not block the SH groups irreversible, and they can be reactivated with BAL. It is suggested that the teratogenic effect of thalidomide can be connected with the possibility of inactivation of the SH groups by this compound.

Animals↗

PubMed1976

Studies of the etiology of thalidomide dysmorphogenesis.

Thalidomide was administered to pregnant rabbits in dosages of 150-250 mg/kg/day on days 8-12 of gestation. These females produced 40 offspring, 21 of which were deformed. Four control females produced 34 offspring, none of which was deformed. The C6 and C7 ganglia of day-13, -15, -17, and -21 control and experimental embryos and fetuses were examined electron microscopically. Degenerative changes were found in the neurons and axons of dorsal root ganglia in day-13 experimental embryos, i.e., at least 16h before the earliest signs of thalidomide dysmelia have been reported in rabbits (Vickers, '67). Since the dorsal root ganglia form in rabbits on days 11 and 12 the changes evident at day 13 indicate that degeneration of neurons and axons may be a pathogenetic factor in thalidomide-induced peripheral deformities.

Abnormalities, Drug-Induced↗

PubMed1979

The teratogenic activity of a thalidomide analogus EM12 in rats on a low-zinc diet.

The relationship between the teratogenicity of EM12, 2-(2,6-dioxopiperiden-3'-yl) phthalimidine, a stable analogue of thalidomide, and zinc status in the maternal animal was investigated using pregnant rats on a low-zinc diet (1 ppm zinc, days 0--14 gestation) as the experimental model. Previous studies with this compound in rats fed a commercial diet at oral doses up to 250 mg/kg per day for three days and intravenous doses up to 10 mg/kg per day for three days failed to produce "typical" thalidomide malformations. However, when a dose of 150 mg/kg was given intraperitoneally to rats on a low-zinc diet, typical thalidomide malformations occurred with an incidence of 57.5%.

Abnormalities, Drug-Induced↗

PubMed1977

[Teratologic-neurotoxicologic studies on biglumide (K-2004) and thalidomide].

Comparison of the teratogenic and neurotoxic influence of thalidomide with the new hypnosedative preparation Biglumide (K-2004) revealed significant differences. Malformations could be seen only after treatment with thalidomide. Some results concerning the thalidomide-treated group of animals could be interpreted as a retardation of development in the posterior root ganglia.

Animals↗

PubMed1992

Determination of thalidomide in plasma and blood by high-performance liquid chromatography: avoiding hydrolytic degradation.

Thalidomide was determined in plasma and blood by reversed-phase high-performance liquid chromatography with ultraviolet detection. The coefficient of variation of the assay was 1-2% over the 0.25-4.0 micrograms/ml concentration range. Hydrolysis of thalidomide during storage and work-up of the samples was avoided by the addition of an equal volume of citrate buffer, pH 1.5. The assay could be applied to the determination of blood concentrations of thalidomide in rats for at least 28 h after a single oral dose, with multiple blood sampling from the same animal.

Animals↗

PubMed1976

Epilepsy: a neurological complication of thalidomide embryopathy.

The possibility of epilepsy resulting from maternal thalidomide ingestion was investigated by obtaining a telephoned neurological history from all suspect families in the United Kingdom in which the specific diagnosis was uncertain. The annual incidence in the first seven years of life was found to be five times the figure for the general population, and the prevalence of active epilepsy is significantly increased in the teenage thalidomide population. That this increased incidence and prevalence of epilepsy is not a chance observation is supported by published clinical and experimental evidence of central nervous system abnormalities in thalidomide embryopathy, in addition to the known neurological effects of the drug in the adult.

Adolescent↗