Complex Anatomic Abnormalities of the Lower Leg Muscles and Tendons Associated With Phocomelia: A Case Report

Musculoskeletal anatomy is widely known to have components that stray from the norm in the form of variant muscle and tendon presence, absence, origin, insertion, and bifurcation. Although these variant muscles and tendons might be deemed incidental and insignificant findings by most, they can be important contributors to pathologic physiology or, more importantly, an option for effective treatment. In the present case report, we describe a patient with phocomelia and Müllerian abnormalities secondary to in utero thalidomide exposure. The patient had experienced recurrent bilateral foot pain accompanied by numbness, stiffness, swelling, and longstanding pes planus. These symptoms persisted despite conservative treatment with orthotics, steroids, and nonsteroidal anti-inflammatory drugs. Radiographic imaging showed dysmorphic and degenerative changes of the ankle and foot joints. Further investigation with magnetic resonance imaging revealed complex anatomic abnormalities, including the absence of the posterior tibialis and peroneus brevis, lateralization of the peroneus longus, and the presence of a variant anterior compartment muscle. The variant structure was likely a previously described anterior compartment variant, anterior fibulocalcaneus, and might have been a source of the recurrent pain. Also, the absence of the posterior tibialis might have caused the pes planus in the present patient, considering that posterior tibialis tendon dysfunction is the most common cause of acquired pes planus. Although thalidomide infrequently affects the lower extremities, its effects on growth and development were likely the cause of this rare array of anatomic abnormalities and resulting ankle and foot pathologic features.     

Thalidomide in the management of epidermolysis bullosa pruriginosa

Epidermolysis bullosa (EB) pruriginosa is a distinctive clinical subtype of dystrophic EB. We report a patient with dominant dystrophic EB pruriginosa, who had an excellent response to systemic thalidomide treatment. The mechanism of action of thalidomide in the management of pruriginous disorders is not yet completely understood. Most recent studies point towards an immunomodulatory action of thalidomide that may suppress excessive production of tumour necrosis factor-alpha and may downregulate certain cell surface adhesion molecules involved in leucocyte migration.     

Thalidomide usage in Wales: the need to follow guidelines

BACKGROUND: Thalidomide is a potentially useful drug for several dermatological disorders. OBJECTIVES: To assess prescribing and monitoring practices for this drug in Wales. METHODS: A questionnaire was completed by 17 of 19 consultant dermatologists concerning thalidomide usage in Wales (population 2.93 million). RESULTS: Eleven of the 17 respondents had used thalidomide in 40 patients. Only two consultants gave information leaflets and only five obtained written consent. Four obtained baseline nerve conduction studies and nine obtained these during therapy. Of seven women of child-bearing age currently taking thalidomide, none had had baseline pregnancy tests. CONCLUSIONS: We describe variability in prescribing practices for thalidomide. Published guidelines are reviewed and suggestions made concerning consent forms, pregnancy testing, nerve conduction studies and patient information.     

Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs

Therapeutics developed and sold as racemates can exhibit a limited therapeutic index because of side effects resulting from the undesired enantiomer (distomer) and/or its metabolites, which at times, forces researchers to abandon valuable scaffolds. Therefore, most chiral drugs are developed as single enantiomers. Unfortunately, the development of some chirally pure drug molecules is hampered by rapid in vivo racemization. The class of compounds known as immunomodulatory drugs derived from thalidomide is developed and sold as racemates because of racemization at the chiral center of the 3-aminoglutarimide moiety. Herein, we show that replacement of the exchangeable hydrogen at the chiral center with deuterium allows the stabilization and testing of individual enantiomers for two thalidomide analogs, including CC-122, a compound currently in human clinical trials for hematological cancers and solid tumors. Using “deuterium-enabled chiral switching” (DECS), in vitro antiinflammatory differences of up to 20-fold are observed between the deuterium-stabilized enantiomers. In vivo, the exposure is dramatically increased for each enantiomer while they retain similar pharmacokinetics. Furthermore, the single deuterated enantiomers related to CC-122 exhibit profoundly different in vivo responses in an NCI-H929 myeloma xenograft model. The (−)-deuterated enantiomer is antitumorigenic, whereas the (+)-deuterated enantiomer has little to no effect on tumor growth. The ability to stabilize and differentiate enantiomers by DECS opens up a vast window of opportunity to characterize the class effects of thalidomide analogs and improve on the therapeutic promise of other racemic compounds, including the development of safer therapeutics and the discovery of new mechanisms and clinical applications for existing therapeutics.Chirality plays an important role in a variety of disciplines, including pharmaceuticals, foods and flavorings, materials science, and agricultural chemicals. In pharmaceuticals, changing just one chiral center can affect critical compound properties, including potency, off-target side effects, and pharmacokinetics (1–5), thus impacting efficacy and therapeutic index. Since the 1990s, drug molecules originally developed as racemates (a racemate is a 1:1 mixture of two mirror-image compounds or enantiomers) have been separated and developed as single preferred enantiomers (eutomers) because of improved synthesis, purification, and analytical methods. This approach, known as chiral switching, resulted in several new therapeutics based on existing drugs, including esomeprazole (Nexium), escitalopram (Lexapro), levalbuterol (Xopenex), eszopiclone (Lunesta), and levomilnacipran (Fetzima). It also led to new Food and Drug Administration guidance for the characterization and development of stereoisomers (6).There are numerous racemic compounds where chiral switching is impossible, because the chiral center has an exchangeable hydrogen that interconverts on a timescale that is incompatible with storage or dosing of a single pure enantiomer. Some examples of drugs that are still marketed as a mixture of two enantiomers include thalidomide, pioglitazone, bupropion, prasugrel, donepezil, and lorazepam. For each of these molecules, the rate of interconversion of enantiomers under physiological conditions is fast compared with the elimination rate of each molecule.Immunomodulatory drugs derived from thalidomide are an important class of antiinflammatory and antitumorigenic drugs, of which thalidomide is the prototype (7, 8). These compounds (Fig. 1) are all characterized by a nitrogen-substituted 3-aminoglutarimide moiety essential for their therapeutic activity with an exchangeable hydrogen at the chiral center. In addition to thalidomide, a number of analogs, including lenalidomide (Revlimid), pomalidomide (Pomalyst and Imnovid), CC-11006, CC-122, and CC-220, have been or are being developed for the treatment of blood cancers and hematological conditions (e.g., multiple myeloma, myelodysplastic syndrome, lymphoma, and chronic lymphocytic leukemia), solid tumors, and inflammatory diseases (e.g., sarcoidosis, systemic sclerosis, and systemic lupus erythematosus). [We tentatively assign N-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]methyl}cyclopropanecarboxamide (compound 1) as CC-11006, a former development compound for hematological cancers. The chemical structure is disclosed in patents and patent applications related explicitly to this 3-aminoglutarimide (9–11). Experimental data are explicitly disclosed for CC-11006 in the pharmacology review sections for new drug applications (NDAs) 021880 and 204026 corresponding to Revlimid and Pomalyst, respectively. The chemical structure of CC-122 is disclosed in figure 5b in International Patent Application No. WO 2012/125459 (12). The experimental data disclosed in this patent and other patent applications related to the explicit chemical structure (12–16) are also identical to the experimental data in published poster abstracts related to CC-122 (17, 18).]Fig. 1.Structures of thalidomide, pomalidomide, lenalidomide, and protonated and deuterated enantiomers of compound 1 [CC-11006; i.e., (S)-H-1, (R)-H-1, (S)-D-1, and (R)-D-1] as well as protonated and deuterated enantiomers of compound 2 [CC-122; (S)-H-2, ( ...The challenges of dosing and maintaining levels of a single preferred enantiomer of thalidomide analogs are apparent comparing the generally short racemization half-life (rac t_1/2) in human plasma or blood with the longer elimination half-life (elim t_1/2) of thalidomide (19–24) (rac t_1/2 = 2–6 h; elim t_1/2 = 3–8 h), lenalidomide (25–27) (rac t_1/2 < 3 h; elim t_1/2 = 3–8 h), and pomalidomide (28–30) (rac t_1/2 < 1 h; elim t_1/2 = 7.5–9.5 h). The propensity to racemize prior to elimination makes it extremely difficult to assess the properties of the individual enantiomers and impedes mechanistic studies. In fact, the broad spectrum of activity for thalidomide analogs has been extensively studied and suggests multiple target sites of action (7, 31–35). Recently, CC-122 has been defined as a pleiotropic pathway modulator (Celgene Corp) because of its broad range of activity (17, 18). In actuality, each enantiomer may have unique pharmacological and safety profiles. Although there is limited data available and the enantiomers interconvert during the time course of the studies, a few groups have shown that the teratogenicity, in vitro antiinflammatory activity, and in vivo efficacy of protonated thalidomide analogs are caused, in large part, by the (S)-enantiomer (22, 36–38). (S)-pomalidomide was originally advanced into clinical trials as ENMD 0995 (39) but soon abandoned because of the rapid racemization of the exchangeable chiral center (28, 29). Finally, it has recently been shown by X-ray crystallography that the (S)-enantiomers of thalidomide, lenalidomide, and pomalidomide preferentially bind a newly identified target, cereblon (CRBN), believed to be responsible for their efficacy and teratogenicity in a cocrystal with the DDB1–CRBN complex, where DDB1 stands for DNA damage-binding protein 1 (40).Attempts to stabilize the (S)-enantiomer of thalidomide analogs have included replacement of the exchangeable hydrogen with methyl (20, 37, 41, 42) or fluorine groups (43, 44). If and when the stable enantiomer of these analogs was studied, none were superior to the racemic, protonated thalidomide analog. The effects observed included similar or decreased potency, increased degradation, increased toxicity, and/or increased teratogenicity. In vitro stabilization of enantiomers has also been achieved by replacement of the carbonyl group adjacent to the chiral center with an oxetane (45). The impact of this change on in vivo dosing or efficacy has not been reported.Recently, deuterium has been explored to stabilize interconverting enantiomers. Deuterium is a stable isotope of hydrogen with a natural abundance of 0.015%, and it is known for its potential to stabilize chemical bonds. Therefore, deuterium is predicted to not affect the pharmacological properties of a compound, contrary to what can be anticipated with methyl, fluoro, or oxetane functional groups. Furthermore, given the natural abundance of deuterium and its ubiquitous use in past human pharmacokinetic studies, the use of deuterium in therapeutics does not present a safety concern.The use of deuterium to stabilize drugs against undesirable metabolism, known as metabolic switching, began in the 1960s (46–51) and is the predominant approach to deuterated drugs today. Metabolic switching can be a challenging strategy, because it is often difficult to translate from in vitro to in vivo (52), is limited to defined metabolic pathways, and requires the synthesis and testing of numerous analogs.The approach that we describe in this paper, deuterium-enabled chiral switching (DECS), is uniquely differentiated from metabolic switching, in that it is based on chemical stability, is generally independent of metabolism, thus resulting in little or no change in pharmacokinetics, translates from in vitro to in vivo, and requires the synthesis and testing of just two analogs.We are the only group, to our knowledge, to previously and herein report the stabilization and differentiated in vitro and in vivo properties of monodeuterated enantiomers of several thalidomide analogs, including reduced degradation, improved pharmacokinetics, and separation of in vitro antiinflammatory effects (53). Yamamoto et al. (54) previously reported the stabilization of monodeuterated thalidomide enantiomers in aqueous solution but did not differentiate their biochemical properties or their pharmacokinetic and pharmacodynamic properties. Another group has shown improved stability, pharmacokinetics, and separation of in vitro pharmacological effects with pentadeuterated lenalidomide enantiomers (55, 56). However, the latter publications do not differentiate the properties in vivo or allow discrimination of the effects of the additional four deuteria on the 3-aminoglutarimide ring and their pharmacodynamic contributions (55, 56).Herein, we report the synthesis, in vitro characterization, and differentiation of stabilized enantiomers of two unique thalidomide analogs, compounds 1 (57) and 2 (CC-122) (58), and for the first time to our knowledge, we differentiate stabilized enantiomers of thalidomide analogs in in vitro and in vivo efficacy models.     

Low-dose vs. high-dose thalidomide for advanced multiple myeloma: a prospective trial from the Intergroupe Francophone du Myélome

This multicentre prospective randomised trial compared the efficacy and safety of two doses of thalidomide in patients with relapsed or refractory myeloma. The study was designed to test the non-inferior efficacy and to confirm the better tolerability of low-dose thalidomide as compared to a higher dose. Four hundred patients were randomly assigned to receive either 100 or 400 mg/day of thalidomide. Dexamethasone treatment was added in both arms for patients with stable disease or treatment failure at 12 weeks. The primary endpoint was 1-year overall survival (OS). Thalidomide 100 mg/day was better tolerated than 400 mg/day with less high-grade somnolence, constipation, nausea/vomiting and peripheral neuropathy (P < 0.001, P = 0.007, P = 0.03 and P = 0.007, respectively). In the per-protocol population (PP), the estimated 1-year OS rates were of 74.5% (n = 149) and 67.3% (n = 156) in the 400 and 100 groups, respectively. The upper limit of the difference between these rates was of 15.6% higher than the non-inferiority acceptable limit of 12.75%, and the hypothesis of non-inferiority of 100 could not be established (P = 0.14). On the other hand, when intent-to-treat (ITT) population was analysed, the non-inferiority was demonstrated because the 1-year OS rates were of 72.8% (n = 195) and 68.8% (n = 205) in the same groups, leading to an upper limit of the difference of 11.49% lower than the non-inferiority acceptable limit. In addition, in patients alive 12 weeks postrandomisation and those who received thalidomide plus dexamethasone, there were no significant differences in response rates, time to progression, progression-free survival and OS between the two groups. Collectively, low-dose thalidomide 100 mg/day has significant activity in advanced myeloma with an improved safety profile and can be a good salvage therapy in combination with dexamethasone.     

Proteasome inhibition in hematologic malignancies

Hematologic malignancies, including multiple myeloma (MM), will account for more than 100,000 new cases of cancer and over 57,000 deaths in the United States in 2003. Treatment of MM is a serious challenge, because despite a variety of available therapies, median survival is short. A new therapeutic area focuses on inhibiting the activity of the proteasome, a 26S protease complex involved in cell cycle regulation, cell adhesion, inflammation, and protein turnover. The novel proteasome inhibitor, bortezomib (Velcade®), was recently approved for use in patients with refractory and relapsed MM and to date is the only proteasome inhibitor to have entered clinical trials. Bortezomib has demonstrated activity with manageable toxicity in a variety of hematologic malignancies in addition to MM, including leukemia and non‐Hodgkin's lymphoma. This article reviews clinical information on bortezomib in hematologic malignancies both as monotherapy and in combination with dexamethasone. Preliminary reports of bortezomib in combination with Doxil (pegylated liposomal doxorubicin), melphalan, and thalidomide are discussed, and current trials are described. Available data suggest that bortezomib will be useful in the treatment of a variety of hematologic malignancies.     

Real‐world health care costs of relapsed/refractory multiple myeloma during the era of novel cancer agents

What is known and objective: High costs of novel agents increasingly put pressure on limited healthcare budgets. Demonstration of their real‐world costs and cost‐effectiveness is often required for reimbursement. However, few published economic evaluations of novel agents for multiple myeloma exist. Moreover, existing cost analyses were heavily based on conventionally treated patients. We investigated real‐world health care costs of relapsed/refractory multiple myeloma in Dutch daily practice. Methods: A retrospective medical chart review was conducted for 139 patients treated between January 2001 and May 2009. Total monthly costs attributable to each cost component were described across all regimens and for bortezomib‐, thalidomide‐ and lenalidomide‐based treatment regimens. Results: Mean monthly total costs (€3,981) varied depending on the sequence of therapy (range: €442–€31,318). Significant cost drivers across all regimens included costs of therapy and hospital admissions. The acquisition costs for novel agents in particular accounted for 32% of mean total monthly costs. Prognostic factors associated with increased mean total monthly costs in multivariate regression analysis included low platelet counts (P = 0·01) and worsening performance status (P < 0·001). Mean total monthly costs of bortezomib‐ and lenalidomide‐based regimens were significantly higher than those for thalidomide‐based regimens in second, third and fourth treatment line. What is new and conclusions: Real‐world costs during treatment of relapsed/refractory multiple myeloma vary greatly. Cost drivers include hospital admissions and acquisition costs of novel agents. Costs also vary by prognostic factors and treatment‐related resource use. Future studies assessing the costs of combination therapy consisting of two or more novel agents are encouraged.     

Intravenous melphalan, thalidomide and prednisone in refractory and relapsed multiple myeloma

OBJECTIVES: Thalidomide combined with conventional chemotherapies including oral melphalan shows significant anti-myeloma activity. To address this issue, feasibility and efficacy of a three drug combination consisting of intravenous (i.v.) melphalan, thalidomide and prednisone [M(i.v.)PT] was evaluated in advanced myeloma patients. PATIENTS AND METHODS: Twenty-four advanced myeloma patients were treated with multiple cycles of a regimen consisting of low dose i.v. melphalan (20 mg/m2) at d 1, thalidomide at the dose of 50-100 mg/d given continuously and oral prednisone at the planned dose of 50 mg/d every other day. Intravenous melphalan was administered every fourth month. Median time from diagnosis was 40 months (range: 8-144 months). Fifteen patients (66%) had previously been treated with a combination of thalidomide and dexamethasone or with thalidomide alone. RESULTS: Overall, on an intent-to treat basis, 14 patients responded: three achieved near complete remission (nCR), seven achieved partial response (PR), four minimal response (MR). Six patients showed stable disease (SD) and four-disease progression. Interestingly, of five patients who had previously progressed while on thalidomide and prednisone, one reached nCR, two PR and one MR. After a median follow up of 14 months, median progression free survival was 9 months. Response duration was longer than that induced by the previous line of treatment in eight patients (33%). Thalidomide-associated toxicity mainly consisted of constipation, tingling and sedation. CONCLUSIONS: M(i.v.)PT is an effective regimen, which can overcome resistance to thalidomide plus prednisone in advanced myeloma with acceptable toxicity.