Minimal Untoward Effects Research Articles

Lentivector Iterations and Pre-Clinical Scale-Up/Toxicity Testing: Targeting Mobilized CD34+ Cells for Correction of Fabry Disease

Fabry disease is a rare lysosomal storage disorder (LSD). We designed multiple recombinant lentivirus vectors (LVs) and tested their ability to engineer expression of human α-galactosidase A (α-gal A) in transduced Fabry patient CD34+ hematopoietic cells. We further investigated the safety and efficacy of a clinically directed vector, LV/AGA, in both ex vivo cell culture studies and animal models. Fabry mice transplanted with LV/AGA-transduced hematopoietic cells demonstrated α-gal A activity increases and lipid reductions in multiple tissues at 6 months after transplantation. Next we found that LV/AGA-transduced Fabry patient CD34+ hematopoietic cells produced even higher levels of α-gal A activity than normal CD34+ hematopoietic cells. We successfully transduced Fabry patient CD34+ hematopoietic cells with “near-clinical grade” LV/AGA in small-scale cultures and then validated a clinically directed scale-up transduction process in a GMP-compliant cell processing facility. LV-transduced Fabry patient CD34+ hematopoietic cells were subsequently infused into NOD/SCID/Fabry (NSF) mice; α-gal A activity corrections and lipid reductions were observed in several tissues 12 weeks after the xenotransplantation. Additional toxicology studies employing NSF mice xenotransplanted with the therapeutic cell product demonstrated minimal untoward effects. These data supported our successful clinical trial application (CTA) to Health Canada and opening of a “first-in-the-world” gene therapy trial for Fabry disease.

Sitagliptin/metformin fixed-dose combination in type 2 diabetes mellitus: an evidence-based review of its place in therapy.

Type 2 diabetes mellitus is a progressive disease associated with significant morbidity and mortality. There is good evidence showing that intensive glycemic control reduces the development and progression of complications. In order to achieve glycemic targets, patients often require a combination of oral therapy and/or insulin in addition to lifestyle modification. Unfortunately, many of the traditional therapies for type 2 diabetes are associated with weight gain and hypoglycemia, resulting in poor compliance and subsequent worsening of glycemic control. The dipeptidyl peptidase-4 inhibitor sitagliptin is a therapy for type 2 diabetes and is available as a fixed-dose combination with metformin. Phase III clinical trials have demonstrated beneficial effects on glycemic control and minimal untoward effects with this combination. In this article, we provide an overview of the pharmacology, efficacy, and safety and examine the role of this combination within current practice.

Once-Daily Nevirapine XR

Nevirapine (NVP) was the first nonnucleoside reverse transcriptase inhibitor (NNRTI) approved by the US Food and Drug Administration (FDA) in 1996, for the treatment of HIV infection. Current treatment guidelines include NVP as a component of a recommended alternative NNRTI regimen, which may be the preferred regimen for patients with established cardiovascular risk factors since NVP has minimal untoward effects on serum lipids. Two randomized and controlled clinical trials established the noninferior virologic efficacy of twice-daily NVP versus ritonavir-boosted atazanavir (ATV/r), a protease inhibitor with limited effects on serum lipids, each drug on a background regimen of once-daily (QD) tenofovir (TDF)/emtricitabine (FTC). An extended-release (XR) formulation of NVP was developed since QD dosing and reduced pill burdens have been shown to improve regimen adherence. This formulation (Viramune XR 400 mg) was recently FDA approved based on the results of 2 randomized, controlled clinical trials. The XR formulation will provide additional treatment options for patients who may benefit from NVP-based regimens.

Mesotherapy - The french connection

Mesotherapy involves the use of multiple intradermal or subcutaneous injections of a mixture of compounds in minute doses, by means of very fine needles, directly over/near the affected sites. Originally invented in France to manage painful medical conditions, it is presently the buzz word in the field of cosmetic dermatology, chiefly to get rid of disfiguring fat. Depending upon the condition treated, the drugs injected, the techniques followed and the number of sessions involved vary. The wider reception of mesotherapy by its stakeholders are probably due to factors like inexpensive equipments, relatively minimal training for providers, much reduced dosage need of the drugs with resultant minimal untoward effects, quicker realization of benefits, minimal invasiveness/pain involved and not the least it is an outpatient procedure. Despite so many plus points, it has to be noted that currently there is a dearth of rigorous scientific studies to prove its efficacy and safety. Further, the average cost per session alone ranges from 200 USD to 600 USD.

The anti-inflammatory effects of levocetirizine - are they clinically relevant or just an interesting additional effect?

Levocetirizine, the R-enantiomer of cetirizine dihydrochloride has pharmacodynamically and pharmacokinetically favourable characteristics, including rapid onset of action, high bioavailability, high affinity for and occupancy of the H1-receptor, limited distribution, minimal hepatic metabolism together with minimal untoward effects. Several well conducted randomised clinical trials have demonstrated the effectiveness of levocetirizine for the treatment of allergic rhinitis and chronic idiopathic urticaria in adults and children. In addition to the treatment for the immediate short-term manifestations of allergic disease, there appears to be a growing trend for the use of levocetirizine as long-term therapy. In addition to its being a potent antihistamine, levocetirizine has several documented anti-inflammatory effects that are observed at clinically relevant concentrations that may enhance its therapeutic benefit. This review will consider the potential or otherwise of the reported anti-inflammatory effects of levocetirizine to enhance its effectiveness in the treatment of allergic disease.

Radiosurgery for metastatic brain tumors

Stereotactic radiosurgery (SRS) precisely delivers high-dose radiation to a small target (usually less than 3-4 cm in diameter), in a single session with steep dose-fall, employing various radiation methods. SRS provides good tumor control for small brain metastases from various primary cancers, with minimal untoward effects on surrounding normal brain. This excellent tumor control prevents neurological death and maintains good activity of daily life. Although surgery with whole-brain radiation therapy (WBRT) remains an important option for patients with a solitary brain metastasis, SRS with or without WBRT should be considered in patients with a limited number of small tumors and a good prognosis. Many reports, as well as both retrospective and prospective reviews, have shown WBRT before or after SRS to improve local control and reduce new distant lesion emergence. However, upfront WBRT does not improve survival. There are two major delivery techniques, Gamma Knife (GK; Elekta AB, Stockholm, Sweden) SRS and linear accelerator (LINIAC)-based SRS. They are based on quite different concepts, and have different techniques and clinical applications. These differences complicate the discussion of the limitations of and indications for SRS and the necessity for prophylactic WBRT. This review discusses numerous aspects of SRS, its value as compared with other treatment modalities, the necessity for prophylactic WBRT with SRS, the limitations of and indications for SRS, and the difference between GK and LINIAC SRS, based on the literature and our experience, and proposes a new strategy for the treatment of brain metastases in view of the available clinical data and experience.

Subcutaneous Implantation of Pure Crystalline Estradiol Pellets for Conception Control

Objectives: Assessment of the contraceptive effectiveness of pure estradiol pellets implanted annually under the skin, thus avoiding the ‘first passage phenomenon’ through the liver, using a modification of Emperaire and Greenblatt’s method. Study Design: 228 women wishing birth control for 1 year or more were included. 5 pellets of estradiol (25 mg each) were implanted initially. At each subsequent annual treatment, 4 pellets were implanted. Withdrawal bleeding was induced monthly with oral norethindrone acetate 5 mg taken for 7 days. Our experience encompassed 8,136 cycles, or 678 women years. The study obtained approval of the local Ethical Committee. Results: Annual continuation rates were 51 per 100 women in the second year, 65 in the third, 72 in the fourth and 84 ± 10.1 annually over the next 6 years. Through 12 years of our study, 2 accidental pregnancies occurred. The annual net cumulative pregnancy rates were 0.44 and 0.48 per 100 women at 1 and 2 years, and reduced to 0.29 at the end of 10 years. Return of fecundity after discontinuing treatment was 53% after 12 months, 81% after 24 months and 89% after 36 months. The mean estradiol levels were 1,413 ± 161 pmol/l one week following the pellet installation. The mean serum estradiol level of the 43 women who were assayed arbitrarily or a year following last insertion was 1,207 pmol/l (range 462–2,904 pmol/l); 22% had serum estradiol levels <1,000 pmol/l and 6.3% (3 women) had levels >1,750 pmol/l. A total of 28 endometrial biopsies were obtained –19 were proliferative, 6 showed slight simple hyperplasia, and three, benign cystic glandular hyperplasia. Conclusion: Subcutaneous implantation of pure estradiol pellets offers excellent birth control, has minimal untoward effects, is simple to insert and can serve as a possible alternative for conception control. It could be considered for 3 indications: for women who have completed family planning; for women in older age group (above 35 years) who are approaching the climacteric; and for women at any age, who need prolonged periods of contraception.

Divided attention-enhancing effects of AF102B and THA in aging monkeys.

The effects of cholinergic drugs proposed for treatment of cognitive impairment in normal aging and dementia on divided attention have been little studied in non-human primates. We tested the hypothesis that cholinergic drugs improve spatial divided attention in primates via a computer task requiring simultaneous tracking of two visual targets in three young and two aged healthy bonnet macaques. Task accuracy (number of correct responses) and reaction time (RT) were measured 2 h after administration of either the m1 agonist +/- -cis-2-methyl-spiro(1,3-oxathiolane-5,3')quinuclidine (AF102B; 0.1-2.1 mg/kg IM) or the cholinesterase inhibitor 9-amino-1,2,3,4-tetrahydroamino-acridine (THA; 0.5-2.0 mg/kg orally). Accuracy increased for four of five monkeys at appropriate doses of one or both cholinomimetics, accompanied in two monkeys by a drop in RT. Responses were less uniform to THA than to AF102B. For the five-monkey group at Best dose, accuracy increased 34% (THA) or 43% (AF102B) above baseline (P<0.05 for both drugs), respectively, with no significant change in RT and with minimal untoward effects. Cholinotherapy may improve divided attention in young and aged healthy primates.

1 alpha-Hydroxy-vitamin D2: a new look at an 'old' compound.

Calcitriol is effective in suppressing PTH levels in haemodialysis patients with hyperparathyroidism but has a low therapeutic index. There is a search for other vitamin D sterols that suppress PTH but cause less hypercalcaemia. We review evidence that 1 alpha-hydroxy-vitamin D2 (1 alpha-D2) may be an effective and safer alternative to calcitriol. In vitamin D-deficient rats, 1 alpha-D2 is equipotent to 1 alpha-D3, which is converted to calcitriol before it acts; but, in normal rats, 1 alpha-D2 is much less toxic at high doses. In osteopenia models, either steroid-induced or following ovariectomy, 1 alpha-D2 is equal to or more effective than 1 alpha-D3 in preventing bone loss but causes less hypercalciuria. Studies in osteoporotic women reveal minimal hypercalciuria with 1 alpha-D2 at doses up to 4 micrograms/day, data suggesting greater safety than reported with calcitriol or 1 alpha-D3. Preliminary data in haemodialysis patients with secondary hyperparathyroidism demonstrate the efficacy of 1 alpha-D2 in suppressing PTH levels with minimal untoward effects on serum Ca and no effects on serum P. Taken together, these observations suggest that 1 alpha-D2 deserves strong consideration as a therapeutic agent for secondary hyperparathyroidism associated with end-stage renal disease.

Urologic applications of a permanent, epithelializing urethral endoprosthesis

Recently, a flexible, self-expanding, permanent endoprosthesis has been developed to maintain patency of stenotic arteries after balloon angioplasty. This device, known as the UroLume Wallstent, is now under active investigation in both Europe and the United States as a treatment for: (1) recurrent bulbar urethral strictures, (2) benign prostatic hyperplasia, and (3) detrusor-external sphincter dyssynergia. Preliminary data demonstrate this device to be an effective treatment for all three indications in select patients and to be associated with minimal untoward effects. If the long-term results are equally encouraging, this unique endoprosthesis will represent a significant advancement for the field of urology.

Implantation of pure crystalline pellets of estradiol for conception control

Estradiol pellet implantation for contraception offers another alternative in conception control. The occurrence of only two pregnancies in 1,668 cycles (Pearl index: 1.42) reflects its efficacy. The advantages over oral contraceptives are: (1) absence of gastrointestional symptoms, (2) minimal untoward effects, (3) no patient failure, and (4) convenience. Progressive stepdown in dose reduces the total amount of steroid used in long-term contraception. Contraceptive effect may not occur during the first month of implantation; adequate precaution should be taken. Because of the efficacy, minimal untoward side effects, and excellent patient acceptability, this regimen may be considered for contraception in developing countries and when other modalities are contraindicated.