Intramuscular Medroxyprogesterone Acetate Research Articles

Quantitative thin layer chromatography for the determination of medroxyprogesterone acetate using a smartphone and open-source image analysis

Intramuscular medroxyprogesterone acetate (MPA) products are commonly used to treat endometriosis and are the most widely used injectable contraceptives worldwide. Therefore, dependable quality screening of MPA injectables is a crucial measure necessary for ensuring that consumers are provided with safe and effective medications. Here, a thin-layer chromatography (TLC) method for MPA identification is combined with image analysis using a smartphone, 3D-printed light box, and open-source ImageJ software. The method's validation included two brands of MPA injectables, both at 150 mg mL−1 dosage. The TLC procedure used was based on the identity test found in The International Pharmacopoeia's Medroxyprogesterone injection monograph. Spots produced on the TLC plates were then photographed using a smartphone camera and quantified using ImageJ's image analysis software. The pixel data collected from each plate's standard spots were compared to the data generated from its sample spots. Data sets collected across multiple TLC plates and numerous days of method performance were evaluated to assess linearity, accuracy, precision, specificity, and robustness. Across the range of 75–125% of the target concentration, the method was found to have linearity of standard spots (with R2 generally greater than 0.99), overall accuracy of 101.0% (4.1% RSD), repeatability pooled standard deviation of 2.44%, intermediate precision pooled standard deviation of 3.68%, and observed demonstration of specificity and robustness. In low and middle-income countries (LMICs), quality screening of pharmaceutical products like MPA injectables can be challenging when testing resources are expensive, difficult to procure, or complex to utilize. The results of the TLC/ImageJ method validation suggest that this simple procedure that requires minimal resources may serve as a viable option for reliable quality screening of MPA levels in injectable suspensions.

Single-dose, subcutaneous recombinant phenylalanine ammonia lyase conjugated with polyethylene glycol in adult patients with phenylketonuria: an open-label, multicentre, phase 1 dose-escalation trial

Phenylketonuria is an inherited disease caused by impaired activity of phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine, leading to accumulation of phenylalanine and subsequent neurocognitive dysfunction. Phenylalanine ammonia lyase is a prokaryotic enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. We aimed to assess the safety, tolerability, pharmacokinetic characteristics, and efficacy of recombinant Anabaena variabilis phenylalanine ammonia lyase (produced in Escherichia coli) conjugated with polyethylene glycol (rAvPAL-PEG) in reducing phenylalanine concentrations in adult patients with phenylketonuria. In this open-label, phase 1, multicentre trial, single subcutaneous injections of rAvPAL-PEG were given in escalating doses (0·001, 0·003, 0·010, 0·030, and 0·100 mg/kg) to adults with phenylketonuria. Participants aged 18 years or older with blood phenylalanine concentrations of 600 μmol/L or higher were recruited from among patients attending metabolic disease clinics in the USA. The primary endpoints were safety and tolerability of rAvPAL-PEG. Secondary endpoints were the pharmacokinetic characteristics of the drug and its effect on concentrations of phenylalanine. Participants and investigators were not masked to assigned dose group. This study is registered with ClinicalTrials.gov, number NCT00925054. 25 participants were recruited from seven centres between May 6, 2008, and April 15, 2009, with five participants assigned to each escalating dose group. All participants were included in the safety population. The most frequently reported adverse events were injection-site reactions and dizziness, which were self-limited and without sequelae. Two participants had serious adverse reactions to intramuscular medroxyprogesterone acetate, a drug that contains polyethylene glycol as an excipient. Three of five participants given the highest dose of rAvPAL-PEG (0·100 mg/kg) developed a generalised skin rash. By the end of the study, all participants had developed antibodies against polyethylene glycol, and some against phenylalanine ammonia lyase as well. Drug concentrations peaked about 89-106 h after administration of the highest dose. Treatment seemed to be effective at reducing blood phenylalanine in all five participants who received the highest dose (mean reduction of 54·2% from baseline), with a nadir about 6 days after injection and an inverse correlation between drug and phenylalanine concentrations in plasma. Phenylalanine returned to near-baseline concentrations about 21 days after the injection. Subcutaneous administration of rAvPAL-PEG in a single dose of up to 0·100 mg/kg was fairly safe and well tolerated in adult patients with phenylketonuria. At the highest dose tested, rAvPAL-PEG reduced blood phenylalanine concentrations. In view of the development of antibodies against polyethylene glycol (and in some cases against phenylalanine ammonia lyase), future studies are needed to assess the effect of repeat dosing. BioMarin Pharmaceutical.

Differential effects of progestins on the brain

Interactions exist between progestins and the γ-aminobutyric acid (GABA) receptor subtype A where C 21-steroids function as activators. Other interactions between progesterone and neurotransmitter systems include stimulation of dopamine release in striatal tissue, stimulation of GnRH release from hypothalamic neurons and inhibition of opioid receptor binding and activation. Cyproterone acetate increases dopaminergic responses and binds to opiate receptors independently of its classical effect on the androgen receptor. Progesterone substitution in perimenopausal women promotes length and quality of sleep. This effect seems most prominent for progesterone administered vaginally. Progestins also play a role in the pathogenesis of migraine. Migraine symptoms occur predominantly during the perimenstrual stage. Women who suffer from menstrual migraine triggered by premenstrual progesterone loss often benefit from cyclic progesterone administration. This may be because progesterone and allopregnenolone reduce meningeal release of substance P and inhibit the development of neurogenic oedema. Women whose migraine symptoms subside during pregnancy, however, benefit from intramuscular medroxyprogesterone acetate. Progesterone, generated from pregnenolone by Schwann cells, also enhances myelin synthesis. Myelination of axons is promoted when progesterone is added to cultures of rat dorsal root ganglia. No reliable data exist with respect to the effects of other progestins on demyelinating disease. Progestins promote the growth of meningioma as progesterone receptors predominate in meningioma tissue. Progesterone and synthetic progestins should therefore not be prescribed in these patients.

Cytologic findings in cervical smears in patients using intramuscular medroxyprogesterone acetate (Depo‐Provera) for contraception

The purpose of the present study was to assess the findings in cervical smears associated with intramuscular depot medroxyprogesterone acetate (Depo-Provera) contraception. Seventy-four cervical smears of reproductive-age patients on Depo-Provera were reviewed for cytologic abnormalities, predominant cell type, and intermediate cell glycogenation (extensive (EGly) = navicular cells / glycogenation in 10 or more high-powered fields (hpf); moderate (MGly) = 5–10 hpf; and focal (FGly) = less than 5 hpf). A control group of 38 nonpregnant patients without hormonal therapy was reviewed. Study group patients' (SGP) age ranged from 16–44 years (average 28.1); control group patients (CGP) from 17–42 years (average 29.4). Time since last menstrual period (LMP) for the SGP was 16.9 months (range 1–96); LMP for CGP was 18.2 days (range 5–33). Four (5.4%) SGP had squamous intraepithelial lesions (SIL), four (5.4%) atypical squamous cells of undetermined significance (ASCUS), and one (1.4%) atypical repair. No CGP had SIL or ASCUS. Seventy-three (98.6%) SGP had intermediate cell (IC) predominance; one had parabasal cell predominance. Of the CGP, 28 (73.7%) had IC predominance, nine (23.7%) superficial cell (SC) predominance and one (2.6%) had near equal IC and SC. EGly was seen in 22 (29.7%) SGP; two (5.3%) in CGP (chi-square 7.53; 0.95 = 3.84). MGly was seen in 29 (39.2%) SGP; 10 (26.3%) in CG. FGly was seen in 17 (22.9%) SGP; 14 (36.8%) in CGP. No glycogenation was seen in six (8.1%) SGP; 12 (31.6%) in CGP. Time since LMP was inversely proportional to glycogenation in SGP: EGly-LMP 11.6 months; MGly-LMP 14.9 months; FGly-LMP 15.0 months; and no glycogenation-LMP 22.5 months. Glycogenation of IC appears inversely proportional to Depo-Provera effect. EGly due to recent Depo-Provera administration mimics changes associated with pregnancy. Diagn. Cytopathol. 2000;23:161–164. © 2000 Wiley-Liss, Inc.

Cytologic findings in cervical smears in patients using intramuscular medroxyprogesterone acetate (Depo-provera) for contraception.

The purpose of the present study was to assess the findings in cervical smears associated with intramuscular depot medroxyprogesterone acetate (Depo-Provera) contraception. Seventy-four cervical smears of reproductive-age patients on Depo-Provera were reviewed for cytologic abnormalities, predominant cell type, and intermediate cell glycogenation (extensive (EGly) = navicular cells / glycogenation in 10 or more high-powered fields (hpf); moderate (MGly) = 5-10 hpf; and focal (FGly) = less than 5 hpf). A control group of 38 nonpregnant patients without hormonal therapy was reviewed. Study group patients' (SGP) age ranged from 16-44 years (average 28.1); control group patients (CGP) from 17-42 years (average 29.4). Time since last menstrual period (LMP) for the SGP was 16.9 months (range 1-96); LMP for CGP was 18.2 days (range 5-33). Four (5.4%) SGP had squamous intraepithelial lesions (SIL), four (5.4%) atypical squamous cells of undetermined significance (ASCUS), and one (1.4%) atypical repair. No CGP had SIL or ASCUS. Seventy-three (98.6%) SGP had intermediate cell (IC) predominance; one had parabasal cell predominance. Of the CGP, 28 (73.7%) had IC predominance, nine (23.7%) superficial cell (SC) predominance and one (2.6%) had near equal IC and SC. EGly was seen in 22 (29.7%) SGP; two (5.3%) in CGP (chi-square 7.53; 0.95 = 3.84). MGly was seen in 29 (39.2%) SGP; 10 (26.3%) in CG. FGly was seen in 17 (22.9%) SGP; 14 (36.8%) in CGP. No glycogenation was seen in six (8.1%) SGP; 12 (31.6%) in CGP. Time since LMP was inversely proportional to glycogenation in SGP: EGly-LMP 11.6 months; MGly-LMP 14.9 months; FGly-LMP 15.0 months; and no glycogenation-LMP 22.5 months. Glycogenation of IC appears inversely proportional to Depo-Provera effect. EGly due to recent Depo-Provera administration mimics changes associated with pregnancy.

Contraceptive management for female adolescents with mental retardation and handicapping disabilities

Adolescent girls with mental retardation and handicapping disabilities have a need for sexual counseling and contraceptive management. Societal attitudes have changed, allowing these patients to experience normal and satisfying sexuality. The reproductive health concerns of these patients are extensive. Contraceptive selection varies with regard to the mental and physical capabilities of individual patients. The use of barrier methods, intrauterine devices, oral contraceptives, intramuscular medroxyprogesterone acetate, and sterilization has been discussed thoroughly in the past. No formal studies have been performed to evaluate the use of subdermal levonorgestrel implants in patients with mental retardation and physical disabilities.

Infarction-nephrectomy for metastatic renal carcinoma: Southwest oncology group study

Thirty patients with metastatic renal cell cancer were treated by renal infarction, followed by delayed nephrectomy. All cases were collected over an eighteen-month period, with a minimum follow-up of one year. There were no complete remissions and only one partial remission, which lasted twenty-one months before progression of disease. Three patients had stable disease for at least six months, but eventually all patients showed evidence of progression. After tumor progression was documented patients were treated with intramuscular medroxyprogesterone acetate (Depo-Provera) 800 mg per week. No patient responded to this therapy. Overall, a 28 per cent one-year survival and a seven-month median survival were realized, which is similar to other series in which no therapy or palliative nephrectomy was performed. We conclude that infarction and nephrectomy is not an effective modality in the treatment of metastatic renal cell carcinoma. In addition, medroxyprogesterone was not shown to be significantly active against renal cancer in this study.

Plasma medroxyprogesterone acetate levels following intramuscular or oral administration in patients with endometrial adenocarcinoma

The concentration of medroxyprogesterone acetate (MPA) in plasma samples taken 24 h after intramuscular or oral administration of 100 mg daily doses of the drug to patients with endometrial adenocarcinoma was measured by radioimmunoassay. In general, a plasma level of about 4 ng/ml was found 24 h after the dose, independent of the route of drug administration. However, in three of the patients to whom intramuscular MPA was given, considerably higher values were found. A maximal plasma level was achieved three hours after ingestion of 100 mg MPA. This was followed by a rapid decline to 20-25% of the peak value after about 12 h. A rather small day-to-day intraindividual variation was found in daily blood samples taken just before administration of the next dose. However, considerable differences were found between individuals and it is concluded that this variation in plasma levels may be reflected in the clinical efficacy of the treatment. Thus further studies in which plasma values and clinical effectiveness are correlated seem to be indicated.

Disturbance of tryptophan metabolism and its correction during hormonal contraception

A relative pyridoxine deficiency was found in 80 % of 100 women using oral contraceptives. This was due to disturbed tryptophan metabolism, expressed in increased xanthurenic acid (XA) excretion ( ≥ 60 μ mol 8 h ) during 8 hours following oral administration of 2 g L-tryptophan. These contraceptives contained a combination of oestrogens and progestogens. Normalization of the excretion was nearly always achieved by giving a large dose of pyridoxine hydrochloride (vitamin B6) ( 100 mg 24 h for 4 weeks). A previously normal XA excretion always showed a significant decrease after treatment with pyridoxine hydrochloride. The blood vitamin B6 concentration is not affected by the use of oral contraceptives or intramuscular medroxyprogesterone acetate (MPA) injections (150 mg every 12 weeks). In the literature, the synthetic oestrogens are regarded as responsible for the disturbance in tryptophan metabolism. The progestogen component of the combined oral contraceptives was found to exert an influence on maximum XA excretion. This could be explained by the intrinsically oestrogenic and anti-oestrogenic properties of the progestogens used. Relative pyridoxine deficiency due to disturbed tryptophan metabolism was found also in 5 out of 15 women who used MPA as contraceptive agent.