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Simultaneous determination of methenamine and formaldehyde in the urine of humans after methenamine administration.

Methenamine (hexamethylenetetramine) and its hydrolysis product formaldehyde are determined in the presence of each other in urine by a spectrophotometric method. Formaldehyde is assayed by a colour reaction with tryptophan, sulphuric acid and ferric chloride after precipitating methenamine by three treatments with mercuric chloride. Methenamine is indirectly analysed by hydrolysis to formaldehyde with dilute hydrochloric acid. Formaldehyde levels as low as 5.0 micrograms ml-1 in the presence of methenamine concentrations as high as 2.5 mg ml-1 can be assayed. Of practical significance is the feature that urine may be stored up to 1 weeks for analysis, by appropriate dilution and freezing, without excessive loss of methenamine or formaldehyde. The method was applied to the dtermination of the bioavailability of methenamine hippurate in ten human volunteers.

Biological Availability

Drug therapy reviews: methenamine mandelate and methenamine hippurate.

The mechanism of action, spectrum of antimicrobial activity, pharmacokinetics, adverse effects, therapeutic use, and dosage of methenamine hippurate and methenamine mandelate are reviewed. The antimicrobial activity of methenamine depends on its conversion in the urine to formaldehyde. Formaldehyde's spectrum of antibacterial activity encompasses all urinary tract pathogens. Urinary concentrations of formaldehyde vary with pH and urine volume; however, there is no documentation that acdification of the urine enhances methenamine's therapeutic activity. Adverse reactions to methenamine, including gastrointestinal intolerance and skin reactions, are mild and reversible and occur infrequently. Methenamine mandelate and hippurate are effective in the prevention of recurrent urinary tract infections except in patients with Foley catheters or who require intermittent catheterization.

Bacteria

Biological fate of methenamine in man. Absorption, renal excretion and passage to umbilical cord blood, amniotic fluid and breast milk.

Methenamine hippurate was administered orally as tablets or granules to healthy volunteers. Plasma concentrations of methenamine reached a maximum 1--2 hours after a single dose and then declined with a half-life of about 4 hours. The apparent distribution volume was similar to that of total body water. Renal clearance of methenamine was somewhat lower than that of creatinine. In cross-over experiments over six days, methenamine recovered in the urine corresponded to about 80 per cent of the dose given per 12 hours, slightly lower values being obtained from granules than from tablets. The efficient renal elimination of methenamine was confirmed in similar studies on patients post-operatively. Methenamine hippurate was also given to healthy pregnant women during labor, a few hours before expected delivery. Methenamine was found to pass the placental barrier. The concentration of methenamine in umbilical cord plasma was low but reached the level in maternal plasma after about 4 hours. In amniotic fluid the methenamine con centration was low and varying. No correlation was obtained to the maternal or umbilical cord plasma levels. The methenamine concentration in breast milk was of the same magnitude as in maternal plasma. It is concluded that methenamine may be safely given to pregnant and lactating women with respect to the ellbeing of the child.

Absorption

Long-term treatment with methenamine hippurate in recurrent urinary tract infection.

Twenty-four patients with a history of recurrent urinary tract infection and in whom residual urine was considered to be a factor of importance for chronicity, have been treated for an average of 16 months with 1 g methenamine hippurate morning and evening. No patient had urinary calculus at the commencement of treatment and neither did any patient have an indwelling catheter. In patients without urinary tract infection or in whom abacteriuria was achieved with methenamine hippurate, the number of reinfections was reduced by approximately two thirds compared to periods prior to treatment. No patient was completely free from infection throughout the whole treatment period. However, in no case did bacteria with extensive resistance appear. When urinary tract infection was treated with methenamine hippurate, abacteriuria was achieved in only 6 of 14 patients. It would therefore seem that this agent is only of limited value for treatment of established infection. In the event of manifest infection it would appear appropriate to treat the infection primarily with antibiotics and to use methenamine hippurate for prophylaxis when abacteriuria has been achieved. No patient developed urinary calculus during treatment with methenamine hippurate and no deterioration of renal function or haematological change was observed.

Adult

Appraisal of ascorbic acid for acidifying the urine of methenamine-treated geriatric patients.

A study was made of 73 elderly patients receiving methenamine and ascorbic acid concurrently. Each patient had an indwelling Foley catheter. Urinary pH was assessed in relation to the dosage of ascorbic acid, duration of therapy, formulation, and dosing intervals for ascorbic acid and methenamine. Statistical analysis revealed a significant increase in urinary pH when the dosage of ascorbic acid was increased. No significant relationships were found between urinary pH and the dosage forms of ascorbic acid, the salt of methenamine used, or the duration of methenamine therapy. Changes in urinary pH at different dosing intervals for ascorbic acid were found to be significant, at the 10 percent level only, for the three-times-daily dose schedule. These data raise a question as to the value of ascorbic acid for acidifying the urine of catheterized patients receiving methenamine therapy.

Aged

Lack of effect of methenamine in suppression of, or prophylaxis against, chronic urinary infection.

Methenamine is frequently prescribed for patients who have chronic urinary infection to suppress bacterial growth during active infection or to prevent recurrence once an infection has been brought under control. We have examined the effect of methenamine mandelate and ascorbic acid on bacteriuria in para- and quadriplegics from a spinal cord unit. Patients with indwelling urinary catheters and those on a program of intermittent catheterization were included. No suppressive or prophylactic effect of this regimen was observed in any of our patients. Methenamine does not appear to be an effective antimicrobial agent in subjects who have an indwelling urinary catheter or in patients with spinal cord injury who are on intermittent catheterization. Since there appears to be reason to question the efficacy of methenamine in situations in which it is usually prescribed, evidence should be sought for a therapeutic effect in other cases. If no benefit is observed, the drug should not be used.

Ascorbic Acid

Topical methenamine therapy for hyperhidrosis.

Methenamine, in a gel stick formulation, effectively decreased palmar and plantar sweating in 24 of 26 individuals studied. All patients had essential hyperhidrosis and were evaluated in a double-blind, placebo-controlled study. Even though methenamine is believed to act by the slow release of formaldehyde, one patient, who had a formaldehyde sensitivity that was proved by a patch test, was able to use the methenamine gel stick without difficulty. Approximately one third of the patients experienced some continuing relief for one to three weeks after discontinuing the trial medication. I conclude that methenamine is a safe, effective addition to the available types of topical therapy for essential hyperhidrosis.

Administration, Topical

Further observations on the potentiation of the antibacterial effect of methenamine by acetohydroxamic acid.

The use of methenamine in the treatment of urinary tract infections due to Proteus species is limited by urine alkalinity. Acetohydroxamic acid, an inhibitor of urease, maintains acidity despite growth of Proteus in urine. Easily achievable concentrations of acetohydroxamic acid in vitro systems that simulated the dynamics of the urinary tract potentiated the antibacterial effect of methenamine against Proteus species. The combined use of a urease inhibitor and methenamine may be effective in the treatment of urinary infection caused by these organisms.

Ammonia

Combined methenamine-silver nitrate and hematoxylin & eosin stain for fungi in tissues.

Initial examination of hematoxylin & eosin-stained tissue from a human brain specimen did not reveal the fungi which were seen in subsequent tissue sections stained with methenamine-silver nitrate. Microabscesses seen in the hematoxylin & eosin-stained sections were not apparent in the methenamine--silver nitrate-stained tissue. Staining with methenamine--silver nitrate and counterstaining with hematoxylin & eosin proved excellent not only for detecting fungus cells, but also for revealing their relationship to the host cellular response in this case and in examples of experimental murine coccidioidomycosis and histoplasmosis.

Animals

Controlled trial comparing co-trimoxazole and methenamine hippurate in the prevention of recurrent urinary tract infections.

To study the effects of continous low doses of antibacterial agents after eradication of bacteriuria in patients with recurrent urinary tract infection, 31 patients with documented recurrent urinary tract infection were allocated alternately to treatment with either co-trimoxazole (400 mg of suphamethoxazole and 80 mg of trimethoprim each night) or methenamine hippurate (1 g each night). The majority of patients (79%) had underlying radiological abnormalities of the renal tract, but normal renal function (the mean serum creatinine level was 1.05 mg per 100 ml). During the study the incidence of bacteriuria and pyuria was significantly lower in the co-trimoxazole-treated group. Patients receiving co-trimoxazole also had fewer acute clinical episodes of urinary tract infection than patients receiving methenamine hippurate. There were no significant side effects from either drug. Two patients with frequent recurrences of infection developed renal calculi. No change in creatinine clearance or maximum urinary concentrating ability was observed over a follow-up period of four to 30 months (mean 10.4 months). Co-trimoxazole is an effective agent in the prophylaxis of urinary tract infection in this highly susceptible group of patients, and in the doses used was superior to methenamine hippurate.

Adult

Treatment of hyperhidrosis with topical methenamine.

Idiopathic palmar and plantar hyperhidrosis is a relatively common disorder of eccrine sweat gland function. Treatment with glutaraldehyde of formaldehyde, although successful, may cause undesirable side effects. Methenamine is a polycyclic organic compound which release ammonia and formaldehyde at acid pH. Five per cent methenamine in a firm stick gel, applied daily to one palmar or plantar surface of 109 patients with hyperhidrosis, resulted in significantly less sweating after one month. No patients were sensitized to formaldehyde.

Chemical Phenomena

Long-term prophylaxis with methenamine hippurate in girls with recurrent urinary tract infections.

Twenty girls, aged 5-12 years, with recurrent urinary tract infections, were treated with methenamine hippurate, Hiprex, for a period of 12 months. The number of infections per patient per year was reduced from 3.1 to 0.7 (p less than 0.001). After prophylaxis was stopped this number increased to 1.4 which is a significantly higher incidence than occurred during treatment (p less than 0.05). A few girls complained of the taste but no side-effects were observed. Methenamine hippurate is a useful alternative in long-term prophylaxis against recurrent urinary tract infections in girls.

Child

Treatment with methenamine hippurate in the patient with a catheter.

Methenamine hippurate, 1 g twice daily, was given for four months to twenty-two elderly female subjects with an indwelling catheter. The incidence of catheter blockage was significantly reduced when compared with the control period of similar duration, although bacteriuria persisted throughout treatment. The incidence of symptomatic urinary tract infection also decreased during treatment with methenamine hippurate.

Aged

GLC determination of methenamine in tablets.

A rapid and sensitive GLC method was developed for the quantitative determination of methenamine in tablets. The method was shown to possess several advantages over the official NF assay. After dissolution of the whole tablet in absolute ethanol and addition of an internal standard (pentylenetetrazol), an aliquot was injected into the gas chromatograph for analysis. The sample was chromatographed using a stainless steel column packed with 10% OV-17 on Chromosorb W-HP. Quantitation was achieved by measuring peak heights. The simplicity, directness, extreme rapidity, and accuracy of the method represents an improvement over the official method and the other proposed assays.

Chromatography, Gas

Effect of short-term high-dose treatment with methenamine hippurate on urinary infection in geriatric patients with an indwelling catheter. IV. Clinical evaluation.

An evaluation has been made of the clinical and laboratory effects of short-term (34 days), high-dose (2g x 3 daily) treatment with methenamine hippurate (MH) of 14 geriatric patients with an indwelling catheter and clinical features of urinary tract infection. During MH treatment the number of catheter changes was halved, each catheter remaining in situ for an average of 12.0 days as compared to 6.2 days in the pre-treatment control period and 5.2 days in the post-treatment control period; the difference is significant (p = 0.008; Friedman two-way analysis of variance). Urine pH was reduced (pH 7.0--6.5--7.0; p = 0.01) and the standard bicarbonate in blood was slightly elevated (24.1--25.7--25.0 mmol/l; p= 0.008) during the MH treatment period, when compared to pre- and post-treatment control periods. It is suggested that MH treatment reduced the complications associated with indwelling catheters due to reduction in urine pH, bacteriuria, and pyuria. Blockage of catheters is thought to be due to intraluminal salt precipitations with trapping of clumps, and is primarily not correlated with urine viscosity.

Aged

Use of methenamine hippurate in male infertility.

In sperm-freezing for infertility patients with low sperm counts, we found that semen containing high numbers of white blood cells, greater than 15 to 20 per high-power field, was both poor in quality and difficult to freeze. In examining these patients carefully, we found that many had smoldering prostatitis and some an overt history of prostatitis. We treated them with methenamine hippurate using various methods and found that by decreasing the white blood cell count in their semen, we could frequently improve the semen quality, particularly sperm motility, also achieve pregnancies in some cases.

Cell Count